Conditions: Influenza, Human
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 228
Healthy volunteers: no

Brief summary:
This 2-arm study will investigate the safety and tolerability of oseltamivir for the treatment of influenza in immunocompromised participants and characterize the effects of oseltamivir in immunocompromised participants on the development of resistant influenza virus. Eligible immunocompromised participants with laboratory-confirmed influenza will be randomized to receive either conventional dose (30 milligrams \[mg\] to 75 mg twice daily orally \[po\], depending on age and weight) or double dose (60 mg-150 mg twice daily po depending on age and weight) olseltamivir for 10 days. Nasal and throat swabs will be taken, and safety evaluations made, at intervals during the study. The anticipated time on study medication is 10 days and the anticipated time on study is 40 days.

Detailed description:

Arms:
arm 1: Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 30 to 75 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 75 mg twice daily for adults/adolescents greater than or equal to (\>/=) 13 years old or placebo-matched to oseltamivir twice daily over 10 days. arm 2: Immunocompromised participants will receive oseltamivir syrup at a dose ranging from 60 to 150 mg based on body weight, twice daily for children (1 to 12 years old) and oseltamivir capsules 150 mg twice daily for adults/adolescents (\>/=13 years old) or placebo matched to oseltamivir twice daily over 10 days.

Interventions: intervention 1: oseltamivir intervention 2: placebo
Intervention descriptions: intervention 1: Dose ranging between 30 to 150 mg orally administered as syrup or capsules (depending on participant's age and weight) po twice daily for 10 days intervention 2: Placebo matched to oseltamivir po twice daily for 10 days

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Double Blind, Randomized, Stratified, Multi-Center Trial 
Evaluating Conventional and Double Dose Oseltamivir In The 
Treatment of Immunocompromised Patients with Influenza 
NCT Number: 
NCT00545532 
Document Date: 
Protocol Version A: 14-Jun-2007 
Protocol Amendment History Version B: 31-Jul-2008 
Protocol Version B: 31-Jul-2008 
Protocol Amendment History Version C: 28-Mar-2011 
Protocol Version C: 28-Mar-2011 
Protocol Version D: 28-Sep-2012 
Protocol Version E: 30-Oct-2013 
Protocol Version F: 18-Jun-2014 
 
 
 
 
 




 
 
 
SYNOPSIS OF PROTOCOL NUMBER NV20234 
  
TITLE 
A double-blind, randomized, stratified, multi-center trial evaluating  
conventional and high dose oseltamivir in the treatment of  
immunocompromised patients with influenza 
SPONSOR 
F. Hoffmann-La Roche LTD  
CLINICAL 
PHASE  
IIIb 
INDICATION 
Treatment of influenza in immunocompromised patients 
OBJECTIVES  
Primary: 
To evaluate prospectively the efficacy of oseltamivir for the 
treatment of influenza in transplant recipients as measured by the 
time to resolution of influenza symptoms 
 
Secondary: 
To evaluate the effects of conventional and high dose oseltamivir 
in transplant recipients on: 
• 
The clinical course of influenza (fever, symptoms, secondary 
illnesses as evidenced by otitis media, bronchitis, pneumonia, 
or sinusitis)  
• 
The virologic course of influenza (proportion shedding and 
viral loads at different time points) 
• 
Patient safety and tolerability  
• 
The development of  resistant influenza virus 
• 
To characterize the population pharmacokinetics of 
oseltamivir (e.g. clearance, volume of distribution) in 
transplant recipients  
TRIAL DESIGN 
This is a double-blind, randomized, multi-center trial of twice 
daily, conventional and high dose oseltamivir for the treatment of 
influenza in immunocompromised patients (as represented by 
transplant recipients).  Subjects will be stratified by age, transplant 
type, time since onset of flu symptoms and treatment start (≤ 24 or 
>24 hours) and vaccination status 
NUMBER OF SUBJECTS 
Approximately 250 (125 per arm) 
NUMBER OF CENTERS 
Approximately 140 centers in the Northern hemisphere 
TARGET POPULATION 
Transplant recipients (liver, kidney, liver and kidney, allogenic 
haematopoietic stem cell transplant), 1 year of age and older 
enrolled during the influenza season.  The subjects will be positive 
for influenza by a rapid diagnostic test at baseline. 
LENGTH OF STUDY  
10 days of treatment, 30 days of follow up.   
INVESTIGATIONAL MEDICINAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
Oseltamivir/placebo dry powder (to be reconstituted to a 
concentration of 12 mg/ml) and 75 mg capsules.  The duration of 
dosing in both adults and children is 10 days. 
 
Conventional dose: 
Children ages 1 - 12 years: Oseltamivir syrup 
≤ 15 kg   
 
30 mg twice daily 
> 15 – 23 kg  
 
45 mg twice daily 
> 23 – 40 kg 
 
60 mg twice daily 
> 40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥  13 years): Oseltamivir capsules  
75 mg twice daily 
 
Subjects randomized to the conventional dose will simultaneously 
Roche Protocol NV20234  (RO640796)  - Page 2 


 
 
 
receive matching placebo so as to blind them and the investigator 
from the high dose arm.  
 
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg   
 
60 mg twice daily 
> 15 – 23 kg  
 
90 mg twice daily 
> 23 – 40 kg 
 
120 mg twice daily 
> 40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Dose adjustments:  In both treatment arms, dosing frequency will 
be decreased to once daily in patients with severe renal impairment 
(Cr Cl in adults between 10-30 ml/min and children between 10-30 
ml/min/1.73M2.). 
COMPARATOR “DRUG” (or STANDARD OF 
CARE) DOSE/ ROUTE/ REGIMEN 
Placebo (from pivotal registration trials in otherwise healthy adults) 
ASSESSMENTS OF: 
 
- 
EFFICACY 
Time to resolution of all influenza symptoms as recorded in the 
diary cards. 
- 
SAFETY 
Adverse events, physical exams, vital signs and clinical laboratory 
evaluations 
- 
PHARMACOKINETICS/
 
PHARMACODYNAMICS  
Pharmacokinetic assessments will be collected as below: 
 
Day 1 (2 ‘early’ samples: 1 – 4 hours post dose but at least 1 hour 
apart) 
Day 6 (2 ‘late’ samples: 4 - 12 hrs post dose, but at least 1 hour 
apart) 
Day 11 (2 ‘early’ samples on Day 11) 
 
Pharmacodynamic assessments will be based on nose and throat 
swabs collected on the days specified in the schedule of 
assessments.   
 
 
PROCEDURES (summary): 
The key procedures are: 
Blood draws for serum chemistry, hematology, PK and serology. 
Nasal and throat swabs for viral culture and RT-PCR. 
 
STATISTICAL ANALYSES: 
Sample size calculations were performed using a two-sided t-test and are based on the comparison with a 
placebo control response in the pivotal registration trials in healthy adults of 112 hours for median time to 
alleviation of all symptoms. Assuming an expected median time to alleviation of symptoms of 78 hours for 
each of the two active treatment groups in this study, and a common standard deviation of 98 hours, then 
111 evaluable subjects per group would give more than 90% power to detect a difference between the 
control and each of the active treatment groups. 
 
The primary endpoint will be time to alleviation of all clinical influenza symptoms, as recorded in the diary 
cards. 
 
For the primary analysis, the following two assessments will be made independently of each other and 
without regard to the outcomes in each case. 
Roche Protocol NV20234  (RO640796)  - Page 3 


 
 
 
• 
Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment approval, a population 
of placebo treated patients will be established to match those of the current study. For this population, 
a median time to resolution of all clinical influenza symptoms will be determined along with its 95% 
confidence interval. 
 
• 
Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in the median times 
to alleviation of symptoms and deriving an associated 95% confidence interval. The methodology will 
be based on the use of the Hodges-Lehmann estimator in the case of censored data. 
Roche Protocol NV20234  (RO640796)  - Page 4 


Table of Contents
1. Background And Rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      13
1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      13
1.1.1 Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      13
1.1.2 Oseltamivir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      15
1.2 Rationale for the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      16
2. Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      16
2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      16
2.2 Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      16
3. Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      17
3.1 Overview of Study Design and Dosing Regimen . . . . . . . . . . . . . . . . .      17
3.1.1 Rationale for Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      18
3.1.1.1 Choice of treatment arms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      18
3.1.1.2 Consistency with previous influenza treatment studies. . . . . . . . . .      19
3.1.1.3 Interpretation of study results . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      19
3.1.2 Rationale for Dose Selection and Adjustment . . . . . . . . . . . . . . . . . .      21
3.1.3 End of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
3.2 Number of Subjects/ Assignment to Treatment Groups . . . . . . . . . . . .      24
3.3 Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4. Study Population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4.2 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4.3 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      25
4.4 Concomitant Medication and Treatment . . . . . . . . . . . . . . . . . . . . . . . .      27
4.5 Criteria for Premature Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . .      27
4.6 Replacement Policy [Ensuring Adequate Numbers of Evaluable
Subjects] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      27
4.6.1 For Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      27
4.6.2 For Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      28
5. Schedule Of Assessments And Procedures . . . . . . . . . . . . . . . . . . . . . . . . . .      29
5.1 Screening Examination and Eligibility Screening Form . . . . . . . . . . . .      30
Roche Protocol NV20234  (RO640796)  - Page 5 


5.2 Procedures for Enrollment of Eligible Subjects . . . . . . . . . . . . . . . . . .      30
5.3 Clinical Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . .      30
5.3.1 Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
5.3.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      33
5.4 Laboratory Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      33
5.5 Pharmacokinetic Assessments [PK] /Pharmacodynamic [PD]
Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
5.5.1 Pharmacokinetic Assessments [PK] . . . . . . . . . . . . . . . . . . . . . . . . . .      34
5.5.2 Pharmacodynamic [PD] Assessments . . . . . . . . . . . . . . . . . . . . . . . .      34
6. Investigational Medicinal Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
6.1 Dose and Schedule of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
6.1.1 Dose Modifications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
6.2 Preparation and Administration of Study Drug . . . . . . . . . . . . . . . . . . .      36
6.3 Blinding and Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
6.4 Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
6.5 Destruction of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
7. Safety Instructions and Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
7.1 Adverse Events (AEs) and Laboratory Abnormalities . . . . . . . . . . . . .      38
7.1.1 Clinical AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
7.1.1.1 Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
7.1.1.2 Drug - Adverse event relationship. . . . . . . . . . . . . . . . . . . . . . . . . .      38
7.1.1.3 Serious Adverse Events [Immediately Reportable to Roche] . . . . .      39
7.1.2 Treatment and Follow-up of AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
7.1.3 Laboratory Test Abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
7.1.4 Follow-up of Abnormal Laboratory Test Values . . . . . . . . . . . . . . . .      39
7.2 Handling of Safety Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
7.2.1 Reporting of Serious Adverse Events [immediately reportable] . . . .      40
7.2.2 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
7.3 Warnings and Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
8. Statistical Considerations And Analytical Plan . . . . . . . . . . . . . . . . . . . . . . .      41
8.1 Primary and Secondary Study Endpoints . . . . . . . . . . . . . . . . . . . . . . .      41
8.1.1 Primary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      41
8.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      41
Roche Protocol NV20234  (RO640796)  - Page 6 


8.1.3 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      41
8.2 Statistical and Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.1 Statistical Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.1.1 Primary Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.1.2 Secondary Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.2 Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.3 Hypothesis Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.4 Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      43
8.2.4.1 Intent to treat population: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      43
8.2.4.2 Intent to treat infected population:. . . . . . . . . . . . . . . . . . . . . . . . . .      43
8.2.4.3 Subpopulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      43
8.2.5 Efficacy Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      43
8.2.5.1 Exclusion of Data from Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . .      44
8.2.5.2 Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      44
8.2.6 Safety Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      44
8.2.7 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      44
8.3 Pharmacokinetic and Pharmacodynamic Analysis . . . . . . . . . . . . . . . .      45
8.3.1 Pharmacokinetic Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      45
8.3.2 Pharmacodynamic Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      45
9. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      45
9.1 Assignment of Preferred Terms and Original Terminology . . . . . . . . .      46
10. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      47
11. Ethical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      49
11.1 Local Regulations/Declaration of Helsinki . . . . . . . . . . . . . . . . . . . . .      49
11.2 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      49
11.3 Independent Ethics Committees/Institutional Review Board . . . . . . .      50
12. Conditions For Modifying The Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . .      50
13. Conditions For Terminating The Study . . . . . . . . . . . . . . . . . . . . . . . . . . . .      50
14. Study Documentation, Crfs And Record Keeping . . . . . . . . . . . . . . . . . . . .      51
14.1 Investigator's Files / Retention of Documents . . . . . . . . . . . . . . . . . . .      51
14.2 Source Documents and Background Data . . . . . . . . . . . . . . . . . . . . . .      51
Roche Protocol NV20234  (RO640796)  - Page 7 


14.3 Audits and Inspections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      51
14.4 Case Report Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      52
15. Monitoring The Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      52
16. Confidentiality Of Trial Documents And Subject Records . . . . . . . . . . . . .      52
17. Publication Of Data And Protection Of Trade Secrets. . . . . . . . . . . . . . . . .      52
Roche Protocol NV20234  (RO640796)  - Page 8 


List of Tables
Table 1 Recommended doses in healthy adults for treatment of influenza . . . .      23
Table 2 Recommended dose modifications for NV 20234 trial subjects . . . . . .      23
Table 3 Schedule of Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      29
Roche Protocol NV20234  (RO640796)  - Page 9 


List of Appendices
Appendix 1 Calculation of Creatinine Clearance and Grading of Chronic
Extensive GVHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      54
Appendix 2 Adult Patient Diary Card and Symptom Record. . . . . . . . . . . . . . .      56
Appendix 3 Diary Card for Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      57
Appendix 4 Adverse Event [AEs] Categories for Determining Relationship to
Test Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      58
Appendix 5 ICH Guidelines for Clinical Safety Data Management,
Definitions and Standards for Expedited Reporting, Topic E2 .      60
Roche Protocol NV20234  (RO640796)  - Page 10 


 
GLOSSARY OF ABBREVIATIONS 
ALT [SGPT] 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
AST [SGOT] 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
b.i.d. 
Bis in die (twice daily) 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cr Cl 
Creatinine Clearance 
CRF 
Case Report Form[s] 
DRAM 
Data Reporting and Analysis Manual 
ESF 
eligibility screening form 
hrs 
Hours 
HA 
Hemagglutinin 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ITT 
Intent to treat 
ITTI 
Intent to treat Influenza Infected 
IVRS 
Interactive Voice Response System 
mg 
Milligram 
mL 
Milliliter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
Roche Protocol NV20234  (RO640796)  - Page 11 


GLOSSARY OF ABBREVIATIONS 
p.o. 
Per os ( by mouth) 
PR 
Pulse rate 
QD 
Once per day 
SAE 
Serious adverse event 
SOT 
Solid organ transplant 
TCID50 
50% Tissue Culture Infectious Dose 
Tmax 
Time of maximum plasma concentration 
t1/2 
Elimination half-life 
µg 
Microgram 
Roche Protocol NV20234  (RO640796)  - Page 12 


PART I: 
STUDY DESIGN AND CONDUCT 
 
1. 
BACKGROUND AND RATIONALE 
1.1 
Background 
Influenza is an acute respiratory infection caused by a virus of the orthomyxovirus family 
which occurs in three forms, influenza A, B and C. Influenza virus types A and B cause 
an acute febrile infection of the respiratory tract characterized by the sudden onset of 
fever, malaise, headaches, myalgias and cough. Influenza causes numerous deaths each 
year [1]. Although difficult to assess, annual influenza epidemics are thought to result in 
between three and five million cases of severe illness, and between 250,000 and 500,000 
deaths every year around the world. [2] 
The influenza viruses are segmented, negative sense, single stranded, lipid encapsulated, 
RNA viruses between 80 and 100 nm in size. Subtypes are defined according to 
glycoproteins present in the viral lipid coat. The haemagglutinin complex (HA) is the 
major surface protein of the virus. The neuraminidase (NA) protein is the second major 
surface protein in the virion and plays a role in enhancing virus penetration of the mucus 
layer around the target cell and in release of virus from the cell surface. The matrix 
proteins, M1 and M2 appear to trigger the disintegration of the M1 complex during virus 
fusion with the cell and may also be involved in the maturation of the HA prior to 
assembly of new virus particles.  
1.1.1 
Influenza 
Influenza infection is usually a self limiting condition. However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus 
may cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death. [3]  The availability of new 
immunosuppressive agents has enhanced the number and survival of solid organ 
transplant (SOT) and haematopoietic stem cell transplant (HSCT) [4] recipients making 
them representative of the larger immunocompromised patient population.   
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality. In a cohort study of influenza viral infection in SOT 
subjects, 30 cases of influenza viral infection were identified. Secondary bacterial 
pneumonia was seen in 17 % of subjects and three SOT recipients (2 liver and one 
kidney) had myositis, myocarditis and bronchiolitis obliterans. Biopsy of the transplanted 
organ was performed in 21 of 30 cases and revealed variable degrees of acute allograft 
rejection in 62 % of subjects. The study concluded that influenza was associated with 
significant morbidity in different groups of SOT recipients [5]  
Among transplant recipients, subjects with HSCT are at the greatest risk for morbidity. In 
a prospective study from the Infectious Diseases Working Party of the European Group 
Roche Protocol NV20234  (RO640796)  - Page 13 


for Blood and Marrow Transplantation, 1973 patients were evaluated for respiratory virus 
infections after stem cell transplant.  The overall mortality was 23% from influenza A 
infection and the direct influenza A-associated mortality was 15.3% in this study. [6] 
The largest study of influenza infections in transplant (allogenic, syngenic or autologous 
HSCT) subjects comes from the Fred Hutchinson Cancer Center, Seattle, USA. In this 
retrospective study, influenza virus was isolated in 62 of 4797 subjects undergoing HSCT 
over a 13-year period. During this period, the Center had a standardized protocol for the 
detection of respiratory pathogens comprising direct fluorescent antibody (DFA) staining 
and viral culture. Because capture of influenza infections and accurate ascertainment of 
all risk factors was less complete after discharge from the health care center, only 
infections that occurred during the first 120 days after transplantation were considered. 
Influenza was defined as the isolation of influenza virus by culture or as evidence of 
influenza antigen detected by DFA in conjunction with consistent symptomatology.  
Antiviral treatment with an M2 inhibitor or oseltamivir (available since 1999) was 
performed at the discretion of the investigator. Unlike the fixed dosing duration 
recommended for antivirals in healthy subjects, in this trial, treatment was continued until 
resolution of presenting signs and symptoms and clearance of virus from respiratory 
secretions. Garrett Nichols, et al, reported as many as 29 % of subjects developed 
pneumonia following influenza infection in this large retrospective study. Ten percent of 
the subjects with influenza died [7].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects. In otherwise healthy adults, elderly 
subjects and children, the median duration of viral shedding in untreated subjects was 70, 
96 and 118 hours respectively. [8] In contrast, in the retrospective HSCT study, influenza 
virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a median 
duration of 168 hours (7 days, range 2 to 37 days) [7]. This median duration of shedding 
included both allogenic and autologous HSCT subjects and both treated and untreated 
subjects. The mean duration of shedding in treated and untreated allogenic HSCT 
subjects was found to be longer than in autologous HSCT subjects (11.1 versus 6.7 days).  
Johny et al, evaluated the use of zanamivir in the treatment of influenza in seven 
allogenic bone marrow transplant subjects. As with the large retrospective HSCT study, 
their standard of care also was to continue zanamivir until symptoms had subsided and it 
was documented that viral excretion had ceased. Viral shedding was checked every 7 
days. Based on this protocol, the median duration of use of zanamivir was 15 days with a 
range of 5 to 44 days. [9] 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir). Due to the emergence of resistant virus, the Center for Disease Control 
(CDC) has made an interim recommendation that neither amantadine nor rimantadine be 
used for the treatment or prophylaxis of influenza in the United States. [10] Oseltamivir 
is therefore one of the main drugs available for the evaluation of the treatment of 
influenza in the immunocompromised population.  
Roche Protocol NV20234  (RO640796)  - Page 14 


1.1.2 
Oseltamivir 
Oseltamivir (Tamiflu®, Ro 64-0796) is an ethyl ester prodrug which is rapidly absorbed 
from the gastrointestinal tract after oral administration and metabolized in the liver by 
high capacity carboxylesterases to form oseltamivir carboxylate (Ro 64-0802), a potent, 
stable and selective inhibitor of influenza A and B neuraminidase enzymes. The active 
form, oseltamivir carboxylate is excreted unchanged by the kidney via glomerular 
filtration and active tubular secretion by the organic anion transport system. The efficacy 
and safety of oseltamivir in influenza treatment and prevention has been established in an 
extensive series of clinical studies in man. 
Oseltamivir has been approved for the treatment of influenza in Europe, the United States 
and most other countries around the world. In adults and adolescents, the recommended 
dose is 75 mg twice daily for five days. In children 1 year of age and older recommended 
doses are 30, 45 or 60 mg bid based on body weight. In all age groups the recommended 
dose is administered bid for 5 days.   
The approval of oseltamivir for the treatment of influenza is based on several controlled 
clinical trials. In the pooled population from these clinical trials encompassing adults 
aged from 13-97 years, many with significant co-morbidity, 1325 subjects were treated 
with oseltamivir (75 mg bid) and 1056 subjects received placebo. A total of seven 
influenza symptoms (both respiratory and constitutional) were captured on the diary card 
for adults. The time to resolution of all symptoms (on the diary card) decreased by 24 
hours; from 124.5 hours in the placebo arm to 100.6 hours with oseltamivir 75 mg bid (p 
< 0.0001).  [8] Further, in adults and adolescents with a proven influenza illness, 
oseltamivir treatment reduced overall antibiotic use for any reason by 26.7 % and the 
incidence of influenza-related lower respiratory tract complications resulting in antibiotic 
therapy by 55 %. The study concluded that oseltamivir treatment of influenza reduces 
lower respiratory tract complications, antibiotic use and hospitalizations in healthy and 
‘at risk’ subjects [11].   
Likewise, in the influenza-infected pediatric population (1 to 12 years of age), oseltamivir 
treatment (n = 217) was compared with placebo (n = 235). There was a reduction  in  the 
median duration of illness (defined based on resolution of temperature, cough, coryza and 
return to pre-illness health and activity) of 36 hours; from 137 hours with placebo to 101 
hours in the oseltamivir treatment arm (p=<0.0001).  The Canadian Acute Respiratory 
Infections Scale (CARIFS), validated for use in children, was used to collect symptom 
data on the pediatric diary card. The CARIFS scale comprised a total of 18 symptoms 
which were evaluated twice daily by the parent or guardian.  There was a similar 
reduction in the time to alleviation of all CARIFS symptoms of 36 hours; from 100 hours 
in the placebo group to 63 hours in the oseltamivir group (p < 0.0001) [12].  
Thus in both adults and children, the time to resolution of all symptoms was significantly 
reduced in the oseltamivir treatment arm compared with placebo.   
Oseltamivir was well-tolerated in clinical trials. Approximately 11,000 subjects have 
received oseltamivir in the development program. The most common adverse events 
reported by adults, the elderly, and children were nausea and vomiting. Serious adverse 
Roche Protocol NV20234  (RO640796)  - Page 15 


events (SAEs) were reported with a low and equal frequency by subjects taking active 
drug and placebo. Full details are given in the Investigator Brochure. [8] 
There have been no controlled studies of oseltamivir treatment or prophylaxis in 
immunocompromised subjects. In the study by Garrett Nichols et al, patients who did not 
receive antiviral therapy shed virus for longer periods (mean duration, 11.3 days) than did 
those who were treated with M2 inhibitors (mean duration, 9.7 days) or neuraminidase 
inhibitors (mean duration, 7.5 days). Therapy with oseltamivir (but not rimantadine) 
appeared to be associated with shorter duration of shedding after controlling for steroid 
dose (p < 0.08). [7].  The efficacy of oseltamivir in the treatment of influenza in the 
immunocompromised population has also been demonstrated in other studies. In another 
small trial of oseltamivir for the treatment of influenza infection in subjects following 
HSCT, only two patients (5.1 %) developed influenza-related pneumonia. [13] In this 
study, all 39 HSCT subjects with influenza were treated with antivirals (oseltamivir or 
amantadine).  In as many as 43 % of subjects, the duration of illness was greater than 7 
days. This is unlike data from healthy adults, suggesting the possible need to evaluate a 
higher dose and/or longer duration of treatment with oseltamivir for this population.    
While the efficacy of antiviral agents for influenza has been demonstrated in the 
otherwise healthy population, it has not been tested prospectively in the 
immunocompromised (transplant) population. [4] There is therefore a need to confirm the 
efficacy of antiviral therapy for influenza in prospective controlled trials in this patient 
population.  
1.2 
Rationale for the Study  
This study is designed to investigate the optimal therapy for influenza in 
immunocompromised transplant recipients. 
The rationale for conducting this study in the immunocompromised population is based 
on the following: 
1. Immunocompromised subjects are at the highest risk for morbidity and mortality 
from influenza 
2. Immunocompromised subjects are at the greatest risk for contracting influenza 
because immunization may be ineffective in this population 
3. There is no drug approved for the treatment of influenza in this population 
2. 
OBJECTIVES  
2.1 
Primary Objective 
The primary objective of the study is to evaluate prospectively the efficacy of oseltamivir 
for the treatment of influenza in transplant recipients as measured by the time to 
resolution of influenza symptoms. 
2.2 
Secondary Objectives   
The secondary objectives of the study are:  
Roche Protocol NV20234  (RO640796)  - Page 16 


To evaluate the effects of conventional and high dose oseltamivir in transplant recipients 
on: 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points) 
• Patient safety and tolerability   
• The development of  resistant influenza virus 
• To characterize the population pharmacokinetics of oseltamivir (e.g. clearance, 
volume of distribution) in transplant recipients  
   
3. 
STUDY DESIGN 
3.1 
Overview of Study Design and Dosing Regimen   
This is a double blind, randomized, stratified, multi-center trial evaluating the efficacy of 
conventional and high dose oseltamivir for the treatment of influenza in 
immunocompromised patients. Immunocompromised transplant recipients who develop 
an influenza-like illness with a positive rapid diagnostic test for influenza, will be 
enrolled during the influenza season.  Patients will be stratified by type of transplant 
[SOT or HSCT], by the time between onset of symptoms and treatment start [≤ 24 hours; 
> 24 hours], influenza vaccination status for current flu season [Yes; No] and by age [≤12 
years; >12 years]. Eligible patients will be consented and randomized to receive 
oseltamivir twice daily for 10 days in one of two treatment arms: conventional dose or 
high dose (double the conventional dose). The primary end point in the study is the time 
to alleviation of all symptoms.  
In this study, immunocompromised subjects will be represented by the transplant 
population. This is justified because the availability of new immunosuppressive agents 
has enhanced the number and survival of SOT and HSCT recipients, making them 
representative of the larger immunocompromised patient population.    
Heterogeneity in the transplant population could confound the assessment of safety and 
efficacy in this study. Consequently, the SOT population in the protocol excludes 
subjects with transplants other than liver, kidney or liver and kidney. However, in order 
to still be representative of the transplant community in particular and the 
immunocompromised community in general, the study specifically includes subjects at 
the greatest risk for morbidity and mortality from influenza - the HSCT subjects. The 
study also excludes subjects with comorbid conditions that might impact the metabolism 
and excretion of the drug. As the prodrug and active drug accumulate in the presence of 
hepatic and severe renal impairment respectively, subjects with hepatic or severe renal 
impairment are excluded from the study.  Other comorbid conditions that might preclude 
the assessment of efficacy and safety are also excluded from the study. These are 
reflected in several of the inclusion and exclusion criteria.  
Roche Protocol NV20234  (RO640796)  - Page 17 


3.1.1 
Rationale for Study Design 
This study incorporates several features that distinguish it from classic placebo controlled 
trials. At the outset, a patient population that represents the general immunocompromised  
population had to be defined. As a placebo control arm was considered unethical in this 
population, an alternative control arm had to be identified. The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial. In order to do this, the 
current study design and end points were designed to be similar to that in the pivotal 
registration trials. The following sections provide rationale and justification for the 
specific aspects of the study design. They also provide information on how the results 
will be used to make recommendations on dose and duration of treatment. 
3.1.1.1 
Choice of treatment arms 
The pivotal registration trials for oseltamivir in healthy adults with influenza had three 
treatment arms, two active (75 mg and 150 mg) and one placebo. Both treatment arms 
were found to be significantly better than placebo. No statistical comparisons were made 
between the two active treatment arms. Evaluation of the results in the two active 
treatment arms did not reveal any clinically meaningful difference. Based on these 
studies, the approved (conventional) dose for the treatment of influenza in adults is 75 
mg. 
A similar trial design was envisaged for this immunocompromised population. In an 
immunocompromised population there is a possibility of increased efficacy with a higher 
dose. In the trials in healthy adults, on day 4 (3 days after the start of treatment), the 
proportion of subjects shedding virus suggested a possible dose response relationship 
(36%, 28% and 23% in the placebo, 75 mg and 150 mg dose arms respectively). In 
healthy adults, this difference in the rate of viral shedding did not translate to any 
difference in clinical response in the two active treatment arms even though both active 
treatment 
arms 
were 
significantly 
better 
than 
the 
placebo 
arm. 
In 
the 
immunocompromised population too it is possible that while there might not be any 
difference between the two active treatment arms, one or both of these dose arms may be 
better than placebo. In this immunocompromised population, there is therefore an even 
greater need to evaluate the efficacy of a higher dose arm.  
As with the trials in healthy adults, the ideal trial design for the current study would be 
one that compared efficacy of the conventional and high dose arms with placebo. 
However, as reviewed in an earlier section 1.1.1 the morbidity and mortality from 
influenza in the immunocompromised population is far greater than that in healthy adults. 
Thus in one study as many as 29 % of subjects with HSCT developed pneumonia 
following influenza infection. [7] In another study in SOT recipients, biopsy of the 
transplanted organ revealed variable degrees of acute allograft rejection in 62 % of 
subjects. [5] Given the extent of morbidity, a placebo control appears unethical. This is 
further supported by a feasibility survey conducted by the Sponsor which demonstrated  
that a majority of transplant sites actually used antivirals (including oseltamivir) to treat 
influenza in this population. It was therefore decided to compare the conventional and 
higher dose arms with the placebo arm from the pivotal registration trials in healthy 
adults with influenza. Although this approach poses limitations, the Sponsor has made 
Roche Protocol NV20234  (RO640796)  - Page 18 


every effort to make sure that the results from such an approach are still meaningful. The 
following sections describe how the study design addresses these limitations.  
3.1.1.2 
Consistency with previous influenza treatment studies 
In order to be able to compare the study findings with the response to placebo in healthy 
adults, this study has been intentionally designed to be consistent with previous 
registration trials for treatment of influenza in healthy adults. Some of the key design 
features consistent with previous studies include: two active treatment arms, subjects with 
influenza like symptoms recruited during the flu season, use of a diary card to capture 
symptoms, primary clinical end point based on diary card assessments, laboratory 
evaluation of virology and serology samples generally similar to previous trials and the 
primary efficacy analysis population is the Intent to treat Infected (ITTI) population. 
Despite the above considerations, there are issues that can preclude the estimation of the 
response to placebo in an immunocompromised population comprising adults and 
children from that in healthy adults with influenza. To further mitigate this, the choice of 
endpoints and their interpretation is vital.    
3.1.1.3 
Interpretation of study results  
Choice of primary end point and comparators 
The current study includes both children and adults. This is because of the significant 
unmet need in both these age groups. The primary end point therefore had to be 
applicable to both age groups. In registration trials in adults, the primary end point was 
the time to resolution of all clinical symptoms (in the diary card). In registration trials in 
children, the primary end point was the reduction in the median duration of illness 
(defined based on temperature, cough, coryza and return to pre-illness health and 
activity). A key secondary end point in children – time to resolution of all clinical 
symptoms showed similar results. The primary endpoint in this study is the time to 
resolution (alleviation) of all symptoms. 
 The median of the primary end point in the active treatment groups (conventional and 
high dose) in this trial will be compared with the median of the time to resolution of 
symptoms in the placebo group from the pivotal registration trials. The high dose arm 
enables the detection of a possible dose response relationship in this immune 
compromised population. As a means to evaluate that possibility, an assessment of the 
relative efficacy of the two dose groups will be made in terms of median time to 
alleviation of symptoms. Section 8.2.5 provides details on the statistical considerations 
and their rationale associated with these comparisons. 
Effect of study design on efficacy end points 
The main limitations of using the response to placebo from previous trials to estimate the 
response in this trial are due to the different populations (healthy versus 
immunocompromised), age groups (adults versus adults and children) and the potential 
difference in virulence of different strains. The potential difference in virulence of the 
predominant influenza viruses may be a confounder whose contribution can not be 
estimated. However the difference in populations and age groups is likely to result in the 
Roche Protocol NV20234  (RO640796)  - Page 19 


placebo response from pivotal registration trials underestimating the time to alleviation in 
the immunocompromised population. This is because the time to alleviation of symptoms 
is shorter in the healthy population compared to the immunocompromised population. 
[13] The placebo response in the pivotal trials will therefore underestimate the response 
in the current trial. The Sponsor is thus using a very conservative approach in comparing 
the active treatment arms in this study with the response to placebo in healthy subjects. If 
one/both of the treatment arms is statistically better than placebo, it is considered that this 
is a meaningful effect for this population.  If both treatment arms are not different from 
placebo and this is seen consistently across several end points, it may be hypothesized 
that the risk from influenza for the immunocompromised population treated with 
oseltamivir is comparable to that for a healthy untreated adult with influenza.   
Possible dosing recommendations based on current study 
Healthy subjects who were given placebo in the previous pivotal oseltamivir treatment 
studies will be used as the control arm for this study.  When the two active treatment 
arms are compared with this placebo control, several outcomes are possible. These 
outcomes will need to be discussed with health authorities.  Some outcomes and possible 
interpretations of the results are presented below:   
1. Conventional and high dose are both shown to be better than placebo: Both treatment 
arms will be compared.  If no difference then the conventional dose would be the 
dose recommended for treatment in this population.  If a difference is seen between 
treatment arms, then an evaluation (including benefit/risk assessment) will be made to 
confirm whether the higher dose should be the recommended dose. 
2. One active treatment arm is superior to placebo while the other is not: In this instance 
the dose that is shown to be superior will be recommended unless other 
considerations such as safety dictate otherwise.  
3. Both conventional and high dose arms are not different from placebo: If this is seen 
consistently across several secondary clinical end points, it may be hypothesized that 
oseltamivir has reduced the risk in the immunocompromised population to the more 
acceptable level in the untreated healthy adult population. 
4. It is also possible that both conventional and high dose treatment have a more 
protracted clinical course than the placebo arm. In this situation, it may be difficult to 
make conclusions about efficacy.  
 
Irrespective of the efficacy outcomes, the study will still provide useful information of 
the safety of oseltamivir in this population.  
Roche Protocol NV20234  (RO640796)  - Page 20 


Possible recommendations for duration of treatment based on the current study 
Once a dose is chosen a determination will need to be made on whether the 
recommended duration of treatment should be 5 or 10 days or longer. This decision will 
be based both on the clinical and virologic course of influenza.   
The recommended duration of treatment for influenza in healthy adults is five days. In 
this study, the duration of dosing is ten days because viral shedding is typically longer in 
the immunocompromised population than in healthy adults. The general standard of care 
for this population has been to treat for as long as the patient continues to shed virus 
(even after the resolution of symptoms) [7] [9]. The duration of treatment for this 
population is therefore individualized based on clinical response and duration of viral 
shedding. It can often be more than 10 days. While it is possible that 10 or more days of 
treatment may be needed [7] [9], it is also possible that 5 days of treatment may still be 
adequate. Therefore, in this study the clinical and virologic course (proportion shedding 
virus at day 6 and later) will be evaluated to make recommendations on the duration of 
dosing. No statistical comparisons will be made.     
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials. However, in order to evaluate a dose response relationship between the two active 
treatment arms in this trial, stratification remains essential.  
Because HSCT recipients are at the greatest risk of morbidity and mortality from 
influenza, patients will be stratified by transplant type (SOT versus HSCT). Patients will 
be stratified by time between onset of symptoms and treatment start (< 24 hours or ≥ 24 
hours) because previous experience in otherwise healthy adults and children has shown 
that patients treated early in their illness respond to treatment better than those who are 
treated later. Patients will also be stratified by age ( ≤ 12 years and > 12 years) because 
otherwise healthy children shed virus longer than otherwise healthy adults. It is expected 
that a similar difference in the duration of viral shedding would exist between 
immunocompromised children and adults. As vaccinated subjects may respond faster to 
therapy, the study is also stratified based on influenza vaccination status for the current 
flu season (Yes; No).   
3.1.2 
Rationale for Dose Selection and Adjustment 
Dose Selection 
The dose of oseltamivir to be used in this study is the conventional, approved dose for 
children and adults in the treatment of influenza. There will be a second higher dose for 
comparison which is two times the conventional dose. This higher dose is used based on 
theoretical considerations which suggest that the higher dose may be associated with 
improved efficacy and decreased emergence of resistance.  
The anticipated pro-drug and metabolite exposures from this higher dose are not expected 
to exceed maximum exposures seen previously in the oseltamivir development program. 
The safety and tolerability of the higher dose regimen has already been demonstrated in 
treatment studies of immunocompetent adult subjects (n = 447). [14] In a study to 
Roche Protocol NV20234  (RO640796)  - Page 21 


demonstrate cardiac safety, in the highest dose group treated with 450 mg b.i.d. for 5 
days [n = 99], no subject had a serious adverse event, nor withdrew prematurely. In Phase 
I studies in adults, oseltamivir has been administered in multiple doses of up to 500 mg 
b.i.d. Doses of 200 mg b.i.d. and greater have been associated with increased 
gastrointestinal adverse effects (nausea and vomiting). [8] In adult subjects with 
creatinine clearances of < 30 mL/min, doses of 100 mg b.i.d. for 6 days were well 
tolerated, despite steady-state oseltamivir carboxylate exposures approximately 10-fold 
higher than those achieved with standard dosing in renally competent individuals. [15] 
No other adverse effects were reported more frequently with higher doses and no serious 
adverse events have been reported within the volunteer studies. Co-administration of 
oseltamivir with food has been demonstrated to substantially reduce the frequency and 
severity of gastrointestinal side effects.  
Thus, the rationale for the higher dose arm in this study is to explore the possibility of 
improved efficacy and decreased emergence of resistance without an undue increase in 
risk.  
Drug interactions with immunosuppressive medications have also been evaluated. The 
pharmacokinetics of oseltamivir and oseltamivir carboxylate after administration of 
75 mg oseltamivir (conventional adult dose) in subjects with a well-functioning, stable 
renal allograft who were being maintained on immunosuppressive therapy were studied. 
These were similar to those described in the literature for adults with comparable degrees 
of renal function. Oseltamivir was well tolerated and had no clinically relevant effect on 
the steady-state pharmacokinetics of cyclosporine A, tacrolimus, or mycophenolate 
mofetil. [8] 
Duration of dosing 
The duration of dosing chosen for this population (10 days) is longer than that in the 
healthy adult and pediatric populations (5 days). This is based on observations that the 
viral shedding and illness are typically longer in immunocompromised patients than it is 
in healthy adults. [7] [13] 
Dose Adjustments 
In this study, dose adjustment for subjects with an estimated Cr Cl between 10 to 30 
mL/min/1.73M2 will comprise decreasing the frequency of administration to once daily. 
This is based on current label recommendations for adults with renal impairment 
(Table 1). 
Roche Protocol NV20234  (RO640796)  - Page 22 


Table 1 
Recommended doses in healthy adults for treatment of 
influenza  
 
Creatinine Clearance 
Recommended dose for treatment 
> 30 (ml/min) 
75 mg twice daily 
> 10 to ≤ 30 (ml/min) 
75 mg once daily or 30 mg suspension twice 
daily 
≤10 (ml/min)   
Not recommended 
dialysis patients 
Not recommended 
 
The dose adjustment recommendations are considered suitable approaches for children 
with renal impairment. This is based on the reasonable assumption that a similar 
relationship exists in both children and adults, between changes in creatinine clearance 
and resultant changes in exposure of oseltamivir and oseltamivir carboxylate. Doses will 
be adjusted for renal impairment in this protocol per the schema below. More detailed 
information on dosing, dose adjustments and maintenance of the blind are provided in 
later sections 6.1, 6.2, 6.3. 
Table 2 
Recommended dose modifications for NV 20234 trial 
subjects 
 
Randomized Dose 
Arm 
Unit dose 
(mg) 
Creatinine Clearance 
(ml/min OR ml/min/M2) 
Dose frequency 
> 30 
Twice daily 
30 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
45 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
60 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
 
 
 
Conventional 
 
75 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
60 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
90 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
120 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
 
 
 
High 
150 
> 10 to ≤ 30 
Once daily 
 
In general, no dose adjustment is considered necessary in subjects with mild-moderate 
hepatic impairment (based on pharmacokinetic findings in adults with chronic hepatic 
impairment) receiving usual therapeutic doses of oseltamivir. [16] However, as the 
Roche Protocol NV20234  (RO640796)  - Page 23 


relevance of these findings to the specific patient population in this study is unclear, 
subjects with overt (based on physical signs and symptoms) hepatic impairment at 
baseline will be excluded from this study as mentioned in section 4.3. 
3.1.3 
End of Study   
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 
days later as shown in the schedule of assessments. A rapid diagnostic test for influenza 
will be performed at the end of the 10 days of treatment. Subjects still having influenza 
based on the rapid diagnostic test will be treated per the local standard of care by the 
principal investigator.  
3.2 
Number of Subjects/ Assignment to Treatment Groups 
A total of approximately 250 patients will be enrolled in this study (approximately 125 
per arm). After screening, patients will be randomly assigned to one of the two active 
treatment groups. 
3.3 
Centers 
This will be a multicenter study with approximately 140 centers in the Northern 
hemisphere. Centers will be activated to recruit patients during the influenza season. The 
centers to be included in the study are those which perform or manage SOTs, HSCTs or 
both.  
4. 
STUDY POPULATION 
4.1 
Overview   
The study population comprises immunocompromised adults (including adolescents) and 
children who have influenza. Additionally, the subjects must not have other medical 
conditions that will preclude the assessment of efficacy or safety. Influenza vaccinated 
and non-vaccinated subjects are eligible to participate in this study.  
Under no circumstances are patients who enroll in this study permitted to be re-
randomized to this study and enrolled for a second course of treatment. 
4.2 
Inclusion Criteria  
• Age greater than or equal to 1 year 
• Rapid diagnostic test positive for influenza in the 24 hours prior to first dose 
• Immunocompromised subject defined as documented: 
• SOT (liver, kidney or both) recipient OR 
• Allogenic HSCT  
• Receiving ongoing immunosuppression, OR, in the investigator’s opinion, not 
immune reconstituted 
• Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza  
Roche Protocol NV20234  (RO640796)  - Page 24 


• Less than or equal to 48 hours between onset of influenza like illness and first dose of 
study drug  
• Acceptable renal function defined as: 
• Most recent creatinine clearance in the 6 months prior to randomization is 
> 30 ml/min in adults and > 30 ml/min /1.73M2  in children. Creatinine 
clearance estimated from serum creatinine (Appendix 1) measured when 
subject is not receiving any renal replacement therapy OR 
• For patients who have not had a creatinine clearance assessment in the 6 
months prior to randomization, baseline creatinine clearance > 10 ml/min 
in adults and > 10 ml/min /1.73M2  in children (Appendix 1) OR 
• For patients whose most recent creatinine clearance in the 6 months prior 
to randomization is < 30 ml/min in adults and < 30 ml/min /1.73M2  in 
children, baseline creatinine clearance > 10 ml/min in adults and > 10 
ml/min /1.73M2  in children (Appendix 1) 
• Parent/guardian willing and able to comply with study requirements and give consent. 
(country specific age cut off)  
• Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• For adult patients, willing and able to comprehend and give written informed consent 
• Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for one reproductive cycle following 
cessation of study therapy   
• Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study medication 
4.3 
Exclusion Criteria  
• SOT within 6 months of the time of randomization  
• Solid Organ Transplant other than liver, kidney or liver and kidney 
• Have in the investigator’s opinion experienced acute rejection in the 4 weeks prior to 
randomization 
• HSCT patients with no evidence of engraftment (engraftment is defined as the point 
at which a patient can maintain a sustained absolute neutrophil count (ANC) of 
>500/mm3 and sustained platelet count of ≥ 20,000/mm3, lasting ≥ 3 consecutive days 
without transfusions)  
• HSCT subjects not discharged from hospital after their initial hospitalization for 
transplantation 
• Have evidence of veno-occlusive disease, acute or chronic extensive graft versus host 
disease at the time of randomization 
Roche Protocol NV20234  (RO640796)  - Page 25 


• Have clinical evidence for hepatic decompensation at the time of randomization 
(clinical icterus, ascites, hepatic encephalopathy, coagulopathy) 
• Have cirrhosis of the liver at the time of randomization 
• Currently or in the six months prior to randomization using T cell depleting 
antibodies (example: antithymocyte globulin, antilymphocyte globulin) for 
management of transplant  
• Have other co-morbid conditions that could affect patient survival or graft function 
including, but not limited to, a post-transplant lymphoproliferative disease (PTLD), 
autoimmune disease including inflammatory bowel disease and psoriasis, untreated 
thyroid disease, and significant active infection 
• Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration 
• Have evidence of active or uncontrolled opportunistic infections (bacterial, fungal, or 
viral - including cytomegalovirus [CMV] or polyoma virus [BKV]) at the time of 
randomization. Patients with HCV or HBV are not excluded. 
• Patients with known HIV infection 
• Patients who are being evaluated or treated for an active malignancy (other than the 
malignancy for which the SOT or HSCT may have been performed) at the time of 
randomization  
• Patients with uncontrolled vascular, neurologic or pulmonary disease. Uncontrolled is 
defined as disease requiring change of therapy or hospitalization in the 4 weeks 
preceding randomization. Change of therapy is defined as dose increase or change of 
medication prior to onset of present influenza like illness. 
• Patients with severe diarrhea or other gastrointestinal disorders which might interfere 
with their ability to absorb oral medication, including diabetic patients with 
previously diagnosed diabetic gastroenteropathy 
• Allergy to the test medication 
• Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation) 
• Influenza vaccination in the 2 weeks prior to randomization 
• Antiviral treatment (example: amantadine, rimantadine, zanamivir and ribavirin) for 
influenza in the 2 weeks prior to randomization 
• Patients taking probenecid medication 
• Patients who are pregnant or breast-feeding   
• Participation in a clinical trial or expanded access trial with an investigational drug in 
the 4 weeks prior to randomization or concomitantly with this study   
Roche Protocol NV20234  (RO640796)  - Page 26 


4.4 
Concomitant Medication and Treatment 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, and additional oseltamivir above that specified for this study) are not 
allowed during the study. Concomitant use of an investigational drug during the study is 
also excluded. Influenza vaccination after randomization is not allowed. Live attenuated 
vaccines may not be advisable for this population. It is possible that concurrent use with 
oseltamivir may render live vaccines ineffective.  
Medications required for the routine care of the patient including those required for 
management of the transplant (excluding lymphocyte depleting antibodies, intravenous 
immunoglobulins) may be continued during the study. Concomitant use of probenecid 
(irrespective of the indication) is not allowed during the study. 
4.5 
Criteria for Premature Withdrawal  
The investigator should discontinue treatment if the creatinine clearance is < 10 ml/min 
in adults or < 10 ml/min/1.73 M2 in children. The investigator should also discontinue 
treatment from all subjects with intercurrent illnesses or adverse events suggestive of 
hepatic decompensation. The investigator also has the right to discontinue treatment in 
the event of intercurrent illness, adverse events, treatment failure, protocol violations, 
administrative reasons or other reasons. 
Subjects have the right to withdraw from the study at any time for any reason.  
An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
The investigator should contact the subject or a responsible relative either by telephone or 
through a personal visit to establish as completely as possible the reason for the 
withdrawal. A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the subject is withdrawing from the study. If the reason 
for removal of a subject from the study is an Adverse Event, the principal specific event 
will be recorded on the CRF. 
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further 
information. The outcome of that discussion should be documented in both the medical 
records and in the CRF.  
4.6 
Replacement Policy [Ensuring Adequate Numbers of 
Evaluable Subjects] 
4.6.1 
For Subjects 
No subject prematurely discontinued from the study for any reason will be replaced.   
Roche Protocol NV20234  (RO640796)  - Page 27 


4.6.2 
For Centers 
A center may be replaced for the following administrative reasons:   
– Excessively slow recruitment. 
– Poor protocol adherence 
Roche Protocol NV20234  (RO640796)  - Page 28 


5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Informed Consent/Assent 
x 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
x 
 
 
Pregnancy Test a 
x 
 
 
 
 
x 
 
x 
Rapid diagnostic test for 
influenza virus shedding  
x 
 
 
 
 
 
x 
 
 
Safety Labs b 
x 
 
 
 
 
x 
 
 
Serology for influenza antibody 
titer  
x 
 
 
 
 
 
 
x 
PK samplingc 
 
x 
 
x 
 
x 
 
 
Physical Examination 
x 
 
 
 
 
x 
 
x 
Vital Signs (including PR, RR, 
temperature, Blood pressure) 
x 
 
x 
x 
x 
x 
x 
x 
Nasal and throat swabs for viral 
shedding and viral loadd 
x 
 
x 
x 
x 
x 
x 
x 
Review of diary card e    
 
 
x 
x 
x 
x 
x 
x 
Drug Administration 
 
 
 
 
 
 
 
 
Collection of unused study 
medication and empty containers 
 
 
 
 
 
x 
 
 
Previous Diseases  
x 
 
 
 
 
 
 
 
Previous/Concomitant 
medications 
x 
 
 
 
 
 
 
 
Adverse Events/Sec Illnesses and 
Treatments 
 
 
 
 
 
 
 
 
Rejection, GVHD 
 
 
 
 
 
 
 
 
a.  Urine pregnancy test for patients of child-bearing potential according to the judgment/discretion of the investigator 
b.  Hematology (CBC with differential) and chemistry (AST, ALT, total bilirubin, urea, Cr). Serum creatinine testing 
may be done at a local laboratory at any time to calculate creatinine clearance and make dose adjustments.  Patient may 
receive his/her first dose prior to Cr Cl results being available, provided certain renal function criteria are met -  see 
[4.2] [5.3] 
 
c.  Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be collected using a sparse 
sampling approach.  [5.5.1] 
d.  Two nasal and one throat swab for viral culture and RT-PCR 
e.  Flu symptoms, temperature, date/ time of oseltamivir dose and food intake will be recorded by the patient on diary 
cards twice daily on days 1 – 10, and once daily thereafter.   
f.  A home visit may be made on day 2 or 3 (for patients who are too ill to come into the clinic) and day 8 
g.  Day 6, 8 visit window = + 1 day; day 11 visit window = ± 1 day. PK assessments can not be done on day 12. Day 15 
and day  40 visit occur approximately 5 and  30 days after the last dose respectively. Day 15 window = ± 1 day. Day 40 
window ± 2 days.  
h.  Only weight to be assessed. Height is not necessary at this visit. Study drug is taken on day 11, only if the first dose 
was taken after 4 PM on Day 1 [5.3] Subjects who are rapid diagnostic positive can be treated per standard of care. 
They will be required to come for their follow-up visits on day 15 and day 40.  
i.  Subjects who discontinue treatment prematurely will have an end of treatment (day 11) assessment at the time of 
treatment discontinuation or the following day. They will be required to attend their follow up visits approximately 5 
and 30 days after the last dose (day 15 and day 40 assessments).  
j. Subjects who discontinue during follow-up will have an end of follow-up (day 40)  assessment. This visit must occur  
within 30 days of the last dose.   
Roche Protocol NV20234  (RO640796)  - Page 29 


5.1 
Screening Examination and Eligibility Screening Form  
Trial sites will be activated during the influenza season.  
All subjects must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed. Screening will take place at the 
baseline visit prior to first dose. 
Subjects will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  
An Eligibility Screening Form [ESF] documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.  
5.2 
Procedures for Enrollment of Eligible Subjects  
Once a subject has fulfilled the entry criteria, he/she will be randomized to one of two 
treatment groups. The subject randomization numbers will be generated by Roche or its 
designee and incorporated into double-blind labeling. 
The investigator or designee will use the CRF pre-printed with the assigned subject 
number and enter the randomization number provided by IVRS for allocation to the 
treatment groups in the appropriate place on each subject’s CRF. 
Randomization will be stratified by transplant type (SOT or HSCT); time between onset 
of symptoms and treatment start (≤ 24 hrs or > 24 hrs), influenza vaccination status (Yes; 
No) and patient’s age (≤ 12 years or > 12 years).  
5.3 
Clinical Assessments and Procedures 
At all visits subjects will receive the routine care for their primary illness (transplant). 
Routine patient care (including the adjustment of doses of any of the immunosuppressive 
drugs) will be dictated by tests performed locally at the trial site. Dose adjustments of 
oseltamivir will be based on serum creatinine done at the local laboratory. All safety labs 
will be sent to a central laboratory. Results for these laboratory parameters will be used 
by the sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 3). Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
Study Day 1 
The baseline and study day 1 assessment may be performed at the same visit. 
Study medication, diary cards, and thermometers will be dispensed. Patients or 
guardians/parents will be instructed how to complete symptom diary cards (Appendix 2) 
(Appendix 3), temperature recording, and treatment administration details, including time 
Roche Protocol NV20234  (RO640796)  - Page 30 


of each oseltamivir dose and food intake. The first diary card will be completed before 
the first dose of study drug.  
The date of the first dose of study drug is defined as study day 1. Once randomized, the 
first dose of study drug will be administered in the clinic. Study day 2 will begin at 12 
midnight of the same calendar day. If the first dose of study drug is taken after 4 pm on 
day 1, the next dose of study drug will be taken in the morning of day 2. In this case, the 
last dose of study drug will be taken on the morning of study day 11.   
If the first dose of study drug is taken prior to 4 pm on day 1, the next dose of study drug 
should be taken in the evening of the same day (i.e. prior to midnight on the same 
calendar day with a minimum of 7 hours between doses). For these patients the last dose 
of study drug will be taken in the evening of study day 10. More information on dosing is 
provided later. (6.1) 
The study will utilize a central safety laboratory. However, to determine the correct dose, 
a local serum creatinine will be drawn at baseline in all subjects and used to calculate 
creatinine clearance to determine if a dose adjustment is necessary. No dose adjustments 
are required for subjects whose creatinine clearance is > 30 ml/min in adults (> 30 
ml/min/1.73 M2  in children). Oseltamivir dosing frequency for patients whose creatinine 
clearance is between 10 to 30 ml/min in adults (10 to 30 ml/min/1.73 M2  in children) 
will be adjusted to once daily.  
For patients who meet the following criteria in section 4.2, dosing will commence only 
after the baseline creatinine clearance are available and if baseline creatinine clearance > 
10 ml/min in adults and > 10 ml/min/1.73M2  in children.  The dose will be adjusted to 
once daily if the baseline Cr Cl is between 10 to 30 ml/min in adults (10 to 30 
ml/min/1.73 M2  in children) 
• most recent creatinine clearance in the 6 months prior is < 30  ml/min in adults and < 
30 ml/min/1.73M2 in children)  
• patients who have not had a creatinine clearance assessment in the 6 months prior to 
randomization 
 
For patients who meet the following criteria in section 4.2 dosing may commence prior to 
availability of baseline Cr Cl. Subjects will receive twice daily doses and dosing will be 
adjusted to once daily if the baseline Cr Cl is between 10 to 30 ml/min in adults (10 to 30 
ml/min/1.73 M2  in children).  
• most  recent creatinine clearance in the 6 months prior is > 30 ml/min  in  adults  and 
> 30 ml/min /1.73M2  in children) 
 
Blood samples will be taken for PK analysis as mentioned in section 5.5.1. 
Study Days 2 - 11 
Study day 2 will begin at 12 midnight of study day 1.  
Roche Protocol NV20234  (RO640796)  - Page 31 


It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study. The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is completing the diary cards, and assess drug 
compliance. During the dosing period, diary card symptoms should be assessed and 
temperature should be recorded at the same time that the study drug is taken.  
Dosage adjustment will be performed based on creatinine clearance as described in the 
Dose Modification section 6.1.1. 
End of treatment Day 11 
The end of treatment visit for all subjects is on day 11 (irrespective of whether they took 
one or two doses on day 1). Subjects who discontinue study medication prematurely  will 
have all day 11 assessments completed at the time of discontinuation or the following 
day.  
After all day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit. If the rapid diagnostic test is positive, the subject may be treated 
per standard of care at the discretion of the investigator.  
All subjects (including those who discontinue study medication prematurely and those 
who are positive for influenza on their rapid diagnostic  test at the end of treatment visit) 
will be required to return for follow up approximately 5 and 30 days after the last dose 
(day 15 and day 40 assessments)    
Study days 12 – 40 
Study day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  
End of Follow-Up Day 40  
All subjects must attend an end of follow-up visit on day 40. This visit is important as it  
is the only post-baseline visit where a serology sample for influenza antibody titers is 
collected.  
If the patient is withdrawn after completion of treatment (after the day 11 assessment),  a 
termination visit should be arranged. This visit should be the end of follow-up visit 
assessment [Day 40]. This visit must occur within 30 days of the last dose.  
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the symptom diary card. 
5.3.1 
Efficacy Assessments  
The primary end point in this study is the time to resolution of all influenza symptoms as 
recorded in the diary cards.  
The clinical efficacy parameters in this study are: 
Roche Protocol NV20234  (RO640796)  - Page 32 


1. Symptoms of influenza-like illness. These are captured in the diary card for both 
adults and children. (Appendix 2) (Appendix 3) Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem). A score 
of zero is considered asymptomatic. The primary end point, time to alleviation of all 
symptoms is comprised of all the symptoms captured in the diary card.  
2. Temperature. This is captured on the diary card. Temperature is used for assessment 
of the primary and several secondary end points.  
5.3.2 
Safety  
Safety parameters in this study include adverse events, vital signs, and clinical laboratory 
evaluations.  
Pre-defined symptoms of influenza captured in the adult and pediatric diary cards are not 
to be reported as adverse events unless they can be further qualified. Thus ‘headache due 
to stress at work’ is reported as an adverse event. However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Adverse events such as bronchitis, pneumonia, otitis media and sinusitis are considered 
secondary illnesses of influenza and should be recorded as adverse events. 
Other adverse events to be expected in the transplant population such as rejection and 
graft versus host disease (in HSCT subjects) will also be collected as adverse events.  
5.4 
Laboratory Assessments 
The laboratory assessments include those for efficacy and safety. 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs. Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments. All swabs are sent to a central laboratory for RT-PCR and 
viral cultures. A phenotypic assay will be performed to determine the susceptibility of the 
last positive viral isolate from each patient. If required, a genotypic assay to determine 
the contribution of both the neuraminidase and haemagglutinin genes to decreased 
susceptibility will be performed.  
During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza. However at the end of 
treatment (day 11), a rapid diagnostic test is permitted for the diagnosis of ongoing 
influenza.  
Safety 
The safety laboratory assessments in this study, including the assessment of serum 
chemistry and hematology will be done at the central laboratory. Serum chemistry 
assessments comprise AST, ALT, total bilirubin, urea and creatinine. Hematology 
assessments include CBC and differential count. The total volume of blood loss for 
laboratory assessments (other than pharmacokinetic sampling) will be approximately 20 
Roche Protocol NV20234  (RO640796)  - Page 33 


mL for the entire duration of the study. Blood loss for pharmacokinetic sampling is 
explained in section 5.5.1. 
Protection of patient confidentiality, section 16 will extend to any data generated from the 
assaying of these samples. Biological samples taken from all patients may be infectious 
and will be classified as “diagnostic specimens” for dispatch purposes. 
The Principal Investigator may draw blood for serum creatinine to be assessed at the local 
laboratory at any time during the study. The Principal Investigator may use the creatinine 
levels to calculate creatinine clearance and adjust dose of study drug if required. 
5.5 
Pharmacokinetic Assessments [PK] /Pharmacodynamic [PD] 
Assessments  
Blood samples will be collected to evaluate the pharmacokinetics of oseltamivir 
according to the Schedule of Assessments (Table 3) and as described below. Further 
details on PK/PD are to be found in sections 8.3.1 and 8.3.2.  
5.5.1 
Pharmacokinetic Assessments [PK] 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected using the following sparse sampling approach: 
       day 1  (2 ‘early’ samples: 1 – 4 hours post dose but at least 1 hour apart) 
       day 6  (2 ‘late’ samples: 4 – 12 hours post dose but at least 1 hour apart) 
       day 11 (2 ‘early’ samples on day 11)*  
*Note: Subjects should attend the clinic as early as possible on the morning of Day 11. 
For those subjects who had their last dose on the morning of Day 11, they should have 2 
samples drawn 1– 4 hours post dose but at least 1 hour apart. For those subjects who 
received their last dose on the evening of Day 10, they should have 2 samples drawn at 
least 1 hour apart, as early as possible on the morning of day 11.  
For adults and adolescents, approximately 2 mL of blood will be taken at each time point, 
therefore the total volume blood loss for pharmacokinetic assessments will be 
approximately 12 mL. For pediatric subjects, not less than approximately 0.6 mL of 
blood will be taken at each time point, as a result the total volume blood loss for 
pharmacokinetic assessments will be approximately 3.6 mL. 
5.5.2 
Pharmacodynamic [PD] Assessments 
Nasal and throat swabs will be collected from individuals on the days specified in the 
schedule of assessments. Specimens will be cultured at a central laboratory. The 
proportion of patients with viral shedding at each visit will be summarized. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/ml) or 75 mg capsules and matching placebo. 
Roche Protocol NV20234  (RO640796)  - Page 34 


The Investigational Medicinal Products will be supplied, packaged individually for each 
subject and labeled in accordance with Roche Standard and local regulation by Roche 
Clinical Trial Supply, Basel, Switzerland.  
6.1 
Dose and Schedule of Study Drug 
Oseltamivir will be given twice daily over 10 days for a total of 20 doses. The doses need 
to be taken at 12 hourly intervals. Under no circumstances is a subject allowed to take 
two doses within 7 hours of each other.  
Patients will be randomized to receive either conventional or high dose of study drug. 
Conventional dose: 
Children ages 1 - 12 years: Oseltamivir syrup 
≤ 15 kg  
 
 
30 mg twice daily 
> 15 – 23 kg   
 
45 mg twice daily 
> 23 – 40 kg  
 
60 mg twice daily 
> 40 kg 
 
 
75 mg twice daily 
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules  
75 mg twice daily 
Subjects randomized to the conventional dose will simultaneously receive matching 
placebo so as to blind them and the investigator from the high dose arm.  
 
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg  
 
 
60 mg twice daily 
> 15 – 23 kg   
 
90 mg twice daily 
> 23 – 40 kg  
 
120 mg twice daily 
> 40 kg 
 
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules  
150 mg twice daily  
6.1.1 
Dose Modifications   
No dose adjustments/modifications are required for subjects whose creatinine clearance is 
> 30 ml/min in adults (> 30 ml/min/1.73 M2  in children). 
In both treatment arms, the dosing frequency will be decreased to once daily in patients 
with severe renal impairment (Cr Cl in adults between 10 – 30 ml/min and children 
between 10 – 30 ml/min/1.73M2). For example, the 75 mg bid frequency will be 
decreased to 75 mg once daily.  
At any time during the study if the investigator feels that renal function is compromised, 
dosing may be decreased to once daily or withheld until such time creatinine clearance 
results are available. Dosing may then be resumed as appropriate based on the creatinine 
clearance. However, it is vital that dosing not be inappropriately withheld for extended 
Roche Protocol NV20234  (RO640796)  - Page 35 


periods of time especially in the first 3 days of treatment when viral titers may be high. It 
is also important that dose modifications are clearly and accurately recorded for 
assessment of pharmacokinetic results.  
For adolescents and children, the creatinine clearance will be estimated using a Schwarz 
equation: (Appendix 1) 
For adults the method of Cockcroft-Gault will be used to estimate creatinine clearance. 
(Appendix 1) 
6.2 
Preparation and Administration of Study Drug  
Oseltamivir will be provided in two forms:  
1. Capsules containing 75 mg of active drug and packaging material consisting of 
pregelatinized starch, povidone, talc and sodium stearyl fumarate. All participants 13 
years and older will receive this dosage form. Oseltamivir capsules should be stored 
at 25ºC.  
2. A pediatric suspension containing 12 mg oseltamivir per ml of reconstituted solution 
and the following excipients: sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor). All participants 12 years and under will receive this dosage form. 
Oseltamivir dry powder for suspension [pediatric syrup] should be stored at 25ºC.  
After reconstitution, the suspension should not be used for longer than 10 days. Store 
constituted suspension under refrigeration at 2º to 8ºC.  Do not freeze. 
 
Matching placebo will be available as capsules and suspension. Subjects in the 
conventional dose arm will get the conventional dose and matching placebo so that they 
are blinded from the high dose arm.  
Each subject will be dispensed a medication pack that will provide enough medication to 
cover 20 doses. For subjects randomized to the conventional dose arm, the medication 
pack will contain a bottle of oseltamivir dry powder or a blister wallet with oseltamivir 
capsules and matching placebo. For subjects randomized to the high dose arm, the 
medication pack will contain two bottles of oseltamivir dry powder or two blister wallets 
with oseltamivir capsules. Irrespective of the treatment group the subject is randomized 
to, for each dose the subject will take the same amount from both bottles or blister wallets 
provided in the medication pack such that the sum of the amounts from each immediate 
container constitutes one dose. 
One dose is to be administered twice per day at approximately 12-hour intervals with a 
light snack or glass of milk or fruit juice. The first dose of study medication will be 
administered in the clinic at the time of randomization. 
6.3 
Blinding and Unblinding 
Randomization will be administered by a central randomization center.  
The Randomization List will not be available at the study center, to the study monitors, 
project statisticians or to the project team at Roche. Emergency codes, or another 
Roche Protocol NV20234  (RO640796)  - Page 36 


adequate method of unblinding, will be implemented before study start, if the identity of 
the test medication is necessary for patient management in the case of a serious adverse 
event. Emergency codes should not be broken except in the case of emergency situations. 
Any request from the investigator for information about the treatment administered to 
study subjects for another purpose must be discussed with Roche/designee.  
As per regulatory reporting requirement, Roche/designee will unblind the identity of the 
study medication for all unexpected [as per IB] serious adverse events that are considered 
by the investigator to be related to study drug. Details of patients who are unblinded 
during the study will be included in the Clinical Study Report. 
All other individuals directly involved in this study will remain blinded until the final 
analysis of the primary parameter.  
The randomization will be stratified by transplant type, duration of symptoms, influenza 
vaccination status and age and will be provided by the Roche randomization group for the 
IVRS vendor.  
6.4 
Assessment of Compliance 
Accountability and subject compliance will be assessed by maintaining adequate “drug 
dispensing” and return records.  
Subjects will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  
A Drug Dispensing Log must be kept current and should contain the following 
information: 
• the identification of the subject [randomization and medication numbers] to whom the 
study medication was dispensed 
• the date[s], quantity of the study medication dispensed to the subject 
• the date[s] and quantity of the study medication returned by the subject 
This inventory must be available for inspection by the Monitor. All supplies, including 
partially used or empty containers and the dispensing logs, must be returned to the 
monitor at the end of the study. 
6.5 
Destruction of Study Drug 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons. In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned and destroyed. Written authorization must be obtained from the sponsor or 
designee at study start up before destruction. 
Roche Protocol NV20234  (RO640796)  - Page 37 


Written documentation of destruction must contain the following: 
– Identity [batch numbers or subject numbers] of investigational product[s] destroyed 
– Quantity of investigational product[s] destroyed 
– Date of destruction 
– Method of destruction 
– Name and signature of responsible person [or company] who destroyed 
investigational products[s] 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
Adverse Events (AEs) and Laboratory Abnormalities 
7.1.1 
Clinical AEs 
Per the International Conference of Harmonization [ICH], an AE is any untoward 
medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign [including 
an abnormal laboratory finding], symptom, or disease temporally associated with the use 
of a medicinal [investigational] product, whether or not considered related to the 
medicinal [investigational] product. Pre-existing conditions which worsen during a study 
are to be reported as AEs. Influenza signs and symptoms reported on the diary card will 
be summarized as efficacy end points and need not be captured as adverse events. 
However, secondary illnesses due to influenza must be reported as adverse events.  
7.1.1.1 
Intensity  
All clinical AEs encountered during the clinical study will be reported on the AE page of 
the CRF.   
Intensity of AEs will be graded on a four -point scale [mild, moderate, severe, 
life-threatening] and reported in detail on the CRF.   
Mild 
discomfort noticed but no disruption of normal daily activity. 
Moderate 
discomfort sufficient to reduce or affect daily activity. 
Severe 
inability to work or perform normal daily activity 
Life Threatening 
represents an immediate threat to life   
7.1.1.2 
Drug - Adverse event relationship 
Relationship of the AE to the treatment should always be assessed by the investigator. 
Description of scales can be found in Appendix 4. 
Roche Protocol NV20234  (RO640796)  - Page 38 


7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
A Serious Adverse Event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. It is any AE that at any dose fulfils at least one 
of the following criteria: 
– is fatal; [results in death; NOTE: death is an outcome, not an event]  
– is Life-Threatening [NOTE: the term "Life-Threatening" refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– required in-patient hospitalization or prolongation of existing hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to. 
(Appendix 5) 
7.1.2 
Treatment and Follow-up of AEs  
AEs, especially those for which the relationship to test “drug” is not “unrelated”, should 
be followed up until they have returned to baseline status or stabilized. If a clear 
explanation is established it should be recorded on the CRF.   
7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will appear printed on laboratory reports provided to the site from 
the central lab.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] 
should be reported as such, in addition to being recorded as an AE in the CRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis 
on the AE page in the CRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication [e.g. dose modification, interruption or 
permanent discontinuation] 
• Requiring a change in concomitant therapy [e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment]. 
7.1.4 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
Roche Protocol NV20234  (RO640796)  - Page 39 


and/or an adequate explanation of the abnormality is found. If a clear explanation is 
established it should be recorded on the CRF.  
7.2 
Handling of Safety Parameters 
7.2.1 
Reporting of Serious Adverse Events [immediately reportable] 
Any clinical AE or abnormal laboratory test value that is serious and which occurs during 
the course of the study [as defined in section 7.1.1.3 above], regardless of the treatment 
arm, must be reported to Roche or designee within one working day of the investigator 
becoming aware of the event [expedited reporting]. 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and up 
until the follow-up visit.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to. (Appendix 5) 
7.2.2 
Pregnancy  
A female subject must be instructed to stop taking the test “drug” and immediately 
inform the investigator if she becomes pregnant during the study. The investigator should 
report all pregnancies within 24 hours to the sponsor or designee. The investigator should 
counsel the subject, and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion 
of the pregnancy.   
Pregnancy occurring in the partner of a male subject participating in the study should be 
reported to the investigator and the sponsor or designee after the pregnant partner’s 
consent has been obtained. The partner should be counseled and followed as described 
above if acceptable, and provides informed consent.  
7.3 
Warnings and Precautions  
Events such as convulsions and those associated with delirium have been reported during 
oseltamivir use in patients with influenza.  In rare cases, the delirium resulted in 
accidental injury.  The contribution of oseltamivir to those events is unknown.  Such 
events have also been reported in patients with influenza who were not taking 
oseltamivir. Patients, especially children and adolescents, should be closely monitored.   
Please refer to the attached Investigator’s Brochure for additional warnings, precautions, 
and other reported adverse events. 
Roche Protocol NV20234  (RO640796)  - Page 40 


8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN   
Full details of all planned analyses will be specified in a separate Data Reporting and 
Analysis Manual (DRAM). The methods described below are an outline of the main 
planned analyses. 
8.1 
Primary and Secondary Study Endpoints 
8.1.1 
Primary Endpoints 
The primary endpoint in this study is the time to alleviation of all clinical influenza 
symptoms (recorded in the diary card). 
8.1.2 
Secondary Endpoints 
The following are secondary endpoints. With the exceptions of viral load and time to 
resolution of fever, they are defined as either the occurrence or non-occurrence of the 
specified events or the presence or absence of the specified symptoms,  
Shedding virus by culture at day 1, 2, 6, 8, 11, 15 and 40 
Shedding virus by RT-PCR at day 1, 2, 6, 8, 11, 15, and 40 
Viral load by culture (log10TCID50/mL) at Day 1, 2, 6, 8, 11, 15, and 40  
Viral load by quantitative RT-PCR at day 1, 2, 6, 8, 11, 15 and 40 
The time (hours) from first dose of study medication until resolution of fever  
 Fever  
Cough   
Coryza   
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or 
sinusitis) at any time during the study. 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or 
sinusitis) at any time during the study that are treated with antibiotics 
Initiation of treatment with antibiotics after randomization  
Hospitalization, and for those who are hospitalized, the duration of hospitalization 
Development of rejection or GVHD 
Baseline, post-baseline and change from baseline in antibody titers 
8.1.3 
Safety 
Safety of the treatment will be evaluated by AEs, laboratory tests, and vital signs.  
All subjects who received at least one dose of treatment and had a safety assessment 
performed post randomization will be included in the safety evaluation. 
Roche Protocol NV20234  (RO640796)  - Page 41 


In addition to routine safety assessments, the proportion of subjects experiencing a 
rejection and/or graft versus host disease will be summarized by treatment group.  
8.2 
Statistical and Analytical Methods  
8.2.1 
Statistical Model  
8.2.1.1 
Primary Variables 
A non-parametric model will be assumed with estimation of medians based on Kaplan-
Meier methods. Subjects without alleviation of symptoms will have their time censored at 
the last available observation that a complete assessment was made. 
For the purpose of comparing treatment groups, it will be assumed that their respective 
distributions for the primary endpoint differ only by a shift in location. 
8.2.1.2 
Secondary Variables  
For the secondary endpoints defined dichotomously in terms of events or symptoms, it 
will be assumed that the number of patients experiencing the event or exhibiting the 
symptom will have a binomial distribution. 
For the continuous endpoint of time to resolution of fever, the same assumptions as for 
the primary endpoint will be made. 
For the continuous endpoints of viral load at Day 1, 2, 6, 8, 11, 15, and 40 no model will 
be assumed.  
8.2.2 
Sample Size 
Sample size calculations were performed using a two-sided t-test and are based on the 
comparison with a placebo control response in the pivotal registration trials in healthy 
adults of 112 hours for median time to alleviation of all symptoms. Assuming an 
expected median time to alleviation of symptoms of 78 hours for each of the two active 
treatment groups in this study, and a common standard deviation of 98 hours, then 111 
evaluable subjects per group would give more than 90% power to detect a difference 
between the control and each of the active treatment groups. It is assumed that as many as 
90 % of subjects enrolled into the study will have influenza, and therefore 124 subjects 
per arm would be required in order to obtain 111 influenza positive subjects. Note that 
this is an approximate calculation, as the final analysis will be based on the difference in 
medians and the corresponding 95% confidence interval from the Kaplan-Meier curves. 
This is however considered as a sufficient indication for the size of the trial and the 
power that is expected.  
8.2.3 
Hypothesis Testing  
Formal hypothesis testing will be not performed, instead inferences will be based on 
comparison of confidence intervals.  
Roche Protocol NV20234  (RO640796)  - Page 42 


8.2.4 
Analysis Populations 
Three main patient populations will be used for the analysis of data from this study; the 
Safety Population, the Intent-to treat Population and the Intent-to-Treat Infected 
Population . Detailed definitions of these populations will be given in the DRAM  
8.2.4.1 
Intent to treat population: 
All patients randomized will be included in the intent to treat population [Patients will be 
assigned to treatment groups as randomized for analysis purposes] 
8.2.4.2 
Intent to treat infected population: 
All patients randomized and with laboratory confirmation of influenza infection (positive 
viral cultures or 4 fold or greater rise in antibody titers) will be included in the intent to 
treat influenza infected population [Patients will be assigned to treatment groups as 
randomized for analysis purposes] 
The ITTI Population will be the primary population for the summary and analysis of the 
primary and secondary efficacy variables. 
8.2.4.3 
Subpopulations 
In order to evaluate the potential for relapse, the following two subpopulations of the 
ITTI population will be evaluated:  
• patients not shedding virus as assessed by culture on Day 11 
• patients not shedding virus as assessed by RT-PCR on Day 11 
Viral shedding and RT-PCR at days 15 and 40 will be evaluated in these subpopulations. 
Based on the proportion of subjects hospitalized, an additional subpopulation may be 
defined to evaluate the length of hospitalization for hospitalized subjects. 
Likewise, based on the proportion of children enrolled additional subpopulations of 
children and adults will be created to evaluate the course of influenza in children and 
adults.  
8.2.5 
Efficacy Analysis 
For the primary analysis, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• Comparison to placebo control from pivotal registration trials  
  
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established to match (in 
terms of efficacy evaluations, duration of observation etc.) those of the current study. 
For this population, a median time to resolution of all clinical influenza symptoms 
will be determined along with its 95% confidence interval. 
 
The median time to resolution of all influenza symptoms will be determined for each 
Roche Protocol NV20234  (RO640796)  - Page 43 


treatment group, along with its 95% confidence interval.  These confidence intervals 
will be compared individually to the placebo control confidence interval described 
above as a potential means of establishing treatment effects. 
•  Assessment of relative efficacy. 
 
The two doses groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval. The methodology will be based on the use of the Hodges-
Lehmann estimator in the case of censored data.  
This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences. For example, if it does not contain 
the value zero a difference will have been established. However, given the study sample 
size this outcome is only likely if a clinically significant difference (e.g. 30% ) exists. 
Although this is not anticipated from the experience in pivotal registration trials in 
normal healthy patients, it cannot be ruled out as a possibility in immunocompromised 
transplant recipients.   
For the dichotomous secondary endpoints, the proportion experiencing the event or 
symptom, and its associated 95% confidence interval will be derived for each treatment 
group. Where possible, the corresponding confidence intervals from the placebo control 
population will be presented for comparison to those derived for the active treatment 
groups in this trial. 
The continuous secondary endpoints time to resolution of fever will be analyzed as for 
the primary endpoint.  
For the continuous endpoints of viral load (log10TCID50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, median, minimum and maximum) will be derived 
for each treatment group. 
8.2.5.1 
Exclusion of Data from Analysis 
No data will be excluded from the primary and secondary efficacy analyses.  
8.2.5.2 
Interim Analysis 
No interim analyses are planned.  
8.2.6 
Safety Data Analysis 
The safety analysis population will include all subjects who receive at least one dose and 
had a safety assessment performed post randomization. All safety parameters will be 
summarized and presented in tables based on this safety population.  
8.2.7 
Other Analyses 
The number and percentage of patients with influenza infection (defined as a positive 
culture from a nasal and/or throat swab or 4 fold or greater rise in antibody titers) will be 
summarized by treatment group for the Intent-to-treat Population. 
Roche Protocol NV20234  (RO640796)  - Page 44 


Further exploratory analysis, (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the DRAM. 
The last positive viral isolate from each patient will be tested for reduced sensitivity to 
oseltamivir. Clonal resistance assays will also be used to evaluate the rate of resistance to 
oseltamivir. These data will be summarized in a report separate from the final study 
report. 
8.3 
Pharmacokinetic and Pharmacodynamic Analysis 
8.3.1 
Pharmacokinetic Analysis   
Nonlinear mixed effects modeling (with software NONMEM) will be used to analyze all 
plasma concentration-time data of oseltamivir and oseltamivir carboxylate following 
oseltamivir 
administration. 
Population 
pharmacokinetic 
parameters 
(clearance, 
distribution volume) will be estimated. The influence of covariates (such as age, gender, 
body weight and calculated creatinine) on these parameters will be investigated. Based on 
the population PK model individual pharmacokinetic parameters such as AUC, Cmax, Cmin 
and tmax may be calculated using Bayesian posthocs. If deemed appropriate and necessary, 
data may be pooled with data from previous studies investigating oseltamivir and 
oseltamivir carboxylate in order to improve model stability.  
8.3.2 
Pharmacodynamic Analysis  
If feasible, the relationship between PK exposure of oseltamivir carboxylate and viral 
shedding response data will be characterized using nonlinear mixed effects modeling 
(using software NONMEM). Relevant population PD parameters will be derived and the 
influence of covariates will be investigated. If deemed appropriate and necessary, data 
may be pooled with data from previous studies investigating oseltamivir and oseltamivir 
carboxylate in order to improve the model stability. 
9. 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs against the investigator’s records by the study monitor [source document 
verification], and the maintenance of a drug–dispensing log by the investigator.  
The data collected will be entered into the study database from the working copy of the 
CRF faxed from the site. 
A comprehensive validation check program will verify the data and discrepancy reports 
will be generated accordingly for resolution by the investigator. As patients complete the 
study [or prematurely withdraw] and their signed CRFs become available, a second data 
entry will be performed from the original, signed CRF. A comparison check will be run 
to identify and resolve any discrepancies between the first and second data entry. 
Throughout the study the Study Management Team [SMT] will review data according to 
the SMT Data Review Plan as described in the Data Quality Plan.  
Roche Protocol NV20234  (RO640796)  - Page 45 


9.1 
Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned by the sponsor to the original 
terms entered on the CRF, using the current version of MedDRA (Medical Dictionary for 
Regulatory Activities terminology) for adverse events and diseases and the INN 
(International Non-Proprietary name) drug terms and procedures dictionary for 
treatments and surgical and medical procedures. 
 
Roche Protocol NV20234  (RO640796)  - Page 46 


10. 
REFERENCES 
 
1. Murphy B.G and Webster R.G.  Orthomyxoviruses. Chapter 46.  Fields Virology 3rd 
Edition, Eds:  Fields B.N, Knipe D.M, Howley P.M et al. Pub Lippincott.Raven.  
1996.  p1397 – 1445.  
2. World Health Organization. Influenza. Fact Sheet No. 211. March, 2003. 
3. Ison Michael, G., P. Mishin Vasiliy, J. Braciale Thomas, G. Hayden-Frederick, and V. 
Gubareva Larisa., Comparative activities of oseltamivir and A-322278 in 
immunocompetent and immunocompromised murine models of influenza virus 
infection. The Journal of infectious diseases, 2006. 193(6): p. 765-72  
4. Ison Michael, G. and G. Hayden Frederick., Viral infections in immunocompromised 
patients: what's new with respiratory viruses? Current opinion in infectious diseases, 
2002. 15(4): p. 355-67 
5. Vilchez Regis, A., K. McCurry, J. Dauber, A. Lacono, B. Griffith, et al., Influenza 
virus infection in adult solid organ transplant recipients. American journal of 
transplantation : official journal of the American Society of Transplantation and the 
American Society of Transplant Surgeons, 2002. 2(3): p. 287-91 
6. Ljungman, P., K.N. Ward, B.N. Crooks, A. Parker, R. Martino, et al., Respiratory 
virus infections after stem cell transplantation: a prospective study from the Infectious 
Diseases Working Party of the European Group for Blood and Marrow 
Transplantation. Bone marrow transplantation, 2001. 28(5): p. 479-84 
7. Nichols, W.G., A. Guthrie Katherine, L. Corey, and M. Boeckh, Influenza infections 
after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of 
antiviral therapy. Clinical infectious diseases : an official publication of the Infectious 
Diseases Society of America, 2004. 39(9): p. 1300-6 
8. Investigator Brochure for Tamiflu® (oseltamivir phosphate) 7th version July 2006.  
9. Johny, A.A., A. Clark, N. Price, D. Carrington, A. Oakhill, and D.I. Marks, The use 
of zanamivir to treat influenza A and B infection after allogeneic stem cell 
transplantation. Bone marrow transplantation, {Bone Marrow Transplant}, Jan 2002, 
vol. 29, no. 2, p. 113 5, ISSN: 0268 3369., 2002 
10. January 14, 2006 CDC Health Alert Notice. CDC Recommends against the use of 
amantadine and rimantadine for the treatment or prophylaxis of influenza in the 
United States during the 2005 – 2006 Influenza season. As assessed on April 3, 2006 
at http://www.cdc.gov/flu/han011406.htm  
11. Kaiser, L., C. Wat, T. Mills, P. Mahoney, P. Ward, et al., Impact of oseltamivir 
treatment 
on 
influenza-related 
lower 
respiratory 
tract 
complications 
and 
hospitalizations. Archives of internal medicine, 2003. 163(14): p. 1667-72  
Roche Protocol NV20234  (RO640796)  - Page 47 


12. Whitley, R.J., F.G. Hayden, K.S. Reisinger, N. Young, R. Dutkowski, D. Ipe, R.G. 
Mills, and P. Ward, Oral oseltamivir treatment of influenza in children. The Pediatric 
infectious disease journal, Feb 2001, vol. 20, no. 2, p. 127 33, ISSN: 0891 3668., 
2001 
13. Machado, C.M., L.S.V. Boas, A.V.A. Mendes, I.F. da Rocha, D. Sturaro, et al., Use 
of Oseltamivir to control influenza complications after bone marrow transplantation. 
Bone marrow transplantation, 2004. 34(2): p. 111-4 
14. Dutkowski, R., B. Thakrar, E. Froehlich, P. Suter, C. Oo, et al., Safety and 
pharmacology of oseltamivir in clinical use. Drug safety : an international journal of 
medical toxicology and drug experience, 2003. 26(11): p. 787-801 
15. He, G., J. Massarella, and P. Ward, Clinical pharmacokinetics of the prodrug 
oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinetics. 1999 Dec. 
37(6):471-84. Review.  
16. Snell, P., N. Dave, K. Wilson, L. Rowell, A. Weil, L. Galitz, and R. Robson, Lack of 
effect of moderate hepatic impairment on the pharmacokinetics of oral oseltamivir 
and its metabolite oseltamivir carboxylate. British journal of clinical pharmacology,  
May 2005, vol. 59, no. 5, p. 598 601 
17. Levey Andrew, S., J. Coresh, E. Balk, T. Kausz Annamaria, A. Levin, et al., National 
Kidney Foundation practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification. Annals of internal medicine, 2003. 139 (2): p. 137-47 
18. Hogg Ronald, J., S. Furth, V. Lemley Kevin, R. Portman, J. Schwartz- George, et al., 
National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical 
practice guidelines for chronic kidney disease in children and adolescents: evaluation, 
classification, and stratification. Pediatrics, 2003. 111(6 Pt 1): p. 1416-21 
19. Ferrara, J.L. and H.J. Deeg, Graft-versus-host disease. The New England journal of 
medicine, 1991. 324(10): p. 667-74 
 
Roche Protocol NV20234  (RO640796)  - Page 48 


PART II: 
ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the subject. For studies conducted in the EU/EEA countries, the 
investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].  
For studies conducted in the USA or under US IND, the investigator will additionally 
ensure that the basic principles of “Good Clinical Practice” as outlined in the current 
version of 21 CFR, subchapter D, part 312, “Responsibilities of Sponsors and 
Investigators”, part 50, “Protection of Human Subjects”, and part 56, “Institutional 
Review Boards”, are adhered to. 
In other countries where “Guideline for Good Clinical Practice” exist Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
Informed Consent  
 It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain written informed consent from each subject 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. For subjects not qualified or incapable of 
giving legal consent, written consent must be obtained from the legally acceptable 
representative. In the case where both the subject and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the entire 
informed consent discussion. After the subject and representative have orally consented 
to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. The 
investigator or designee must also explain that the subjects are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason. The Case Report 
Forms [CRFs] for this study contain a section for documenting informed subject consent, 
and this must be completed appropriately. If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and updated 
if necessary. All subjects [including those already being treated] should be informed of 
the new information, given a copy of the revised form and give their consent to continue 
in the study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written consent. 
 
Roche Protocol NV20234  (RO640796)  - Page 49 


11.3 
Independent Ethics Committees/Institutional Review Board  
Independent Ethics Committees [non-US]: This protocol and any accompanying 
material provided to the subject [such as subject information sheets or descriptions of the 
study used to obtain informed consent] as well as any advertising or compensation given 
to the patient, will be submitted by the investigator to an Independent Ethics Committee. 
Approval from the committee must be obtained before starting the study, and should be 
documented in a letter to the investigator specifying the date on which the committee met 
and granted the approval. 
Any modifications made to the protocol after receipt of the Independent Ethics 
Committee approval must also be submitted by the investigator to the Committee in 
accordance with local procedures and regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee. If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee. 
Institutional Review Board [US]: It is the understanding of the sponsor that this 
protocol [and any modifications] as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board. This board must operate in 
accordance with the current Federal Regulations. A letter or certificate of approval will 
be sent by the investigator to the  sponsor or designee prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between 
an appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial].  Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Clinical Science Leader/Clinical Pharmacologist and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required. Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial subjects, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g. change in monitor[s], change of telephone 
number[s]. 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
Roche Protocol NV20234  (RO640796)  - Page 50 


14. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
14.1 
Investigator's Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] subject clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence etc.  
Subject clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and subject screening and enrollment logs. 
The Investigator must keep these two categories of documents on file for at least 15 years 
after completion or discontinuation of the study. After that period of time the documents 
may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them to 
another location, Roche must be notified in advance. 
If the Investigator can not guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit. Where source 
documents are required for the continued care of the patient, appropriate copies should be 
made for storing outside of the site. 
14.2 
Source Documents and Background Data 
The investigator shall supply the sponsor or designee on request with any required 
background data from the study documentation or clinic records. This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected. In 
case of special problems and/or governmental queries or requests for audit inspections, it 
is also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. 
14.3 
Audits and Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development   
Quality Assurance Unit or its designees, or to health authority inspectors after appropriate 
notification. The verification of the CRF data must be by direct inspection of source 
documents. 
Roche Protocol NV20234  (RO640796)  - Page 51 


14.4 
Case Report Forms 
For each patient enrolled, a CRF must be completed and signed by the principal 
investigator or authorized delegate from the study staff. This also applies to records for 
those patients who fail to complete the study [even during a pre-randomization screening 
period if a CRF was initiated]. If a patient withdraws from the study, the reason must be 
noted on the CRF. If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
All forms should be typed or filled out using indelible ink, and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed 
and dated by the investigator or his/her authorized delegate. The investigator should 
ensure the accuracy, completeness, legibility, and timeliness of the data reported to the  
sponsor or designee in the CRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitor should have access to laboratory 
test reports and other patient records needed to verify the entries on the CRF. The 
investigator [or his/her deputy] agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the  sponsor or designee, subjects should not be identified by their names, 
but by an identification code. The investigator should keep a subject enrollment log 
showing codes, names and addresses. The investigator should maintain documents not for 
submission to Roche, e.g., subjects’ written consent forms, in strict confidence. 
17. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission. This allows the  sponsor or designee to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator. 
In accord with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
Roche Protocol NV20234  (RO640796)  - Page 52 


Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel. Authorship will be determined by mutual agreement. 
Roche Protocol NV20234  (RO640796)  - Page 53 


 
Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD  
 
Calculation of Creatinine Clearance 
Conversion Factor for Serum Creatinine: 
Conventional Units (mg/dL) = SI Units (µmol/L) ÷ 88.4   
Age = number of years (12 years 11 months = 12 years) 
 
Estimated Creatinine Clearance according to Cockcroft-Gault [17] 
 (for patients ≥ 18 years): 
¾ Males 
Creatinine  
Clearance (mL/min) = 
 
[(140 – age) X Body Weight (kg)] ÷ [72 X Serum Creatinine (mg/dL)] 
 
¾ Females  
Creatinine Clearance = above equation X 0.85 
 
 
 
Estimated Creatinine Clearance according to Schwartz equation [18]  
(for patients < 18 years): 
Creatinine Clearance 
(mL/min/1.73 M2) = 
 
k X Height (cms) ÷  Serum Creatinine (mg/dL) 
 
Value for k:  
k 
Age (years) 
0.45 
< 2 
0.55 
≥ 2 to < 13 
0.7 
≥ 13 to < 18 (males) 
 
Roche Protocol NV20234  (RO640796)  - Page 54 


 
Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD (Cont.) 
 
Grading of Chronic GVHD [19] 
 
Type of Disease 
Extent of Disease 
Limited 
Localized 
skin 
involvement, 
liver 
dysfunction or both 
Extensive 
Generalized skin involvement 
 
Localized 
skin 
involvement 
or 
liver 
dysfunction plus any one of the following: 
   1. Chronic aggressive hepatitis, bridging 
necrosis or cirrhosis 
   2. Eye involvement (Schirmer’s test, < 5 
mm) 
   3. Involvement of mucosalivary glands 
   4. Mucosal involvement (on lip biopsy) 
   5. Involvement of other target organs  
 
 
 
 
 
Roche Protocol NV20234  (RO640796)  - Page 55 


 
Appendix 2 
Adult Patient Diary Card and Symptom Record  
The purpose of the diary card is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study. Temperature, date and 
time of drug administration, intake of food will also be recorded on the patient diary card. 
Scoring of Symptoms 
Please answer All of the questions yourself by checking one box for each row. 
The information you provide is very important and will remain strictly confidential. 
 
 
 
 
    absent 
 mild 
        moderate 
      severe 
 
 
 
 
        0                  1 
 
2 
         3 
 
 
 
Roche Protocol NV20234  (RO640796)  - Page 56 


 
Appendix 3 
Diary Card for Children  
Date and time of intake of food will also be recorded on the patient diary card. 
  
 
Temperature:  
 
 
.  
ºC/F 
Symptoms of influenza-like illness 
Please mark one box only per question 
Item 
 
No 
Problem 
0 
 
Minor 
Problem 
1 
 
Moderate 
Problem 
2 
 
Major 
Problem 
3 
Don’t Know 
or not 
Applicable 
1. 
Poor appetite........................................
 
 
 
 
 
2. 
Not sleeping well.................................
 
 
 
 
 
3. 
Irritable, cranky, fussy.........................
 
 
 
 
 
4. 
Feels unwell.........................................
 
 
 
 
 
5. 
Low energy, tired.................................
 
 
 
 
 
6. 
Not playing well ..................................
 
 
 
 
 
7. 
Crying more than usual........................
 
 
 
 
 
8. 
Needing extra care...............................
 
 
 
 
 
9. 
Clinginess............................................
 
 
 
 
 
10. Headache .............................................
 
 
 
 
 
11. Sore throat ...........................................
 
 
 
 
 
12.   Muscle aches or pains..........................
 
 
 
 
 
13. Fever....................................................
 
 
 
 
 
14. Cough ..................................................
 
 
 
 
 
15. Nasal congestion, runny nose ..............
 
 
 
 
 
16. Vomiting..............................................
 
 
 
 
 
17. Not interested in what’s going on 
 
 
 
 
 
18. Unable to get to get out of bed 
 
 
 
 
 
This form was filled out by:          
                                                        1. 
 Parent 
 
2. 
 Other relative 
 
3. 
Nanny 
 
4. 
Subject 
 
5. 
 Other     specify______________________________________________ 
 
Date of Assessment 
 
 
 
 
 
 
 
dd 
mm 
yy 
Time of Assessment 
 
 
 
 
 
h 
min 
Roche Protocol NV20234  (RO640796)  - Page 57 


 
Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug 
 
PROBABLE [must have first three] 
This category applies to those AEs which are considered, with a high degree of certainty, to 
be related to the test drug.  An AE may be considered probable, if: 
1. It follows a reasonable temporal sequence from administration of the drug. 
2. It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the subject. 
3. It disappears or decreases on cessation or reduction in dose.  [There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., [1] bone marrow depression, [2] tardive 
dyskinesias.] 
4. It follows a known pattern of response to the suspected drug. 
5. It reappears upon rechallenge. 
 
POSSIBLE [must have first two] 
1. This category applies to those AEs in which the connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possible if, or when: 
2. It follows a reasonable temporal sequence from administration of the drug. 
3. It may have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
4. It follows a known pattern of response to the suspected drug. 
 
REMOTE [must have first two] 
1. In general, this category is applicable to an AE which meets the following criteria: 
2. It does not follow a reasonable temporal sequence from administration of the drug. 
3. It may readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
4. It does not follow a known pattern of response to the suspected drug. 
5. It does not reappear or worsen when the drug is readministered. 
 
UNRELATED 
This category is applicable to those AEs which are judged to be clearly and 
incontrovertibly due only to extraneous causes [disease, environment, etc.] and do not meet 
the criteria for drug relationship listed under remote, possible, or probable. 
 
 
 
Roche Protocol NV20234  (RO640796)  - Page 58 


 
Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug (Cont.) 
 
 
 
Probable 
Possible 
Remote 
Unrelated 
Clearly due to extraneous causes 
– 
– 
– 
+ 
 
 
 
 
 
Reasonable temporal association with drug 
administration 
+ 
+ 
– 
– 
 
 
 
 
 
May be produced by subject clinical state, 
etc. 
– 
+ 
+ 
+ 
 
 
 
 
 
Known response pattern to suspected drug 
+ 
+ 
– 
– 
 
 
 
 
 
Disappears or decreases on cessation or 
reduction in dose 
+ 
– 
– 
– 
 
 
 
 
 
Reappears on rechallenge 
+ 
– 
– 
– 
Roche Protocol NV20234  (RO640796)  - Page 59 


 
Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– is fatal; [results in death] [NOTE: death is an outcome, not an event] 
– is Life-Threatening    [NOTE: the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– required in-patient hospitalization or prolongation of existing hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the 
outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the  sponsor or designee is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definitions above. These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator. For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply)  
– Pre-existing/Underlying disease - specify  
– Study treatment – specify the drug(s) related to the event 
– Other treatment (concomitant or previous) – specify 
– Protocol-related procedure 
– Other (e.g. accident, new or intercurrent illness) - specify 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be clinically 
serious. 
Roche Protocol NV20234  (RO640796)  - Page 60 


 
Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
[Cont.] 
 
A serious adverse event occurring during the study or which comes to the attention of the 
investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will 
include copies of hospital case reports, autopsy reports and other documents when 
requested and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs page 
of the CRF: intensity, relationship to test substance, action taken, and outcome to date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor  
ROCHE HEADQUARTERS CONTACT for SAEs: Clinical Operations/Clinical Science  
Within the US, weekends, holidays and after 5:00 pm, call 
 and ask for 
the physician on call.  Outside the US, call the local emergency contact number provided 
by the Monitor. 
 
Roche Protocol NV20234  (RO640796)  - Page 61 


AMENDMENT HISTORY FOR PROTOCOL NV20234B 
 
1. 
SUBJECT:  ADDITION OF EUDRACT AND IND NUMBERS TO COVER 
PAGE  
Reason for change:    
The EudraCT and IND numbers were inadvertently left off of the cover page. 
Section:  Cover page 
New text: 
IND Number: 53,093 
EudraCT Number: 2006-002468-24 
Old text: 
None 
 
2. 
SUBJECT:  ADDITION OF A MORE TIMELY ASSESSMENT OF 
BASELINE NASAL AND THROAT SWAB SAMPLES FOR OSELTAMIVIR-
RESISTANT VIRUS  
Reason for change:    
A significant increase in oseltamivir-resistant viruses circulating within many countries 
was identified by routine influenza virus surveillance during the 2007/2008 influenza 
season.  These viruses have been characterized as influenza A H1N1 and they carry the 
H274Y mutation.  This mutation confers a high level of resistance to oseltamivir, but not 
to amantadine, rimantadine, or zanamivir.  Because oseltamivir–resistant viruses may 
continue to circulate during future influenza seasons, baseline nasal and throat swab 
samples will be assessed for the presence of the H274Y-mutated influenza virus using a 
real-time PCR assay.  Results will be reported promptly to clinical sites to assist in 
determining the most appropriate treatment options for individual patients. 
Section 3.1.1  Rationale for Study Design  
New text: 
This study incorporates several features that distinguish it from classic placebo controlled 
trials. At the outset, a patient population that represents the general immunocompromised  
population had to be defined. As a placebo control arm was considered unethical in this 
population, an alternative control arm had to be identified. The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial. In order to do this, the 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 1 


current study design and end points were designed to be similar to that in the pivotal 
registration trials.   
Routine influenza surveillance during the 2007/2008 influenza season showed a 
significant increase in the global circulation of an oseltamivir-resistant influenza 
virus (A H1N1 with H274Y mutation).  Therefore, baseline nasal and throat swab 
samples will be assessed for the presence of the H274Y-mutated influenza virus and 
results will be reported to clinical sites to assist in determining the most appropriate 
treatment options for individual patients. 
The following sections provide rationale and justification for the specific aspects of the 
study design. They also provide information on how the results will be used to make 
recommendations on dose and duration of treatment. 
Old text: 
This study incorporates several features that distinguish it from classic placebo controlled 
trials. At the outset, a patient population that represents the general immunocompromised 
population had to be defined. As a placebo control arm was considered unethical in this 
population, an alternative control arm had to be identified. The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial. In order to do this, the 
current study design and end points were designed to be similar to that in the pivotal 
registration trials. The following sections provide rationale and justification for the 
specific aspects of the study design. They also provide information on how the results 
will be used to make recommendations on dose and duration of treatment. 
Section  5  Schedule of Assessments and Procedures  
New text: 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Nasal and throat swabs for viral 
shedding and viral load c, d 
x 
 
x 
x 
x 
x 
x 
x 
 
c.  Baseline swab samples will be assessed for the presence of influenza A H1N1 with H274Y mutation. 
d.  Two nasal and one throat swab for viral culture and RT-PCR.   
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 2 


Old text: 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Nasal and throat swabs for viral 
shedding and viral load d 
x 
 
x 
x 
x 
x 
x 
x 
 
c.  .  Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be collected using a sparse 
sampling approach.  [5.5.1] 
d.  Two nasal and one throat swab for viral culture and RT-PCR 
Section 5.3  Clinical Assessments and Procedures 
 
 
 
Study Day 1 
New text: 
Baseline nasal and throat swab samples will be assessed for the presence of 
oseltamivir-resistant influenza A H1N1 with H274Y mutation.  As soon as they are 
available, results will be reported to the sites to assist in patient management. 
Old text: 
None 
Section 5.4  Laboratory Assessments 
New text: 
Nasal and throat swabs. Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments. All swabs are sent to a central laboratory for RT-PCR and 
viral cultures.  Baseline samples will be assessed for the presence of oseltamivir-
resistant influenza A H1N1 with the H274Y resistance mutation using a real-time 
PCR assay.  A phenotypic assay will be performed to determine the susceptibility of the 
last positive viral isolate from each patient. If required, a genotypic assay to determine 
the contribution of both the neuraminidase and haemagglutinin genes to decreased 
susceptibility will be performed.  
During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza. However, in order to 
assist in patient management, the results of the assay to detect influenza A H1N1 
H274Y at baseline will be reported to the sites as soon as they are available.  At the 
end of treatment (day 11), a rapid diagnostic test is permitted for the diagnosis of ongoing 
influenza. 
Old text: 
Nasal and throat swabs. Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments. All swabs are sent to a central laboratory for RT-PCR and 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 3 


viral cultures. A phenotypic assay will be performed to determine the susceptibility of the 
last positive viral isolate from each patient. If required, a genotypic assay to determine 
the contribution of both the neuraminidase and haemagglutinin genes to decreased 
susceptibility will be performed.  
During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza. However at the end of 
treatment (day 11), a rapid diagnostic test is permitted for the diagnosis of ongoing 
influenza. 
 
3. 
SUBJECT:  ADDITION OF NEW CRITERION FOR PREMATURE 
WITHDRAWAL OF PATIENTS FROM STUDY TREATMENT IF 
ADDITIONAL ANTIVIRALS ARE ADDED TO THE PATIENT’S 
TREATMENT REGIMEN 
Reason for change:    
Because of the addition of testing for oseltamivir-resistant influenza A H1N1 H274Y at 
baseline, it is envisioned that some investigators may decide that it is in the best interest 
of the patient to treat with another influenza antiviral.  In these situations, the patient 
must be discontinued from study drug to avoid confounding the safety profile and 
efficacy analyses of oseltamivir in this study. 
Section 4.5  Criteria for Premature Withdrawal   
New text: 
The investigator must discontinue treatment with study drug if the patient is to be 
treated concomitantly with another antiviral for influenza, for example, 
amantadine, rimantadine, or zanamavir.  However, all patients, including those who 
discontinue study drug prematurely and/or are treated with another antiviral, will 
be required to return for follow up approximately 5 and 30 days after the last dose 
of study medication (day 15 and day 40 assessments). 
Old text: 
None. 
 
4. 
SUBJECT:  REPLACEMENT OF PATIENTS WHO ARE IDENTIFIED AS 
HAVING OSELTAMIVIR-RESISTANT INFLUENZA VIRUS AT BASELINE 
Reason for change:    
The number of patients enrolled into this study with influenza A H1N1 H274Y at 
baseline cannot be predicted.  Therefore, a priori assumptions on how  many additional 
patients need to be enrolled to maintain the required number of patients who are 
evaluable for efficacy cannot be made.  To ensure that the number of evaluable patients 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 4 


enrolled is sufficient for the primary efficacy analysis, unevaluable patients infected with 
the oseltamivir-resistant influenza virus at baseline will be replaced by enrolling 
additional patients on a rolling basis. 
Section Synopsis: Number of Subjects 
New text: 
A minimum of 250 (125 per arm) 
Old text: 
Approximately 250 (125 per arm) 
Section 3.2  Number of Subjects/Assignment to Treatment Groups 
New text: 
A minimum of  250 patients will be enrolled in this study (approximately 125 per arm). 
Old text: 
A total of approximately 250 patients will be enrolled in this study (approximately 125 
per arm). 
Section 4.6.1  Replacement Policy [Ensuring Adequate Numbers of 
Evaluable Patients] For Subjects 
New text: 
In order to maintain the required number of patients who are evaluable for efficacy, 
patients who are identified as being infected with influenza A H1N1 H274Y at 
baseline will be replaced by enrolling additional patients on a rolling basis.  
Replacement patients will be stratified and randomized to treatment in the same 
manner as original patients.  Replacement patients will not be “selected” by dose 
group or strata (age, vaccination status, transplant type, time between symptom 
onset and treatment) to match the patients whom they replace. 
Old text: 
No subject prematurely discontinued from the study for any reason will be replaced. 
Section 8.2.2  Sample Size 
New text: 
Sample size calculations were performed using a two-sided t-test and are based on the 
comparison with a placebo control response in the pivotal registration trials in healthy 
adults of 112 hours for median time to alleviation of all symptoms. Assuming an 
expected median time to alleviation of symptoms of 78 hours for each of the two active 
treatment groups in this study, and a common standard deviation of 98 hours, then 111 
evaluable subjects per group would give more than 90% power to detect a difference 
between the control and each of the active treatment groups. It is assumed that as many as 
90 % of subjects enrolled into the study who are identified as not being infected with 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 5 


influenza A H1N1 H274Y will have influenza, and therefore 124 such subjects per arm 
would be required in order to obtain 111 influenza positive subjects. Note that this is an 
approximate calculation, as the final analysis will be based on the difference in medians 
and the corresponding 95% confidence interval from the Kaplan-Meier curves. 
 
This is however considered as a sufficient indication for the number of required 
subjects and the power that is expected. The maximum number of subjects enrolled in 
the trial will depend upon the number of subjects identified with the oseltamivir 
resistant virus who will be replaced. 
Old text: 
Sample size calculations were performed using a two-sided t-test and are based on the 
comparison with a placebo control response in the pivotal registration trials in healthy 
adults of 112 hours for median time to alleviation of all symptoms. Assuming an 
expected median time to alleviation of symptoms of 78 hours for each of the two active 
treatment groups in this study, and a common standard deviation of 98 hours, then 111 
evaluable subjects per group would give more than 90% power to detect a difference 
between the control and each of the active treatment groups. It is assumed that as many as 
90 % of subjects enrolled into the study will have influenza, and therefore 124 subjects 
per arm would be required in order to obtain 111 influenza positive subjects. Note that 
this is an approximate calculation, as the final analysis will be based on the difference in 
medians and the corresponding 95% confidence interval from the Kaplan-Meier curves. 
This is however considered as a sufficient indication for the size of the trial and the 
power that is expected. 
 
5. 
SUBJECT:  CLARIFICATION OF ALLOWED USE OF OTHER 
ANTIVIRALS  
Reason for change:    
In some cases, the investigator may decide that it is in the best interest of the patient to 
treat his/her influenza with another antiviral, for example if oseltamivir-resistant virus is 
identified at baseline or if the patient is positive for influenza by rapid diagnostic test on 
day 11. In these cases, treatment with other antivirals will be allowed, as long as 
treatment with study oseltamivir is discontinued. 
Section 4.4  Concomitant Medication and Treatment 
New text: 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, and additional oseltamivir above that specified for this study) are not 
allowed during the 10-day treatment phase of the study. Concomitant use of an 
investigational drug during the study is also excluded.  
Old text: 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, and additional oseltamivir above that specified for this study) are not 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 6 


allowed during the study. Concomitant use of an investigational drug during the study is 
also excluded.  
 
6. 
SUBJECT:  EXCLUSION OF SPECIFIC DATA FROM EFFICACY 
ANALYSES 
Reason for change:    
Patients who are treated with other antivirals after discontinuing oseltamivir treatment 
will be required to return for follow-up approximately 5 and 30 days after the last dose of 
study medication.  Efficacy data collected from such patients after other antiviral 
treatment commences will be excluded from the primary and secondary efficacy analyses 
so as not to confound them.  Such patients will be considered failures to oseltamivir 
treatment. 
Section 8.2.5.1  Exclusion of Data from Analysis 
New Text: 
Efficacy data collected from any patient who begins treatment with another 
antiviral for influenza (for example, amantadine, rimantadine, or zanamavir), after 
the other antiviral treatment commences, will be excluded from the primary and 
secondary efficacy analyses.  Such patients will be considered failures to oseltamivir 
treatment in the analyses.  Further details will be provided in the DRAM. 
Old Text: 
No data will be excluded from the primary and secondary efficacy analyses. 
 
7. 
SUBJECT:  REVISION OF DEFINITION OF ITTI POPULATION  
Reason for change:    
For the primary efficacy analysis of this study, the time to resolution of all influenza 
symptoms in both treatment groups will be compared to that of the placebo control from 
the pivotal oseltamivir registration trials.  Oseltamivir-resistant viruses were never 
identified in baseline samples from patients participating in the registration trials.  In 
order to maintain consistency with the control population and in an effort to conduct a 
fair comparison, patients identified as infected with oseltamivir-resistant influenza A 
H1N1 H274Y at baseline will be excluded from the ITTI primary efficacy analysis 
population. 
Section 8.2.4.2  Intent to treat infected population 
All patients randomized and with laboratory confirmation of influenza infection (positive 
viral cultures or 4 fold or greater rise in antibody titers), excluding patients infected 
with oseltamivir-resistant influenza A H1N1 H274Y at baseline, will be included in 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 7 


the intent to treat influenza infected population [Patients will be assigned to treatment 
groups as randomized for analysis purposes] 
The ITTI Population will be the primary population for the summary and analysis of the 
primary and secondary efficacy variables. 
Old text: 
All patients randomized and with laboratory confirmation of influenza infection (positive 
viral cultures or 4 fold or greater rise in antibody titers) will be included in the intent to 
treat influenza infected population [Patients will be assigned to treatment groups as 
randomized for analysis purposes] 
The ITTI Population will be the primary population for the summary and analysis of the 
primary and secondary efficacy variables. 
 
8. 
SUBJECT:  DELETION OF SAMPLING FOR PHARMACOKINETICS 
ANALYSIS  
Reason for change:    
During the first influenza season in which this study was conducted, mandatory sampling 
for pharmacokinetics analysis was identified as being inconvenient for patients and 
detrimental to participation in the study.  Revision of the mandatory sampling to optional 
sampling was considered, but this would decrease the robustness of the analysis due to 
the estimated decrease in the number of evaluable samples collected.  The value of the 
pharmacokinetics/pharmacodynamics analyses was therefore reassessed and it was 
decided that it would be in the best interest of the patients and the study to delete 
pharmacokinetics/pharmacodynamics from the protocol. 
Section Synopsis: Objectives 
New text: 
None 
Old text: 
To characterize the population pharmacokinetics of oseltamivir (e.g. clearance, volume of 
distribution) in transplant recipients 
Section Synopsis: Assessments of Pharmacokinetics / 
Pharmacodynamics 
New text: 
None 
Old text: 
Pharmacokinetic assessments will be collected as below: 
 
Day 1 (2 ‘early’ samples: 1 – 4 hours post dose but at least 1 hour apart) 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 8 


Day 6 (2 ‘late’ samples: 4 - 12 hrs post dose, but at least 1 hour apart) 
Day 11 (2 ‘early’ samples on Day 11) 
 
Pharmacodynamic assessments will be based on nose and throat swabs collected on the 
days specified in the schedule of assessments.   
Section Synopsis: Procedures 
New text: 
The key procedures are: 
Blood draws for serum chemistry, hematology, and serology 
Old text: 
The key procedures are: 
Blood draws for serum chemistry, hematology, PK and serology 
Section 5  Schedule of Assessments and Procedures 
New text: 
None. 
Old text: 
5 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 1 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
PK samplingc 
 
x 
 
x 
 
x 
 
 
c.  Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected using a sparse sampling approach.  [5.5.1] 
g.  …PK assessments cannot be done on day 12. 
Section 5.3  Clinical Assessments and Procedures 
New text: 
None. 
Old text: 
Blood samples will be taken for PK analysis as mentioned in section 5.5.1. 
Section 5.4  Laboratory Assessments 
New text: 
The total volume of blood loss for laboratory assessments will be approximately 20 mL 
for the entire duration of the study. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 9 


Old text: 
The total volume of blood loss for laboratory assessments (other than pharmacokinetic 
sampling) will be approximately 20 mL for the entire duration of the study. Blood loss 
for pharmacokinetic sampling is explained in section 5.5.1. 
Section 5.5  Pharmacokinetic Assessments [PK]/Pharmacodynamic 
Assessments [PD] 
New text: 
None 
Old text: 
5.5 
Pharmacokinetic Assessments [PK] /Pharmacodynamic [PD] 
Assessments  
Blood samples will be collected to evaluate the pharmacokinetics of oseltamivir 
according to the Schedule of Assessments (Table 3) and as described below. Further 
details on PK/PD are to be found in sections 8.3.1 and 8.3.2.  
5.5.1 Pharmacokinetic Assessments [PK] 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected using the following sparse sampling approach: 
       day 1  (2 ‘early’ samples: 1 – 4 hours post dose but at least 1 hour apart) 
       day 6  (2 ‘late’ samples: 4 – 12 hours post dose but at least 1 hour apart) 
       day 11 (2 ‘early’ samples on day 11)*  
*Note: Subjects should attend the clinic as early as possible on the morning of Day 11. 
For those subjects who had their last dose on the morning of Day 11, they should have 2 
samples drawn 1– 4 hours post dose but at least 1 hour apart. For those subjects who 
received their last dose on the evening of Day 10, they should have 2 samples drawn at 
least 1 hour apart, as early as possible on the morning of day 11.  
For adults and adolescents, approximately 2 mL of blood will be taken at each time point, 
therefore the total volume blood loss for pharmacokinetic assessments will be 
approximately 12 mL. For pediatric subjects, not less than approximately 0.6 mL of 
blood will be taken at each time point, as a result the total volume blood loss for 
pharmacokinetic assessments will be approximately 3.6 mL. 
5.5.2 Pharmacodynamic [PD] Assessments 
Nasal and throat swabs will be collected from individuals on the days specified in the 
schedule of assessments. Specimens will be cultured at a central laboratory. The 
proportion of patients with viral shedding at each visit will be summarized. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 10 


Section 8.3  Pharmacokinetic and Pharmacodynamic Analysis 
New text: 
None. 
Old text: 
8.3 
Pharmacokinetic and Pharmacodynamic Analysis 
8.3.1 Pharmacokinetic Analysis   
Nonlinear mixed effects modeling (with software NONMEM) will be used to analyze all 
plasma concentration-time data of oseltamivir and oseltamivir carboxylate following 
oseltamivir 
administration. 
Population 
pharmacokinetic 
parameters 
(clearance, 
distribution volume) will be estimated. The influence of covariates (such as age, gender, 
body weight and calculated creatinine) on these parameters will be investigated. Based on 
the population PK model individual pharmacokinetic parameters such as AUC, Cmax, Cmin 
and tmax may be calculated using Bayesian posthocs. If deemed appropriate and necessary, 
data may be pooled with data from previous studies investigating oseltamivir and 
oseltamivir carboxylate in order to improve model stability.  
8.3.2 Pharmacodynamic Analysis  
If feasible, the relationship between PK exposure of oseltamivir carboxylate and viral 
shedding response data will be characterized using nonlinear mixed effects modeling 
(using software NONMEM). Relevant population PD parameters will be derived and the 
influence of covariates will be investigated. If deemed appropriate and necessary, data 
may be pooled with data from previous studies investigating oseltamivir and oseltamivir 
carboxylate in order to improve the model stability. 
 
9. 
SUBJECT:  DELETION OF FOOD INTAKE QUESTION FROM DIARY 
QUESTIONS 
Reason for change:    
Information regarding intake of food in relationship to time of oseltamivir dosing was 
important for pharmacokinetics analyses.  Because pharmacokinetics analyses have been 
deleted from the protocol, this information is no longer necessary. 
Section 5.  Schedule of Assessments and Procedures 
New text: 
e.  Flu symptoms, temperature, and date/ time of oseltamivir dose will be recorded by the patient on diary cards twice 
daily on days 1 – 10, and once daily thereafter 
Old text: 
e.  Flu symptoms, temperature, date/ time of oseltamivir dose and food intake will be recorded by the patient on diary 
cards twice daily on days 1 – 10, and once daily thereafter. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 11 


Section 5.3  Clinical Assessments and Procedures 
New text: 
Study Day 1 
Patients or guardians/parents will be instructed how to complete symptom diary cards 
(Appendix 2) (Appendix 3), temperature recording, and treatment administration details, 
including time of each oseltamivir dose. 
Old text: 
Study Day 1 
Patients or guardians/parents will be instructed how to complete symptom diary cards 
(Appendix 2) (Appendix 3), temperature recording, and treatment administration details, 
including time of each oseltamivir dose and food intake. 
Section Appendix 2 
Adult Patient Diary Card and Symptom Record 
New text: 
Appendix 2 
Adult Patient Diary Card and Symptom Record 
Temperature and date and time of drug administration will also be recorded on the 
patient diary card. 
Old text: 
Appendix 2 
Adult Patient Diary Card and Symptom Record 
Temperature, date and time of drug administration, intake of food will also be recorded 
on the patient diary card. 
Section Appendix 3 
Diary Card for Children   
New text: 
Appendix 3 
Diary Card for Children  
Temperature and date and time of drug administration will also be recorded on the 
patient diary card 
Old text: 
Appendix 3 
Diary Card for Children  
Date and time of intake of food will also be recorded on the patient diary card. 
 
10. 
SUBJECT:  REVISION OF EXPLANATION OF LABORATORY 
ASSESSMENTS TO INCLUDE VIRAL SHEDDING AND SEROLOGY 
Reason for change:    
Viral shedding and serology were inadvertently left out of the explanation of laboratory 
assessments. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 12 


Section 5.4  Laboratory Assessments 
New text: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments. All swabs are sent to a central laboratory for RT-PCR and 
viral cultures. Influenza virus shedding will be assessed.   
 
Serology.  Blood samples for influenza antibody titer will be collected according to 
the Schedule of Assessments. 
Old text: 
Nasal and throat swabs. Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments. All swabs are sent to a central laboratory for RT-PCR and 
viral cultures. 
 
11. 
SUBJECT:  REPLACEMENT OF PAPER PATIENT DIARIES WITH 
ELECTRONIC PATIENT DIARIES 
Reason for change:    
In order to improve data quality, paper patient diaries (used in the first influenza season 
during which this study was conducted) will be replaced with electronic patient diaries.  
Electronic patient diaries will capture all of the information recorded on paper patient 
diaries with the added benefit of automatically controlling for simple but frequent 
recording errors, such as impossible dates and doses.  Diary data previously collected on 
paper diaries by patients participating in season 1 will be used along with diary data 
collected in the electronic diaries for the efficacy analyses in this study. 
Section Synopsis: Assessments of Efficacy 
New text: 
Time to resolution of all influenza symptoms as recorded in the patient diary. 
Old text: 
Time to resolution of all influenza symptoms as recorded in the diary cards. 
Section 3.1.1.2  Consistency with previous influenza treatment 
studies 
New text: 
Some of the key design features consistent with previous studies include: two active 
treatment arms, subjects with influenza like symptoms recruited during the flu season, 
use of a patient diary to capture symptoms, primary clinical end point based on diary 
assessments, laboratory evaluation of virology and serology samples generally similar to 
previous trials and the primary efficacy analysis population is the Intent to treat Infected 
(ITTI) population. 
 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 13 


Old text: 
Some of the key design features consistent with previous studies include: two active 
treatment arms, subjects with influenza like symptoms recruited during the flu season, 
use of a diary card to capture symptoms, primary clinical end point based on diary card 
assessments, laboratory evaluation of virology and serology samples generally similar to 
previous trials and the primary efficacy analysis population is the Intent to treat Infected 
(ITTI) population. 
Section 5. Schedule of Assessments and Procedures   
New text: 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Review of electronic diary data e  
   
 
 
 
 
 
 
 
 
e.  Flu symptoms, temperature, and date/ time of oseltamivir dose will be recorded by the patient in electronic patient 
diaries twice daily on days 1 – 10, and once daily thereafter.   
Old text: 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Review of diary card e    
 
 
x 
x 
x 
x 
x 
x 
e.  Flu symptoms, temperature, date/ time of oseltamivir dose and food intake will be recorded by the patient on diary 
cards twice daily on days 1 – 10, and once daily thereafter.   
Section 5.3  Clinical Assessments and Procedures 
New text: 
Study Day 1 
Study medication, electronic diaries, and thermometers will be dispensed. Patients or 
guardians/parents will be instructed how to complete electronic symptom diaries 
(Appendix 2) (Appendix 3), temperature recording, and treatment administration details, 
including time of each oseltamivir dose. The first diary entries will be made at the site 
before the first dose of study drug.  
Study Days 2-11 
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study. The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is entering data into the electronic diary 
properly, and assess drug compliance. During the dosing period, diary symptoms should 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 14 


be assessed and temperature should be recorded at the same time that the study drug is 
taken. 
End of Follow-Up Day 40 
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the electronic diary. 
Old text: 
Study Day 1 
Study medication, diary cards, and thermometers will be dispensed. Patients or 
guardians/parents will be instructed how to complete symptom diary cards (Appendix 2) 
(Appendix 3), temperature recording, and treatment administration details, including time 
of each oseltamivir dose and food intake. The first diary card will be completed before 
the first dose of study drug.  
Study Days 2-11 
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study. The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is completing the diary cards, and assess drug 
compliance. During the dosing period, diary card symptoms should be assessed and 
temperature should be recorded at the same time that the study drug is taken. 
End of Follow-Up Day 40 
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the symptom diary card. 
Section 5.3.1  Efficacy Assessments 
New text: 
The primary end point in this study is the time to resolution of all influenza symptoms as 
recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness. These are captured in the diary for both adults 
and children. (Apendix 2) (Appendix 3). Influenza symptoms are graded on a nominal 
scale from zero (absent/no problem) to 3 (severe or major problem). A score of zero 
is considered asymptomatic. The primary end point, time to alleviation of all 
symptoms is comprised of all the symptoms captured in the diary.  
2. Temperature. This is captured in the diary. Temperature is used for assessment of the 
primary and several secondary end points. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 15 


Old text: 
The primary end point in this study is the time to resolution of all influenza symptoms as 
recorded in the diary cards.  
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness. These are captured in the diary card for both 
adults and children. (Appendix 2) (Appendix 3). Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem). A score 
of zero is considered asymptomatic. The primary end point, time to alleviation of all 
symptoms is comprised of all the symptoms captured in the diary card.  
2. Temperature. This is captured on the diary card. Temperature is used for assessment 
of the primary and several secondary end points. 
Section 5.3.2 Safety   
New text: 
Pre-defined symptoms of influenza captured in the adult and pediatric diaries are not to 
be reported as adverse events unless they can be further qualified. Thus ‘headache due to 
stress at work’ is reported as an adverse event. However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Old text: 
Pre-defined symptoms of influenza captured in the adult and pediatric diary cards are not 
to be reported as adverse events unless they can be further qualified. Thus ‘headache due 
to stress at work’ is reported as an adverse event. However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Section 7.1.1  Clinical AEs 
New text: 
Influenza signs and symptoms reported on the patient diary will be summarized as 
efficacy end points and need not be captured as adverse events. 
Old text: 
Influenza signs and symptoms reported on the diary card will be summarized as efficacy 
end points and need not be captured as adverse events.  
Section 8.1.1  Primary Endpoints 
New text: 
The primary endpoint in this study is the time to alleviation of all clinical influenza 
symptoms (recorded in the patient diary). 
Old text: 
The primary endpoint in this study is the time to alleviation of all clinical influenza 
symptoms (recorded in the diary card). 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 16 


Section  Appendix 2 
Adult Patient Diary Card and Symptom Record  
New text: 
Appendix 2 
Adult Patient Diary Data and Symptom Record  
The purpose of the electronic diary is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study. Temperature and date 
and time of drug administration will also be recorded on the electronic patient diary. 
Old text: 
Appendix 2 
Adult Patient Diary Card and Symptom Record  
The purpose of the diary card is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study. Temperature, date and 
time of drug administration, intake of food will also be recorded on the patient diary card. 
Section Appendix 3 
Diary Card for Children   
New text: 
Appendix 3 
Diary Data for Children  
Temperature and date and time of drug administration will also be recorded on the 
electronic patient diary. 
Old text: 
Appendix 3 
Diary Card for Children  
Date and time of intake of food will also be recorded on the patient diary card. 
 
12. 
SUBJECT:  INCREASE IN TIME ALLOWED FOR SCREENING 
Reason for change:    
Although screening and baseline assessments and procedures are usually completed on 
the same day, it may be more convenient for some patients to be screened prior to the 
baseline visit, randomization, and first dose. 
Section 5.1  Screening Examination and Eligibility Screening Form 
New text: 
All subjects must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed. Screening will take place at the 
baseline visit prior to first dose.  However, if necessary, screening may take place the 
day before the baseline visit, as long as the patient is randomized and receives 
his/her first dose of study medication within 48 hours of influenza symptom onset. 
Old text: 
All subjects must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed. Screening will take place at the 
baseline visit prior to first dose. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 17 


 
13. 
SUBJECT:  INCREASE IN WINDOWS AROUND DAY 2/3 AND DAY 6 
VISITS 
Reason for change:    
Windows around the day 2/3 and Day 6 visits will be increased to make more convenient 
for patients. 
Section 5.  Schedule of Assessments and Procedures 
New text: 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f,g 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
g.  Day 2/3 visit window = + 1 day.  Day 6 visit window = + /- 1 day. Day 8 visit window = +1 day….   
Old text: 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
g.  Day 6, 8 visit window = + 1 day….   
 
14. 
SUBJECT:  CLARIFICATION REGARDING WITHDRAWAL FROM 
STUDY MEDICATION FOR LOW CREATININE CLEARANCE AND 
HEPATIC DECOMPENSATION 
Reason for change:    
Criteria for premature withdrawal have been revised to more clearly emphasize that 
patients with low creatinine clearance or hepatic decompensation must be withdrawn 
from study medication. 
Section 4.5 Criteria for Premature Withdrawal 
New text: 
The investigator must discontinue treatment if the creatinine clearance is < 10 ml/min in 
adults or < 10 ml/min/1.73 M2 in children. The investigator must also discontinue 
treatment from all subjects with intercurrent illnesses or adverse events suggestive of 
hepatic decompensation. 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 18 


Old text: 
The investigator should discontinue treatment if the creatinine clearance is < 10 ml/min 
in adults or < 10 ml/min/1.73 M2 in children. The investigator should also discontinue 
treatment from all subjects with intercurrent illnesses or adverse events suggestive of 
hepatic decompensation. 
 
15. 
SUBJECT:  REVISION OF WARNINGS AND PRECAUTIONS 
Reason for change:    
Warnings and Precautions section has been revised to provide additional information and 
clarification. 
Section 7.3 Warnings and Precautions 
New text: 
Events such as convulsions and delirium (including symptoms such as altered level of 
consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, 
anxiety, nightmares) have been reported during oseltamivir use in patients with 
influenza, predominately in children and adolescents.  In rare cases, these events 
resulted in accidental injury.  The contribution of oseltamivir to those events is unknown.  
Such events have also been reported in patients with influenza who were not taking 
oseltamivir. Patients, especially children and adolescents, should be closely monitored 
for signs of abnormal behavior. 
Old text: 
Events such as convulsions and those associated with delirium have been reported 
during oseltamivir use in patients with influenza.  In rare cases, the delirium resulted in 
accidental injury.  The contribution of oseltamivir to those events is unknown.  Such 
events have also been reported in patients with influenza who were not taking 
oseltamivir. Patients, especially children and adolescents, should be closely monitored. 
 
16. 
SUBJECT:  REVISION OF CALCULATION OF ESTIMATED CREATININE 
CLEARANCE TO INCLUDE FEMALES ≥ 13 TO < 18 YEARS OLD 
Reason for change:    
“k” value for Schwartz equation for females ≥ 13 to < 18 years old was inadvertently left 
out. 
Section Appendix 1 Calculation of Creatinine Clearance and Grading 
of Chronic Extensive GVHD 
New text: 
Value for k:  
k 
Age (years) 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 19 


0.45 
< 2 
0.55 
≥ 2 to < 13 
0.7 
≥ 13 to < 18 (males) 
0.55 
≥ 13 to < 18 
(females) 
 
Old text: 
Value for k:  
k 
Age (years) 
0.45 
< 2 
0.55 
≥ 2 to < 13 
0.7 
≥ 13 to < 18 (males) 
 
CONFIDENTIAL  Roche Protocol NV20234B Amendment History (Ro 64-0796)   - Page 20 




 
SYNOPSIS OF PROTOCOL NUMBER NV20234B 
  
TITLE 
A double-blind, randomized, stratified, multi-center trial evaluating  
conventional and high dose oseltamivir in the treatment of  
immunocompromised patients with influenza 
SPONSOR 
F. Hoffmann-La Roche LTD  
CLINICAL 
PHASE  
IIIb 
INDICATION 
Treatment of influenza in immunocompromised patients 
OBJECTIVES  
Primary: 
To evaluate prospectively the efficacy of oseltamivir for the 
treatment of influenza in transplant recipients as measured by the 
time to resolution of influenza symptoms 
 
Secondary: 
To evaluate the effects of conventional and high dose oseltamivir 
in transplant recipients on: 
• 
The clinical course of influenza (fever, symptoms, secondary 
illnesses as evidenced by otitis media, bronchitis, pneumonia, 
or sinusitis)  
• 
The virologic course of influenza (proportion shedding and 
viral loads at different time points) 
• 
Patient safety and tolerability  
• 
The development of  resistant influenza virus 
 
TRIAL DESIGN 
This is a double-blind, randomized, multi-center trial of twice 
daily, conventional and high dose oseltamivir for the treatment of 
influenza in immunocompromised patients (as represented by 
transplant recipients).  Subjects will be stratified by age, transplant 
type, time since onset of flu symptoms and treatment start (≤ 24 or 
>24 hours) and vaccination status 
NUMBER OF SUBJECTS 
A minimum of 250 (125 per arm) 
NUMBER OF CENTERS 
Approximately 140 centers in the Northern hemisphere 
TARGET POPULATION 
Transplant recipients (liver, kidney, liver and kidney, allogenic 
haematopoietic stem cell transplant), 1 year of age and older 
enrolled during the influenza season.  The subjects will be positive 
for influenza by a rapid diagnostic test at baseline. 
LENGTH OF STUDY  
10 days of treatment, 30 days of follow up.   
INVESTIGATIONAL MEDICINAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
Oseltamivir/placebo dry powder (to be reconstituted to a 
concentration of 12 mg/ml) and 75 mg capsules.  The duration of 
dosing in both adults and children is 10 days. 
 
Conventional dose: 
Children ages 1 - 12 years: Oseltamivir syrup 
≤ 15 kg   
 
30 mg twice daily 
> 15 – 23 kg  
 
45 mg twice daily 
> 23 – 40 kg 
 
60 mg twice daily 
> 40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥  13 years): Oseltamivir capsules  75 
mg twice daily 
 
Subjects randomized to the conventional dose will simultaneously 
receive matching placebo so as to blind them and the investigator 
from the high dose arm.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 2 


 
 
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg   
 
60 mg twice daily 
> 15 – 23 kg  
 
90 mg twice daily 
> 23 – 40 kg 
 
120 mg twice daily 
> 40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Dose adjustments:  In both treatment arms, dosing frequency will 
be decreased to once daily in patients with severe renal impairment 
(Cr Cl in adults between 10-30 ml/min and children between 10-30 
ml/min/1.73M2.). 
COMPARATOR “DRUG” (or STANDARD OF 
CARE) DOSE/ ROUTE/ REGIMEN 
Placebo (from pivotal registration trials in otherwise healthy adults) 
ASSESSMENTS OF: 
 
- 
EFFICACY 
Time to resolution of all influenza symptoms as recorded in the 
patient diary. 
- 
SAFETY 
Adverse events, physical exams, vital signs and clinical laboratory 
evaluations 
 
PROCEDURES (summary): 
The key procedures are: 
Blood draws for serum chemistry, hematology, and serology. 
Nasal and throat swabs for viral culture and RT-PCR. 
 
STATISTICAL ANALYSES: 
Sample size calculations were performed using a two-sided t-test and are based on the comparison with a 
placebo control response in the pivotal registration trials in healthy adults of 112 hours for median time to 
alleviation of all symptoms. Assuming an expected median time to alleviation of symptoms of 78 hours for 
each of the two active treatment groups in this study, and a common standard deviation of 98 hours, then 
111 evaluable subjects per group would give more than 90% power to detect a difference between the 
control and each of the active treatment groups. 
 
The primary endpoint will be time to alleviation of all clinical influenza symptoms, as recorded in the diary 
cards. 
 
For the primary analysis, the following two assessments will be made independently of each other and 
without regard to the outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment approval, a population 
of placebo treated patients will be established to match those of the current study. For this population, 
a median time to resolution of all clinical influenza symptoms will be determined along with its 95% 
confidence interval. 
 
• 
Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in the median times 
to alleviation of symptoms and deriving an associated 95% confidence interval. The methodology will 
be based on the use of the Hodges-Lehmann estimator in the case of censored data. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 3 


Table of Contents
1. Background And Rationale. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      11
1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      11
1.1.1 Influenza . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      11
1.1.2 Oseltamivir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      13
1.2 Rationale for the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      14
2. Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      14
2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      14
2.2 Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      14
3. Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      15
3.1 Overview of Study Design and Dosing Regimen . . . . . . . . . . . . . . . . .      15
3.1.1 Rationale for Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      16
3.1.1.1 Choice of treatment arms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      16
3.1.1.2 Consistency with previous influenza treatment studies. . . . . . . . . .      17
3.1.1.3 Interpretation of study results . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      17
3.1.2 Rationale for Dose Selection and Adjustment . . . . . . . . . . . . . . . . . .      19
3.1.3 End of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
3.2 Number of Subjects/ Assignment to Treatment Groups . . . . . . . . . . . .      22
3.3 Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
4. Study Population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
4.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
4.2 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
4.3 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      23
4.4 Concomitant Medication and Treatment . . . . . . . . . . . . . . . . . . . . . . . .      25
4.5 Criteria for Premature Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . .      25
4.6 Replacement Policy [Ensuring Adequate Numbers of Evaluable
Subjects] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      26
4.6.1 For Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      26
4.6.2 For Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      26
5. Schedule Of Assessments And Procedures . . . . . . . . . . . . . . . . . . . . . . . . . .      27
5.1 Screening Examination and Eligibility Screening Form . . . . . . . . . . . .      28
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 4 


5.2 Procedures for Enrollment of Eligible Subjects . . . . . . . . . . . . . . . . . .      28
5.3 Clinical Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . .      28
5.3.1 Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      31
5.3.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      31
5.4 Laboratory Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      31
6. Investigational Medicinal Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
6.1 Dose and Schedule of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
6.1.1 Dose Modifications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      33
6.2 Preparation and Administration of Study Drug . . . . . . . . . . . . . . . . . . .      33
6.3 Blinding and Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
6.4 Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
6.5 Destruction of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
7. Safety Instructions and Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
7.1 Adverse Events (AEs) and Laboratory Abnormalities . . . . . . . . . . . . .      35
7.1.1 Clinical AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
7.1.1.1 Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
7.1.1.2 Drug - Adverse event relationship. . . . . . . . . . . . . . . . . . . . . . . . . .      36
7.1.1.3 Serious Adverse Events [Immediately Reportable to Roche] . . . . .      36
7.1.2 Treatment and Follow-up of AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
7.1.3 Laboratory Test Abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
7.1.4 Follow-up of Abnormal Laboratory Test Values . . . . . . . . . . . . . . . .      37
7.2 Handling of Safety Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
7.2.1 Reporting of Serious Adverse Events [immediately reportable] . . . .      37
7.2.2 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
7.3 Warnings and Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
8. Statistical Considerations And Analytical Plan . . . . . . . . . . . . . . . . . . . . . . .      38
8.1 Primary and Secondary Study Endpoints . . . . . . . . . . . . . . . . . . . . . . .      38
8.1.1 Primary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
8.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
8.1.3 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2 Statistical and Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.1 Statistical Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.1.1 Primary Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 5 


8.2.1.2 Secondary Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.2 Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
8.2.3 Hypothesis Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
8.2.4 Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
8.2.4.1 Intent to treat population: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      40
8.2.4.2 Intent to treat infected population:. . . . . . . . . . . . . . . . . . . . . . . . . .      40
8.2.4.3 Subpopulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      41
8.2.5 Efficacy Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      41
8.2.5.1 Exclusion of Data from Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.5.2 Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.6 Safety Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
8.2.7 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
9. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      42
9.1 Assignment of Preferred Terms and Original Terminology . . . . . . . . .      43
10. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      44
11. Ethical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      46
11.1 Local Regulations/Declaration of Helsinki . . . . . . . . . . . . . . . . . . . . .      46
11.2 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      46
11.3 Independent Ethics Committees/Institutional Review Board . . . . . . .      47
12. Conditions For Modifying The Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . .      47
13. Conditions For Terminating The Study . . . . . . . . . . . . . . . . . . . . . . . . . . . .      47
14. Study Documentation, Crfs And Record Keeping . . . . . . . . . . . . . . . . . . . .      48
14.1 Investigator's Files / Retention of Documents . . . . . . . . . . . . . . . . . . .      48
14.2 Source Documents and Background Data . . . . . . . . . . . . . . . . . . . . . .      48
14.3 Audits and Inspections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      48
14.4 Case Report Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      49
15. Monitoring The Study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      49
16. Confidentiality Of Trial Documents And Subject Records . . . . . . . . . . . . .      49
17. Publication Of Data And Protection Of Trade Secrets. . . . . . . . . . . . . . . . .      49
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 6 


List of Tables
Table 1 Recommended doses in healthy adults for treatment of influenza . . . .      21
Table 2 Recommended dose modifications for NV 20234 trial subjects . . . . . .      21
Table 3 Schedule of Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      27
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 7 


List of Appendices
Appendix 1 Calculation of Creatinine Clearance and Grading of Chronic
Extensive GVHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      51
Appendix 2 Adult Patient Diary Data and Symptom Record. . . . . . . . . . . . . . .      53
Appendix 3 Diary Data for Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      54
Appendix 4 Adverse Event [AEs] Categories for Determining Relationship to
Test Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      55
Appendix 5 ICH Guidelines for Clinical Safety Data Management,
Definitions and Standards for Expedited Reporting, Topic E2 .      57
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 8 


 
GLOSSARY OF ABBREVIATIONS 
ALT [SGPT] 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
AST [SGOT] 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
b.i.d. 
Bis in die (twice daily) 
BP 
blood pressure 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
Cr Cl 
Creatinine Clearance 
CRF 
Case Report Form[s] 
DRAM 
Data Reporting and Analysis Manual 
ESF 
eligibility screening form 
hrs 
Hours 
HA 
Hemagglutinin 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ITT 
Intent to treat 
ITTI 
Intent to treat Influenza Infected 
IVRS 
Interactive Voice Response System 
mg 
Milligram 
mL 
Milliliter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 9 


GLOSSARY OF ABBREVIATIONS 
p.o. 
Per os ( by mouth) 
PR 
Pulse rate 
QD 
Once per day 
SAE 
Serious adverse event 
SOT 
Solid organ transplant 
TCID50 
50% Tissue Culture Infectious Dose 
Tmax 
Time of maximum plasma concentration 
t1/2 
Elimination half-life 
µg 
Microgram 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 10 


PART I: 
STUDY DESIGN AND CONDUCT 
 
1. 
BACKGROUND AND RATIONALE 
1.1 
Background 
Influenza is an acute respiratory infection caused by a virus of the orthomyxovirus family 
which occurs in three forms, influenza A, B and C. Influenza virus types A and B cause 
an acute febrile infection of the respiratory tract characterized by the sudden onset of 
fever, malaise, headaches, myalgias and cough. Influenza causes numerous deaths each 
year [1]. Although difficult to assess, annual influenza epidemics are thought to result in 
between three and five million cases of severe illness, and between 250,000 and 500,000 
deaths every year around the world. [2] 
The influenza viruses are segmented, negative sense, single stranded, lipid encapsulated, 
RNA viruses between 80 and 100 nm in size. Subtypes are defined according to 
glycoproteins present in the viral lipid coat. The haemagglutinin complex (HA) is the 
major surface protein of the virus. The neuraminidase (NA) protein is the second major 
surface protein in the virion and plays a role in enhancing virus penetration of the mucus 
layer around the target cell and in release of virus from the cell surface. The matrix 
proteins, M1 and M2 appear to trigger the disintegration of the M1 complex during virus 
fusion with the cell and may also be involved in the maturation of the HA prior to 
assembly of new virus particles.  
1.1.1 
Influenza 
Influenza infection is usually a self limiting condition. However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus 
may cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death. [3]  The availability of new 
immunosuppressive agents has enhanced the number and survival of solid organ 
transplant (SOT) and haematopoietic stem cell transplant (HSCT) [4] recipients making 
them representative of the larger immunocompromised patient population.   
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality. In a cohort study of influenza viral infection in SOT 
subjects, 30 cases of influenza viral infection were identified. Secondary bacterial 
pneumonia was seen in 17 % of subjects and three SOT recipients (2 liver and one 
kidney) had myositis, myocarditis and bronchiolitis obliterans. Biopsy of the transplanted 
organ was performed in 21 of 30 cases and revealed variable degrees of acute allograft 
rejection in 62 % of subjects. The study concluded that influenza was associated with 
significant morbidity in different groups of SOT recipients [5]  
Among transplant recipients, subjects with HSCT are at the greatest risk for morbidity. In 
a prospective study from the Infectious Diseases Working Party of the European Group 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 11 


for Blood and Marrow Transplantation, 1973 patients were evaluated for respiratory virus 
infections after stem cell transplant.  The overall mortality was 23% from influenza A 
infection and the direct influenza A-associated mortality was 15.3% in this study. [6] 
The largest study of influenza infections in transplant (allogenic, syngenic or autologous 
HSCT) subjects comes from the Fred Hutchinson Cancer Center, Seattle, USA. In this 
retrospective study, influenza virus was isolated in 62 of 4797 subjects undergoing HSCT 
over a 13-year period. During this period, the Center had a standardized protocol for the 
detection of respiratory pathogens comprising direct fluorescent antibody (DFA) staining 
and viral culture. Because capture of influenza infections and accurate ascertainment of 
all risk factors was less complete after discharge from the health care center, only 
infections that occurred during the first 120 days after transplantation were considered. 
Influenza was defined as the isolation of influenza virus by culture or as evidence of 
influenza antigen detected by DFA in conjunction with consistent symptomatology.  
Antiviral treatment with an M2 inhibitor or oseltamivir (available since 1999) was 
performed at the discretion of the investigator. Unlike the fixed dosing duration 
recommended for antivirals in healthy subjects, in this trial, treatment was continued until 
resolution of presenting signs and symptoms and clearance of virus from respiratory 
secretions. Garrett Nichols, et al, reported as many as 29 % of subjects developed 
pneumonia following influenza infection in this large retrospective study. Ten percent of 
the subjects with influenza died [7].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects. In otherwise healthy adults, elderly 
subjects and children, the median duration of viral shedding in untreated subjects was 70, 
96 and 118 hours respectively. [8] In contrast, in the retrospective HSCT study, influenza 
virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a median 
duration of 168 hours (7 days, range 2 to 37 days) [7]. This median duration of shedding 
included both allogenic and autologous HSCT subjects and both treated and untreated 
subjects. The mean duration of shedding in treated and untreated allogenic HSCT 
subjects was found to be longer than in autologous HSCT subjects (11.1 versus 6.7 days).  
Johny et al, evaluated the use of zanamivir in the treatment of influenza in seven 
allogenic bone marrow transplant subjects. As with the large retrospective HSCT study, 
their standard of care also was to continue zanamivir until symptoms had subsided and it 
was documented that viral excretion had ceased. Viral shedding was checked every 7 
days. Based on this protocol, the median duration of use of zanamivir was 15 days with a 
range of 5 to 44 days. [9] 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir). Due to the emergence of resistant virus, the Center for Disease Control 
(CDC) has made an interim recommendation that neither amantadine nor rimantadine be 
used for the treatment or prophylaxis of influenza in the United States. [10] Oseltamivir 
is therefore one of the main drugs available for the evaluation of the treatment of 
influenza in the immunocompromised population.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 12 


1.1.2 
Oseltamivir 
Oseltamivir (Tamiflu®, Ro 64-0796) is an ethyl ester prodrug which is rapidly absorbed 
from the gastrointestinal tract after oral administration and metabolized in the liver by 
high capacity carboxylesterases to form oseltamivir carboxylate (Ro 64-0802), a potent, 
stable and selective inhibitor of influenza A and B neuraminidase enzymes. The active 
form, oseltamivir carboxylate is excreted unchanged by the kidney via glomerular 
filtration and active tubular secretion by the organic anion transport system. The efficacy 
and safety of oseltamivir in influenza treatment and prevention has been established in an 
extensive series of clinical studies in man. 
Oseltamivir has been approved for the treatment of influenza in Europe, the United States 
and most other countries around the world. In adults and adolescents, the recommended 
dose is 75 mg twice daily for five days. In children 1 year of age and older recommended 
doses are 30, 45 or 60 mg bid based on body weight. In all age groups the recommended 
dose is administered bid for 5 days.   
The approval of oseltamivir for the treatment of influenza is based on several controlled 
clinical trials. In the pooled population from these clinical trials encompassing adults 
aged from 13-97 years, many with significant co-morbidity, 1325 subjects were treated 
with oseltamivir (75 mg bid) and 1056 subjects received placebo. A total of seven 
influenza symptoms (both respiratory and constitutional) were captured on the diary card 
for adults. The time to resolution of all symptoms (on the diary card) decreased by 24 
hours; from 124.5 hours in the placebo arm to 100.6 hours with oseltamivir 75 mg bid (p 
< 0.0001).  [8] Further, in adults and adolescents with a proven influenza illness, 
oseltamivir treatment reduced overall antibiotic use for any reason by 26.7 % and the 
incidence of influenza-related lower respiratory tract complications resulting in antibiotic 
therapy by 55 %. The study concluded that oseltamivir treatment of influenza reduces 
lower respiratory tract complications, antibiotic use and hospitalizations in healthy and 
‘at risk’ subjects [11].   
Likewise, in the influenza-infected pediatric population (1 to 12 years of age), oseltamivir 
treatment (n = 217) was compared with placebo (n = 235). There was a reduction  in  the 
median duration of illness (defined based on resolution of temperature, cough, coryza and 
return to pre-illness health and activity) of 36 hours; from 137 hours with placebo to 101 
hours in the oseltamivir treatment arm (p=<0.0001).  The Canadian Acute Respiratory 
Infections Scale (CARIFS), validated for use in children, was used to collect symptom 
data on the pediatric diary card. The CARIFS scale comprised a total of 18 symptoms 
which were evaluated twice daily by the parent or guardian.  There was a similar 
reduction in the time to alleviation of all CARIFS symptoms of 36 hours; from 100 hours 
in the placebo group to 63 hours in the oseltamivir group (p < 0.0001) [12].  
Thus in both adults and children, the time to resolution of all symptoms was significantly 
reduced in the oseltamivir treatment arm compared with placebo.   
Oseltamivir was well-tolerated in clinical trials. Approximately 11,000 subjects have 
received oseltamivir in the development program. The most common adverse events 
reported by adults, the elderly, and children were nausea and vomiting. Serious adverse 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 13 


events (SAEs) were reported with a low and equal frequency by subjects taking active 
drug and placebo. Full details are given in the Investigator Brochure. [8] 
There have been no controlled studies of oseltamivir treatment or prophylaxis in 
immunocompromised subjects. In the study by Garrett Nichols et al, patients who did not 
receive antiviral therapy shed virus for longer periods (mean duration, 11.3 days) than did 
those who were treated with M2 inhibitors (mean duration, 9.7 days) or neuraminidase 
inhibitors (mean duration, 7.5 days). Therapy with oseltamivir (but not rimantadine) 
appeared to be associated with shorter duration of shedding after controlling for steroid 
dose (p < 0.08). [7].  The efficacy of oseltamivir in the treatment of influenza in the 
immunocompromised population has also been demonstrated in other studies. In another 
small trial of oseltamivir for the treatment of influenza infection in subjects following 
HSCT, only two patients (5.1 %) developed influenza-related pneumonia. [13] In this 
study, all 39 HSCT subjects with influenza were treated with antivirals (oseltamivir or 
amantadine).  In as many as 43 % of subjects, the duration of illness was greater than 7 
days. This is unlike data from healthy adults, suggesting the possible need to evaluate a 
higher dose and/or longer duration of treatment with oseltamivir for this population.    
While the efficacy of antiviral agents for influenza has been demonstrated in the 
otherwise healthy population, it has not been tested prospectively in the 
immunocompromised (transplant) population. [4] There is therefore a need to confirm the 
efficacy of antiviral therapy for influenza in prospective controlled trials in this patient 
population.  
1.2 
Rationale for the Study  
This study is designed to investigate the optimal therapy for influenza in 
immunocompromised transplant recipients. 
The rationale for conducting this study in the immunocompromised population is based 
on the following: 
1. Immunocompromised subjects are at the highest risk for morbidity and mortality 
from influenza 
2. Immunocompromised subjects are at the greatest risk for contracting influenza 
because immunization may be ineffective in this population 
3. There is no drug approved for the treatment of influenza in this population 
2. 
OBJECTIVES  
2.1 
Primary Objective 
The primary objective of the study is to evaluate prospectively the efficacy of oseltamivir 
for the treatment of influenza in transplant recipients as measured by the time to 
resolution of influenza symptoms. 
2.2 
Secondary Objectives   
The secondary objectives of the study are:  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 14 


To evaluate the effects of conventional and high dose oseltamivir in transplant recipients 
on: 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points) 
• Patient safety and tolerability   
• The development of  resistant influenza virus 
• To characterize the population pharmacokinetics of oseltamivir (e.g. clearance, 
volume of distribution) in transplant recipients  
   
3. 
STUDY DESIGN 
3.1 
Overview of Study Design and Dosing Regimen   
This is a double blind, randomized, stratified, multi-center trial evaluating the efficacy of 
conventional and high dose oseltamivir for the treatment of influenza in 
immunocompromised patients. Immunocompromised transplant recipients who develop 
an influenza-like illness with a positive rapid diagnostic test for influenza, will be 
enrolled during the influenza season.  Patients will be stratified by type of transplant 
[SOT or HSCT], by the time between onset of symptoms and treatment start [≤ 24 hours; 
> 24 hours], influenza vaccination status for current flu season [Yes; No] and by age [≤12 
years; >12 years]. Eligible patients will be consented and randomized to receive 
oseltamivir twice daily for 10 days in one of two treatment arms: conventional dose or 
high dose (double the conventional dose). The primary end point in the study is the time 
to alleviation of all symptoms.  
In this study, immunocompromised subjects will be represented by the transplant 
population. This is justified because the availability of new immunosuppressive agents 
has enhanced the number and survival of SOT and HSCT recipients, making them 
representative of the larger immunocompromised patient population.    
Heterogeneity in the transplant population could confound the assessment of safety and 
efficacy in this study. Consequently, the SOT population in the protocol excludes 
subjects with transplants other than liver, kidney or liver and kidney. However, in order 
to still be representative of the transplant community in particular and the 
immunocompromised community in general, the study specifically includes subjects at 
the greatest risk for morbidity and mortality from influenza - the HSCT subjects. The 
study also excludes subjects with comorbid conditions that might impact the metabolism 
and excretion of the drug. As the prodrug and active drug accumulate in the presence of 
hepatic and severe renal impairment respectively, subjects with hepatic or severe renal 
impairment are excluded from the study.  Other comorbid conditions that might preclude 
the assessment of efficacy and safety are also excluded from the study. These are 
reflected in several of the inclusion and exclusion criteria.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 15 


3.1.1 
Rationale for Study Design 
This study incorporates several features that distinguish it from classic placebo controlled 
trials. At the outset, a patient population that represents the general immunocompromised  
population had to be defined. As a placebo control arm was considered unethical in this 
population, an alternative control arm had to be identified. The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial. In order to do this, the 
current study design and end points were designed to be similar to that in the pivotal 
registration trials.  
Routine influenza surveillance during the 2007/2008 influenza season showed a 
significant increase in the global circulation of an oseltamivir-resistant influenza 
virus (A H1N1 with H274Y mutation).  Therefore, baseline nasal and throat swab 
samples will be assessed for the presence of the H274Y-mutated influenza virus and 
results will be reported to clinical sites to assist in determining the most appropriate 
treatment options for individual patients. 
The following sections provide rationale and justification for the specific aspects of the 
study design. They also provide information on how the results will be used to make 
recommendations on dose and duration of treatment. 
3.1.1.1 
Choice of treatment arms 
The pivotal registration trials for oseltamivir in healthy adults with influenza had three 
treatment arms, two active (75 mg and 150 mg) and one placebo. Both treatment arms 
were found to be significantly better than placebo. No statistical comparisons were made 
between the two active treatment arms. Evaluation of the results in the two active 
treatment arms did not reveal any clinically meaningful difference. Based on these 
studies, the approved (conventional) dose for the treatment of influenza in adults is 75 
mg. 
A similar trial design was envisaged for this immunocompromised population. In an 
immunocompromised population there is a possibility of increased efficacy with a higher 
dose. In the trials in healthy adults, on day 4 (3 days after the start of treatment), the 
proportion of subjects shedding virus suggested a possible dose response relationship 
(36%, 28% and 23% in the placebo, 75 mg and 150 mg dose arms respectively). In 
healthy adults, this difference in the rate of viral shedding did not translate to any 
difference in clinical response in the two active treatment arms even though both active 
treatment 
arms 
were 
significantly 
better 
than 
the 
placebo 
arm. 
In 
the 
immunocompromised population too it is possible that while there might not be any 
difference between the two active treatment arms, one or both of these dose arms may be 
better than placebo. In this immunocompromised population, there is therefore an even 
greater need to evaluate the efficacy of a higher dose arm.  
As with the trials in healthy adults, the ideal trial design for the current study would be 
one that compared efficacy of the conventional and high dose arms with placebo. 
However, as reviewed in an earlier section 1.1.1 the morbidity and mortality from 
influenza in the immunocompromised population is far greater than that in healthy adults. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 16 


Thus in one study as many as 29 % of subjects with HSCT developed pneumonia 
following influenza infection. [7] In another study in SOT recipients, biopsy of the 
transplanted organ revealed variable degrees of acute allograft rejection in 62 % of 
subjects. [5] Given the extent of morbidity, a placebo control appears unethical. This is 
further supported by a feasibility survey conducted by the Sponsor which demonstrated  
that a majority of transplant sites actually used antivirals (including oseltamivir) to treat 
influenza in this population. It was therefore decided to compare the conventional and 
higher dose arms with the placebo arm from the pivotal registration trials in healthy 
adults with influenza. Although this approach poses limitations, the Sponsor has made 
every effort to make sure that the results from such an approach are still meaningful. The 
following sections describe how the study design addresses these limitations.  
3.1.1.2 
Consistency with previous influenza treatment studies 
In order to be able to compare the study findings with the response to placebo in healthy 
adults, this study has been intentionally designed to be consistent with previous 
registration trials for treatment of influenza in healthy adults. Some of the key design 
features consistent with previous studies include: two active treatment arms, subjects with 
influenza like symptoms recruited during the flu season, use of a patient diary to capture 
symptoms, primary clinical end point based on diary assessments, laboratory evaluation 
of virology and serology samples generally similar to previous trials and the primary 
efficacy analysis population is the Intent to treat Infected (ITTI) population. 
Despite the above considerations, there are issues that can preclude the estimation of the 
response to placebo in an immunocompromised population comprising adults and 
children from that in healthy adults with influenza. To further mitigate this, the choice of 
endpoints and their interpretation is vital.    
3.1.1.3 
Interpretation of study results  
Choice of primary end point and comparators 
The current study includes both children and adults. This is because of the significant 
unmet need in both these age groups. The primary end point therefore had to be 
applicable to both age groups. In registration trials in adults, the primary end point was 
the time to resolution of all clinical symptoms (in the diary card). In registration trials in 
children, the primary end point was the reduction in the median duration of illness 
(defined based on temperature, cough, coryza and return to pre-illness health and 
activity). A key secondary end point in children – time to resolution of all clinical 
symptoms showed similar results. The primary endpoint in this study is the time to 
resolution (alleviation) of all symptoms. 
 The median of the primary end point in the active treatment groups (conventional and 
high dose) in this trial will be compared with the median of the time to resolution of 
symptoms in the placebo group from the pivotal registration trials. The high dose arm 
enables the detection of a possible dose response relationship in this immune 
compromised population. As a means to evaluate that possibility, an assessment of the 
relative efficacy of the two dose groups will be made in terms of median time to 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 17 


alleviation of symptoms. Section 8.2.5 provides details on the statistical considerations 
and their rationale associated with these comparisons. 
Effect of study design on efficacy end points 
The main limitations of using the response to placebo from previous trials to estimate the 
response in this trial are due to the different populations (healthy versus 
immunocompromised), age groups (adults versus adults and children) and the potential 
difference in virulence of different strains. The potential difference in virulence of the 
predominant influenza viruses may be a confounder whose contribution can not be 
estimated. However the difference in populations and age groups is likely to result in the 
placebo response from pivotal registration trials underestimating the time to alleviation in 
the immunocompromised population. This is because the time to alleviation of symptoms 
is shorter in the healthy population compared to the immunocompromised population. 
[13] The placebo response in the pivotal trials will therefore underestimate the response 
in the current trial. The Sponsor is thus using a very conservative approach in comparing 
the active treatment arms in this study with the response to placebo in healthy subjects. If 
one/both of the treatment arms is statistically better than placebo, it is considered that this 
is a meaningful effect for this population.  If both treatment arms are not different from 
placebo and this is seen consistently across several end points, it may be hypothesized 
that the risk from influenza for the immunocompromised population treated with 
oseltamivir is comparable to that for a healthy untreated adult with influenza.   
Possible dosing recommendations based on current study 
Healthy subjects who were given placebo in the previous pivotal oseltamivir treatment 
studies will be used as the control arm for this study.  When the two active treatment 
arms are compared with this placebo control, several outcomes are possible. These 
outcomes will need to be discussed with health authorities.  Some outcomes and possible 
interpretations of the results are presented below:   
1. Conventional and high dose are both shown to be better than placebo: Both treatment 
arms will be compared.  If no difference then the conventional dose would be the 
dose recommended for treatment in this population.  If a difference is seen between 
treatment arms, then an evaluation (including benefit/risk assessment) will be made to 
confirm whether the higher dose should be the recommended dose. 
2. One active treatment arm is superior to placebo while the other is not: In this instance 
the dose that is shown to be superior will be recommended unless other 
considerations such as safety dictate otherwise.  
3. Both conventional and high dose arms are not different from placebo: If this is seen 
consistently across several secondary clinical end points, it may be hypothesized that 
oseltamivir has reduced the risk in the immunocompromised population to the more 
acceptable level in the untreated healthy adult population. 
4. It is also possible that both conventional and high dose treatment have a more 
protracted clinical course than the placebo arm. In this situation, it may be difficult to 
make conclusions about efficacy.  
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 18 


Irrespective of the efficacy outcomes, the study will still provide useful information of 
the safety of oseltamivir in this population.  
Possible recommendations for duration of treatment based on the current study 
Once a dose is chosen a determination will need to be made on whether the 
recommended duration of treatment should be 5 or 10 days or longer. This decision will 
be based both on the clinical and virologic course of influenza.   
The recommended duration of treatment for influenza in healthy adults is five days. In 
this study, the duration of dosing is ten days because viral shedding is typically longer in 
the immunocompromised population than in healthy adults. The general standard of care 
for this population has been to treat for as long as the patient continues to shed virus 
(even after the resolution of symptoms) [7] [9]. The duration of treatment for this 
population is therefore individualized based on clinical response and duration of viral 
shedding. It can often be more than 10 days. While it is possible that 10 or more days of 
treatment may be needed [7] [9], it is also possible that 5 days of treatment may still be 
adequate. Therefore, in this study the clinical and virologic course (proportion shedding 
virus at day 6 and later) will be evaluated to make recommendations on the duration of 
dosing. No statistical comparisons will be made.     
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials. However, in order to evaluate a dose response relationship between the two active 
treatment arms in this trial, stratification remains essential.  
Because HSCT recipients are at the greatest risk of morbidity and mortality from 
influenza, patients will be stratified by transplant type (SOT versus HSCT). Patients will 
be stratified by time between onset of symptoms and treatment start (< 24 hours or ≥ 24 
hours) because previous experience in otherwise healthy adults and children has shown 
that patients treated early in their illness respond to treatment better than those who are 
treated later. Patients will also be stratified by age ( ≤ 12 years and > 12 years) because 
otherwise healthy children shed virus longer than otherwise healthy adults. It is expected 
that a similar difference in the duration of viral shedding would exist between 
immunocompromised children and adults. As vaccinated subjects may respond faster to 
therapy, the study is also stratified based on influenza vaccination status for the current 
flu season (Yes; No).   
3.1.2 
Rationale for Dose Selection and Adjustment 
Dose Selection 
The dose of oseltamivir to be used in this study is the conventional, approved dose for 
children and adults in the treatment of influenza. There will be a second higher dose for 
comparison which is two times the conventional dose. This higher dose is used based on 
theoretical considerations which suggest that the higher dose may be associated with 
improved efficacy and decreased emergence of resistance.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 19 


The anticipated pro-drug and metabolite exposures from this higher dose are not expected 
to exceed maximum exposures seen previously in the oseltamivir development program. 
The safety and tolerability of the higher dose regimen has already been demonstrated in 
treatment studies of immunocompetent adult subjects (n = 447). [14] In a study to 
demonstrate cardiac safety, in the highest dose group treated with 450 mg b.i.d. for 5 
days [n = 99], no subject had a serious adverse event, nor withdrew prematurely. In Phase 
I studies in adults, oseltamivir has been administered in multiple doses of up to 500 mg 
b.i.d. Doses of 200 mg b.i.d. and greater have been associated with increased 
gastrointestinal adverse effects (nausea and vomiting). [8] In adult subjects with 
creatinine clearances of < 30 mL/min, doses of 100 mg b.i.d. for 6 days were well 
tolerated, despite steady-state oseltamivir carboxylate exposures approximately 10-fold 
higher than those achieved with standard dosing in renally competent individuals. [15] 
No other adverse effects were reported more frequently with higher doses and no serious 
adverse events have been reported within the volunteer studies. Co-administration of 
oseltamivir with food has been demonstrated to substantially reduce the frequency and 
severity of gastrointestinal side effects.  
Thus, the rationale for the higher dose arm in this study is to explore the possibility of 
improved efficacy and decreased emergence of resistance without an undue increase in 
risk.  
Drug interactions with immunosuppressive medications have also been evaluated. The 
pharmacokinetics of oseltamivir and oseltamivir carboxylate after administration of 
75 mg oseltamivir (conventional adult dose) in subjects with a well-functioning, stable 
renal allograft who were being maintained on immunosuppressive therapy were studied. 
These were similar to those described in the literature for adults with comparable degrees 
of renal function. Oseltamivir was well tolerated and had no clinically relevant effect on 
the steady-state pharmacokinetics of cyclosporine A, tacrolimus, or mycophenolate 
mofetil. [8] 
Duration of dosing 
The duration of dosing chosen for this population (10 days) is longer than that in the 
healthy adult and pediatric populations (5 days). This is based on observations that the 
viral shedding and illness are typically longer in immunocompromised patients than it is 
in healthy adults. [7] [13] 
Dose Adjustments 
In this study, dose adjustment for subjects with an estimated Cr Cl between 10 to 30 
mL/min/1.73M2 will comprise decreasing the frequency of administration to once daily. 
This is based on current label recommendations for adults with renal impairment 
(Table 1). 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 20 


Table 1 
Recommended doses in healthy adults for treatment of 
influenza  
 
Creatinine Clearance 
Recommended dose for treatment 
> 30 (ml/min) 
75 mg twice daily 
> 10 to ≤ 30 (ml/min) 
75 mg once daily or 30 mg suspension twice 
daily 
≤10 (ml/min)   
Not recommended 
dialysis patients 
Not recommended 
 
The dose adjustment recommendations are considered suitable approaches for children 
with renal impairment. This is based on the reasonable assumption that a similar 
relationship exists in both children and adults, between changes in creatinine clearance 
and resultant changes in exposure of oseltamivir and oseltamivir carboxylate. Doses will 
be adjusted for renal impairment in this protocol per the schema below. More detailed 
information on dosing, dose adjustments and maintenance of the blind are provided in 
later sections 6.1, 6.2, 6.3. 
Table 2 
Recommended dose modifications for NV 20234 trial 
subjects 
 
Randomized Dose 
Arm 
Unit dose 
(mg) 
Creatinine Clearance 
(ml/min OR ml/min/M2) 
Dose frequency 
> 30 
Twice daily 
30 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
45 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
60 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
 
 
 
Conventional 
 
75 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
60 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
90 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
120 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
 
 
 
High 
150 
> 10 to ≤ 30 
Once daily 
 
In general, no dose adjustment is considered necessary in subjects with mild-moderate 
hepatic impairment (based on pharmacokinetic findings in adults with chronic hepatic 
impairment) receiving usual therapeutic doses of oseltamivir. [16] However, as the 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 21 


relevance of these findings to the specific patient population in this study is unclear, 
subjects with overt (based on physical signs and symptoms) hepatic impairment at 
baseline will be excluded from this study as mentioned in section 4.3. 
3.1.3 
End of Study   
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 
days later as shown in the schedule of assessments. A rapid diagnostic test for influenza 
will be performed at the end of the 10 days of treatment. Subjects still having influenza 
based on the rapid diagnostic test will be treated per the local standard of care by the 
principal investigator.  
3.2 
Number of Subjects/ Assignment to Treatment Groups 
A minimum of 250 patients will be enrolled in this study (approximately 125 per arm). 
After screening, patients will be randomly assigned to one of the two active treatment 
groups. 
3.3 
Centers 
This will be a multicenter study with approximately 140 centers in the Northern 
hemisphere. Centers will be activated to recruit patients during the influenza season. The 
centers to be included in the study are those which perform or manage SOTs, HSCTs or 
both.  
4. 
STUDY POPULATION 
4.1 
Overview   
The study population comprises immunocompromised adults (including adolescents) and 
children who have influenza. Additionally, the subjects must not have other medical 
conditions that will preclude the assessment of efficacy or safety. Influenza vaccinated 
and non-vaccinated subjects are eligible to participate in this study.  
Under no circumstances are patients who enroll in this study permitted to be re-
randomized to this study and enrolled for a second course of treatment. 
4.2 
Inclusion Criteria  
• Age greater than or equal to 1 year 
• Rapid diagnostic test positive for influenza in the 24 hours prior to first dose 
• Immunocompromised subject defined as documented: 
• SOT (liver, kidney or both) recipient OR 
• Allogenic HSCT  
• Receiving ongoing immunosuppression, OR, in the investigator’s opinion, not 
immune reconstituted 
• Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 22 


• Less than or equal to 48 hours between onset of influenza like illness and first dose of 
study drug  
• Acceptable renal function defined as: 
• Most recent creatinine clearance in the 6 months prior to randomization is 
> 30 ml/min in adults and > 30 ml/min /1.73M2  in children. Creatinine 
clearance estimated from serum creatinine (Appendix 1) measured when 
subject is not receiving any renal replacement therapy OR 
• For patients who have not had a creatinine clearance assessment in the 6 
months prior to randomization, baseline creatinine clearance > 10 ml/min 
in adults and > 10 ml/min /1.73M2  in children (Appendix 1) OR 
• For patients whose most recent creatinine clearance in the 6 months prior 
to randomization is < 30 ml/min in adults and < 30 ml/min /1.73M2  in 
children, baseline creatinine clearance > 10 ml/min in adults and > 10 
ml/min /1.73M2  in children (Appendix 1) 
• Parent/guardian willing and able to comply with study requirements and give consent. 
(country specific age cut off)  
• Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• For adult patients, willing and able to comprehend and give written informed consent 
• Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for one reproductive cycle following 
cessation of study therapy   
• Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study medication 
4.3 
Exclusion Criteria  
• SOT within 6 months of the time of randomization  
• Solid Organ Transplant other than liver, kidney or liver and kidney 
• Have in the investigator’s opinion experienced acute rejection in the 4 weeks prior to 
randomization 
• HSCT patients with no evidence of engraftment (engraftment is defined as the point 
at which a patient can maintain a sustained absolute neutrophil count (ANC) of 
>500/mm3 and sustained platelet count of ≥ 20,000/mm3, lasting ≥ 3 consecutive days 
without transfusions)  
• HSCT subjects not discharged from hospital after their initial hospitalization for 
transplantation 
• Have evidence of veno-occlusive disease, acute or chronic extensive graft versus host 
disease at the time of randomization 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 23 


• Have clinical evidence for hepatic decompensation at the time of randomization 
(clinical icterus, ascites, hepatic encephalopathy, coagulopathy) 
• Have cirrhosis of the liver at the time of randomization 
• Currently or in the six months prior to randomization using T cell depleting 
antibodies (example: antithymocyte globulin, antilymphocyte globulin) for 
management of transplant  
• Have other co-morbid conditions that could affect patient survival or graft function 
including, but not limited to, a post-transplant lymphoproliferative disease (PTLD), 
autoimmune disease including inflammatory bowel disease and psoriasis, untreated 
thyroid disease, and significant active infection 
• Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration 
• Have evidence of active or uncontrolled opportunistic infections (bacterial, fungal, or 
viral - including cytomegalovirus [CMV] or polyoma virus [BKV]) at the time of 
randomization. Patients with HCV or HBV are not excluded. 
• Patients with known HIV infection 
• Patients who are being evaluated or treated for an active malignancy (other than the 
malignancy for which the SOT or HSCT may have been performed) at the time of 
randomization  
• Patients with uncontrolled vascular, neurologic or pulmonary disease. Uncontrolled is 
defined as disease requiring change of therapy or hospitalization in the 4 weeks 
preceding randomization. Change of therapy is defined as dose increase or change of 
medication prior to onset of present influenza like illness. 
• Patients with severe diarrhea or other gastrointestinal disorders which might interfere 
with their ability to absorb oral medication, including diabetic patients with 
previously diagnosed diabetic gastroenteropathy 
• Allergy to the test medication 
• Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation) 
• Influenza vaccination in the 2 weeks prior to randomization 
• Antiviral treatment (example: amantadine, rimantadine, zanamivir and ribavirin) for 
influenza in the 2 weeks prior to randomization 
• Patients taking probenecid medication 
• Patients who are pregnant or breast-feeding   
• Participation in a clinical trial or expanded access trial with an investigational drug in 
the 4 weeks prior to randomization or concomitantly with this study   
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 24 


4.4 
Concomitant Medication and Treatment 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, and additional oseltamivir above that specified for this study) are not 
allowed during the 10-day treatment phase of the study. Concomitant use of an 
investigational drug during the study is also excluded. Influenza vaccination after 
randomization is not allowed. Live attenuated vaccines may not be advisable for this 
population. It is possible that concurrent use with oseltamivir may render live vaccines 
ineffective.  
Medications required for the routine care of the patient including those required for 
management of the transplant (excluding lymphocyte depleting antibodies, intravenous 
immunoglobulins) may be continued during the study. Concomitant use of probenecid 
(irrespective of the indication) is not allowed during the study. 
4.5 
Criteria for Premature Withdrawal  
The investigator must discontinue treatment if the creatinine clearance is < 10 ml/min in 
adults or < 10 ml/min/1.73 M2 in children. The investigator must also discontinue 
treatment from all subjects with intercurrent illnesses or adverse events suggestive of 
hepatic decompensation. The investigator also has the right to discontinue treatment in 
the event of intercurrent illness, adverse events, treatment failure, protocol violations, 
administrative reasons or other reasons. 
The investigator must discontinue treatment with study drug if the patient is to be 
treated concomitantly with another antiviral for influenza, for example, 
amantadine, rimantadine, or zanamavir.  However, all patients, including those who 
discontinue study drug prematurely and/or are treated with another antiviral, will 
be required to return for follow up approximately 5 and 30 days after the last dose 
of study medication (day 15 and day 40 assessments). 
Subjects have the right to withdraw from the study at any time for any reason.  
An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided. Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
The investigator should contact the subject or a responsible relative either by telephone or 
through a personal visit to establish as completely as possible the reason for the 
withdrawal. A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the subject is withdrawing from the study. If the reason 
for removal of a subject from the study is an Adverse Event, the principal specific event 
will be recorded on the CRF. 
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further 
information. The outcome of that discussion should be documented in both the medical 
records and in the CRF.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 25 


4.6 
Replacement Policy [Ensuring Adequate Numbers of 
Evaluable Subjects] 
4.6.1 
For Subjects 
In order to maintain the required number of patients who are evaluable for efficacy, 
patients who are identified as being infected with influenza A H1N1 H274Y at 
baseline will be replaced by enrolling additional patients on a rolling basis.  
Replacement patients will be stratified and randomized to treatment in the same 
manner as original patients.  Replacement patients will not be “selected” by dose 
group or strata (age, vaccination status, transplant type, time between symptom 
onset and treatment) to match the patients whom they replace. 
4.6.2 
For Centers 
A center may be replaced for the following administrative reasons:   
– Excessively slow recruitment. 
– Poor protocol adherence 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 26 


5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 3 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f,g 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Informed Consent/Assent 
x 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
x 
 
 
Pregnancy Test a 
x 
 
 
 
 
x 
 
x 
Rapid diagnostic test for 
influenza virus shedding  
x 
 
 
 
 
 
x 
 
 
Safety Labs b 
x 
 
 
 
 
x 
 
 
Serology for influenza antibody 
titer  
x 
 
 
 
 
 
 
x 
Physical Examination 
x 
 
 
 
 
x 
 
x 
Vital Signs (including PR, RR, 
temperature, Blood pressure) 
x 
 
x 
x 
x 
x 
x 
x 
Nasal and throat swabs for viral 
shedding and viral load c, d 
x 
 
x 
x 
x 
x 
x 
x 
Review of electronic diary data e    
 
 
x 
x 
x 
x 
x 
x 
Drug Administration 
 
 
 
 
 
 
 
 
Collection of unused study 
medication and empty containers 
 
 
 
 
 
x 
 
 
Previous Diseases  
x 
 
 
 
 
 
 
 
Previous/Concomitant 
medications 
x 
 
 
 
 
 
 
 
Adverse Events/Sec Illnesses and 
Treatments 
 
 
 
 
 
 
 
 
Rejection, GVHD 
 
 
 
 
 
 
 
 
a.  Urine pregnancy test for patients of child-bearing potential according to the judgment/discretion of the investigator 
b.  Hematology (CBC with differential) and chemistry (AST, ALT, total bilirubin, urea, Cr). Serum creatinine testing 
may be done at a local laboratory at any time to calculate creatinine clearance and make dose adjustments.  Patient may 
receive his/her first dose prior to Cr Cl results being available, provided certain renal function criteria are met -  see 
[4.2] [5.3] 
 
c   Baseline swab samples will be assessed for the presence of influenza A H1N1 with H274Y mutation. 
d.  Two nasal and one throat swab for viral culture and RT-PCR 
e.  Flu symptoms, temperature, and date/ time of oseltamivir dose will be recorded by the patient in electronic patient 
diaries twice daily on days 1 – 10, and once daily thereafter.   
f.  A home visit may be made on day 2 or 3 (for patients who are too ill to come into the clinic) and day 8 
g.  Day 2/3 visit window = +1 day.  Day 6 visit window = +/- 1 day; Day 8 visit window = +1 day.  Day 11 visit 
window = ± 1 day. Day 15 and day  40 visit occur approximately 5 and  30 days after the last dose respectively. Day 15 
window = ± 1 day. Day 40 window ± 2 days.  
h.  Only weight to be assessed. Height is not necessary at this visit. Study drug is taken on day 11, only if the first dose 
was taken after 4 PM on Day 1 [5.3] Subjects who are rapid diagnostic positive can be treated per standard of care. 
They will be required to come for their follow-up visits on day 15 and day 40.  
i.  Subjects who discontinue treatment prematurely will have an end of treatment (day 11) assessment at the time of 
treatment discontinuation or the following day. They will be required to attend their follow up visits approximately 5 
and 30 days after the last dose (day 15 and day 40 assessments).  
j. Subjects who discontinue during follow-up will have an end of follow-up (day 40)  assessment. This visit must occur  
within 30 days of the last dose.   
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 27 


5.1 
Screening Examination and Eligibility Screening Form  
Trial sites will be activated during the influenza season.  
All subjects must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed. Screening will take place at the 
baseline visit prior to first dose.  However, if necessary, screening may take place the 
day before the baseline visit, as long as the patient is randomized and receives 
his/her first dose of study medication within 48 hours of influenza symptom onset. 
Subjects will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  
An Eligibility Screening Form [ESF] documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.  
5.2 
Procedures for Enrollment of Eligible Subjects  
Once a subject has fulfilled the entry criteria, he/she will be randomized to one of two 
treatment groups. The subject randomization numbers will be generated by Roche or its 
designee and incorporated into double-blind labeling. 
The investigator or designee will use the CRF pre-printed with the assigned subject 
number and enter the randomization number provided by IVRS for allocation to the 
treatment groups in the appropriate place on each subject’s CRF. 
Randomization will be stratified by transplant type (SOT or HSCT); time between onset 
of symptoms and treatment start (≤ 24 hrs or > 24 hrs), influenza vaccination status (Yes; 
No) and patient’s age (≤ 12 years or > 12 years).  
5.3 
Clinical Assessments and Procedures 
At all visits subjects will receive the routine care for their primary illness (transplant). 
Routine patient care (including the adjustment of doses of any of the immunosuppressive 
drugs) will be dictated by tests performed locally at the trial site. Dose adjustments of 
oseltamivir will be based on serum creatinine done at the local laboratory. All safety labs 
will be sent to a central laboratory. Results for these laboratory parameters will be used 
by the sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 3). Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
Study Day 1 
The baseline and study day 1 assessment may be performed at the same visit. 
Study medication, electronic diaries, and thermometers will be dispensed. Patients or 
guardians/parents will be instructed how to complete electronic symptom diaries 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 28 


(Appendix 2) (Appendix 3), temperature recording, and treatment administration details, 
including time of each oseltamivir dose.  The first diary entries will be made at the site 
before the first dose of study drug.  
Baseline nasal and throat swab samples will be assessed for the presence of 
oseltamivir-resistant influenza A H1N1 with H274Y mutation.  As soon as they are 
available, results will be reported to the sites to assist in patient management. 
The date of the first dose of study drug is defined as study day 1. Once randomized, the 
first dose of study drug will be administered in the clinic. Study day 2 will begin at 12 
midnight of the same calendar day. If the first dose of study drug is taken after 4 pm on 
day 1, the next dose of study drug will be taken in the morning of day 2. In this case, the 
last dose of study drug will be taken on the morning of study day 11.   
If the first dose of study drug is taken prior to 4 pm on day 1, the next dose of study drug 
should be taken in the evening of the same day (i.e. prior to midnight on the same 
calendar day with a minimum of 7 hours between doses). For these patients the last dose 
of study drug will be taken in the evening of study day 10. More information on dosing is 
provided later. 6.1 
The study will utilize a central safety laboratory. However, to determine the correct dose, 
a local serum creatinine will be drawn at baseline in all subjects and used to calculate 
creatinine clearance to determine if a dose adjustment is necessary. No dose adjustments 
are required for subjects whose creatinine clearance is > 30 ml/min in adults (> 30 
ml/min/1.73 M2  in children). Oseltamivir dosing frequency for patients whose creatinine 
clearance is between 10 to 30 ml/min in adults (10 to 30 ml/min/1.73 M2  in children) 
will be adjusted to once daily.  
For patients who meet the following criteria in section 4.2, dosing will commence only 
after the baseline creatinine clearance are available and if baseline creatinine clearance > 
10 ml/min in adults and > 10 ml/min/1.73M2  in children.  The dose will be adjusted to 
once daily if the baseline Cr Cl is between 10 to 30 ml/min in adults (10 to 30 
ml/min/1.73 M2  in children) 
• most recent creatinine clearance in the 6 months prior is < 30  ml/min in adults and < 
30 ml/min/1.73M2 in children)  
• patients who have not had a creatinine clearance assessment in the 6 months prior to 
randomization 
 
For patients who meet the following criteria in section 4.2 dosing may commence prior to 
availability of baseline Cr Cl. Subjects will receive twice daily doses and dosing will be 
adjusted to once daily if the baseline Cr Cl is between 10 to 30 ml/min in adults (10 to 30 
ml/min/1.73 M2  in children).  
• most  recent creatinine clearance in the 6 months prior is > 30 ml/min  in  adults  and 
> 30 ml/min /1.73M2  in children) 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 29 


Study Days 2 - 11 
Study day 2 will begin at 12 midnight of study day 1.  
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study. The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is entering data into the electronic diary 
properly, and assess drug compliance. During the dosing period, diary symptoms should 
be assessed and temperature should be recorded at the same time that the study drug is 
taken.  
Dosage adjustment will be performed based on creatinine clearance as described in the 
Dose Modification section 6.1.1. 
End of treatment Day 11 
The end of treatment visit for all subjects is on day 11 (irrespective of whether they took 
one or two doses on day 1). Subjects who discontinue study medication prematurely  will 
have all day 11 assessments completed at the time of discontinuation or the following 
day.  
After all day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit. If the rapid diagnostic test is positive, the subject may be treated 
per standard of care at the discretion of the investigator.  
All subjects (including those who discontinue study medication prematurely and those 
who are positive for influenza on their rapid diagnostic  test at the end of treatment visit) 
will be required to return for follow up approximately 5 and 30 days after the last dose 
(day 15 and day 40 assessments)    
Study days 12 – 40 
Study day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  
End of Follow-Up Day 40  
All subjects must attend an end of follow-up visit on day 40. This visit is important as it  
is the only post-baseline visit where a serology sample for influenza antibody titers is 
collected.  
If the patient is withdrawn after completion of treatment (after the day 11 assessment),  a 
termination visit should be arranged. This visit should be the end of follow-up visit 
assessment [Day 40]. This visit must occur within 30 days of the last dose.  
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the electronic diary. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 30 


5.3.1 
Efficacy Assessments  
The primary end point in this study is the time to resolution of all influenza symptoms as 
recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness. These are captured in the diary for both adults 
and children. (Appendix 2) (Appendix 3) Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem). A score 
of zero is considered asymptomatic. The primary end point, time to alleviation of all 
symptoms is comprised of all the symptoms captured in the diary.  
2. Temperature. This is captured in the diary. Temperature is used for assessment of the 
primary and several secondary end points.  
5.3.2 
Safety  
Safety parameters in this study include adverse events, vital signs, and clinical laboratory 
evaluations.  
Pre-defined symptoms of influenza captured in the adult and pediatric diaries are not to 
be reported as adverse events unless they can be further qualified. Thus ‘headache due to 
stress at work’ is reported as an adverse event. However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Adverse events such as bronchitis, pneumonia, otitis media and sinusitis are considered 
secondary illnesses of influenza and should be recorded as adverse events. 
Other adverse events to be expected in the transplant population such as rejection and 
graft versus host disease (in HSCT subjects) will also be collected as adverse events.  
5.4 
Laboratory Assessments 
The laboratory assessments include those for efficacy and safety. 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs. Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments. All swabs are sent to a central laboratory for RT-PCR and 
viral cultures.  Influenza virus shedding will be assessed.  Baseline samples will be 
assessed for the presence of oseltamivir-resistant influenza A H1N1 with the H274Y 
resistance mutation using a real-time PCR assay.  A phenotypic assay will be 
performed to determine the susceptibility of the last positive viral isolate from each 
patient. If required, a genotypic assay to determine the contribution of both the 
neuraminidase and haemagglutinin genes to decreased susceptibility will be performed.  
During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza.  However, in order to 
assist in patient management, the results of the assay to detect influenza A H1N1 
H274Y at baseline will be reported to the sites as soon as they are available.  At the 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 31 


end of treatment (day 11), a rapid diagnostic test is permitted for the diagnosis of ongoing 
influenza.  
Serology.  Blood samples for influenza antibody titer will be collected according to 
the Schedule of Assessments. 
 
Safety 
The safety laboratory assessments in this study, including the assessment of serum 
chemistry and hematology will be done at the central laboratory. Serum chemistry 
assessments comprise AST, ALT, total bilirubin, urea and creatinine. Hematology 
assessments include CBC and differential count. The total volume of blood loss for 
laboratory assessments will be approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality, section 16 will extend to any data generated from the 
assaying of these samples. Biological samples taken from all patients may be infectious 
and will be classified as “diagnostic specimens” for dispatch purposes. 
The Principal Investigator may draw blood for serum creatinine to be assessed at the local 
laboratory at any time during the study. The Principal Investigator may use the creatinine 
levels to calculate creatinine clearance and adjust dose of study drug if required. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/ml) or 75 mg capsules and matching placebo. 
The Investigational Medicinal Products will be supplied, packaged individually for each 
subject and labeled in accordance with Roche Standard and local regulation by Roche 
Clinical Trial Supply, Basel, Switzerland.  
6.1 
Dose and Schedule of Study Drug 
Oseltamivir will be given twice daily over 10 days for a total of 20 doses. The doses need 
to be taken at 12 hourly intervals. Under no circumstances is a subject allowed to take 
two doses within 7 hours of each other.  
Patients will be randomized to receive either conventional or high dose of study drug. 
Conventional dose: 
Children ages 1 - 12 years: Oseltamivir syrup 
≤ 15 kg  
 
 
30 mg twice daily 
> 15 – 23 kg   
 
45 mg twice daily 
> 23 – 40 kg  
 
60 mg twice daily 
> 40 kg 
 
 
75 mg twice daily 
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules  
75 mg twice daily 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 32 


Subjects randomized to the conventional dose will simultaneously receive matching 
placebo so as to blind them and the investigator from the high dose arm.  
 
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg  
 
 
60 mg twice daily 
> 15 – 23 kg   
 
90 mg twice daily 
> 23 – 40 kg  
 
120 mg twice daily 
> 40 kg 
 
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules  
150 mg twice daily  
6.1.1 
Dose Modifications   
No dose adjustments/modifications are required for subjects whose creatinine clearance is 
> 30 ml/min in adults (> 30 ml/min/1.73 M2  in children). 
In both treatment arms, the dosing frequency will be decreased to once daily in patients 
with severe renal impairment (Cr Cl in adults between 10 – 30 ml/min and children 
between 10 – 30 ml/min/1.73M2). For example, the 75 mg bid frequency will be 
decreased to 75 mg once daily.  
At any time during the study if the investigator feels that renal function is compromised, 
dosing may be decreased to once daily or withheld until such time creatinine clearance 
results are available. Dosing may then be resumed as appropriate based on the creatinine 
clearance. However, it is vital that dosing not be inappropriately withheld for extended 
periods of time especially in the first 3 days of treatment when viral titers may be high. It 
is also important that dose modifications are clearly and accurately recorded for 
assessment of pharmacokinetic results.  
For adolescents and children, the creatinine clearance will be estimated using a Schwarz 
equation: (Appendix 1) 
For adults the method of Cockcroft-Gault will be used to estimate creatinine clearance. 
(Appendix 1) 
6.2 
Preparation and Administration of Study Drug  
Oseltamivir will be provided in two forms:  
1. Capsules containing 75 mg of active drug and packaging material consisting of 
pregelatinized starch, povidone, talc and sodium stearyl fumarate. All participants 13 
years and older will receive this dosage form. Oseltamivir capsules should be stored 
at 25ºC.  
2. A pediatric suspension containing 12 mg oseltamivir per ml of reconstituted solution 
and the following excipients: sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor). All participants 12 years and under will receive this dosage form. 
Oseltamivir dry powder for suspension [pediatric syrup] should be stored at 25ºC.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 33 


After reconstitution, the suspension should not be used for longer than 10 days. Store 
constituted suspension under refrigeration at 2º to 8ºC.  Do not freeze. 
 
Matching placebo will be available as capsules and suspension. Subjects in the 
conventional dose arm will get the conventional dose and matching placebo so that they 
are blinded from the high dose arm.  
Each subject will be dispensed a medication pack that will provide enough medication to 
cover 20 doses. For subjects randomized to the conventional dose arm, the medication 
pack will contain a bottle of oseltamivir dry powder or a blister wallet with oseltamivir 
capsules and matching placebo. For subjects randomized to the high dose arm, the 
medication pack will contain two bottles of oseltamivir dry powder or two blister wallets 
with oseltamivir capsules. Irrespective of the treatment group the subject is randomized 
to, for each dose the subject will take the same amount from both bottles or blister wallets 
provided in the medication pack such that the sum of the amounts from each immediate 
container constitutes one dose. 
One dose is to be administered twice per day at approximately 12-hour intervals with a 
light snack or glass of milk or fruit juice. The first dose of study medication will be 
administered in the clinic at the time of randomization. 
6.3 
Blinding and Unblinding 
Randomization will be administered by a central randomization center.  
The Randomization List will not be available at the study center, to the study monitors, 
project statisticians or to the project team at Roche. Emergency codes, or another 
adequate method of unblinding, will be implemented before study start, if the identity of 
the test medication is necessary for patient management in the case of a serious adverse 
event. Emergency codes should not be broken except in the case of emergency situations. 
Any request from the investigator for information about the treatment administered to 
study subjects for another purpose must be discussed with Roche/designee.  
As per regulatory reporting requirement, Roche/designee will unblind the identity of the 
study medication for all unexpected [as per IB] serious adverse events that are considered 
by the investigator to be related to study drug. Details of patients who are unblinded 
during the study will be included in the Clinical Study Report. 
All other individuals directly involved in this study will remain blinded until the final 
analysis of the primary parameter.  
The randomization will be stratified by transplant type, duration of symptoms, influenza 
vaccination status and age and will be provided by the Roche randomization group for the 
IVRS vendor.  
6.4 
Assessment of Compliance 
Accountability and subject compliance will be assessed by maintaining adequate “drug 
dispensing” and return records.  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 34 


Subjects will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  
A Drug Dispensing Log must be kept current and should contain the following 
information: 
• the identification of the subject [randomization and medication numbers] to whom the 
study medication was dispensed 
• the date[s], quantity of the study medication dispensed to the subject 
• the date[s] and quantity of the study medication returned by the subject 
This inventory must be available for inspection by the Monitor. All supplies, including 
partially used or empty containers and the dispensing logs, must be returned to the 
monitor at the end of the study. 
6.5 
Destruction of Study Drug 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons. In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned and destroyed. Written authorization must be obtained from the sponsor or 
designee at study start up before destruction. 
Written documentation of destruction must contain the following: 
– Identity [batch numbers or subject numbers] of investigational product[s] destroyed 
– Quantity of investigational product[s] destroyed 
– Date of destruction 
– Method of destruction 
– Name and signature of responsible person [or company] who destroyed 
investigational products[s] 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
Adverse Events (AEs) and Laboratory Abnormalities 
7.1.1 
Clinical AEs 
Per the International Conference of Harmonization [ICH], an AE is any untoward 
medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign [including 
an abnormal laboratory finding], symptom, or disease temporally associated with the use 
of a medicinal [investigational] product, whether or not considered related to the 
medicinal [investigational] product. Pre-existing conditions which worsen during a study 
are to be reported as AEs. Influenza signs and symptoms reported on the patient diary 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 35 


will be summarized as efficacy end points and need not be captured as adverse events.  
However, secondary illnesses due to influenza must be reported as adverse events.  
7.1.1.1 
Intensity  
All clinical AEs encountered during the clinical study will be reported on the AE page of 
the CRF.   
Intensity of AEs will be graded on a four -point scale [mild, moderate, severe, 
life-threatening] and reported in detail on the CRF.   
Mild 
discomfort noticed but no disruption of normal daily activity. 
Moderate 
discomfort sufficient to reduce or affect daily activity. 
Severe 
inability to work or perform normal daily activity 
Life Threatening 
represents an immediate threat to life   
7.1.1.2 
Drug - Adverse event relationship 
Relationship of the AE to the treatment should always be assessed by the investigator. 
Description of scales can be found in Appendix 4. 
7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
A Serious Adverse Event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution. It is any AE that at any dose fulfils at least one 
of the following criteria: 
– is fatal; [results in death; NOTE: death is an outcome, not an event]  
– is Life-Threatening [NOTE: the term "Life-Threatening" refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– required in-patient hospitalization or prolongation of existing hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to. 
(Appendix 5) 
7.1.2 
Treatment and Follow-up of AEs  
AEs, especially those for which the relationship to test “drug” is not “unrelated”, should 
be followed up until they have returned to baseline status or stabilized. If a clear 
explanation is established it should be recorded on the CRF.   
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7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will appear printed on laboratory reports provided to the site from 
the central lab.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] 
should be reported as such, in addition to being recorded as an AE in the CRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, i.e., 
meeting one or more of the following conditions, should be recorded as a single diagnosis 
on the AE page in the CRF: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication [e.g. dose modification, interruption or 
permanent discontinuation] 
• Requiring a change in concomitant therapy [e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment]. 
7.1.4 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found. If a clear explanation is 
established it should be recorded on the CRF.  
7.2 
Handling of Safety Parameters 
7.2.1 
Reporting of Serious Adverse Events [immediately reportable] 
Any clinical AE or abnormal laboratory test value that is serious and which occurs during 
the course of the study [as defined in section 7.1.1.3 above], regardless of the treatment 
arm, must be reported to Roche or designee within one working day of the investigator 
becoming aware of the event [expedited reporting]. 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and up 
until the follow-up visit.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to. (Appendix 5) 
7.2.2 
Pregnancy  
A female subject must be instructed to stop taking the test “drug” and immediately 
inform the investigator if she becomes pregnant during the study. The investigator should 
report all pregnancies within 24 hours to the sponsor or designee. The investigator should 
counsel the subject, and discuss the risks of continuing with the pregnancy and the 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 37 


possible effects on the fetus. Monitoring of the patient should continue until conclusion 
of the pregnancy.   
Pregnancy occurring in the partner of a male subject participating in the study should be 
reported to the investigator and the sponsor or designee after the pregnant partner’s 
consent has been obtained. The partner should be counseled and followed as described 
above if acceptable, and provides informed consent.  
7.3 
Warnings and Precautions  
Events such as convulsions and delirium (including symptoms such as altered level of 
consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, 
anxiety, nightmares) have been reported during oseltamivir use in patients with 
influenza, predominately in children and adolescents.  In rare cases, these events 
resulted in accidental injury.  The contribution of oseltamivir to those events is unknown.  
Such events have also been reported in patients with influenza who were not taking 
oseltamivir. Patients, especially children and adolescents, should be closely monitored 
for signs of abnormal behavior. 
 
Please refer to the attached Investigator’s Brochure for additional warnings, precautions, 
and other reported adverse events. 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN   
Full details of all planned analyses will be specified in a separate Data Reporting and 
Analysis Manual (DRAM). The methods described below are an outline of the main 
planned analyses. 
8.1 
Primary and Secondary Study Endpoints 
8.1.1 
Primary Endpoints 
The primary endpoint in this study is the time to alleviation of all clinical influenza 
symptoms (recorded in the patient diary). 
8.1.2 
Secondary Endpoints 
The following are secondary endpoints. With the exceptions of viral load and time to 
resolution of fever, they are defined as either the occurrence or non-occurrence of the 
specified events or the presence or absence of the specified symptoms,  
Shedding virus by culture at day 1, 2, 6, 8, 11, 15 and 40 
Shedding virus by RT-PCR at day 1, 2, 6, 8, 11, 15, and 40 
Viral load by culture (log10TCID50/mL) at Day 1, 2, 6, 8, 11, 15, and 40  
Viral load by quantitative RT-PCR at day 1, 2, 6, 8, 11, 15 and 40 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 38 


The time (hours) from first dose of study medication until resolution of fever  
 Fever  
Cough   
Coryza   
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or 
sinusitis) at any time during the study. 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or 
sinusitis) at any time during the study that are treated with antibiotics 
Initiation of treatment with antibiotics after randomization  
Hospitalization, and for those who are hospitalized, the duration of hospitalization 
Development of rejection or GVHD 
Baseline, post-baseline and change from baseline in antibody titers 
8.1.3 
Safety 
Safety of the treatment will be evaluated by AEs, laboratory tests, and vital signs.  
All subjects who received at least one dose of treatment and had a safety assessment 
performed post randomization will be included in the safety evaluation. 
In addition to routine safety assessments, the proportion of subjects experiencing a 
rejection and/or graft versus host disease will be summarized by treatment group.  
8.2 
Statistical and Analytical Methods  
8.2.1 
Statistical Model  
8.2.1.1 
Primary Variables 
A non-parametric model will be assumed with estimation of medians based on Kaplan-
Meier methods. Subjects without alleviation of symptoms will have their time censored at 
the last available observation that a complete assessment was made. 
For the purpose of comparing treatment groups, it will be assumed that their respective 
distributions for the primary endpoint differ only by a shift in location. 
8.2.1.2 
Secondary Variables  
For the secondary endpoints defined dichotomously in terms of events or symptoms, it 
will be assumed that the number of patients experiencing the event or exhibiting the 
symptom will have a binomial distribution. 
For the continuous endpoint of time to resolution of fever, the same assumptions as for 
the primary endpoint will be made. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 39 


For the continuous endpoints of viral load at Day 1, 2, 6, 8, 11, 15, and 40 no model will 
be assumed.  
8.2.2 
Sample Size 
Sample size calculations were performed using a two-sided t-test and are based on the 
comparison with a placebo control response in the pivotal registration trials in healthy 
adults of 112 hours for median time to alleviation of all symptoms. Assuming an 
expected median time to alleviation of symptoms of 78 hours for each of the two active 
treatment groups in this study, and a common standard deviation of 98 hours, then 111 
evaluable subjects per group would give more than 90% power to detect a difference 
between the control and each of the active treatment groups. It is assumed that as many as 
90 % of subjects enrolled into the study who are identified as not being infected with 
influenza A H1N1 H274Y will have influenza, and therefore 124 such subjects per arm 
would be required in order to obtain 111 influenza positive subjects. Note that this is an 
approximate calculation, as the final analysis will be based on the difference in medians 
and the corresponding 95% confidence interval from the Kaplan-Meier curves. This is 
however considered as a sufficient indication for the number of required subjects and 
the power that is expected. The maximum number of subjects enrolled in the trial will 
depend upon the number of subjects identified with the oseltamivir resistant virus 
who will be replaced. 
8.2.3 
Hypothesis Testing  
Formal hypothesis testing will be not performed, instead inferences will be based on 
comparison of confidence intervals.  
8.2.4 
Analysis Populations 
Three main patient populations will be used for the analysis of data from this study; the 
Safety Population, the Intent-to treat Population and the Intent-to-Treat Infected 
Population . Detailed definitions of these populations will be given in the DRAM  
8.2.4.1 
Intent to treat population: 
All patients randomized will be included in the intent to treat population [Patients will be 
assigned to treatment groups as randomized for analysis purposes] 
8.2.4.2 
Intent to treat infected population: 
All patients randomized and with laboratory confirmation of influenza infection (positive 
viral cultures or 4 fold or greater rise in antibody titers), excluding patients infected 
with oseltamivir-resistant influenza A H1N1 H274Y at baseline, will be included in 
the intent to treat influenza infected population [Patients will be assigned to treatment 
groups as randomized for analysis purposes] 
The ITTI Population will be the primary population for the summary and analysis of the 
primary and secondary efficacy variables. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 40 


8.2.4.3 
Subpopulations 
In order to evaluate the potential for relapse, the following two subpopulations of the 
ITTI population will be evaluated:  
• patients not shedding virus as assessed by culture on Day 11 
• patients not shedding virus as assessed by RT-PCR on Day 11 
Viral shedding and RT-PCR at days 15 and 40 will be evaluated in these subpopulations. 
Based on the proportion of subjects hospitalized, an additional subpopulation may be 
defined to evaluate the length of hospitalization for hospitalized subjects. 
Likewise, based on the proportion of children enrolled additional subpopulations of 
children and adults will be created to evaluate the course of influenza in children and 
adults.  
8.2.5 
Efficacy Analysis 
For the primary analysis, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• Comparison to placebo control from pivotal registration trials 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established to match (in 
terms of efficacy evaluations, duration of observation etc.) those of the current study. 
For this population, a median time to resolution of all clinical influenza symptoms 
will be determined along with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.  These confidence intervals 
will be compared individually to the placebo control confidence interval described 
above as a potential means of establishing treatment effects. 
• Assessment of relative efficacy 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval. The methodology will be based on the use of the Hodges-
Lehmann estimator in the case of censored data.  
This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences. For example, if it does not contain 
the value zero a difference will have been established. However, given the study sample 
size this outcome is only likely if a clinically significant difference (e.g. 30% ) exists. 
Although this is not anticipated from the experience in pivotal registration trials in 
normal healthy patients, it cannot be ruled out as a possibility in immunocompromised 
transplant recipients.   
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For the dichotomous secondary endpoints, the proportion experiencing the event or 
symptom, and its associated 95% confidence interval will be derived for each treatment 
group. Where possible, the corresponding confidence intervals from the placebo control 
population will be presented for comparison to those derived for the active treatment 
groups in this trial. 
The continuous secondary endpoints time to resolution of fever will be analyzed as for 
the primary endpoint.  
For the continuous endpoints of viral load (log10TCID50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, median, minimum and maximum) will be derived 
for each treatment group. 
8.2.5.1 
Exclusion of Data from Analysis 
Efficacy data collected from any patient who begins treatment with another 
antiviral for influenza (for example, amantadine, rimantadine, or zanamavir), after 
the other antiviral treatment commences, will be excluded from the primary and 
secondary efficacy analyses.  Such patients will be considered failures to oseltamivir 
treatment in the analyses.  Further details will be provided in the DRAM. 
8.2.5.2 
Interim Analysis 
No interim analyses are planned.  
8.2.6 
Safety Data Analysis 
The safety analysis population will include all subjects who receive at least one dose and 
had a safety assessment performed post randomization. All safety parameters will be 
summarized and presented in tables based on this safety population.  
8.2.7 
Other Analyses 
The number and percentage of patients with influenza infection (defined as a positive 
culture from a nasal and/or throat swab or 4 fold or greater rise in antibody titers) will be 
summarized by treatment group for the Intent-to-treat Population. 
Further exploratory analysis, (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the DRAM. 
The last positive viral isolate from each patient will be tested for reduced sensitivity to 
oseltamivir. Clonal resistance assays will also be used to evaluate the rate of resistance to 
oseltamivir. These data will be summarized in a report separate from the final study 
report. 
9. 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 42 


Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs against the investigator’s records by the study monitor [source document 
verification], and the maintenance of a drug–dispensing log by the investigator.  
The data collected will be entered into the study database from the working copy of the 
CRF faxed from the site. 
A comprehensive validation check program will verify the data and discrepancy reports 
will be generated accordingly for resolution by the investigator. As patients complete the 
study [or prematurely withdraw] and their signed CRFs become available, a second data 
entry will be performed from the original, signed CRF. A comparison check will be run 
to identify and resolve any discrepancies between the first and second data entry. 
Throughout the study the Study Management Team [SMT] will review data according to 
the SMT Data Review Plan as described in the Data Quality Plan.  
9.1 
Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned by the sponsor to the original 
terms entered on the CRF, using the current version of MedDRA (Medical Dictionary for 
Regulatory Activities terminology) for adverse events and diseases and the INN 
(International Non-Proprietary name) drug terms and procedures dictionary for 
treatments and surgical and medical procedures. 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 43 


10. 
REFERENCES 
 
1. Murphy B.G and Webster R.G.  Orthomyxoviruses. Chapter 46.  Fields Virology 3rd 
Edition, Eds:  Fields B.N, Knipe D.M, Howley P.M et al. Pub Lippincott.Raven.  
1996.  p1397 – 1445.  
2. World Health Organization. Influenza. Fact Sheet No. 211. March, 2003. 
3. Ison Michael, G., P. Mishin Vasiliy, J. Braciale Thomas, G. Hayden-Frederick, and V. 
Gubareva Larisa., Comparative activities of oseltamivir and A-322278 in 
immunocompetent and immunocompromised murine models of influenza virus 
infection. The Journal of infectious diseases, 2006. 193(6): p. 765-72  
4. Ison Michael, G. and G. Hayden Frederick., Viral infections in immunocompromised 
patients: what's new with respiratory viruses? Current opinion in infectious diseases, 
2002. 15(4): p. 355-67 
5. Vilchez Regis, A., K. McCurry, J. Dauber, A. Lacono, B. Griffith, et al., Influenza 
virus infection in adult solid organ transplant recipients. American journal of 
transplantation : official journal of the American Society of Transplantation and the 
American Society of Transplant Surgeons, 2002. 2(3): p. 287-91 
6. Ljungman, P., K.N. Ward, B.N. Crooks, A. Parker, R. Martino, et al., Respiratory 
virus infections after stem cell transplantation: a prospective study from the Infectious 
Diseases Working Party of the European Group for Blood and Marrow 
Transplantation. Bone marrow transplantation, 2001. 28(5): p. 479-84 
7. Nichols, W.G., A. Guthrie Katherine, L. Corey, and M. Boeckh, Influenza infections 
after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of 
antiviral therapy. Clinical infectious diseases : an  official publication of the 
Infectious Diseases Society of America, 2004. 39(9): p. 1300-6 
8. Investigator Brochure for Tamiflu® (oseltamivir phosphate) 7th version July 2006.  
9. Johny, A.A., A. Clark, N. Price, D. Carrington, A. Oakhill, and D.I. Marks, The use 
of zanamivir to treat influenza A and B infection after allogeneic stem cell 
transplantation. Bone marrow transplantation, {Bone Marrow Transplant}, Jan 2002, 
vol. 29, no. 2, p. 113 5, ISSN: 0268 3369., 2002 
10. January 14, 2006 CDC Health Alert Notice. CDC Recommends against the use of 
amantadine and rimantadine for the treatment or prophylaxis of influenza in the 
United States during the 2005 – 2006 Influenza season. As assessed on April 3, 2006 
at http://www.cdc.gov/flu/han011406.htm  
11. Kaiser, L., C. Wat, T. Mills, P. Mahoney, P. Ward, et al., Impact of oseltamivir 
treatment 
on 
influenza-related 
lower 
respiratory 
tract 
complications 
and 
hospitalizations. Archives of internal medicine, 2003. 163(14): p. 1667-72  
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 44 


12. Whitley, R.J., F.G. Hayden, K.S. Reisinger, N. Young, R. Dutkowski, D. Ipe, R.G. 
Mills, and P. Ward, Oral oseltamivir treatment of influenza in children. The Pediatric 
infectious disease journal, Feb 2001, vol. 20, no. 2, p. 127 33, ISSN: 0891 3668., 
2001 
13. Machado, C.M., L.S.V. Boas, A.V.A. Mendes, I.F. da Rocha, D. Sturaro, et al., Use 
of Oseltamivir to control influenza complications after bone marrow transplantation. 
Bone marrow transplantation, 2004. 34(2): p. 111-4 
14. Dutkowski, R., B. Thakrar, E. Froehlich, P. Suter, C. Oo, et al., Safety and 
pharmacology of oseltamivir in clinical use. Drug safety : an international journal of 
medical toxicology and drug experience, 2003. 26(11): p. 787-801 
15. He, G., J. Massarella, and P. Ward, Clinical pharmacokinetics of the prodrug 
oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinetics. 1999 Dec. 
37(6):471-84. Review.  
16. Snell, P., N. Dave, K. Wilson, L. Rowell, A. Weil, L. Galitz, and R. Robson, Lack of 
effect of moderate hepatic impairment on the pharmacokinetics of oral oseltamivir 
and its metabolite oseltamivir carboxylate. British journal of clinical pharmacology,  
May 2005, vol. 59, no. 5, p. 598 601 
17. Levey Andrew, S., J. Coresh, E. Balk, T. Kausz Annamaria, A. Levin, et al., National 
Kidney Foundation practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification. Annals of internal medicine, 2003. 139 (2): p. 137-47 
18. Hogg Ronald, J., S. Furth, V. Lemley Kevin, R. Portman, J. Schwartz- George, et al., 
National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical 
practice guidelines for chronic kidney disease in children and adolescents: evaluation, 
classification, and stratification. Pediatrics, 2003. 111(6 Pt 1): p. 1416-21 
19. Ferrara, J.L. and H.J. Deeg, Graft-versus-host disease. The New England journal of 
medicine, 1991. 324(10): p. 667-74 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 45 


PART II: 
ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the subject. For studies conducted in the EU/EEA countries, the 
investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].  
For studies conducted in the USA or under US IND, the investigator will additionally 
ensure that the basic principles of “Good Clinical Practice” as outlined in the current 
version of 21 CFR, subchapter D, part 312, “Responsibilities of Sponsors and 
Investigators”, part 50, “Protection of Human Subjects”, and part 56, “Institutional 
Review Boards”, are adhered to. 
In other countries where “Guideline for Good Clinical Practice” exist Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
Informed Consent  
 It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain written informed consent from each subject 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study. For subjects not qualified or incapable of 
giving legal consent, written consent must be obtained from the legally acceptable 
representative. In the case where both the subject and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the entire 
informed consent discussion. After the subject and representative have orally consented 
to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. The 
investigator or designee must also explain that the subjects are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason. The Case Report 
Forms [CRFs] for this study contain a section for documenting informed subject consent, 
and this must be completed appropriately. If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and updated 
if necessary. All subjects [including those already being treated] should be informed of 
the new information, given a copy of the revised form and give their consent to continue 
in the study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written consent. 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 46 


11.3 
Independent Ethics Committees/Institutional Review Board  
Independent Ethics Committees [non-US]:  This protocol and any accompanying 
material provided to the subject [such as subject information sheets or descriptions of the 
study used to obtain informed consent] as well as any advertising or compensation given 
to the patient, will be submitted by the investigator to an Independent Ethics Committee. 
Approval from the committee must be obtained before starting the study, and should be 
documented in a letter to the investigator specifying the date on which the committee met 
and granted the approval. 
Any modifications made to the protocol after receipt of the Independent Ethics 
Committee approval must also be submitted by the investigator to the Committee in 
accordance with local procedures and regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee. If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee. 
Institutional Review Board [US]:  It is the understanding of the sponsor that this 
protocol [and any modifications] as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board. This board must operate in 
accordance with the current Federal Regulations. A letter or certificate of approval will 
be sent by the investigator to the  sponsor or designee prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between 
an appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial].  Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Clinical Science Leader/Clinical Pharmacologist and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required. Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial subjects, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g. change in monitor[s], change of telephone 
number[s]. 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 47 


14. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
14.1 
Investigator's Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] subject clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence etc.  
Subject clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and subject screening and enrollment logs. 
The Investigator must keep these two categories of documents on file for at least 15 years 
after completion or discontinuation of the study. After that period of time the documents 
may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them to 
another location, Roche must be notified in advance. 
If the Investigator can not guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit. Where source 
documents are required for the continued care of the patient, appropriate copies should be 
made for storing outside of the site. 
14.2 
Source Documents and Background Data 
The investigator shall supply the sponsor or designee on request with any required 
background data from the study documentation or clinic records. This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected. In 
case of special problems and/or governmental queries or requests for audit inspections, it 
is also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. 
14.3 
Audits and Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development   
Quality Assurance Unit or its designees, or to health authority inspectors after appropriate 
notification. The verification of the CRF data must be by direct inspection of source 
documents. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 48 


14.4 
Case Report Forms 
For each patient enrolled, a CRF must be completed and signed by the principal 
investigator or authorized delegate from the study staff. This also applies to records for 
those patients who fail to complete the study [even during a pre-randomization screening 
period if a CRF was initiated]. If a patient withdraws from the study, the reason must be 
noted on the CRF. If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
All forms should be typed or filled out using indelible ink, and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed 
and dated by the investigator or his/her authorized delegate. The investigator should 
ensure the accuracy, completeness, legibility, and timeliness of the data reported to the  
sponsor or designee in the CRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them. The monitor should have access to laboratory 
test reports and other patient records needed to verify the entries on the CRF. The 
investigator [or his/her deputy] agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to the  sponsor or designee, subjects should not be identified by their names, 
but by an identification code. The investigator should keep a subject enrollment log 
showing codes, names and addresses. The investigator should maintain documents not for 
submission to Roche, e.g., subjects’ written consent forms, in strict confidence. 
17. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission. This allows the  sponsor or designee to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator. 
In accord with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 49 


Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel. Authorship will be determined by mutual agreement. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 50 


Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD  
 
Calculation of Creatinine Clearance 
Conversion Factor for Serum Creatinine: 
Conventional Units (mg/dL) = SI Units (µmol/L) ÷ 88.4   
Age = number of years (12 years 11 months = 12 years) 
 
Estimated Creatinine Clearance according to Cockcroft-Gault [17] 
 (for patients ≥ 18 years): 
¾ Males 
Creatinine  
Clearance (mL/min) = 
 
[(140 – age) X Body Weight (kg)] ÷ [72 X Serum Creatinine (mg/dL)] 
 
¾ Females  
Creatinine Clearance = above equation X 0.85 
 
Estimated Creatinine Clearance according to Schwartz equation [18]  
(for patients < 18 years): 
Creatinine Clearance 
(mL/min/1.73 M2) = 
 
k X Height (cms) ÷  Serum Creatinine (mg/dL) 
 
Value for k:  
k 
Age (years) 
0.45 
< 2 
0.55 
≥ 2 to < 13 
0.7 
≥ 13 to < 18 (males) 
0.55 
≥ 13 to < 18 
(females) 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 51 


Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD (Cont.) 
 
Grading of Chronic GVHD [19] 
 
Type of Disease 
Extent of Disease 
Limited 
Localized 
skin 
involvement, 
liver 
dysfunction or both 
Extensive 
Generalized skin involvement 
 
Localized 
skin 
involvement 
or 
liver 
dysfunction plus any one of the following: 
   1. Chronic aggressive hepatitis, bridging 
necrosis or cirrhosis 
   2. Eye involvement (Schirmer’s test, < 5 
mm) 
   3. Involvement of mucosalivary glands 
   4. Mucosal involvement (on lip biopsy) 
   5. Involvement of other target organs  
 
 
 
 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 52 


Appendix 2 
Adult Patient Diary Data and Symptom Record  
The purpose of the electronic diary is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study. Temperature and date 
and time of drug administration will also be recorded on the electronic patient diary. 
Scoring of Symptoms 
Please answer All of the questions yourself by checking one box for each row. 
The information you provide is very important and will remain strictly confidential. 
 
 
 
 
    absent 
 mild 
        moderate 
      severe 
 
 
 
 
        0                  1 
 
2 
         3 
 
 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 53 


Appendix 3 
Diary Data for Children  
Temperature and date and time of drug administration will also be recorded on the 
electronic patient diary. 
  
 
Temperature:  
 
 
.  
ºC/F 
Symptoms of influenza-like illness 
Please mark one box only per question 
Item 
 
No 
Problem 
0 
 
Minor 
Problem 
1 
 
Moderate 
Problem 
2 
 
Major 
Problem 
3 
Don’t Know 
or not 
Applicable 
1. 
Poor appetite........................................
 
 
 
 
 
2. 
Not sleeping well.................................
 
 
 
 
 
3. 
Irritable, cranky, fussy.........................
 
 
 
 
 
4. 
Feels unwell.........................................
 
 
 
 
 
5. 
Low energy, tired.................................
 
 
 
 
 
6. 
Not playing well ..................................
 
 
 
 
 
7. 
Crying more than usual........................
 
 
 
 
 
8. 
Needing extra care...............................
 
 
 
 
 
9. 
Clinginess............................................
 
 
 
 
 
10. Headache .............................................
 
 
 
 
 
11. Sore throat ...........................................
 
 
 
 
 
12.   Muscle aches or pains..........................
 
 
 
 
 
13. Fever....................................................
 
 
 
 
 
14. Cough ..................................................
 
 
 
 
 
15. Nasal congestion, runny nose ..............
 
 
 
 
 
16. Vomiting..............................................
 
 
 
 
 
17. Not interested in what’s going on 
 
 
 
 
 
18. Unable to get to get out of bed 
 
 
 
 
 
This form was filled out by:          
                                                        1. 
 Parent 
 
2. 
 Other relative 
 
3. 
Nanny 
 
4. 
Subject 
 
5. 
 Other     specify______________________________________________ 
 
Date of Assessment 
 
 
 
 
 
 
 
dd 
mm 
yy 
Time of Assessment 
 
 
 
 
 
h 
min 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 54 


Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug 
 
PROBABLE [must have first three] 
This category applies to those AEs which are considered, with a high degree of certainty, to 
be related to the test drug.  An AE may be considered probable, if: 
1. It follows a reasonable temporal sequence from administration of the drug. 
2. It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the subject. 
3. It disappears or decreases on cessation or reduction in dose.  [There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., [1] bone marrow depression, [2] tardive 
dyskinesias.] 
4. It follows a known pattern of response to the suspected drug. 
5. It reappears upon rechallenge. 
 
POSSIBLE [must have first two] 
1. This category applies to those AEs in which the connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possible if, or when: 
2. It follows a reasonable temporal sequence from administration of the drug. 
3. It may have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
4. It follows a known pattern of response to the suspected drug. 
 
REMOTE [must have first two] 
1. In general, this category is applicable to an AE which meets the following criteria: 
2. It does not follow a reasonable temporal sequence from administration of the drug. 
3. It may readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
4. It does not follow a known pattern of response to the suspected drug. 
5. It does not reappear or worsen when the drug is readministered. 
 
UNRELATED 
This category is applicable to those AEs which are judged to be clearly and 
incontrovertibly due only to extraneous causes [disease, environment, etc.] and do not meet 
the criteria for drug relationship listed under remote, possible, or probable. 
 
 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 55 


Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug (Cont.) 
 
 
 
Probable 
Possible 
Remote 
Unrelated 
Clearly due to extraneous causes 
– 
– 
– 
+ 
 
 
 
 
 
Reasonable temporal association with drug 
administration 
+ 
+ 
– 
– 
 
 
 
 
 
May be produced by subject clinical state, 
etc. 
– 
+ 
+ 
+ 
 
 
 
 
 
Known response pattern to suspected drug 
+ 
+ 
– 
– 
 
 
 
 
 
Disappears or decreases on cessation or 
reduction in dose 
+ 
– 
– 
– 
 
 
 
 
 
Reappears on rechallenge 
+ 
– 
– 
– 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 56 


Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– is fatal; [results in death] [NOTE: death is an outcome, not an event] 
– is Life-Threatening    [NOTE: the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– required in-patient hospitalization or prolongation of existing hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the 
outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the  sponsor or designee is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definitions above. These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator. For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply)  
– Pre-existing/Underlying disease - specify  
– Study treatment – specify the drug(s) related to the event 
– Other treatment (concomitant or previous) – specify 
– Protocol-related procedure 
– Other (e.g. accident, new or intercurrent illness) - specify 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be clinically 
serious. 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 57 


Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
[Cont.] 
 
A serious adverse event occurring during the study or which comes to the attention of the 
investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will 
include copies of hospital case reports, autopsy reports and other documents when 
requested and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs page 
of the CRF: intensity, relationship to test substance, action taken, and outcome to date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor  
ROCHE HEADQUARTERS CONTACT for SAEs: Clinical Operations/Clinical Science  
Within the US, weekends, holidays and after 5:00 pm, call 
 and ask for 
the physician on call.  Outside the US, call the local emergency contact number provided 
by the Monitor. 
 
CONFIDENTIAL  Roche Protocol NV20234B  (Ro 64-0796)  - Page 58 


AMENDMENT HISTORY FOR PROTOCOL NV20234C 
 
1. 
SUBJECT:  MODIFICATION OF INCLUSION CRITERION TO BROADEN 
THE TIME BETWEEN ONSET OF INFLUENZA LIKE ILLNESS AND 
FIRST DOSE OF STUDY DRUG TO WITHIN 96 HOURS 
Reason for change:   
Over the last several seasons, the majority of subjects were ineligible to be screened as 
they had been symptomatic for > 48 hours when they presented at the study site. 
2. 
SUBJECT: DIAGNOSIS OF INFLUENZA BY PCR AND CULTURE IN 
ADDITION TO A RAPID DIAGNOSTIC 
Reason for change:  
Among patients who were screened there was a high screen failure rate possibly due to 
the low sensitivity of rapid diagnostic tests.  Therefore, influenza confirmation by PCR or 
culture at baseline will be allowed. 
3. 
SUBJECT:  BROADENING OF THE TARGET IMMUNOCOMPROMISED 
STUDY POPULATION   
Reason for change:  
Transplant guidelines recommend the use of anti-virals for treatment of influenza.  The 
availability of anti-virals outside the scope of a clinical trial precludes the need for this 
population to participate in a clinical trial.  
4. 
SUBJECT:  MODIFICATION OF THE STUDY OBJECTIVES WHICH 
EVALUATE EFFICACY AND SAFETY, AND STATISTICAL ANALYSES 
Reason for change:   
A placebo arm was always (versions A and B) considered unethical for this population.  
In order to make comparisons, the efficacy data for the oseltamivir arms from this study 
were to be compared to the placebo arm from pivotal registration trials in healthy 
subjects.  Consequently version A and B of the protocol were designed to be similar to 
pivotal registration trials, ie only patients with influenza symptoms for < 48 h were to be 
enrolled.  There were several limitations to this original approach, the main being that it 
is known that healthy children, adults and the elderly clear the influenza virus faster than 
the immunocompromised subject.   
The need to enroll patients within 48 hours of the onset of influenza resulted in several 
patients being ineligible for screening.  This required modification of the inclusion 
criteria to allow patients who had been symptomatic with influenza for more than 48 
hours to be enrolled in the study.  This imposed an even greater limitation on the ability 
to compare data between healthy subjects on placebo enrolled within 48 hours from 
pivotal registration trials with immunocompromised subjects who received oseltamivir 
within 96 hours.  
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 1 


Furthermore, since the original study design, and particularly following the pandemic, 
there has been increasing evidence for efficacy in the immunocompromised population.  
National guidelines now recommend the use of anti-virals for the treatment of influenza 
in the transplant population.  In immunocompromised patients, however, there remains 
the risk for resistance.  It was therefore decided to revise the primary objective of this 
study to the descriptive characterization of safety, tolerability and resistance.   
5. 
SUBJECT:  MODIFICATION OF SAMPLE SIZE 
Reason for change:   
The original sample size was determined to provide an adequate number of patients for 
analysis with a primary objective of efficacy.  The sample size has been revised to reflect 
the amended primary objective of safety/tolerability and the development of resistant 
influenza virus, whilst still allowing for an adequate number of patients with influenza A.  
6. 
SUBJECT:  RENAL IMPAIRMENT   
Reason for change:   
While the dosing recommended for patients with renal failure in version B of the protocol 
continues to be safe, it is anticipated that Roche will develop more specific dosing 
guidelines for patients with renal failure.  It was therefore decided to discontinue study 
medication for all patients with renal failure (CrCl < 60mL/min/1.73M2).   
7. 
SUBJECT:  DELETING SPECIFIC RESISTANCE MUTATIONS 
Reason for change:   
Due to the circulation of a wild type oseltamivir resistant H274Y strain of influenza A 
H1N1 in the 2007/8 and 2008/9 Northern hemisphere influenza seasons, baseline PCR to 
detect the strain was introduced in version B of the protocol.  With resistance being one 
of the primary objectives of the study, PCR testing for several more strains is planned.  
As the processing and handling of these tests will take time, test results will not be 
available in a timely manner and therefore will not be reported to the clinical trial site. 
8. 
SUBJECT:  PARTICIPATING CENTERS 
Reason for change:   
The number of estimated participating centers was adjusted to be more accurate. 
9. 
SUBJECT:  CORRECTIONS TO PREVIOUS PROTOCOL VERSION B  
Reason for change:   
Correction of administrative errors that were discovered after publication of Amendment 
B.  
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 2 


Section Synopsis Objectives   
New text: 
Primary: 
To evaluate prospectively the safety and tolerability of oseltamivir for the treatment of 
influenza in immunocompromised patients and characterize the effects of 
oseltamivir in immunocompromised patients on the development of resistant 
influenza virus. 
Secondary: 
To 
evaluate 
the 
effects 
of 
conventional 
and 
high 
dose 
oseltamivir 
in 
immunocompromised patients on: 
• The time to resolution of influenza symptoms 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points) 
 
Old text: 
Primary: 
To evaluate prospectively the efficacy of oseltamivir for the treatment of influenza in 
transplant recipients as measured by the time to resolution of influenza symptoms. 
Secondary: 
To evaluate the effects of conventional and high dose oseltamivir in transplant recipients 
on: 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points) 
• Patient safety and tolerability  
• The development of  resistant influenza virus 
 
Section Synopsis Trial Design   
New text: 
This is a double-blind, randomized, multi-center trial of twice daily, conventional and 
high dose oseltamivir for the treatment of influenza in immunocompromised patients.  
Subjects will be stratified by age (≤ 12, > 12 years), transplant status (yes, no), time 
since onset of influenza symptoms and treatment start (up to 96 hours) (≤ 48 or > 48 
hours) and vaccination status (yes, no). 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 3 


Old text: 
This is a double-blind, randomized, multi-center trial of twice daily, conventional and 
high dose oseltamivir for the treatment of influenza in immunocompromised patients (as 
represented by transplant recipients).  Subjects will be stratified by age, transplant type, 
time since onset of flu symptoms and treatment start (≤ 24 or >24 hours) and vaccination 
status. 
Section Synopsis Number of Subjects   
New text: 
A minimum of 166 (83 per arm) to allow an adequate number of influenza A patients 
per arm; including 50 transplant recipients.     
Old text: 
A minimum of 250 (125 per arm). 
Section Synopsis Number of Centers 
New text: 
Approximately 100 - 110 centers in the Northern hemisphere. 
Old text: 
Approximately 140 centers in the Northern hemisphere. 
Section Synopsis Target Population   
New text: 
Patients immunocompromised due to a primary or secondary immunodeficiency, 1 
year of age and older.  The subjects will be positive for influenza by a rapid diagnostic 
test, PCR or virus culture at baseline.   
Old text: 
Transplant recipients (liver, kidney, liver and kidney, allogenic haematopoietic stem cell 
transplant), 1 year of age and older enrolled during the influenza season. 
Section Synopsis Investigational Medicinal Product(s) 
Dose/Route/Regimen 
New text: 
Dose adjustments:  In both treatment arms, patients whose CrCl decreases to 
< 60ml/min/1.73M2 will discontinue study medication. 
Old text: 
Dose adjustments:  In both treatment arms, dosing frequency will be decreased to once 
daily in patients with severe renal impairment (CrCl in adults between 10-30 ml/min and 
children between 10-30 ml/min/1.73M2). 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 4 


Section  Synopsis Assessments of:  
New text: 
ASSESSMENTS OF: 
 
- 
SAFETY 
Adverse events, physical exams, vital signs, clinical laboratory 
evaluations 
- 
RESISTANCE 
Development of resistance 
- 
EFFICACY 
Time to resolution of all influenza symptoms as recorded in 
the patient diary. 
 
Old text: 
ASSESSMENTS OF: 
 
- 
EFFICACY 
Time to resolution of all influenza symptoms as recorded in the 
patient diary. 
- 
SAFETY 
Adverse events, physical exams, vital signs and clinical laboratory 
evaluations 
 
Section Synopsis Statistical Analyses   
New text: 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 
90% of enrolled patients will have laboratory-confirmed influenza, there will be 
75 patients in each treatment arm in the population evaluable for the development 
of resistance.  The following table shows the 95% Pearson-Clopper confidence 
intervals that would result with a sample size of 75 patients in a treatment arm if 
certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of 
development of resistance will be monitored in a blinded fashion, in order to ensure 
a reasonable precision for the estimation is maintained.  Additional patients may be 
enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the 
assessment of safety.  This number of patients would provide estimates of adverse 
event rates with similar precision. 
For the primary objective of evaluating the safety of oseltamivir conventional and 
high dose treatments, AEs, laboratory tests, and vital signs will be summarized and 
compared with the known safety profile of the drug.  For the summary of the 
development of resistance for each treatment arm, 95% confidence intervals will be 
provided with the estimated rates.   
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 5 


For the secondary objective of evaluating the efficacy of oseltamivir as measured by 
the time to resolution of influenza symptoms, the following two assessments will be 
made independently of each other and without regard to the outcomes in each case. 
• Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is 
comparable to patients in the current study.  For this population, a median time 
to resolution of all clinical influenza symptoms will be determined along with its 
95% confidence interval. 
• Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference 
in the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval.  
Old text: 
Sample size calculations were performed using a two-sided t-test and are based on the 
comparison with a placebo control response in the pivotal registration trials in healthy 
adults of 112 hours for median time to alleviation of all symptoms. Assuming an 
expected median time to alleviation of symptoms of 78 hours for each of the two active 
treatment groups in this study, and a common standard deviation of 98 hours, then 111 
evaluable subjects per group would give more than 90% power to detect a difference 
between the control and each of the active treatment groups. 
The primary endpoint will be time to alleviation of all clinical influenza symptoms, as 
recorded in the diary cards. 
For the primary analysis, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established to match those 
of the current study. For this population, a median time to resolution of all clinical 
influenza symptoms will be determined along with its 95% confidence interval. 
• Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval. The methodology will be based on the use of the Hodges-
Lehmann estimator in the case of censored data. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 6 


Section GLOSSARY OF ABBREVIATIONS 
New text: 
None.  Text deleted. 
Old text: 
DRAM 
Data Reporting and Analysis Manual 
 
Section GLOSSARY OF ABBREVIATIONS 
New text: 
AIDS 
Acquired immunodeficiency syndrome 
ALL 
Acute lymphocytic leukemia 
AML 
Acute myeloid leukemia 
CDC 
Centers for Disease Control and Prevention 
CML 
Chronic myeloid leukemia 
HIV 
Human immunodeficiency virus 
SAP 
Statistical Analysis Plan 
SCID 
Severe combined immunodeficiency 
 
Old text: 
None.  Text added. 
Section 1.1.1 Influenza in the Immunodeficient Population 
New text: 
Influenza infection is usually a self limiting condition. However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus 
may cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death [3].  
Conditions that compromise immunity may be classified based on etiology into 
primary (genetic) and secondary (acquired) immunodeficiency.  Of the 
immunodeficient conditions, the ones that affect cell mediated immunity are likely 
to have adverse outcomes following viral infections [20]. 
Primary immunodeficiency  
Primary immunodeficiencies are relatively common, may be either congenital or 
manifest later in life and are classified according to whether the genetic defect 
affects T or B cells or both [20].  There are four groups of disorders: severe 
combined immunodeficiency (SCID), primary T cell deficiency (e.g. CD8 deficiency, 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 7 


DiGeorge syndrome), predominantly antibody deficiency (e.g. common variable 
immunodeficiency, 
selective 
IgA 
deficiency) 
and 
other 
well-defined 
immunodeficiency syndromes (e.g. Wiskott Aldrich syndrome) [20].  
Of the primary immunodeficiencies, antibody deficiencies are the most frequent. 
However some of the more common antibody deficiency conditions (isolated IgA 
deficiency, IgG subclass deficiency and common variable immunodeficiency) have 
intact cell-mediated immunity and therefore the clinical course of viral infections 
(unless complicated by bacterial infections) does not differ significantly from that in 
the normal host [20].  A list of primary immunodeficiency disorders at risk for viral 
infections is provided in Appendix 6A.  The incidence of some of these conditions 
has been estimated.  The incidence of SCID is 1 in 100,000 to 1 in 1,000,000 [20].  
The more severe forms of primary immunodeficiency are relatively rare, have their 
onset early in life, and all too frequently result in death during childhood [20].  
Secondary Immunodeficiency 
Secondary immunodeficiencies are not caused by intrinsic abnormalities in 
development of T and B cells [20].  Secondary immunodeficiency may result from 
diseases (human immunodeficiency virus [HIV], hematologic malignancy) or 
immunosuppressive and cytotoxic drugs (such as those used for treatment of 
transplant recipients, collagen vascular disease, malignancies). 
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T cell count of < 200/µL are highly 
susceptible 
to 
opportunistic 
disease 
[20]. 
 
Studies 
in 
HIV/acquired 
immunodeficiency syndrome (AIDS) subjects have shown an increased risk for 
heart and lung-related hospitalizations during the influenza season compared to 
other times of the year, prolonged duration of influenza symptoms, increased risk 
for influenza-related complications and a higher risk of influenza-related death [21]. 
Several hematologic malignancies affect the immune system (Appendix 7).  Several 
authors have reported influenza in children and adults with hematologic 
malignancies [22, 23, 24, 25]. 
Secondary immunodeficiency due to drugs (e.g. transplant recipients, collagen 
vascular disease, malignancies) 
The enhanced survival of the transplant population following the availability of 
newer immunosuppressive drugs has made them representative of the 
immunocompromised population in general; and secondary immunodeficiency due 
to drugs, in particular. 
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality.  In a cohort study of influenza viral infection in solid 
organ transplant (SOT) subjects, 30 cases of influenza viral infection were identified.  
Secondary bacterial pneumonia was seen in 17% of subjects and three SOT recipients 
(2 liver and one kidney) had myositis, myocarditis and bronchiolitis obliterans.  Biopsy 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 8 


of the transplanted organ was performed in 21 of 30 cases and revealed variable degrees 
of acute allograft rejection in 62% of subjects.  The study concluded that influenza was 
associated with significant morbidity in different groups of SOT recipients [5].  
Among transplant recipients, subjects with hematopoetic stem cell transplant (HSCT) 
are at the greatest risk for morbidity.  In a prospective study from the Infectious Diseases 
Working Party of the European Group for Blood and Marrow Transplantation, 1973 
patients were evaluated for respiratory virus infections after stem cell transplant.  The 
overall mortality was 23% from influenza A infection and the direct influenza A-
associated mortality was 15.3% in this study [6].  A large retrospective study (4797 
subjects undergoing HSCT over a 13-year period) identified 62 patients with 
influenza of whom as many as 29% (18 of 62 patients) developed pneumonia.  Ten 
percent of the subjects with influenza died [7].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects. In otherwise healthy adults, elderly 
subjects and children, the median duration of viral shedding in untreated subjects was 70, 
96 and 118 hours respectively [8].  In contrast, in the retrospective HSCT study, 
influenza virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a 
median duration of 168 hours (7 days, range 2 to 37 days) [7]. 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir). 
Old text: 
Influenza infection is usually a self limiting condition. However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus 
may cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death. [3]  The availability of new 
immunosuppressive agents has enhanced the number and survival of solid organ 
transplant (SOT) and haematopoietic stem cell transplant (HSCT) [4] recipients making 
them representative of the larger immunocompromised patient population.   
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality. In a cohort study of influenza viral infection in SOT 
subjects, 30 cases of influenza viral infection were identified. Secondary bacterial 
pneumonia was seen in 17 % of subjects and three SOT recipients (2 liver and one 
kidney) had myositis, myocarditis and bronchiolitis obliterans. Biopsy of the transplanted 
organ was performed in 21 of 30 cases and revealed variable degrees of acute allograft 
rejection in 62 % of subjects. The study concluded that influenza was associated with 
significant morbidity in different groups of SOT recipients [5].  
Among transplant recipients, subjects with HSCT are at the greatest risk for morbidity. In 
a prospective study from the Infectious Diseases Working Party of the European Group 
for Blood and Marrow Transplantation, 1973 patients were evaluated for respiratory virus 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 9 


infections after stem cell transplant.  The overall mortality was 23% from influenza A 
infection and the direct influenza A-associated mortality was 15.3% in this study [6]. 
The largest study of influenza infections in transplant (allogenic, syngenic or autologous 
HSCT) subjects comes from the Fred Hutchinson Cancer Center, Seattle, USA. In this 
retrospective study, influenza virus was isolated in 62 of 4797 subjects undergoing HSCT 
over a 13-year period. During this period, the Center had a standardized protocol for the 
detection of respiratory pathogens comprising direct fluorescent antibody (DFA) staining 
and viral culture. Because capture of influenza infections and accurate ascertainment of 
all risk factors was less complete after discharge from the health care center, only 
infections that occurred during the first 120 days after transplantation were considered. 
Influenza was defined as the isolation of influenza virus by culture or as evidence of 
influenza antigen detected by DFA in conjunction with consistent symptomatology.  
Antiviral treatment with an M2 inhibitor or oseltamivir (available since 1999) was 
performed at the discretion of the investigator. Unlike the fixed dosing duration 
recommended for antivirals in healthy subjects, in this trial, treatment was continued until 
resolution of presenting signs and symptoms and clearance of virus from respiratory 
secretions. Garrett Nichols, et al, reported as many as 29 % of subjects developed 
pneumonia following influenza infection in this large retrospective study. Ten percent of 
the subjects with influenza died [7].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects. In otherwise healthy adults, elderly 
subjects and children, the median duration of viral shedding in untreated subjects was 70, 
96 and 118 hours respectively. [8] In contrast, in the retrospective HSCT study, influenza 
virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a median 
duration of 168 hours (7 days, range 2 to 37 days) [7]. This median duration of shedding 
included both allogenic and autologous HSCT subjects and both treated and untreated 
subjects. The mean duration of shedding in treated and untreated allogenic HSCT 
subjects was found to be longer than in autologous HSCT subjects (11.1 versus 6.7 days).  
Johny et al, evaluated the use of zanamivir in the treatment of influenza in seven 
allogenic bone marrow transplant subjects.  As with the large retrospective HSCT study, 
their standard of care also was to continue zanamivir until symptoms had subsided and it 
was documented that viral excretion had ceased. Viral shedding was checked every 7 
days. Based on this protocol, the median duration of use of zanamivir was 15 days with a 
range of 5 to 44 days [9]. 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir). Due to the emergence of resistant virus, the Center for Disease Control 
(CDC) has made an interim recommendation that neither amantadine nor rimantadine be 
used for the treatment or prophylaxis of influenza in the United States. [10] Oseltamivir 
is therefore one of the main drugs available for the evaluation of the treatment of 
influenza in the immunocompromised population. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 10 


Section 1.1.2 Oseltamivir 
New text: 
The safety profile of oseltamivir has been well characterized for the prophylaxis 
indication in a prospective randomized placebo controlled trial conducted in the 
adult and pediatric immunocompromised (HSCT and SOT) population.  In the 
oseltamivir group, the indications for transplant included hematologic malignancies 
(acute and chronic leukemias, multiple myeloma and myelodysplastic syndrome), 
lymphoid malignancies (Hodgkins or non-Hodgkins lymphomas), primary 
immunodeficiencies (Wiskott-Aldrich syndrome, X-linked lymphoproliferative 
disease and severe combined immunodeficiency).  Other rare indications included 
bone marrow aplasia, paroxysmal nocturnal haemoglobinuria, myelofibrosis and 
multiple sclerosis.  In the safety population, there were 239 subjects randomized to 
the conventional dose of oseltamivir and 238 to placebo.  The total number of 
adverse events reported in the placebo group (361 events) was generally similar to 
that in the oseltamivir group (323 events).  Diarrhea was the most frequently 
reported adverse event (placebo, 8%; oseltamivir, 6%).  There were no deaths in the 
oseltamivir group.  Oseltamivir was found to be safe in immunosuppressed 
transplant recipients [26]. 
Limited safety and/or efficacy of oseltamivir for the treatment indication is available 
from several case reports in children and adolescents.  Oseltamivir was shown to be 
safe and/or effective in HIV infected children (n=10) [27], children (age 3 to 12 
years) with acute lymphocytic leukemia (ALL) (n=10) [25], in a nosocomial H1N1 
outbreak in a pediatric (children aged 10 months to 13 years) oncology ward (n=8) 
[24], in children and adolescents (age 2 to 19 years) with malignancies (ALL, 
neuroblastoma, brain tumor, non-Hodgkin’s lymphoma, osteosarcoma, Ewing 
sarcoma, myelodysplasia, acute myeloid leukemia (AML), Wilms tumor, aplastic 
anemia, chronic myeloid leukemia (CML) and acute promyelocytic leukemia) 
(n=51) [22], in children aged 4 to 14 years on immunosuppressive drugs (n=5) [28] 
and in children (aged 5 months to 5 years) with bone marrow transplant (n=3) [29]. 
Oseltamivir has also been shown to be safe and/or effective in mixed populations of 
children and adults (62 patients) with HSCT [7], and in a large epidemiologic study 
(n=221) with SOT [30].  
Finally, 
oseltamivir 
has 
been 
shown 
to 
be 
safe 
and/or 
effective 
in 
immunocompromised adults with HSCT [13] and adults with lung transplant [31, 
32, 33].  
The dose of oseltamivir was the same as the conventional dose in a majority of these 
reports.  In one report as many as 25 adult patients received twice the conventional 
dose [30] while in another report, three of nine adult patients received twice the 
conventional dose [33].  Treatment with oseltamivir generally ranged from 5 to 10 
days [32, 33, 30] and occasionally until the patient was symptom free [32, 33].  In 
exceptional cases treatment was given for as long as 20 days [22] or for as long as 
the patient was positive by RT-PCR [25]. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 11 


There 
is 
some 
concern 
about 
the 
development 
of 
resistance 
in 
the 
immunocompromised population.  During the pandemic influenza season, more 
than 23,000 clinical isolates of novel H1N1 pandemic virus were tested for resistance 
in the 6 international WHO regions.  A total of 225 isolates (from 225 subjects) were 
resistant (H275Y mutation in the neuraminidase coding sequence) to oseltamivir for 
an approximate incidence of 1%.  Information on immune status was available for 
142 of 225 patients.  Among the 142 patients, 56 (40%) were immunocompromised 
[34].  Prolonged viral replication and lack of immune-mediated virus clearance in 
immunosuppressed patients treated with antivirals can result in a higher incidence 
of selection of drug-resistant viruses, a phenomenon that has been documented 
previously [35, 36]. 
Old text: 
There have been no controlled studies of oseltamivir treatment or prophylaxis in 
immunocompromised subjects. In the study by Garrett Nichols et al, patients who did not 
receive antiviral therapy shed virus for longer periods (mean duration, 11.3 days) than did 
those who were treated with M2 inhibitors (mean duration, 9.7 days) or neuraminidase 
inhibitors (mean duration, 7.5 days). Therapy with oseltamivir (but not rimantadine) 
appeared to be associated with shorter duration of shedding after controlling for steroid 
dose (p < 0.08). [7].  The efficacy of oseltamivir in the treatment of influenza in the 
immunocompromised population has also been demonstrated in other studies. In another 
small trial of oseltamivir for the treatment of influenza infection in subjects following 
HSCT, only two patients (5.1 %) developed influenza-related pneumonia. [13] In this 
study, all 39 HSCT subjects with influenza were treated with antivirals (oseltamivir or 
amantadine).  In as many as 43 % of subjects, the duration of illness was greater than 7 
days. This is unlike data from healthy adults, suggesting the possible need to evaluate a 
higher dose and/or longer duration of treatment with oseltamivir for this population.    
While the efficacy of antiviral agents for influenza has been demonstrated in the 
otherwise healthy population, it has not been tested prospectively in the 
immunocompromised (transplant) population. [4] There is therefore a need to confirm the 
efficacy of antiviral therapy for influenza in prospective controlled trials in this patient 
population. 
Section 1.2 Rationale for the Study 
New text: 
Because of the increasing body of evidence (Section 1.1.2), oseltamivir is now 
recommended in national guidelines as an option for the treatment of influenza in 
the transplant population [40].  As the transplant population is considered 
representative of the immunocompromised population, the primary objective of this 
study is to evaluate safety and resistance, while evaluating efficacy as a secondary 
objective. 
Old text: 
This study is designed to investigate the optimal therapy for influenza in 
immunocompromised transplant recipients. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 12 


The rationale for conducting this study in the immunocompromised population is based 
on the following: 
1. Immunocompromised subjects are at the highest risk for morbidity and mortality 
from influenza 
2. Immunocompromised subjects are at the greatest risk for contracting influenza 
because immunization may be ineffective in this population 
3. There is no drug approved for the treatment of influenza in this population 
 
Section 2.1 Primary Objective 
New text: 
The primary objective of the study is to evaluate prospectively the safety and 
tolerability of oseltamivir for the treatment of influenza in immunocompromised 
patients and characterize the effects of oseltamivir in immunocompromised patients 
on the development of resistant influenza virus. 
Old text: 
The primary objective of the study is to evaluate prospectively the efficacy of oseltamivir 
for the treatment of influenza in transplant recipients as measured by the time to 
resolution of influenza symptoms. 
Section 2.2 Secondary Objectives 
New text: 
To 
evaluate 
the 
effects 
of 
conventional 
and 
high 
dose 
oseltamivir 
in 
immunocompromised patients on: 
• The time to resolution of influenza symptoms. 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis).  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points). 
 
Old text: 
To evaluate the effects of conventional and high dose oseltamivir in transplant recipients 
on: 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points) 
• Patient safety and tolerability  
• The development of  resistant influenza virus  
• To characterize the population pharmacokinetics of oseltamivir (e.g. clearance, 
volume of distribution) in transplant recipients 
 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 13 


Section 3.1 Overview of Study Design and Dosing Regimen 
New text: 
This is a double blind, randomized, stratified, multi-center trial of conventional and high 
dose oseltamivir for the treatment of influenza in immunocompromised patients.  
Immunocompromised patients who develop an influenza-like illness with a positive 
rapid diagnostic test, PCR, or viral culture for influenza, will be enrolled during the 
influenza season.  Patients will be stratified by transplant status [yes, no], the time 
between onset of influenza symptoms and treatment start (up to 96 hours) [≤ 48 hours; 
> 48 hours], influenza vaccination status for current influenza season [Yes; No] and by 
age [≤ 12 years; > 12 years].  Eligible patients will be consented and randomized to 
receive oseltamivir twice daily for 10 days in one of two treatment arms: conventional 
dose or high dose (double the conventional dose). 
Old text: 
This is a double blind, randomized, stratified, multi-center trial evaluating the efficacy of 
conventional and high dose oseltamivir for the treatment of influenza in 
immunocompromised patients. Immunocompromised transplant recipients who develop 
an influenza-like illness with a positive rapid diagnostic test for influenza, will be 
enrolled during the influenza season.  Patients will be stratified by type of transplant 
[SOT or HSCT], by the time between onset of symptoms and treatment start [≤ 24 hours; 
> 24 hours], influenza vaccination status for current flu season [Yes; No] and by age 
[≤12 years; >12 years]. Eligible patients will be consented and randomized to receive 
oseltamivir twice daily for 10 days in one of two treatment arms: conventional dose or 
high dose (double the conventional dose). The primary end point in the study is the time 
to alleviation of all symptoms.  
In this study, immunocompromised subjects will be represented by the transplant 
population. This is justified because the availability of new immunosuppressive agents 
has enhanced the number and survival of SOT and HSCT recipients, making them 
representative of the larger immunocompromised patient population.    
Heterogeneity in the transplant population could confound the assessment of safety and 
efficacy in this study. Consequently, the SOT population in the protocol excludes 
subjects with transplants other than liver, kidney or liver and kidney. However, in order 
to still be representative of the transplant community in particular and the 
immunocompromised community in general, the study specifically includes subjects at 
the greatest risk for morbidity and mortality from influenza - the HSCT subjects. The 
study also excludes subjects with comorbid conditions that might impact the metabolism 
and excretion of the drug. As the prodrug and active drug accumulate in the presence of 
hepatic and severe renal impairment respectively, subjects with hepatic or severe renal 
impairment are excluded from the study.  Other comorbid conditions that might preclude 
the assessment of efficacy and safety are also excluded from the study. These are 
reflected in several of the inclusion and exclusion criteria. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 14 


Section 3.1.1 Rationale for Study Design 
New text: 
This study incorporates several features that distinguish it from classic placebo controlled 
trials.  
There is no placebo control arm in this study as it was considered unethical for this 
high risk population.  The development of resistance following treatment with 
oseltamivir (one of the primary objectives of the study) is an objective assessment 
(determined by laboratory tests) and is unlikely to be impacted by the absence of a 
placebo arm.  
As a placebo control arm was considered unethical in this population, an alternative 
control arm had to be identified for efficacy end points.  The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial.  In order to do this, the 
end points were designed to be similar to that in the pivotal registration trials.  
The following sections provide rationale and justification for specific aspects of the study 
design which differ from the currently approved dosing for influenza or from 
previous pivotal registration trials.  They also provide information on how the results 
will be used to make recommendations on dose and duration of treatment. 
Old text: 
This study incorporates several features that distinguish it from classic placebo controlled 
trials. At the outset, a patient population that represents the general immunocompromised  
population had to be defined. As a placebo control arm was considered unethical in this 
population, an alternative control arm had to be identified. The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial. In order to do this, the 
current study design and end points were designed to be similar to that in the pivotal 
registration trials.  
Routine influenza surveillance during the 2007/2008 influenza season showed a 
significant increase in the global circulation of an oseltamivir-resistant influenza virus (A 
H1N1 with H274Y mutation).  Therefore, baseline nasal and throat swab samples will be 
assessed for the presence of the H274Y-mutated influenza virus and results will be 
reported to clinical sites to assist in determining the most appropriate treatment options 
for individual patients. 
The following sections provide rationale and justification for the specific aspects of the 
study design. They also provide information on how the results will be used to make 
recommendations on dose and duration of treatment. 
Section 3.1.1.1 Choice of Treatment Arms and Duration of Treatment 
New text: 
The currently approved dose of oseltamivir for the treatment indication is the 
conventional dose with a duration of five days.  In this study a conventional and 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 15 


high dose (twice the conventional dose) are being evaluated.  The pivotal registration 
trials for oseltamivir in healthy adults with influenza had three treatment arms, two active 
(75 mg and 150 mg) and one placebo.  Both treatment arms were found to be 
significantly better than placebo.  No statistical comparisons were made between the two 
active treatment arms.  Evaluation of the results in the two active treatment arms did not 
reveal any clinically meaningful difference.  However, the proportion of subjects 
shedding virus on day 4 (3 days after the start of treatment), suggested a possible 
dose response relationship (36%, 28% and 23% in the placebo, 75 mg and 150 mg 
dose arms respectively).  Because defective immune-mediated virus clearance in 
immunosuppressed patients treated with antivirals can result in a higher incidence 
of selection of drug-resistant viruses, it was decided to use both the conventional and 
high dose arm for this study.  A longer duration of treatment was chosen because a 
large retrospective study has shown that  the median duration of viral shedding of 
7 days [7] was greater for HSCT recipients than that seen in the healthy children, 
adult and elderly population with influenza (Section 1.1.1) [8]. 
Old text: 
The pivotal registration trials for oseltamivir in healthy adults with influenza had three 
treatment arms, two active (75 mg and 150 mg) and one placebo. Both treatment arms 
were found to be significantly better than placebo. No statistical comparisons were made 
between the two active treatment arms. Evaluation of the results in the two active 
treatment arms did not reveal any clinically meaningful difference. Based on these 
studies, the approved (conventional) dose for the treatment of influenza in adults is 
75 mg. 
A similar trial design was envisaged for this immunocompromised population. In an 
immunocompromised population there is a possibility of increased efficacy with a higher 
dose. In the trials in healthy adults, on day 4 (3 days after the start of treatment), the 
proportion of subjects shedding virus suggested a possible dose response relationship 
(36%, 28% and 23% in the placebo, 75 mg and 150 mg dose arms respectively). In 
healthy adults, this difference in the rate of viral shedding did not translate to any 
difference in clinical response in the two active treatment arms even though both active 
treatment 
arms 
were 
significantly 
better 
than 
the 
placebo 
arm. 
In 
the 
immunocompromised population too it is possible that while there might not be any 
difference between the two active treatment arms, one or both of these dose arms may be 
better than placebo. In this immunocompromised population, there is therefore an even 
greater need to evaluate the efficacy of a higher dose arm.  
As with the trials in healthy adults, the ideal trial design for the current study would be 
one that compared efficacy of the conventional and high dose arms with placebo. 
However, as reviewed in an earlier section 1.1.1 the morbidity and mortality from 
influenza in the immunocompromised population is far greater than that in healthy adults. 
Thus in one study as many as 29 % of subjects with HSCT developed pneumonia 
following influenza infection. [7] In another study in SOT recipients, biopsy of the 
transplanted organ revealed variable degrees of acute allograft rejection in 62 % of 
subjects. [5] Given the extent of morbidity, a placebo control appears unethical. This is 
further supported by a feasibility survey conducted by the Sponsor which demonstrated  
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that a majority of transplant sites actually used antivirals (including oseltamivir) to treat 
influenza in this population. It was therefore decided to compare the conventional and 
higher dose arms with the placebo arm from the pivotal registration trials in healthy 
adults with influenza. Although this approach poses limitations, the Sponsor has made 
every effort to make sure that the results from such an approach are still meaningful. The 
following sections describe how the study design addresses these limitations. 
Section 3.1.1.2 Inclusion of Patients Symptomatic up to 96 Hours 
(new section-previous section replaced) 
New text: 
In immunocompromised patients, time from onset of symptoms to seeking medical 
attention (presentation at the clinic) of > 48 hours has been shown in several case 
reports [37, 31, 32, 33] including two instances of nosocomial outbreaks in children 
[29, 24].  This notwithstanding, oseltamivir has been shown to be effective in 
immunocompromised populations that included patients treated with oseltamivir 
beyond 48 hours of presentation; patients with lung transplant (median time to 
presentation 3 days) [31], bone marrow transplant (treatment started more than 
48 hours after onset of symptoms in all three patients) [29], organ transplant (62 out 
of 221 patients started treatment after  96 hours) [30] and children with ALL (one 
child presented after 3 days and two children after 5 days of symptoms) [25]. 
In a prospective, observational study involving adults hospitalized with influenza, 
the study authors concluded that ‘Weakened host defenses slow viral clearance, 
whereas antivirals started within the first four days of illness enhance viral 
clearance’ [38].  
Additionally, in November 2009, in a communication for clinicians on antiviral 
treatments for H1N1, the US Centers for Disease Control and Prevention (CDC) 
stated that while antiviral treatment is most effective when started early; both 
outpatients with risk factors and hospitalized patients still benefit when treatment 
with oseltamivir is started more than 48 hours after illness onset [39]. 
Old text: 
Replaced Section 3.1.1.2 Consistency with Previous Influenza Treatment Studies 
In order to be able to compare the study findings with the response to placebo in healthy 
adults, this study has been intentionally designed to be consistent with previous 
registration trials for treatment of influenza in healthy adults. Some of the key design 
features consistent with previous studies include: two active treatment arms, subjects with 
influenza like symptoms recruited during the flu season, use of a patient diary to capture 
symptoms, primary clinical end point based on diary assessments, laboratory evaluation 
of virology and serology samples generally similar to previous trials and the primary 
efficacy analysis population is the Intent to treat Infected (ITTI) population. 
Despite the above considerations, there are issues that can preclude the estimation of the 
response to placebo in an immunocompromised population comprising adults and 
children from that in healthy adults with influenza. To further mitigate this, the choice of 
endpoints and their interpretation is vital. 
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Section 3.1.1.3 Interpretation of Study Results 
New text: 
Safety and tolerability and the development of resistance are the primary objectives 
of this study.  These will be characterized descriptively.  For the secondary objective 
of efficacy, the subset of the population enrolled in the first 48 hours will be 
compared with placebo patients from pivotal registration trials (where patients were 
enrolled in the first two days of illness).  Sections 8.2.5, 8.2.6, and 8.2.7 provide 
details on the statistical considerations and their rationale associated with these 
comparisons. 
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials.  However, in order to evaluate a dose response relationship between the two active 
treatment arms in this trial, stratification remains essential.  
Patients will be stratified by transplant status (yes, no) because transplant patients 
form a relatively large homogenous group in this study and might influence 
outcome.  
Patients will be stratified by time between onset of symptoms and treatment start (< 48 
hours or ≥ 48 hours) because previous experience in otherwise healthy adults and 
children has shown that patients treated early in their illness respond to treatment better 
than those who are treated later. Patients will also be stratified by age (≤ 12 years and 
> 12 years) because otherwise healthy children shed virus longer than otherwise healthy 
adults.  It is expected that a similar difference in the duration of viral shedding would 
exist between immunocompromised children and adults.  As vaccinated subjects may 
respond faster to therapy, the study is also stratified based on influenza vaccination status 
for the current influenza season (Yes; No). 
Old text: 
Choice of primary end point and comparators 
The current study includes both children and adults. This is because of the significant 
unmet need in both these age groups. The primary end point therefore had to be 
applicable to both age groups. In registration trials in adults, the primary end point was 
the time to resolution of all clinical symptoms (in the diary card). In registration trials in 
children, the primary end point was the reduction in the median duration of illness 
(defined based on temperature, cough, coryza and return to pre-illness health and 
activity). A key secondary end point in children – time to resolution of all clinical 
symptoms showed similar results. The primary endpoint in this study is the time to 
resolution (alleviation) of all symptoms. 
The median of the primary end point in the active treatment groups (conventional and 
high dose) in this trial will be compared with the median of the time to resolution of 
symptoms in the placebo group from the pivotal registration trials. The high dose arm 
enables the detection of a possible dose response relationship in this immune 
compromised population. As a means to evaluate that possibility, an assessment of the 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 18 


relative efficacy of the two dose groups will be made in terms of median time to 
alleviation of symptoms. Section 8.2.5 provides details on the statistical considerations 
and their rationale associated with these comparisons. 
Effect of study design on efficacy end points 
The main limitations of using the response to placebo from previous trials to estimate the 
response in this trial are due to the different populations (healthy versus 
immunocompromised), age groups (adults versus adults and children) and the potential 
difference in virulence of different strains. The potential difference in virulence of the 
predominant influenza viruses may be a confounder whose contribution can not be 
estimated. However the difference in populations and age groups is likely to result in the 
placebo response from pivotal registration trials underestimating the time to alleviation in 
the immunocompromised population. This is because the time to alleviation of symptoms 
is shorter in the healthy population compared to the immunocompromised population. 
[13] The placebo response in the pivotal trials will therefore underestimate the response 
in the current trial. The Sponsor is thus using a very conservative approach in comparing 
the active treatment arms in this study with the response to placebo in healthy subjects. If 
one/both of the treatment arms is statistically better than placebo, it is considered that this 
is a meaningful effect for this population.  If both treatment arms are not different from 
placebo and this is seen consistently across several end points, it may be hypothesized 
that the risk from influenza for the immunocompromised population treated with 
oseltamivir is comparable to that for a healthy untreated adult with influenza.   
Possible dosing recommendations based on current study 
Healthy subjects who were given placebo in the previous pivotal oseltamivir treatment 
studies will be used as the control arm for this study.  When the two active treatment 
arms are compared with this placebo control, several outcomes are possible. These 
outcomes will need to be discussed with health authorities.  Some outcomes and possible 
interpretations of the results are presented below:   
1. Conventional and high dose are both shown to be better than placebo: Both treatment 
arms will be compared.  If no difference then the conventional dose would be the 
dose recommended for treatment in this population.  If a difference is seen between 
treatment arms, then an evaluation (including benefit/risk assessment) will be made to 
confirm whether the higher dose should be the recommended dose. 
2. One active treatment arm is superior to placebo while the other is not: In this instance 
the dose that is shown to be superior will be recommended unless other 
considerations such as safety dictate otherwise.  
3. Both conventional and high dose arms are not different from placebo: If this is seen 
consistently across several secondary clinical end points, it may be hypothesized that 
oseltamivir has reduced the risk in the immunocompromised population to the more 
acceptable level in the untreated healthy adult population. 
4. It is also possible that both conventional and high dose treatment have a more 
protracted clinical course than the placebo arm. In this situation, it may be difficult to 
make conclusions about efficacy.  
 
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Irrespective of the efficacy outcomes, the study will still provide useful information of 
the safety of oseltamivir in this population.  
Possible recommendations for duration of treatment based on the current study 
Once a dose is chosen a determination will need to be made on whether the 
recommended duration of treatment should be 5 or 10 days or longer. This decision will 
be based both on the clinical and virologic course of influenza.   
The recommended duration of treatment for influenza in healthy adults is five days. In 
this study, the duration of dosing is ten days because viral shedding is typically longer in 
the immunocompromised population than in healthy adults. The general standard of care 
for this population has been to treat for as long as the patient continues to shed virus 
(even after the resolution of symptoms) [7] [9]. The duration of treatment for this 
population is therefore individualized based on clinical response and duration of viral 
shedding. It can often be more than 10 days. While it is possible that 10 or more days of 
treatment may be needed [7] [9], it is also possible that 5 days of treatment may still be 
adequate. Therefore, in this study the clinical and virologic course (proportion shedding 
virus at day 6 and later) will be evaluated to make recommendations on the duration of 
dosing. No statistical comparisons will be made.     
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials. However, in order to evaluate a dose response relationship between the two active 
treatment arms in this trial, stratification remains essential.  
Because HSCT recipients are at the greatest risk of morbidity and mortality from 
influenza, patients will be stratified by transplant type (SOT versus HSCT). Patients will 
be stratified by time between onset of symptoms and treatment start (< 24 hours or ≥ 24 
hours) because previous experience in otherwise healthy adults and children has shown 
that patients treated early in their illness respond to treatment better than those who are 
treated later. Patients will also be stratified by age ( ≤ 12 years and > 12 years) because 
otherwise healthy children shed virus longer than otherwise healthy adults. It is expected 
that a similar difference in the duration of viral shedding would exist between 
immunocompromised children and adults. As vaccinated subjects may respond faster to 
therapy, the study is also stratified based on influenza vaccination status for the current 
flu season (Yes; No). 
Section 3.1.2 Rationale for Dose Selection and Adjustment 
New text: 
Dose Adjustments 
In this study, patients whose CrCl decreases to < 60mL/min/1.73M2 will be 
discontinued from treatment. 
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Old text: 
Dose Adjustments 
In this study, dose adjustment for subjects with an estimated Cr Cl between 10 to 30 
mL/min/1.73M2 will comprise decreasing the frequency of administration to once daily. 
This is based on current label recommendations for adults with renal impairment 
(Table 1). 
Table 1 
Recommended doses in healthy adults for treatment of influenza  
Creatinine Clearance 
Recommended dose for treatment 
> 30 (ml/min) 
75 mg twice daily 
> 10 to ≤ 30 (ml/min) 
75 mg once daily or 30 mg suspension twice 
daily 
≤10 (ml/min)   
Not recommended 
dialysis patients 
Not recommended 
 
The dose adjustment recommendations are considered suitable approaches for children 
with renal impairment. This is based on the reasonable assumption that a similar 
relationship exists in both children and adults, between changes in creatinine clearance 
and resultant changes in exposure of oseltamivir and oseltamivir carboxylate. Doses will 
be adjusted for renal impairment in this protocol per the schema below. More detailed 
information on dosing, dose adjustments and maintenance of the blind are provided in 
later sections 6.1, 6.2, 6.3. 
Table 2 
Recommended dose modifications for NV 20234 trial subjects 
Randomized Dose 
Arm 
Unit dose 
(mg) 
Creatinine Clearance 
(ml/min OR ml/min/M2) 
Dose frequency 
> 30 
Twice daily 
30 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
45 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
60 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
 
 
 
Conventional 
 
75 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
60 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
90 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
120 
> 10 to ≤ 30 
Once daily 
> 30 
Twice daily 
 
 
 
High 
150 
> 10 to ≤ 30 
Once daily 
 
In general, no dose adjustment is considered necessary in subjects with mild-moderate 
hepatic impairment (based on pharmacokinetic findings in adults with chronic hepatic 
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impairment) receiving usual therapeutic doses of oseltamivir. [16] However, as the 
relevance of these findings to the specific patient population in this study is unclear, 
subjects with overt (based on physical signs and symptoms) hepatic impairment at 
baseline will be excluded from this study as mentioned in section 4.3. 
Section 3.2 Number of Subjects/ Assignment to Treatment Groups    
New text: 
A minimum of 166 patients (approximately 83 per arm) to allow an adequate number 
of influenza A patients, including 50 transplant recipients will be enrolled in this 
study. 
Old text: 
A minimum of 250 patients will be enrolled in this study (approximately 125 per arm). 
Section  3.3 Centers  
New text: 
This will be a multicenter study with approximately 100-110 centers in the Northern 
hemisphere. 
Old text: 
This will be a multicenter study with approximately 140 centers in the Northern 
hemisphere.  Centers will be activated to recruit patients during the influenza season. The 
centers to be included in the study are those which perform or manage SOTs, HSCTs or 
both. 
Section 4.1 Overview 
New text: 
Principal investigators will review oseltamivir resistance patterns of strains 
circulating in the area and weigh the risk versus the benefit before enrolling patients 
with a potentially resistant strain. 
Old text: 
None.  Text added. 
Section 4.2 Inclusion Criteria   
New text: 
• Age greater than or equal to 1 year 
• Rapid diagnostic test, PCR, or viral culture positive for influenza in the 96 hours 
prior to first dose 
• Immunocompromised subject defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in  Appendix 6)  OR 
o Secondary immunodeficiency 
 SOT with ongoing immunosuppression OR 
 Allogenic HSCT with ongoing immunosuppression OR 
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 HIV with CD4 count < 200/mm3 OR 
 Hematologic malignancies (representative examples in 
Appendix 7) OR 
 Systemic (eg. enteric, sc, im or iv) immunosuppressive therapy, 
irrespective of medical indication, started at least 12 weeks 
prior to, and ongoing at the time of first dose of study drug 
(representative examples in Appendix 8) 
• Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza 
• In patients with history or clinical presentation at randomization suggestive of 
renal failure; a CrCl > 60ml/min/1.73M2 
• Less than or equal to 96 hours between onset of influenza like illness and first dose of 
study drug 
• Parent/guardian willing and able to comply with study requirements and give consent, 
(country specific age cut off) 
• Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• For adult patients, willing and able to comprehend and give written informed consent  
• Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for females for one reproductive cycle 
following cessation of study therapy 
• Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study medication 
 
Old text: 
• Age greater than or equal to 1 year 
• Rapid diagnostic test positive for influenza in the 24 hours prior to first dose 
• Immunocompromised subject defined as documented: 
o SOT (liver, kidney or both) recipient OR 
o Allogenic HSCT  
• Receiving ongoing immunosuppression, OR, in the investigator’s opinion, not 
immune reconstituted 
• Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza  
• Less than or equal to 48 hours between onset of influenza like illness and first dose of 
study drug  
• Acceptable renal function defined as: 
o Most recent creatinine clearance in the 6 months prior to randomization is 
> 30 ml/min in adults and > 30 ml/min /1.73M2  in children. Creatinine 
clearance estimated from serum creatinine (Appendix 1) measured when 
subject is not receiving any renal replacement therapy OR 
o For patients who have not had a creatinine clearance assessment in the 6 
months prior to randomization, baseline creatinine clearance > 10 ml/min 
in adults and > 10 ml/min /1.73M2  in children (Appendix 1) OR 
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o For patients whose most recent creatinine clearance in the 6 months prior 
to randomization is < 30 ml/min in adults and < 30 ml/min /1.73M2  in 
children, baseline creatinine clearance > 10 ml/min in adults and 
> 10 ml/min /1.73M2  in children (Appendix 1) 
• Parent/guardian willing and able to comply with study requirements and give consent. 
(country specific age cut off)  
• Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• For adult patients, willing and able to comprehend and give written informed consent 
• Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for one reproductive cycle following 
cessation of study therapy   
o Females of childbearing potential must have a negative urine pregnancy 
test prior to start of study medication 
 
Section 4.3 Exclusion Criteria   
New text: 
• SOT within 6 months of the time of randomization 
• Have in the investigator’s opinion experienced acute rejection in the 4 weeks prior to 
randomization 
• HSCT patients with no evidence of engraftment (engraftment is defined as the point 
at which a patient can maintain a sustained absolute neutrophil count (ANC) of 
>500/mm3 and sustained platelet count of  ≥  20,000/mm3, lasting  ≥ 3 consecutive 
days without transfusions) 
• HSCT subjects not discharged from hospital after their initial hospitalization for 
transplantation 
• Have clinical evidence for hepatic decompensation at the time of randomization 
(clinical icterus, ascites, hepatic encephalopathy, coagulopathy) 
• Have cirrhosis of the liver at the time of randomization 
• Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration 
• Have evidence of active or uncontrolled opportunistic infections (bacterial, fungal, or 
viral-including cytomegalovirus [CMV] or polyoma virus [BKV]) at the time of 
randomization.  Patients with HCV or HBV are not excluded 
• Patients with co-morbid conditions which are uncontrolled.  Uncontrolled is defined 
as disease requiring change of therapy or hospitalization in the 4 weeks preceding 
randomization.  Change of therapy is defined as dose increase or change of 
medication prior to onset of present influenza like illness 
• Patients with gastrointestinal disorders which might interfere with their ability to 
absorb oral medication  
• Allergy to the test medication 
• Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation) 
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• Influenza vaccination with live attenuated vaccine in the 2 weeks prior to 
randomization 
• Antiviral treatment (example: amantadine, rimantadine, oseltamivir, laninamivir, 
peramivir, zanamivir and ribavirin) for influenza in the 2 weeks prior to 
randomization 
 
Old text: 
• SOT within 6 months of the time of randomization  
• Solid Organ Transplant other than liver, kidney or liver and kidney 
• Have in the investigator’s opinion experienced acute rejection in the 4 weeks prior to 
randomization 
• HSCT patients with no evidence of engraftment (engraftment is defined as the point 
at which a patient can maintain a sustained absolute neutrophil count (ANC) of 
>500/mm3 and sustained platelet count of ≥ 20,000/mm3, lasting ≥ 3 consecutive days 
without transfusions)  
• HSCT subjects not discharged from hospital after their initial hospitalization for 
transplantation 
• Have evidence of veno-occlusive disease, acute or chronic extensive graft versus host 
disease at the time of randomization 
• Have clinical evidence for hepatic decompensation at the time of randomization 
(clinical icterus, ascites, hepatic encephalopathy, coagulopathy) 
• Have cirrhosis of the liver at the time of randomization 
• Currently or in the six months prior to randomization using T cell depleting 
antibodies (example: antithymocyte globulin, antilymphocyte globulin) for 
management of transplant  
• Have other co-morbid conditions that could affect patient survival or graft function 
including, but not limited to, a post-transplant lymphoproliferative disease (PTLD), 
autoimmune disease including inflammatory bowel disease and psoriasis, untreated 
thyroid disease, and significant active infection 
• Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration 
• Have evidence of active or uncontrolled opportunistic infections (bacterial, fungal, or 
viral - including cytomegalovirus [CMV] or polyoma virus [BKV]) at the time of 
randomization. Patients with HCV or HBV are not excluded. 
• Patients with known HIV infection 
• Patients who are being evaluated or treated for an active malignancy (other than the 
malignancy for which the SOT or HSCT may have been performed) at the time of 
randomization  
• Patients with uncontrolled vascular, neurologic or pulmonary disease. Uncontrolled is 
defined as disease requiring change of therapy or hospitalization in the 4 weeks 
preceding randomization. Change of therapy is defined as dose increase or change of 
medication prior to onset of present influenza like illness 
• Patients with severe diarrhea or other gastrointestinal disorders which might interfere 
with their ability to absorb oral medication, including diabetic patients with 
previously diagnosed diabetic gastroenteropathy 
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• Allergy to the test medication 
• Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation) 
• Influenza vaccination in the 2 weeks prior to randomization 
• Antiviral treatment (example: amantadine, rimantadine, zanamivir and ribavirin) for 
influenza in the 2 weeks prior to randomization 
 
Section 4.4 Concomitant Medication and Treatment 
New text: 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, laninamivir, peramivir, and additional oseltamivir above that 
specified for this study) are not allowed during the 10-day treatment phase of the study. 
Concomitant use of an investigational drug during the study is also excluded. Live 
attenuated vaccines may not be advisable for this population.  It is possible that 
concurrent use with oseltamivir may render live vaccines ineffective.  
Medications required for the routine care of the patient may be continued during the 
study.  Concomitant use of probenecid (irrespective of the indication) is not allowed 
during the study. 
Old text: 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, and additional oseltamivir above that specified for this study) are not 
allowed during the 10-day treatment phase of the study. 
Concomitant use of an investigational drug during the study is also excluded. Influenza 
vaccination after randomization is not allowed. Live attenuated vaccines may not be 
advisable for this population. It is possible that concurrent use with oseltamivir may 
render live vaccines ineffective.  
Medications required for the routine care of the patient including those required for 
management of the transplant (excluding lymphocyte depleting antibodies, intravenous 
immunoglobulins) may be continued during the study. Concomitant use of probenecid 
(irrespective of the indication) is not allowed during the study. 
Section 4.5 Criteria for Premature Withdrawal 
New text: 
The investigator must discontinue treatment if the creatinine clearance is < 60 ml/min in 
adults or < 60 ml/min/1.73 M2 in children. 
Old text: 
The investigator must discontinue treatment if the creatinine clearance is < 10 ml/min in 
adults or < 10 ml/min/1.73 M2 in children. 
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New text: 
The investigator must discontinue treatment with study drug if the patient is to be treated 
concomitantly with another antiviral for influenza, for example, amantadine, rimantadine, 
laninamivir, peramivir, or zanamavir.   
Old text: 
The investigator must discontinue treatment with study drug if the patient is to be treated 
concomitantly with another antiviral for influenza, for example, amantadine, rimantadine, 
or zanamavir.   
Section 4.6.1 For Subjects    
New text: 
No subject prematurely discontinued from the study for any reason will be replaced. 
Old text: 
In order to maintain the required number of patients who are evaluable for efficacy, 
patients who are identified as being infected with influenza A H1N1 H274Y at baseline 
will be replaced by enrolling additional patients on a rolling basis.  Replacement patients 
will be stratified and randomized to treatment in the same manner as original patients.  
Replacement patients will not be “selected” by dose group or strata (age, vaccination 
status, transplant type, time between symptom onset and treatment) to match the patients 
whom they replace. 
Section 5 Table 3 Schedule of Assessments  
New text: 
None.  Row deleted. 
Old text: 
Serology for influenza antibody 
titer  
x 
 
 
 
 
 
 
x 
 
Section 5 Table 3 Schedule of Assessments footnotes b and c 
New text: 
b. Hematology (CBC with differential) and chemistry (AST, ALT, total bilirubin, urea, 
Cr). Serum creatinine testing may be done at a local laboratory when clinically 
indicated to calculate creatinine clearance. 
c. Baseline swab samples will be assessed for the presence of resistance mutations. 
 
Old text: 
b. Hematology (CBC with differential) and chemistry (AST, ALT, total bilirubin, urea, 
Cr). Serum creatinine testing may be done at a local laboratory at any time to calculate 
creatinine clearance and make dose adjustments.  Patient may receive his/her first dose 
prior to Cr Cl results being available, provided certain renal function criteria are met -  
see [4.2] [5.3]. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 27 


c. Baseline swab samples will be assessed for the presence of influenza A H1N1 with 
H274Y mutation. 
 
Section 5.1 Screening Examination and Eligibility Screening Form  
New text: 
None. Text deleted. 
Old text: 
Trial sites will be activated during the influenza season.  
New text: 
However, if necessary, screening may take place the day before the baseline visit, as long 
as the patient is randomized and receives his/her first dose of study medication within 
96 hours of influenza symptom onset. 
Old text: 
However, if necessary, screening may take place the day before the baseline visit, as long 
as the patient is randomized and receives his/her first dose of study medication within 48 
hours of influenza symptom onset. 
Section 5.2 Procedures for Enrollment of Eligible Subjects  
New text: 
Randomization will be stratified by transplant status (Yes; No); time between onset of 
symptoms and treatment start (≤ 48 hrs or > 48 hrs), influenza vaccination status (Yes; 
No) and patient’s age (≤ 12 years or > 12 years). 
Old text: 
Randomization will be stratified by transplant type (SOT or HSCT); time between onset 
of symptoms and treatment start (≤ 24 hrs or > 24 hrs), influenza vaccination status (Yes; 
No) and patient’s age (≤ 12 years or > 12 years). 
Section 5.3 Clinical Assessments and Procedures   
New text: (text deleted) 
At all visits subjects will receive the routine care for their primary illness. Routine patient 
care (including the adjustment of doses of any of the immunosuppressive drugs) will be 
dictated by tests performed locally at the trial site. 
Old text: 
At all visits subjects will receive the routine care for their primary illness (transplant). 
Routine patient care (including the adjustment of doses of any of the immunosuppressive 
drugs) will be dictated by tests performed locally at the trial site. Dose adjustments of 
oseltamivir will be based on serum creatinine done at the local laboratory. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 28 


Study Day 1 
New text: 
Baseline nasal and throat swab samples will be assessed for the presence of oseltamivir-
resistance mutations.   
Old text: 
Baseline nasal and throat swab samples will be assessed for the presence of oseltamivir-
resistant influenza A H1N1 with H274Y mutation.  As soon as they are available, results 
will be reported to the sites to assist in patient management. 
New text: 
None.  Text deleted. 
Old text: 
The study will utilize a central safety laboratory. However, to determine the correct dose, 
a local serum creatinine will be drawn at baseline in all subjects and used to calculate 
creatinine clearance to determine if a dose adjustment is necessary. No dose adjustments 
are required for subjects whose creatinine clearance is > 30 ml/min in adults 
(> 30 ml/min/1.73 M2  in children). Oseltamivir dosing frequency for patients whose 
creatinine clearance is between 10 to 30 ml/min in adults (10 to 30 ml/min/1.73 M2  in 
children) will be adjusted to once daily.  
For patients who meet the following criteria in section 4.2, dosing will commence only 
after the baseline creatinine clearance are available and if baseline creatinine clearance 
> 10 ml/min in adults and > 10 ml/min/1.73M2 in children.  The dose will be adjusted to 
once daily if the baseline Cr Cl is between 10 to 30 ml/min in adults (10 to 
30 ml/min/1.73 M2 in children). 
• most recent creatinine clearance in the 6 months prior is < 30 ml/min in adults and 
< 30 ml/min/1.73M2 in children).  
• patients who have not had a creatinine clearance assessment in the 6 months prior to 
randomization. 
 
For patients who meet the following criteria in section 4.2, dosing may commence prior 
to availability of baseline Cr Cl. Subjects will receive twice daily doses and dosing will 
be adjusted to once daily if the baseline Cr Cl is between 10 to 30 ml/min in adults (10 to 
30 ml/min/1.73 M2 in children).  
• most  recent creatinine clearance in the 6 months prior is > 30 ml/min in adults and 
> 30 ml/min /1.73M2 in children) 
 
New text: 
None.  Text deleted. 
Old text: 
Dosage adjustment will be performed based on creatinine clearance as described in the 
Dose Modification section 6.1.1. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 29 


New text: (text deleted) 
End of Follow-Up Day 40  
All subjects must attend an end of follow-up visit on day 40. 
Old text: 
End of Follow-Up Day 40  
All subjects must attend an end of follow-up visit on day 40. This visit is important as it  
is the only post-baseline visit where a serology sample for influenza antibody titers is 
collected. 
Section 5.3.1 Efficacy Assessments 
New text: 
The primary efficacy end point in this study is the time to resolution of all influenza 
symptoms as recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness.  These are captured in the diary for both adults 
and children. (Appendix 2) (Appendix 3) Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem).  A score 
of zero is considered asymptomatic.  The primary efficacy end point, time to 
alleviation of all symptoms is comprised of all the symptoms captured in the diary.  
2. Temperature.  This is captured in the diary.  Temperature is used for assessment of 
the primary and several secondary efficacy end points. 
 
Old text: 
The primary end point in this study is the time to resolution of all influenza symptoms as 
recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness. These are captured in the diary for both adults 
and children. (Appendix 2) (Appendix 3) Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem). A score 
of zero is considered asymptomatic. The primary end point, time to alleviation of all 
symptoms is comprised of all the symptoms captured in the diary.  
2. Temperature. This is captured in the diary. Temperature is used for assessment of the 
primary and several secondary end points. 
 
Section 5.4 Laboratory Assessments  
Efficacy 
New text: 
Baseline samples will be assessed for the presence of oseltamivir-resistance mutations.   
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 30 


Old text: 
Baseline samples will be assessed for the presence of oseltamivir-resistant influenza A 
H1N1 with the H274Y resistance mutation using a real-time PCR assay.   
New text: 
None.  Text deleted. 
Old text: 
Serology.  Blood samples for influenza antibody titer will be collected according to the 
Schedule of Assessments. 
Section 5.4 Laboratory Assessments 
Safety 
New text: 
None.  Text deleted. 
Old text: 
However, in order to assist in patient management, the results of the assay to detect 
influenza A H1N1 H274Y at baseline will be reported to the sites as soon as they are 
available.   
New text: 
The Principal Investigator may draw blood for serum creatinine to be assessed at the local 
laboratory when clinically indicated during the study to calculate creatinine clearance. 
Old text: 
The Principal Investigator may draw blood for serum creatinine to be assessed at the local 
laboratory at any time during the study. The Principal Investigator may use the creatinine 
levels to calculate creatinine clearance and adjust dose of study drug if required. 
Section 6.1.1 Dose Modifications 
New text: 
No dose modifications will be allowed on study. 
Old text: 
No dose adjustments/modifications are required for subjects whose creatinine clearance is 
> 30 ml/min in adults (> 30 ml/min/1.73 M2  in children). 
In both treatment arms, the dosing frequency will be decreased to once daily in patients 
with severe renal impairment (Cr Cl in adults between 10 – 30 ml/min and children 
between 10 – 30 ml/min/1.73M2). For example, the 75 mg bid frequency will be 
decreased to 75 mg once daily.  
At any time during the study if the investigator feels that renal function is compromised, 
dosing may be decreased to once daily or withheld until such time creatinine clearance 
results are available. Dosing may then be resumed as appropriate based on the creatinine 
clearance. However, it is vital that dosing not be inappropriately withheld for extended 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 31 


periods of time especially in the first 3 days of treatment when viral titers may be high. It 
is also important that dose modifications are clearly and accurately recorded for 
assessment of pharmacokinetic results.  
For adolescents and children, the creatinine clearance will be estimated using a Schwarz 
equation: (Appendix 1). 
For adults the method of Cockcroft-Gault will be used to estimate creatinine clearance. 
(Appendix 1). 
Section 6.3 Blinding and Unblinding 
New text: 
The randomization will be stratified by transplant status, duration of symptoms, 
influenza vaccination status and age and will be provided by the Roche randomization 
group for the IVRS vendor. 
Old text: 
The randomization will be stratified by transplant type, duration of symptoms, influenza 
vaccination status and age and will be provided by the Roche randomization group for the 
IVRS vendor. 
Section 7.2.2 Pregnancy 
New text: 
A female subject must be instructed to stop taking the test “drug” and immediately 
inform the investigator if she becomes pregnant during the study. The investigator should 
report all pregnancies within 24 hours to the sponsor or designee. The investigator should 
counsel the subject, and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion 
of the pregnancy.  Pregnancies occurring within 28 days of treatment completion 
should be reported to Roche. 
Old text: 
A female subject must be instructed to stop taking the test “drug” and immediately 
inform the investigator if she becomes pregnant during the study. The investigator should 
report all pregnancies within 24 hours to the sponsor or designee. The investigator should 
counsel the subject, and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion 
of the pregnancy.   
Pregnancy occurring in the partner of a male subject participating in the study should be 
reported to the investigator and the sponsor or designee after the pregnant partner’s 
consent has been obtained. The partner should be counseled and followed as described 
above if acceptable, and provides informed consent. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 32 


Section 8 Statistical Considerations and Analytical Plan  
New text: 
Full details of all planned analyses will be specified in a separate Statistical Analysis 
Plan (SAP) for the safety and efficacy variables and in the Resistance Plan for the 
development of resistance.   
Old text: 
Full details of all planned analyses will be specified in a separate Data Reporting and 
Analysis Manual (DRAM).  
Section 8.1.1 Primary Endpoints 
New text: 
The primary endpoints for safety will be assessments of adverse events, physical 
exams, vital signs and clinical laboratory evaluations.  The primary endpoint of 
development of resistance will be determined from the genotypic and phenotypic 
variables measured post baseline and is described further in the Resistance Plan. 
Old text: 
The primary endpoint in this study is the time to alleviation of all clinical influenza 
symptoms (recorded in the patient diary). 
Section 8.1.2 Secondary Endpoints  
New text: 
The following are secondary endpoints which measure efficacy, the primary of which 
is time to alleviation of all clinical symptoms.  With the exception of this variable, 
viral load and time to resolution of fever, they are defined as either the occurrence or 
non-occurrence of the specified events or the presence or absence of the specified 
symptoms. 
The time (hours) to alleviation of all clinical influenza symptoms (recorded in 
the patient diary) 
Old text: 
The following are secondary endpoints. With the exceptions of viral load and time to 
resolution of fever, they are defined as either the occurrence or non-occurrence of the 
specified events or the presence or absence of the specified symptoms. 
New text: 
None.  Text deleted. 
Old text: 
Baseline, post-baseline and change from baseline in antibody titers. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 33 


Section 8.1.3 Safety  
New text: 
Safety of the treatment will be evaluated by AEs, physical exams, clinical laboratory 
tests, and vital signs. 
Old text: 
Safety of the treatment will be evaluated by AEs, laboratory tests, and vital signs.  
All subjects who received at least one dose of treatment and had a safety assessment 
performed post randomization will be included in the safety evaluation. 
Section 8.2.1.1 (Title changed)  
New text:  Time to Event Variables 
Old text:  Primary Variables 
Section 8.2.1.2 (Title changed)   
New text:  Dichotomous Variables and Viral Load 
Old text:  Secondary Variables 
New text: 
For the endpoints defined dichotomously in terms of events or symptoms including the 
development of resistance, it will be assumed that the number of patients experiencing 
the event or exhibiting the symptom will have a binomial distribution. 
Old text: 
For the secondary endpoints defined dichotomously in terms of events or symptoms, it 
will be assumed that the number of patients experiencing the event or exhibiting the 
symptom will have a binomial distribution. 
For the continuous endpoint of time to resolution of fever, the same assumptions as for 
the primary endpoint will be made. 
Section 8.2.2 Sample Size  
New text: 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 
90% of enrolled patients will have laboratory-confirmed influenza, there will be 75 
patients in each treatment arm in the population evaluable for the development of 
resistance.  The following table shows the 95% Pearson-Clopper confidence 
intervals that would result with a sample size of 75 patients in a treatment arm if 
certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of 
development resistance will be monitored in a blinded fashion, in order to ensure a 
reasonable precision for the estimation.  An additional number of patients may be 
enrolled if necessary. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 34 


Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the 
assessment of safety.  This number of patients would provide estimates of adverse 
event rates with similar precision. 
Old text: 
Sample size calculations were performed using a two-sided t-test and are based on the 
comparison with a placebo control response in the pivotal registration trials in healthy 
adults of 112 hours for median time to alleviation of all symptoms. Assuming an 
expected median time to alleviation of symptoms of 78 hours for each of the two active 
treatment groups in this study, and a common standard deviation of 98 hours, then 111 
evaluable subjects per group would give more than 90% power to detect a difference 
between the control and each of the active treatment groups. It is assumed that as many as 
90 % of subjects enrolled into the study who are identified as not being infected with 
influenza A H1N1 H274Y will have influenza, and therefore 124 such subjects per arm 
would be required in order to obtain 111 influenza positive subjects. Note that this is an 
approximate calculation, as the final analysis will be based on the difference in medians 
and the corresponding 95% confidence interval from the Kaplan-Meier curves. This is 
however considered as a sufficient indication for the number of required subjects and the 
power that is expected. The maximum number of subjects enrolled in the trial will 
depend upon the number of subjects identified with the oseltamivir resistant virus who 
will be replaced. 
Section 8.2.4 Analysis Populations 
New text: 
Detailed definitions of these populations will be given in the SAP. 
Old text: 
Detailed definitions of these populations will be given in the DRAM. 
Section 8.2.4.2 Intent to Treat Infected Population 
New text: 
All patients randomized and with laboratory confirmation of influenza infection, 
excluding patients infected with oseltamivir-resistant influenza at baseline, will be 
included in the intent to treat influenza infected population [Patients will be assigned to 
treatment groups as randomized for analysis purposes]. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 35 


The ITTI Population will be the primary population for the summary and analysis of the 
development of resistance and the efficacy variables. 
Old text: 
All patients randomized and with laboratory confirmation of influenza infection (positive 
viral cultures or 4 fold or greater rise in antibody titers), excluding patients infected with 
oseltamivir-resistant influenza A H1N1 H274Y at baseline, will be included in the intent 
to treat influenza infected population [Patients will be assigned to treatment groups as 
randomized for analysis purposes]. 
The ITTI Population will be the primary population for the summary and analysis of the 
primary and secondary efficacy variables. 
Section 8.2.4.3 Subpopulations  
New text: 
A subpopulation of the ITTI population will be defined comprising patients who 
received their first dose of study medication within 48 hours of influenza symptom 
onset for the comparison of efficacy endpoints with the age appropriate placebo 
treated patients (pediatric or adult) from the registration trials. 
Old text: 
None.  Text added. 
Section 8.2.5 Efficacy Analysis 
New text: 
For the analysis of time to alleviation of all clinical symptoms, the following two 
assessments will be made independently of each other and without regard to the 
outcomes in each case. 
• Comparison to placebo control from pivotal registration trials  
 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is 
comparable to the subpopulation of patients in the current study whose first dose 
of study medication was within 48 hours of symptom onset.  For this population, a 
median time to resolution of all clinical influenza symptoms will be determined along 
with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.  These confidence intervals 
will be compared individually to the placebo control confidence interval described 
above as a potential means of establishing treatment effects. 
• Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval.  
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 36 


This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences.  For example, if it does not contain 
the value zero a difference will have been established.   
For the dichotomous endpoints, the proportion experiencing the event or symptom, and 
its associated 95% confidence interval will be derived for each treatment group.  Where 
possible, the corresponding confidence intervals from the placebo control population will 
be presented for comparison to those derived for the active treatment groups in this trial. 
The continuous secondary endpoint time to resolution of fever will be analyzed as for the 
primary efficacy endpoint.  
For the continuous endpoints of viral load (log10TCID50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, standard deviation, median, minimum and 
maximum) will be derived for each treatment group. 
Old text: 
For the primary analysis, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established to match (in 
terms of efficacy evaluations, duration of observation etc.) those of the current study. 
For this population, a median time to resolution of all clinical influenza symptoms 
will be determined along with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.  These confidence intervals 
will be compared individually to the placebo control confidence interval described 
above as a potential means of establishing treatment effects. 
• Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval. The methodology will be based on the use of the Hodges-
Lehmann estimator in the case of censored data.  
This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences. For example, if it does not contain 
the value zero a difference will have been established. However, given the study sample 
size this outcome is only likely if a clinically significant difference (e.g. 30% ) exists. 
Although this is not anticipated from the experience in pivotal registration trials in 
normal healthy patients, it cannot be ruled out as a possibility in immunocompromised 
transplant recipients.   
For the dichotomous secondary endpoints, the proportion experiencing the event or 
symptom, and its associated 95% confidence interval will be derived for each treatment 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 37 


group. Where possible, the corresponding confidence intervals from the placebo control 
population will be presented for comparison to those derived for the active treatment 
groups in this trial. 
The continuous secondary endpoints time to resolution of fever will be analyzed as for 
the primary endpoint.  
For the continuous endpoints of viral load (log10TCID50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, median, minimum and maximum) will be derived 
for each treatment group. 
Section 8.2.7 Analysis of Resistance (new section added) 
New text: 
For the summary of the development of resistance for each treatment arm, 95% 
confidence intervals will be provided with the estimated rates.  Further details are 
available in the Resistance Plan for NV20234.  These data will be summarized in a 
report separate from the final study report. 
Old text: 
None.  Text added. 
Section 8.2.7.1 Exclusion of Data from Analysis 
New text: 
Efficacy data collected from any patient who begins treatment with another antiviral for 
influenza (for example, amantadine, rimantadine, laninamivir, peramivir, or 
zanamavir), after the other antiviral treatment commences, will be excluded from the 
primary and secondary efficacy analyses.  Such patients will be considered failures to 
oseltamivir treatment in the analyses.  Further details will be provided in the SAP. 
Old text: 
Efficacy data collected from any patient who begins treatment with another antiviral for 
influenza (for example, amantadine, rimantadine, or zanamavir), after the other antiviral 
treatment commences, will be excluded from the primary and secondary efficacy 
analyses.  Such patients will be considered failures to oseltamivir treatment in the 
analyses.  Further details will be provided in the DRAM. 
Section 8.2.8 Other Analyses  
New text: 
Further exploratory analysis, (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the SAP. 
Old text: 
The number and percentage of patients with influenza infection (defined as a positive 
culture from a nasal and/or throat swab or 4 fold or greater rise in antibody titers) will be 
summarized by treatment group for the Intent-to-treat Population. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 38 


Further exploratory analysis, (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the DRAM. 
The last positive viral isolate from each patient will be tested for reduced sensitivity to 
oseltamivir.  Clonal resistance assays will also be used to evaluate the rate of resistance to 
oseltamivir.  These data will be summarized in a report separate from the final study 
report. 
Section 10 References 
New text:  updated version of IB and references 20-40 added 
8. 
Investigator Brochure for Tamiflu® (oseltamivir phosphate) 11th version June 
2010. 
1. 
Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. 
Harrison's Principles of Internal Medicine. 17th ed. The McGraw Hill 
companies, Inc; 2008.  
2. 
CDC http://www.cdc.gov/flu/protect/hiv-flu.htm as assessed on 27 October 
2010. 
3. 
Caselli D , Carraro F, Castagnola E, Ziino O, Frenos S, et al. Morbidity of 
pandemic H1N1 influenza in children with cancer. Pediatr Blood Cancer. 
2010;55:226–28. 
4. 
Tramontana AR , George B, Hurt AC, Doyle JS, Langan K, et al. 
Oseltamivir resistance in adult oncology and hematology patients infected 
with pandemic (H1N1) 2009 virus, Australia. Emerging Infectious Diseases. 
2010;16(7):1068-75. 
5. 
Chironna M, Tafuri S, Santoro N, Prato R, Quarto M, et al. A nosocomial 
outbreak of 2009 pandemic influenza A (H1N1) in a pediatric oncology ward 
in Italy (October-November 2009), Eurosurveillance. 7 Jan 2010;15(1). 
6. 
Launes C, Rives S, Catala A, Berrueco R, Toll T , et al. pandemic influenza A 
(2009 H1N1) in children with acute lymphoblastic leukemia. Br J Haematol. 
Jun 2010;149(6):874-8. 
7. 
Clinical Study Report Protocol NV20235 Research Report No. 
 
8. 
AIDS 2010, DOI:10.1097/QAD.0b013e32833d2096. 
9. 
Akyuz S, Yilmaz A, Bulbul M, Erdogan O, Renda R, et al. Do 
immunosupressive patients really have a severe outcome with H1N1 virus 
infection? Journal of Tropical Pediatrics. 2010. 
10. 
Mellouli F, Ouederni M, Dhouib N, Hajkacem MA, Slim A, et al. Successful 
treatment of influenza A virus by oseltamivir in bone marrow transplant 
recipients. Pediatr Transplantation. 2010;14:178–181. 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 39 


11. 
Kumar D, Michaels MG, Morris MI, Green M, Avery RK, et al on behalf of 
the American Society of Transplant H1N1 Collaborative Study Group. 
Lancet. 2010 Aug;10;pg 521 -6. 
12. 
Fox BD, Raviv Y, Rozengarten D, Rusanov V, Bakal I, et al. Pandemic 
influenza (H1N1): Impact on lung transplant recipients and candidates. J 
Heart Lung Transplant. 2010. 
13. 
Ng BJH, Glanville AR, D’Costa J, Snell G, Musk M, et al. The combined 
Australian experience with human swine influenza H1N1 in lung transplant 
recipients. S141 (abstract). 
14. 
Ison MG, Sharma A, Shepard JO, Wain JC, Ginns LC. Outcome of 
Influenza Infection Managed With Oseltamivir in Lung Transplant 
Recipients. J Heart Lung Transplant 2008;27:282-88. 
15. 
Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: 
January 2010. Wkly Epidemiol Rec 2009b; 85(6): 37-40. 
16. 
Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of 
drug-resistant influenza virus from immunocompromised patients: a case 
series. J Infect Dis 2006; 193(6): 760-764. 
17. 
Hayden FG. Antiviral resistance in influenza viruses: clinical and 
epidemiological aspects. In: Antimicrobial drug resistance: clinical and 
epidemiological aspects, Vol 2 (Infectious Diseases). (Ed. Mayers DL). 
Humana Press, 2009; 1st: 1011-1034. 
18. 
Klein, Marina B., Ying Lu, Lina DelBalso, Stephanie Cote´ and Guy Boivin. 
Influenza virus Infection Is a Primary Cause of Febrile Respiratory Illness in 
HIV Infected Adults, Despite Vaccination. Clinical Infectious Diseases 2007; 
45:234–40. 
19. 
Lee N, Chan PK, Hui DS, Rainer TH, Wong E, Choi KW, Lui GC, Wong BC, 
Wong RY, Lam WY, Chu IM, Lai RW, Cockram CS, Sung JJ. Viral loads 
and duration of viral shedding in adult patients hospitalized with influenza. J 
Infect Dis. 2009 Aug 15;200(4):492-500. 
20. 
Quick Facts for Clinicians on Antiviral Treatments for H1N1 Influenza. 2009 
Nov. From http://www.cdc.gov/H1N1flu/antivirals/facts_clinicians.htm 
accessed on May 14th, 2010. 
21. 
Allen U, Blumberg EA, Fischer SA, Green M, Ison MG, Kotton CN, et al. 
American Society of Transplantation (AST) Infectious Diseases Community 
of Practice / Transplant Infectious Disease Section of The Transplantation 
Society (TTS) Guidance On Novel Influenza A/H1N1. [cited 2010 Oct 28]. 
2009 Dec 03. Available from: www.a-s-t.org/files/pdf/ast_h1n1_guidance.pdf. 
22. 
Katzung BG, Masters SB, Trevor AJ (ed). Basic and clinical pharmacology. 
11th edition. Tata McGraw-Hill Companies, Inc., New York: 2009: 971-80.  
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23. 
Salvana EMT, Salata RA. Infectious complications associated with 
monoclonal antibodies and related small molecules. Clin Microbiol Rev. 2009 
Apr;22(2): 274-90. 
 
Old text:  references 4, 9 and 16 deleted 
4. Ison Michael, G. and G. Hayden Frederick., Viral infections in 
immunocompromised patients: what's new with respiratory viruses? Current 
opinion in infectious diseases, 2002. 15(4): p. 355-67. 
8. Investigator Brochure for Tamiflu® (oseltamivir phosphate) 7th version July 
2006. 
9. Johny, A.A., A. Clark, N. Price, D. Carrington, A. Oakhill, and D.I. Marks, The 
use of zanamivir to treat influenza A and B infection after allogeneic stem cell 
transplantation. Bone marrow transplantation, {Bone Marrow Transplant}, Jan 
2002, vol. 29, no. 2, p. 113 5, ISSN: 0268 3369., 2002. 
16. Snell, P., N. Dave, K. Wilson, L. Rowell, A. Weil, L. Galitz, and R. Robson, Lack 
of effect of moderate hepatic impairment on the pharmacokinetics of oral 
oseltamivir and its metabolite oseltamivir carboxylate. British journal of clinical 
pharmacology,  May 2005, vol. 59, no. 5, p. 598 601. 
 
Section Appendices 6, 7, 8 
New text:   
Appendix 6 Primary Immunodeficiency Conditions 
Category 
Conditions 
Adenosine deaminse (ADA) deficiency 
Artemis deficiency (SCIDA) 
CD45 deficiency 
Cernunnos deficiency 
DNA ligase IV (LIG4) deficiency 
Interleukin receptor γ chain deficiency (X-linked SCID) 
Janus-associated kinase 3 (JAK3) deficiency 
Recombinase activating gene (RAG 1 / 2) deficiency  
Reticular dysgenesis 
Severe Combined 
Immunodeficiency (SCID) 
TAP- 1 or TAP- 2 deficiency (MHC class I deficiency) 
CD8 deficiency 
diGeorge syndrome  
Interleukin 7 receptor α (IL7RA) deficiency 
MHC class II deficiency 
LCK deficiency 
Orai 1 deficiency 
Nude syndrome (wing helix nude deficiency) 
Purine nucleotide phosphorylase (PNP) deficiency 
T cell receptor deficiency (CD 3γ, δ, ε,  and ζ 
deficiencies) 
Primary T cell Deficiency 
Zap 70 tyrosine kinase deficiency 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 41 


X-Linked CD40 ligand deficiency 
X- Linked IKK-γ (NEMO) deficiency 
Predominantly Antibody 
Deficiency 
CD40 deficiency 
Interferon γ receptor deficiency 
Other Well-Defined 
immunodeficiency Syndromes 
X-Linked lymphoproliferative syndrome 
Adapted from Table 310-2: p2056 reference 20. 
 
Appendix 7 Hematologic Malignancies and their Effect on Immune System 
Malignancy 
Effect on immunity 
ALL, lymphomas 
suppression of hematopoiesis, neutropenia, 
lymphocyte dysfunction 
CLL, small lymphocytic lymphoma 
hypogammaglobulinemia, increased susceptibility 
to infections, autoimmune anemia or 
thrombocytopenia 
Hairy cell leukemia, myelodysplastic syndromes 
pancytopenia 
peripheral T cell and NK neoplasms 
lymphocyte dysfunction, increase in immature 
cells 
Hodgkin’s disease  
suppression of cell-mediated immunity 
AML 
neutropenia, anemia, thrombocytopenia, 
predisposed to infections, lymphocyte dysfunction
CML 
anemia, granulocyte dysfunction in some patients 
in early phase and in most patients in blast phase
Adapted from reference 20. 
 
Appendix 8 Immunosuppressive Medications 
Class 
Category 
Drugs 
Corticosteroids 
- 
Glucocorticoids (oral, sc, im, iv) 
Alkylating agents 
cyclophosphamide, busulfan, 
mechlorethamine, chlorambucil, 
melphalan, carmustine, lomustine, 
ifosfamide, procarbazine, dacarbazine, 
temozolomide, cisplatin, carboplatin, 
oxaliplatin 
Anti-metabolites 
methotrexate, 6-mercaptopurine, 
azathioprine 
Anti-tumor antibiotics 
bleomycin, actinomycin D, mitomycin 
C, etoposide, topotecan, irinotecan, 
doxorubicin, daunorubicin, idarubicin, 
epirubicin, mitoxantrone 
Anti-mitotic agents 
vincristine, vinblastine, vinorelbine, 
paclitaxel, docetaxel, estramustine 
phosphate, NAB-paclitaxel 
Cytotoxic agents[20] 
Molecularly targeted 
agents 
imatinib, tretinoin,  bexarotene, 
denileukin,  diftitox, gefitinib, 
erlotinib, dasatinib, sorafenib, 
sunitinib 
Calcineurin inhibitors 
- 
cyclosporine, tacrolimus 
mTOR inhibitors 
(proliferation-signal 
inhibitors) 
- 
sirolimus, everolimus 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 42 


Immunosuppressive 
antibodies 
- 
anti lymphocyte and antithymocyte 
globulins (ALG and ATG) 
Adalimumab 
Infliximab 
Cetrolizumab 
Etarnecept 
Basiliximab 
Inhibitors of  pro 
inflammatory cytokines 
Daclizumab 
Adhesion cell modulators Natalizumab 
Abatacept 
Alefacept 
T-cell inhibitors 
Muromonab 
Rituximab 
90Y-Ibritumomab 
B-cell inhibitors 
131I-Tositumomab 
Anti-CD33 
Gemtuzumab 
Monoclonal antibodies [41, 42] 
Anti- CD52 
Alemtuzumab 
Others 
- 
mycophenolate mofetil, thalidomide 
Compiled from Table 81-2: p521-24 reference 20 and references 41, 42. 
 
Old text: 
None.  Text added. 
10. 
SUBJECT: REPORTING OF SERIOUS ADVERSE EVENT FROM 
SCREENING 
Reason for change:  
To clarify that not only serious adverse events that occur after the first dose of study 
medication but also events that occur between screening and the first dose are to be 
reported.    
Section 7.2.1 Reporting of Serious Adverse Events [immediately 
reportable] 
New text: 
Any clinical AE or abnormal laboratory test value that is serious [as defined in Section 
7.1.1.3 above] and which occurs during the course of the study, regardless of the 
treatment arm, occurring from the enrollment visit (start of study screening 
procedures), must be reported to Roche or designee within one working day of the 
investigator becoming aware of the event [expedited reporting]. 
Old text: 
Any clinical AE or abnormal laboratory test value that is serious and which occurs during 
the course of the study [as defined in section 7.1.1.3 above], regardless of the treatment 
arm, must be reported to Roche or designee within one working day of the investigator 
becoming aware of the event [expedited reporting]. 
 
CONFIDENTIAL  Roche Protocol NV20234C Amendment History (Ro 64-0796)   - Page 43 




 
 
SYNOPSIS OF PROTOCOL NUMBER NV20234C 
TITLE 
A 
double-blind, 
randomized, 
stratified, 
multi-center 
trial 
evaluating  conventional and high dose oseltamivir in the 
treatment of  immunocompromised patients with influenza 
SPONSOR 
F. Hoffmann-La Roche LTD  
CLINICAL 
PHASE  
IIIb 
INDICATION 
Treatment of influenza in immunocompromised patients 
OBJECTIVES  
Primary: 
To evaluate prospectively the safety and tolerability of 
oseltamivir 
for 
the 
treatment 
of 
influenza 
in 
immunocompromised patients and characterize the effects of 
oseltamivir 
in 
immunocompromised 
patients 
on 
the 
development of resistant influenza virus 
 
Secondary: 
To evaluate the effects of conventional and high dose oseltamivir 
in immunocompromised patients on: 
• 
The time to resolution of influenza symptoms 
• 
The clinical course of influenza (fever, symptoms, secondary 
illnesses as evidenced by otitis media, bronchitis, pneumonia, 
or sinusitis)  
• 
The virologic course of influenza (proportion shedding and 
viral loads at different time points) 
 
TRIAL DESIGN 
This is a double-blind, randomized, multi-center trial of twice 
daily, conventional and high dose oseltamivir for the treatment of 
influenza in immunocompromised patients.  Subjects will be 
stratified by age (≤ 12, > 12 years), transplant status (yes, no), 
time since onset of flu symptoms and treatment start (up to 96 
hours) (≤ 48 or > 48 hours) and vaccination status (yes, no) 
NUMBER OF SUBJECTS 
A minimum of 166 (83 per arm) to allow an adequate number 
of influenza A patients per arm; including 50 transplant 
recipients.   
NUMBER OF CENTERS 
Approximately 100 - 110 centers in the Northern hemisphere 
TARGET POPULATION 
Patients immunocompromised due to a primary or secondary 
immunodeficiency, 1 year of age and older.  The subjects will be 
positive for influenza by a rapid diagnostic test, PCR or virus 
culture at baseline. 
LENGTH OF STUDY  
10 days of treatment, 30 days of follow up.   
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 2 


 
 
INVESTIGATIONAL MEDICINAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
Oseltamivir/placebo dry powder (to be reconstituted to a 
concentration of 12 mg/ml) and 75 mg capsules.  The duration of 
dosing in both adults and children is 10 days. 
 
Conventional dose: 
Children ages 1 - 12 years: Oseltamivir syrup 
≤ 15 kg   
 
30 mg twice daily 
> 15 – 23 kg  
 
45 mg twice daily 
> 23 – 40 kg 
 
60 mg twice daily 
> 40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules 
75 mg twice daily 
 
Subjects randomized to the conventional dose will simultaneously 
receive matching placebo so as to blind them and the investigator 
from the high dose arm.  
 
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg   
 
60 mg twice daily 
> 15 – 23 kg  
 
90 mg twice daily 
> 23 – 40 kg 
 
120 mg twice daily 
> 40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Dose adjustments:  In both treatment arms, patients whose CrCl 
decreases to < 60ml/min/1.73M2 will discontinue study 
medication. 
COMPARATOR “DRUG” (or STANDARD 
OF CARE) DOSE/ ROUTE/ REGIMEN 
Placebo (from pivotal registration trials in otherwise healthy 
adults) 
ASSESSMENTS OF: 
 
- 
SAFETY 
Adverse events, physical exams, vital signs, clinical laboratory 
evaluations 
- 
RESISTANCE 
Development of resistance 
- 
EFFICACY 
Time to resolution of all clinical influenza symptoms as 
recorded in the patient diary. 
 
PROCEDURES (summary): 
The key procedures are: 
Blood draws for serum chemistry, hematology, and serology. 
Nasal and throat swabs for viral culture and RT-PCR. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 3 


 
 
STATISTICAL ANALYSES: 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 
90% of enrolled patients will have laboratory-confirmed influenza, there will be 75 
patients in each treatment arm in the population evaluable for the development of 
resistance.  The following table shows the 95% Pearson-Clopper confidence 
intervals that would result with a sample size of 75 patients in a treatment arm if 
certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of 
development of resistance will be monitored in a blinded fashion, in order to ensure 
a reasonable precision for the estimation is maintained.  Additional patients may be 
enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the 
assessment of safety.  This number of patients would provide estimates of adverse 
event rates with similar precision. 
For the primary objective of evaluating the safety of oseltamivir conventional and 
high dose treatments, AEs, laboratory tests, and vital signs will be summarized and 
compared with the known safety profile of the drug.  For the summary of the 
development of resistance for each treatment arm, 95% confidence intervals will be 
provided with the estimated rates.   
For the secondary objective of evaluating the efficacy of oseltamivir as measured by 
the time to resolution of influenza symptoms, the following two assessments will be 
made independently of each other and without regard to the outcomes in each case. 
• Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is 
comparable to patients in the current study.  For this population, a median time 
to resolution of all clinical influenza symptoms will be determined along with its 
95% confidence interval. 
• Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference 
in the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval.  
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 4 


Table of Contents
1. Background and Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      13
1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      13
1.1.1 Influenza in the Immunodeficient Population . . . . . . . . . . . . . . . . . .      13
1.1.2 Oseltamivir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      15
1.2 Rationale for the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      17
2. Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      17
2.1 Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      17
2.2 Secondary Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      18
3. Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      18
3.1 Overview of Study Design and Dosing Regimen . . . . . . . . . . . . . . . . .      18
3.1.1 Rationale for Study Design. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      18
3.1.1.1 Choice of Treatment Arms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      19
3.1.1.2 Inclusion of Patients Symptomatic up to 96 Hours . . . . . . . . . . . . .      19
3.1.1.3 Interpretation of Study Results . . . . . . . . . . . . . . . . . . . . . . . . . . . .      19
3.1.2 Rationale for Dose Selection and Adjustment . . . . . . . . . . . . . . . . . .      20
3.1.3 End of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      21
3.2 Number of Subjects/ Assignment to Treatment Groups . . . . . . . . . . . .      21
3.3 Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      21
4. Study Population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      21
4.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      21
4.2 Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
4.3 Exclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      22
4.4 Concomitant Medication and Treatment . . . . . . . . . . . . . . . . . . . . . . . .      23
4.5 Criteria for Premature Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4.6 Replacement Policy [Ensuring Adequate Numbers of Evaluable
Subjects] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4.6.1 For Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
4.6.2 For Centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      24
5. Schedule of Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . .      25
5.1 Screening Examination and Eligibility Screening Form . . . . . . . . . . . .      26
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 5 


5.2 Procedures for Enrollment of Eligible Subjects . . . . . . . . . . . . . . . . . .      26
5.3 Clinical Assessments and Procedures . . . . . . . . . . . . . . . . . . . . . . . . . .      26
5.3.1 Efficacy Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      28
5.3.2 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      28
5.4 Laboratory Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      28
6. Investigational Medicinal Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      29
6.1 Dose and Schedule of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . .      29
6.1.1 Dose Modifications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      30
6.2 Preparation and Administration of Study Drug . . . . . . . . . . . . . . . . . . .      30
6.3 Blinding and Unblinding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      31
6.4 Assessment of Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      31
6.5 Destruction of Study Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
7. Safety Instructions and Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
7.1 Adverse Events (AEs) and Laboratory Abnormalities . . . . . . . . . . . . .      32
7.1.1 Clinical AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
7.1.1.1 Intensity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      32
7.1.1.2 Drug - Adverse Event Relationship. . . . . . . . . . . . . . . . . . . . . . . . .      33
7.1.1.3 Serious Adverse Events [Immediately Reportable to Roche] . . . . .      33
7.1.2 Treatment and Follow-up of AEs . . . . . . . . . . . . . . . . . . . . . . . . . . . .      33
7.1.3 Laboratory Test Abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      33
7.1.4 Follow-up of Abnormal Laboratory Test Values . . . . . . . . . . . . . . . .      34
7.2 Handling of Safety Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
7.2.1 Reporting of Serious Adverse Events [Immediately Reportable] . . .      34
7.2.2 Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
7.3 Warnings and Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      34
8. Statistical Considerations and Analytical Plan . . . . . . . . . . . . . . . . . . . . . . . .      35
8.1 Primary and Secondary Study Endpoints . . . . . . . . . . . . . . . . . . . . . . .      35
8.1.1 Primary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
8.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      35
8.1.3 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
8.2 Statistical and Analytical Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
8.2.1 Statistical Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
8.2.1.1 Time to Event Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 6 


8.2.1.2 Dichotomous Variables and Viral Load . . . . . . . . . . . . . . . . . . . . .      36
8.2.2 Sample Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      36
8.2.3 Hypothesis Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
8.2.4 Analysis Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
8.2.4.1 Intent to Treat Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
8.2.4.2 Intent to Treat Infected Population . . . . . . . . . . . . . . . . . . . . . . . . .      37
8.2.4.3 Subpopulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      37
8.2.5 Efficacy Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      38
8.2.6 Safety Data Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.7 Analysis of Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.7.1 Exclusion of Data from Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.7.2 Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
8.2.8 Other Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
9. Data Quality Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      39
9.1 Assignment of Preferred Terms and Original Terminology . . . . . . . . .      40
10. References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      41
11. Ethical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      45
11.1 Local Regulations/Declaration of Helsinki . . . . . . . . . . . . . . . . . . . . .      45
11.2 Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      45
11.3 Independent Ethics Committees/Institutional Review Board . . . . . . .      46
12. Conditions for Modifying the Protocol. . . . . . . . . . . . . . . . . . . . . . . . . . . . .      46
13. Conditions for Terminating the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      46
14. Study Documentation, CRFs and Record Keeping . . . . . . . . . . . . . . . . . . .      47
14.1 Investigator's Files / Retention of Documents . . . . . . . . . . . . . . . . . . .      47
14.2 Source Documents and Background Data . . . . . . . . . . . . . . . . . . . . . .      47
14.3 Audits and Inspections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      47
14.4 Case Report Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      48
15. Monitoring the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      48
16. Confidentiality of Trial Documents and Subject Records . . . . . . . . . . . . . .      48
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 7 


17. Publication of Data and Protection of Trade Secrets . . . . . . . . . . . . . . . . . .      48
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 8 


List of Tables
Table 1 Schedule of Assessments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      25
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 9 


List of Appendices
Appendix 1 Calculation of Creatinine Clearance and Grading of Chronic
Extensive GVHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      50
Appendix 2 Adult Patient Diary Data and Symptom Record. . . . . . . . . . . . . . .      52
Appendix 3 Diary Data for Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      53
Appendix 4 Adverse Event [AEs] Categories for Determining Relationship to
Test Drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      54
Appendix 5 ICH Guidelines for Clinical Safety Data Management,
Definitions and Standards for Expedited Reporting, Topic E2 .      56
Appendix 6 Primary Immunodeficiency Conditions . . . . . . . . . . . . . . . . . . . . .      58
Appendix 7 Hematologic Malignancies and their Effect on the Immune
System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      59
Appendix 8 Immunosuppressive Medications . . . . . . . . . . . . . . . . . . . . . . . . . .      60
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 10 


GLOSSARY OF ABBREVIATIONS 
 
AIDS 
Acquired immunodeficiency syndrome 
ALT [SGPT] 
Alanine aminotransferase 
ALL 
Acute lymphocytic leukemia 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
AST [SGOT] 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
b.i.d. 
Bis in die (twice daily) 
BP 
Blood pressure 
CARIFS 
Canadian acute respiratory infections scale 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CML 
Chronic myeloid leukemia 
Cr Cl 
Creatinine clearance 
CRF 
Case report form[s] 
ESF 
Eligibility screening form 
GVHD 
Graft versus host disease 
hrs 
Hours 
HA 
Hemagglutinin 
HIV 
Human immunodeficiency virus 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ITT 
Intent to treat 
ITTI 
Intent to treat influenza infected 
IVRS 
Interactive voice response system 
mg 
Milligram 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 11 


GLOSSARY OF ABBREVIATIONS 
 
mL 
Milliliter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
p.o. 
Per os (by mouth) 
PR 
Pulse rate 
QD 
Once per day 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCID 
Severe combined immunodeficiency 
SOT 
Solid organ transplant 
TCID50 
50% tissue culture infectious dose 
Tmax 
Time of maximum plasma concentration 
t1/2 
Elimination half-life 
µg 
Microgram 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 12 


PART I: 
STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND AND RATIONALE 
1.1 
Background 
Influenza is an acute respiratory infection caused by a virus of the orthomyxovirus family 
which occurs in three forms, influenza A, B and C. Influenza virus types A and B cause 
an acute febrile infection of the respiratory tract characterized by the sudden onset of 
fever, malaise, headaches, myalgias and cough. Influenza causes numerous deaths each 
year [1]. Although difficult to assess, annual influenza epidemics are thought to result in 
between three and five million cases of severe illness, and between 250,000 and 500,000 
deaths every year around the world [2]. 
The influenza viruses are segmented, negative sense, single stranded, lipid encapsulated, 
RNA viruses between 80 and 100 nm in size. Subtypes are defined according to 
glycoproteins present in the viral lipid coat. The haemagglutinin complex (HA) is the 
major surface protein of the virus. The neuraminidase (NA) protein is the second major 
surface protein in the virion and plays a role in enhancing virus penetration of the mucus 
layer around the target cell and in release of virus from the cell surface. The matrix 
proteins, M1 and M2 appear to trigger the disintegration of the M1 complex during virus 
fusion with the cell and may also be involved in the maturation of the HA prior to 
assembly of new virus particles.  
1.1.1 
Influenza in the Immunodeficient Population 
Influenza infection is usually a self limiting condition. However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus 
may cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death [3].   
Conditions that compromise immunity may be classified based on etiology into 
primary (genetic) and secondary (acquired) immunodeficiency.  Of the 
immunodeficient conditions, the ones that affect cell mediated immunity are likely 
to have adverse outcomes following viral infections [20]. 
Primary immunodeficiency  
Primary immunodeficiencies are relatively common, may be either congenital or 
manifest later in life and are classified according to whether the genetic defect 
affects T or B cells or both [20].  There are four groups of disorders: severe 
combined immunodeficiency (SCID), primary T cell deficiency (e.g. CD8 deficiency, 
DiGeorge syndrome), predominantly antibody deficiency (e.g. common variable 
immunodeficiency, 
selective 
IgA 
deficiency) 
and 
other 
well-defined 
immunodeficiency syndromes (e.g. Wiskott Aldrich syndrome) [20].  
Of the primary immunodeficiencies, antibody deficiencies are the most frequent.  
However, some of the more common antibody deficiency conditions (isolated IgA 
deficiency, IgG subclass deficiency and common variable immunodeficiency) have 
intact cell-mediated immunity and therefore the clinical course of viral infections 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 13 


(unless complicated by bacterial infections) does not differ significantly from that in 
the normal host [20].  A list of primary immunodeficiency disorders at risk for viral 
infections is provided in Appendix 6.  The incidence of some of these conditions has 
been estimated.  The incidence of SCID is 1 in 100,000 to 1 in 1,000,000 [20].  The 
more severe forms of primary immunodeficiency are relatively rare, have their 
onset early in life, and all too frequently result in death during childhood [20].  
Secondary Immunodeficiency 
Secondary immunodeficiencies are not caused by intrinsic abnormalities in 
development of T and B cells [20].  Secondary immunodeficiency may result from 
diseases (human immunodeficiency virus [HIV], hematologic malignancy) or 
immunosuppressive and cytotoxic drugs (such as those used for treatment of 
transplant recipients, collagen vascular disease, malignancies).  
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T cell count of < 200/µL are highly 
susceptible 
to 
opportunistic 
disease 
[20]. 
 
Studies 
in 
HIV/acquired 
immunodeficiency syndrome (AIDS) subjects have shown an increased risk for 
heart and lung-related hospitalizations during the influenza season compared to 
other times of the year, prolonged duration of influenza symptoms, increased risk 
for influenza-related complications and a higher risk of influenza-related death [21]. 
Several hematologic malignancies affect the immune system (Appendix 7).  Several 
authors have reported influenza in children and adults with hematologic 
malignancies [22, 23, 24, 25].  
Secondary immunodeficiency due to drugs (e.g. transplant recipients, collagen 
vascular disease, malignancies) 
The enhanced survival of the transplant population following the availability of 
newer immunosuppressive drugs has made them representative of the 
immunocompromised population in general; and secondary immunodeficiency due 
to drugs, in particular. 
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality.  In a cohort study of influenza viral infection in solid 
organ transplant (SOT) subjects, 30 cases of influenza viral infection were identified.  
Secondary bacterial pneumonia was seen in 17% of subjects and three SOT recipients (2 
liver and one kidney) had myositis, myocarditis and bronchiolitis obliterans.  Biopsy of 
the transplanted organ was performed in 21 of 30 cases and revealed variable degrees of 
acute allograft rejection in 62% of subjects.  The study concluded that influenza was 
associated with significant morbidity in different groups of SOT recipients [5]. 
Among transplant recipients, subjects with hematopoetic stem cell transplant (HSCT) 
are at the greatest risk for morbidity.  In a prospective study from the Infectious Diseases 
Working Party of the European Group for Blood and Marrow Transplantation, 1973 
patients were evaluated for respiratory virus infections after stem cell transplant.  The 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 14 


overall mortality was 23% from influenza A infection and the direct influenza A-
associated mortality was 15.3% in this study [6].  A large retrospective study 
(4797 subjects undergoing HSCT over a 13-year period) identified 62 patients with 
influenza of whom as many as 29% (18 of 62 patients) developed pneumonia.  Ten 
percent of the subjects with influenza died [7].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects. In otherwise healthy adults, elderly 
subjects and children, the median duration of viral shedding in untreated subjects was 70, 
96 and 118 hours respectively [8].  In contrast, in the retrospective HSCT study, 
influenza virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a 
median duration of 168 hours (7 days, range 2 to 37 days) [7]. 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir).  
1.1.2 
Oseltamivir 
Oseltamivir (Tamiflu®, Ro 64-0796) is an ethyl ester prodrug which is rapidly absorbed 
from the gastrointestinal tract after oral administration and metabolized in the liver by 
high capacity carboxylesterases to form oseltamivir carboxylate (Ro 64-0802), a potent, 
stable and selective inhibitor of influenza A and B neuraminidase enzymes.  The active 
form, oseltamivir carboxylate is excreted unchanged by the kidney via glomerular 
filtration and active tubular secretion by the organic anion transport system.  The efficacy 
and safety of oseltamivir in influenza treatment and prevention has been established in an 
extensive series of clinical studies in man. 
Oseltamivir has been approved for the treatment of influenza in Europe, the United States 
and most other countries around the world. In adults and adolescents, the recommended 
dose is 75 mg twice daily for five days.  In children 1 year of age and older recommended 
doses are 30, 45 or 60 mg bid based on body weight.  In all age groups the recommended 
dose is administered bid for 5 days.   
The approval of oseltamivir for the treatment of influenza is based on several controlled 
clinical trials.  In the pooled population from these clinical trials encompassing adults 
aged from 13-97 years, many with significant co-morbidity, 1325 subjects were treated 
with oseltamivir (75 mg bid) and 1056 subjects received placebo.  A total of seven 
influenza symptoms (both respiratory and constitutional) were captured on the diary card 
for adults.  The time to resolution of all symptoms (on the diary card) decreased by 
24 hours; from 124.5 hours in the placebo arm to 100.6 hours with oseltamivir 75 mg bid 
(p < 0.0001) [8].  Further, in adults and adolescents with a proven influenza illness, 
oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% and the 
incidence of influenza-related lower respiratory tract complications resulting in antibiotic 
therapy by 55%.  The study concluded that oseltamivir treatment of influenza reduces 
lower respiratory tract complications, antibiotic use and hospitalizations in healthy and 
‘at risk’ subjects [11].   
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Likewise, in the influenza-infected pediatric population (1 to 12 years of age), oseltamivir 
treatment (n = 217) was compared with placebo (n = 235).  There was a reduction  in  the 
median duration of illness (defined based on resolution of temperature, cough, coryza and 
return to pre-illness health and activity) of 36 hours; from 137 hours with placebo to 101 
hours in the oseltamivir treatment arm (p=<0.0001).  The Canadian Acute Respiratory 
Infections Scale (CARIFS), validated for use in children, was used to collect symptom 
data on the pediatric diary card.  The CARIFS scale comprised a total of 18 symptoms 
which were evaluated twice daily by the parent or guardian.  There was a similar 
reduction in the time to alleviation of all CARIFS symptoms of 36 hours; from 100 hours 
in the placebo group to 63 hours in the oseltamivir group (p < 0.0001) [12].  
Thus in both adults and children, the time to resolution of all symptoms was significantly 
reduced in the oseltamivir treatment arm compared with placebo.   
Oseltamivir was well-tolerated in clinical trials.  Approximately 11,000 subjects have 
received oseltamivir in the development program.  The most common adverse events 
reported by adults, the elderly, and children were nausea and vomiting.  Serious adverse 
events (SAEs) were reported with a low and equal frequency by subjects taking active 
drug and placebo.  Full details are given in the Investigator Brochure [8]. 
The safety profile of oseltamivir has been well characterized for the prophylaxis 
indication in a prospective randomized placebo controlled trial conducted in the 
adult and pediatric immunocompromised (HSCT and SOT) population.  In the 
oseltamivir group, the indications for transplant included hematologic malignancies 
(acute and chronic leukemias, multiple myeloma and myelodysplastic syndrome), 
lymphoid malignancies (Hodgkins or non-Hodgkins lymphomas), primary 
immunodeficiencies (Wiskott-Aldrich syndrome, X-linked lymphoproliferative 
disease and severe combined immunodeficiency).  Other rare indications included 
bone marrow aplasia, paroxysmal nocturnal hemoglobinuria, myelofibrosis and 
multiple sclerosis.  In the safety population, there were 239 subjects randomized to 
the conventional dose of oseltamivir and 238 to placebo.  The total number of 
adverse events reported in the placebo group (361 events) was generally similar to 
that in the oseltamivir group (323 events).  Diarrhea was the most frequently 
reported adverse event (placebo, 8%; oseltamivir, 6%).  There were no deaths in the 
oseltamivir group.  Oseltamivir was found to be safe in immunosuppressed 
transplant recipients [26]. 
Limited safety and/or efficacy of oseltamivir for the treatment indication is available 
from several case reports in children and adolescents.  Oseltamivir was shown to be 
safe and/or effective in HIV infected children (n=10) [27], children (age 3 to 12 
years) with acute lymphocytic leukemia (ALL) (n=10) [25], in a nosocomial H1N1 
outbreak in a pediatric (children aged 10 months to 13 years) oncology ward (n=8) 
[24], in children and adolescents (age 2 to 19 years) with malignancies (ALL, 
neuroblastoma, brain tumor, non-Hodgkin’s lymphoma, osteosarcoma, Ewing 
sarcoma, myelodysplasia, acute myeloid leukemia (AML), Wilms tumor, aplastic 
anemia, chronic myeloid leukemia (CML) and acute promyelocytic leukemia) 
(n=51) [22], in children aged 4 to 14 years on immunosuppressive drugs (n=5) [28] 
and in children (aged 5 months to 5 years) with bone marrow transplant (n=3) [29].  
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 16 


Oseltamivir has also been shown to be safe and/or effective in mixed populations of 
children and adults (62 patients) with HSCT [7], and in a large epidemiologic study 
(n=221) with SOT [30].  
Finally, 
oseltamivir 
has 
been 
shown 
to 
be 
safe 
and/or 
effective 
in 
immunocompromised adults with HSCT [13] and adults with lung transplant [31, 
32, 33].  
The dose of oseltamivir was the same as the conventional dose in a majority of these 
reports.  In one report as many as 25 adult patients received twice the conventional 
dose [30] while in another report, three of nine adult patients received twice the 
conventional dose [33].  Treatment with oseltamivir generally ranged from 5 to 10 
days [32, 33, 30] and occasionally until the patient was symptom free [32, 33].  In 
exceptional cases treatment was given for as long as 20 days [22] or for as long as 
the patient was positive by RT-PCR [25]. 
There 
is 
some 
concern 
about 
the 
development 
of 
resistance 
in 
the 
immunocompromised population.  During the pandemic influenza season, more 
than 23,000 clinical isolates of novel H1N1 pandemic virus were tested for resistance 
in the 6 international WHO regions.  A total of 225 isolates (from 225 subjects) were 
resistant (H275Y mutation in the neuraminidase coding sequence) to oseltamivir for 
an approximate incidence of 1%.  Information on immune status was available for 
142 of 225 patients.  Among the 142 patients, 56 (40%) were immunocompromised 
[34].  Prolonged viral replication and lack of immune-mediated virus clearance in 
immunosuppressed patients treated with antivirals can result in a higher incidence 
of selection of drug-resistant viruses, a phenomenon that has been documented 
previously [35, 36].  
1.2 
Rationale for the Study  
Because of the increasing body of evidence (Section 1.1.2), oseltamivir is now 
recommended in national guidelines as an option for the treatment of influenza in 
the transplant population [40].  As the transplant population is considered 
representative of the immunocompromised population, the primary objective of this 
study is to evaluate safety and resistance, while evaluating efficacy as a secondary 
objective. 
2. 
OBJECTIVES  
2.1 
Primary Objective 
The primary objective of the study is to evaluate prospectively the safety and 
tolerability of oseltamivir for the treatment of influenza in immunocompromised 
patients and characterize the effects of oseltamivir in immunocompromised patients 
on the development of resistant influenza virus. 
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2.2 
Secondary Objectives   
The secondary objectives of the study are:  
To 
evaluate 
the 
effects 
of 
conventional 
and 
high 
dose 
oseltamivir 
in 
immunocompromised patients on: 
• The time to resolution of influenza symptoms. 
• The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis).  
• The virologic course of influenza (proportion shedding and viral loads at different 
time points). 
 
3. 
STUDY DESIGN 
3.1 
Overview of Study Design and Dosing Regimen   
This is a double blind, randomized, stratified, multi-center trial of conventional and high 
dose oseltamivir for the treatment of influenza in immunocompromised patients.  
Immunocompromised patients who develop an influenza-like illness with a positive 
rapid diagnostic test, PCR, or viral culture for influenza, will be enrolled during the 
influenza season.  Patients will be stratified by transplant status [yes, no], the time 
between onset of influenza symptoms and treatment start (up to 96 hours) [≤ 48 hours; 
> 48 hours], influenza vaccination status for current influenza season [Yes; No] and by 
age [≤ 12 years; > 12 years].  Eligible patients will be consented and randomized to 
receive oseltamivir twice daily for 10 days in one of two treatment arms: conventional 
dose or high dose (double the conventional dose).  
3.1.1 
Rationale for Study Design 
This study incorporates several features that distinguish it from classic placebo controlled 
trials.  
There is no placebo control arm in this study as it was considered unethical for this 
high risk population.  The development of resistance following treatment with 
oseltamivir (one of the primary objectives of the study) is an objective assessment 
(determined by laboratory tests) and is unlikely to be impacted by the absence of a 
placebo arm.  
As a placebo control arm was considered unethical in this population, an alternative 
control arm had to be identified for efficacy end points.  The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial.  In order to do this, the 
end points were designed to be similar to that in the pivotal registration trials.  
The following sections provide rationale and justification for specific aspects of the study 
design which differ from the currently approved dosing for influenza or from 
previous pivotal registration trials.  They also provide information on how the results 
will be used to make recommendations on dose and duration of treatment. 
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3.1.1.1 
Choice of Treatment Arms 
The currently approved dose of oseltamivir for the treatment indication is the 
conventional dose with a duration of five days.  In this study a conventional and 
high dose (twice the conventional dose) are being evaluated.  The pivotal registration 
trials for oseltamivir in healthy adults with influenza had three treatment arms, two active 
(75 mg and 150 mg) and one placebo.  Both treatment arms were found to be 
significantly better than placebo.  No statistical comparisons were made between the two 
active treatment arms.  Evaluation of the results in the two active treatment arms did not 
reveal any clinically meaningful difference.  However, the proportion of subjects 
shedding virus on day 4 (3 days after the start of treatment), suggested a possible 
dose response relationship (36%, 28% and 23% in the placebo, 75 mg and 150 mg 
dose arms respectively).  Because defective immune-mediated virus clearance in 
immunosuppressed patients treated with antivirals can result in a higher incidence 
of selection of drug-resistant viruses, it was decided to use both the conventional and 
high dose arm for this study.  A longer duration of treatment was chosen because a 
large retrospective study has shown that the median duration of viral shedding of 
7 days [7] was greater for HSCT recipients than that seen in the healthy children, 
adult and elderly population with influenza (Section 1.1.1) [8].  
3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours 
In immunocompromised patients, time from onset of symptoms to seeking medical 
attention (presentation at the clinic) of > 48 hours has been shown in several case 
reports [37, 31, 32, 33] including two instances of nosocomial outbreaks in children 
[29, 24].  This notwithstanding, oseltamivir has been shown to be effective in 
immunocompromised populations that included patients treated with oseltamivir 
beyond 48 hours of presentation; patients with lung transplant (median time to 
presentation 3 days) [31], bone marrow transplant (treatment started more than 
48 hours after onset of symptoms in all three patients) [29], organ transplant (62 out 
of 221 patients started treatment after 96 hours) [30] and children with ALL (one 
child presented after 3 days and two children after 5 days of symptoms) [25]. 
In a prospective, observational study involving adults hospitalized with influenza, 
the study authors concluded that ‘Weakened host defenses slow viral clearance, 
whereas antivirals started within the first four days of illness enhance viral 
clearance’ [38].  
Additionally, in November 2009, in a communication for clinicians on antiviral 
treatments for H1N1, the US Centers for Disease Control and Prevention (CDC) 
stated that while antiviral treatment is most effective when started early; both 
outpatients with risk factors and hospitalized patients still benefit when treatment 
with oseltamivir is started more than 48 hours after illness onset [39].   
3.1.1.3 
Interpretation of Study Results  
Safety and tolerability and the development of resistance are the primary objectives 
of this study.  These will be characterized descriptively.  For the secondary objective 
of efficacy, the subset of the population enrolled in the first 48 hours will be 
compared with placebo patients from pivotal registration trials (where patients were 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 19 


enrolled in the first two days of illness).  Sections 8.2.5, 8.2.6, and 8.2.7 provide 
details on the statistical considerations and their rationale associated with these 
comparisons. 
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials.  However, in order to evaluate a dose response relationship between the two active 
treatment arms in this trial, stratification remains essential.  
Patients will be stratified by transplant status (yes, no) because transplant patients 
form a relatively large homogenous group in this study and might influence 
outcome.  
Patients will be stratified by time between onset of symptoms and treatment start 
(< 48 hours or ≥ 48 hours) because previous experience in otherwise healthy adults and 
children has shown that patients treated early in their illness respond to treatment better 
than those who are treated later.  Patients will also be stratified by age (≤ 12 years and 
> 12 years) because otherwise healthy children shed virus longer than otherwise healthy 
adults.  It is expected that a similar difference in the duration of viral shedding would 
exist between immunocompromised children and adults.  As vaccinated subjects may 
respond faster to therapy, the study is also stratified based on influenza vaccination status 
for the current influenza season (Yes; No).  
3.1.2 
Rationale for Dose Selection and Adjustment 
Dose Selection 
The dose of oseltamivir to be used in this study is the conventional, approved dose for 
children and adults in the treatment of influenza.  There will be a second higher dose for 
comparison which is two times the conventional dose.  This higher dose is used based on 
theoretical considerations which suggest that the higher dose may be associated with 
improved efficacy and decreased emergence of resistance.  
The anticipated pro-drug and metabolite exposures from this higher dose are not expected 
to exceed maximum exposures seen previously in the oseltamivir development program.  
The safety and tolerability of the higher dose regimen has already been demonstrated in 
treatment studies of immunocompetent adult subjects (n = 447) [14].  In a study to 
demonstrate cardiac safety, in the highest dose group treated with 450 mg b.i.d. for 
5 days [n = 99], no subject had a serious adverse event, nor withdrew prematurely.  In 
Phase I studies in adults, oseltamivir has been administered in multiple doses of up to 
500 mg b.i.d.  Doses of 200 mg b.i.d. and greater have been associated with increased 
gastrointestinal adverse effects (nausea and vomiting) [8].  In adult subjects with 
creatinine clearances of ≤ 30 mL/min, doses of 100 mg b.i.d. for 6 days were well 
tolerated, despite steady-state oseltamivir carboxylate exposures approximately 10-fold 
higher than those achieved with standard dosing in renally competent individuals [15].  
No other adverse effects were reported more frequently with higher doses and no serious 
adverse events have been reported within the volunteer studies.  Co-administration of 
oseltamivir with food has been demonstrated to substantially reduce the frequency and 
severity of gastrointestinal side effects.  
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Thus, the rationale for the higher dose arm in this study is to explore the possibility of 
improved efficacy and decreased emergence of resistance without an undue increase in 
risk.  
Drug interactions with immunosuppressive medications have also been evaluated.  The 
pharmacokinetics of oseltamivir and oseltamivir carboxylate after administration of 
75 mg oseltamivir (conventional adult dose) in subjects with a well-functioning, stable 
renal allograft who were being maintained on immunosuppressive therapy were studied.  
These were similar to those described in the literature for adults with comparable degrees 
of renal function.  Oseltamivir was well tolerated and had no clinically relevant effect on 
the steady-state pharmacokinetics of cyclosporine A, tacrolimus, or mycophenolate 
mofetil [8]. 
Duration of Dosing 
The duration of dosing chosen for this population (10 days) is longer than that in the 
healthy adult and pediatric populations (5 days).  This is based on observations that the 
viral shedding and illness are typically longer in immunocompromised patients than it is 
in healthy adults [7, 13]. 
Dose Adjustments 
In this study, patients whose CrCl decreases to < 60mL/min/1.73M2 will be 
discontinued from treatment. 
3.1.3 
End of Study 
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 
days later as shown in the schedule of assessments.  A rapid diagnostic test for influenza 
will be performed at the end of the 10 days of treatment.  Subjects still having influenza 
based on the rapid diagnostic test will be treated per the local standard of care by the 
principal investigator.  
3.2 
Number of Subjects/ Assignment to Treatment Groups 
A minimum of 166 patients (approximately 83 per arm) to allow an adequate number 
of influenza A patients, including 50 transplant recipients will be enrolled in this 
study.  After screening, patients will be randomly assigned to one of the two active 
treatment groups. 
3.3 
Centers 
This will be a multicenter study with approximately 100-110 centers in the Northern 
hemisphere.  
4. 
STUDY POPULATION 
4.1 
Overview 
The study population comprises immunocompromised adults (including adolescents) and 
children who have influenza.  Additionally, the subjects must not have other medical 
conditions that will preclude the assessment of efficacy or safety.  Influenza vaccinated 
and non-vaccinated subjects are eligible to participate in this study.  Principal 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 21 


investigators will review oseltamivir resistance patterns of strains circulating in the 
area and weigh the risk versus the benefit before enrolling patients with a 
potentially resistant strain. 
Under no circumstances are patients who enroll in this study permitted to be re-
randomized to this study and enrolled for a second course of treatment. 
4.2 
Inclusion Criteria 
• Age greater than or equal to 1 year 
• Rapid diagnostic test, PCR, or viral culture positive for influenza in the 96 hours 
prior to first dose 
• Immunocompromised subject defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in Appendix 6) OR 
o Secondary immunodeficiency 
 SOT with ongoing immunosuppression OR 
 Allogenic HSCT with ongoing immunosuppression OR 
 HIV with CD4 count < 200/mm3 OR 
 Hematologic malignancies (representative examples in 
Appendix 7) OR 
 Systemic (e.g. enteric, sc, im or iv) immunosuppressive 
therapy, irrespective of medical indication, started at least 
12 weeks prior to, and ongoing at the time of first dose of study 
drug (representative examples in Appendix 8) 
• Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza 
• In patients with history or clinical presentation at randomization suggestive of 
renal failure; a CrCl > 60 ml/min/1.73M2 
• Less than or equal to 96 hours between onset of influenza like illness and first dose of 
study drug 
• Parent/guardian willing and able to comply with study requirements and give consent, 
(country specific age cut off) 
• Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• For adult patients, willing and able to comprehend and give written informed consent  
• Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for females for one reproductive cycle 
following cessation of study therapy 
• Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study medication 
 
4.3 
Exclusion Criteria 
• SOT within 6 months of the time of randomization. 
• Have in the investigator’s opinion experienced acute rejection in the 4 weeks prior to 
randomization. 
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• HSCT patients with no evidence of engraftment (engraftment is defined as the point 
at which a patient can maintain a sustained absolute neutrophil count (ANC) of 
> 500/mm3 and sustained platelet count of  ≥ 20,000/mm3, lasting  ≥ 3 consecutive 
days without transfusions). 
• HSCT subjects not discharged from hospital after their initial hospitalization for 
transplantation. 
• Have clinical evidence for hepatic decompensation at the time of randomization 
(clinical icterus, ascites, hepatic encephalopathy, coagulopathy). 
• Have cirrhosis of the liver at the time of randomization. 
• Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration. 
• Have evidence of active or uncontrolled opportunistic infections (bacterial, fungal, or 
viral-including cytomegalovirus [CMV] or polyoma virus [BKV]) at the time of 
randomization.  Patients with HCV or HBV are not excluded. 
• Patients with co-morbid conditions which are uncontrolled.  Uncontrolled is defined 
as disease requiring change of therapy or hospitalization in the 4 weeks preceding 
randomization.  Change of therapy is defined as dose increase or change of 
medication prior to onset of present influenza like illness. 
• Patients with gastrointestinal disorders which might interfere with their ability to 
absorb oral medication.  
• Allergy to the test medication. 
• Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation). 
• Influenza vaccination with live attenuated vaccine in the 2 weeks prior to 
randomization. 
• Antiviral treatment (example: amantadine, rimantadine, oseltamivir, laninamivir, 
peramivir, zanamivir and ribavirin) for influenza in the 2 weeks prior to 
randomization. 
• Patients taking probenecid medication. 
• Patients who are pregnant or breast-feeding.   
• Participation in a clinical trial or expanded access trial with an investigational drug in 
the 4 weeks prior to randomization or concomitantly with this study.   
 
4.4 
Concomitant Medication and Treatment 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, laninamivir, peramivir, and additional oseltamivir above that 
specified for this study) are not allowed during the 10-day treatment phase of the study.  
Concomitant use of an investigational drug during the study is also excluded.  Live 
attenuated vaccines may not be advisable for this population. It is possible that concurrent 
use with oseltamivir may render live vaccines ineffective.  
Medications required for the routine care of the patient may be continued during the 
study.  Concomitant use of probenecid (irrespective of the indication) is not allowed 
during the study. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 23 


4.5 
Criteria for Premature Withdrawal  
The investigator must discontinue treatment if the creatinine clearance is < 60 ml/min in 
adults or < 60 ml/min/1.73 M2 in children.  The investigator must also discontinue 
treatment from all subjects with intercurrent illnesses or adverse events suggestive of 
hepatic decompensation.  The investigator also has the right to discontinue treatment in 
the event of intercurrent illness, adverse events, treatment failure, protocol violations, 
administrative reasons or other reasons. 
The investigator must discontinue treatment with study drug if the patient is to be treated 
concomitantly with another antiviral for influenza, for example, amantadine, rimantadine, 
laninamivir, peramivir, or zanamavir.  However, all patients, including those who 
discontinue study drug prematurely and/or are treated with another antiviral, will be 
required to return for follow up approximately 5 and 30 days after the last dose of study 
medication (day 15 and day 40 assessments). 
Subjects have the right to withdraw from the study at any time for any reason.  
An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
The investigator should contact the subject or a responsible relative either by telephone or 
through a personal visit to establish as completely as possible the reason for the 
withdrawal.  A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the subject is withdrawing from the study.  If the reason 
for removal of a subject from the study is an Adverse Event, the principal specific event 
will be recorded on the CRF. 
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further 
information.  The outcome of that discussion should be documented in both the medical 
records and in the CRF.  
4.6 
Replacement Policy [Ensuring Adequate Numbers of 
Evaluable Subjects] 
4.6.1 
For Subjects 
No subject prematurely discontinued from the study for any reason will be replaced. 
4.6.2 
For Centers 
A center may be replaced for the following administrative reasons:   
– Excessively slow recruitment. 
– Poor protocol adherence. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 24 


5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES 
Table 1 
Schedule of Assessments 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 3f,g 
6 g 
8 f, g 
11g, h, i 
15g   
40 g, j 
Informed Consent/Assent 
x 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
x 
 
 
Pregnancy Test a 
x 
 
 
 
 
x 
 
x 
Rapid diagnostic test for 
influenza virus shedding  
x 
 
 
 
 
 
x 
 
 
Safety Labs b 
x 
 
 
 
 
x 
 
 
Physical Examination 
x 
 
 
 
 
x 
 
x 
Vital Signs (including PR, RR, 
temperature, Blood pressure) 
x 
 
x 
x 
x 
x 
x 
x 
Nasal and throat swabs for viral 
shedding and viral load c, d 
x 
 
x 
x 
x 
x 
x 
x 
Review of electronic diary data e    
 
 
x 
x 
x 
x 
x 
x 
Drug Administration 
 
 
 
 
 
 
 
 
Collection of unused study 
medication and empty containers 
 
 
 
 
 
x 
 
 
Previous Diseases  
x 
 
 
 
 
 
 
 
Previous/Concomitant 
medications 
x 
 
 
 
 
 
 
 
Adverse Events/Sec Illnesses and 
Treatments 
 
 
 
 
 
 
 
 
Rejection, Graft versus host 
disease (GVHD) 
 
 
 
 
 
 
 
 
a  Urine pregnancy test for patients of child-bearing potential according to the judgment/discretion of the 
investigator. 
b  Hematology (CBC with differential) and chemistry (AST, ALT, total bilirubin, urea, Cr). Serum 
creatinine testing may be done at a local laboratory when clinically indicated to calculate creatinine 
clearance. 
c  Baseline swab samples will be assessed for the presence of resistance mutations. 
d  Two nasal and one throat swab for viral culture and RT-PCR. 
e  Influenza symptoms, temperature, and date/ time of oseltamivir dose will be recorded by the patient in 
electronic patient diaries twice daily on days 1 – 10, and once daily thereafter.   
f  A home visit may be made on day 2 or 3 (for patients who are too ill to come into the clinic) and day 8. 
g  Day 2/3 visit window = +1 day.  Day 6 visit window = +/- 1 day; Day 8 visit window = +1 day.  Day 11 
visit window = ± 1 day. Day 15 and day 40 visit occur approximately 5 and 30 days after the last dose 
respectively. Day 15 window = ± 1 day. Day 40 window ± 2 days.  
h  Only weight to be assessed. Height is not necessary at this visit. Study drug is taken on day 11, only if 
the first dose was taken after 4 PM on Day 1 [5.3] Subjects who are rapid diagnostic positive can be 
treated per standard of care. They will be required to come for their follow-up visits on day 15 and 
day 40.  
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 25 


Table 1 
Schedule of Assessments (Cont.) 
i  Subjects who discontinue treatment prematurely will have an end of treatment (day 11) assessment at 
the time of treatment discontinuation or the following day. They will be required to attend their follow 
up visits approximately 5 and 30 days after the last dose (day 15 and day 40 assessments).  
j  Subjects who discontinue during follow-up will have an end of follow-up (day 40) assessment. This 
visit must occur within 30 days of the last dose.   
 
5.1 
Screening Examination and Eligibility Screening Form  
All subjects must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed. Screening will take place at the 
baseline visit prior to first dose.  However, if necessary, screening may take place the day 
before the baseline visit, as long as the patient is randomized and receives his/her first 
dose of study medication within 96 hours of influenza symptom onset. 
Subjects will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  
An Eligibility Screening Form [ESF] documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.  
5.2 
Procedures for Enrollment of Eligible Subjects  
Once a subject has fulfilled the entry criteria, he/she will be randomized to one of two 
treatment groups. The subject randomization numbers will be generated by Roche or its 
designee and incorporated into double-blind labeling. 
The investigator or designee will use the CRF pre-printed with the assigned subject 
number and enter the randomization number provided by IVRS for allocation to the 
treatment groups in the appropriate place on each subject’s CRF. 
Randomization will be stratified by transplant status (Yes; No); time between onset of 
symptoms and treatment start (≤ 48 hrs or > 48 hrs), influenza vaccination status (Yes; 
No) and patient’s age (≤ 12 years or > 12 years).  
5.3 
Clinical Assessments and Procedures 
At all visits subjects will receive the routine care for their primary illness.  Routine 
patient care (including the adjustment of doses of any of the immunosuppressive drugs) 
will be dictated by tests performed locally at the trial site.  All safety labs will be sent to a 
central laboratory.  Results for these laboratory parameters will be used by the 
sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 1).  Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 26 


Study Day 1 
The baseline and study day 1 assessment may be performed at the same visit. 
Study medication, electronic diaries, and thermometers will be dispensed.  Patients or 
guardians/parents will be instructed how to complete electronic symptom diaries 
(Appendix 2) (Appendix 3), temperature recording, and treatment administration details, 
including time of each oseltamivir dose.  The first diary entries will be made at the site 
before the first dose of study drug.  
Baseline nasal and throat swab samples will be assessed for the presence of oseltamivir-
resistance mutations.   
The date of the first dose of study drug is defined as study day 1.  Once randomized, the 
first dose of study drug will be administered in the clinic. Study day 2 will begin at 12 
midnight of the same calendar day.  If the first dose of study drug is taken after 4 pm on 
day 1, the next dose of study drug will be taken in the morning of day 2.  In this case, the 
last dose of study drug will be taken on the morning of study day 11.   
If the first dose of study drug is taken prior to 4 pm on day 1, the next dose of study drug 
should be taken in the evening of the same day (i.e. prior to midnight on the same 
calendar day with a minimum of 7 hours between doses).  For these patients the last dose 
of study drug will be taken in the evening of study day 10. More information on dosing is 
provided later (Section 6.1). 
Study Days 2 - 11 
Study day 2 will begin at 12 midnight of study day 1.  
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study.  The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is entering data into the electronic diary 
properly, and assess drug compliance.  During the dosing period, diary symptoms should 
be assessed and temperature should be recorded at the same time that the study drug is 
taken.  
End of Treatment Day 11 
The end of treatment visit for all subjects is on day 11 (irrespective of whether they took 
one or two doses on day 1).  Subjects who discontinue study medication prematurely will 
have all day 11 assessments completed at the time of discontinuation or the following 
day.  
After all day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit.  If the rapid diagnostic test is positive, the subject may be treated 
per standard of care at the discretion of the investigator.  
All subjects (including those who discontinue study medication prematurely and those 
who are positive for influenza on their rapid diagnostic test at the end of treatment visit) 
will be required to return for follow up approximately 5 and 30 days after the last dose 
(day 15 and day 40 assessments).    
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 27 


Study Days 12 – 40 
Study day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  
End of Follow-Up Day 40  
All subjects must attend an end of follow-up visit on day 40.  
If the patient is withdrawn after completion of treatment (after the day 11 assessment), a 
termination visit should be arranged.  This visit should be the end of follow-up visit 
assessment [Day 40].  This visit must occur within 30 days of the last dose.  
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the electronic diary. 
5.3.1 
Efficacy Assessments 
The primary efficacy end point in this study is the time to resolution of all influenza 
symptoms as recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness.  These are captured in the diary for both adults 
and children (Appendix 2) (Appendix 3).  Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem).  A score 
of zero is considered asymptomatic.  The primary efficacy end point, time to 
alleviation of all symptoms is comprised of all the symptoms captured in the diary.  
2. Temperature.  This is captured in the diary.  Temperature is used for assessment of 
the primary and several secondary efficacy end points.  
 
5.3.2 
Safety 
Safety parameters in this study include adverse events, vital signs, and clinical laboratory 
evaluations.  
Pre-defined symptoms of influenza captured in the adult and pediatric diaries are not to 
be reported as adverse events unless they can be further qualified.  Thus ‘headache due to 
stress at work’ is reported as an adverse event.  However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Adverse events such as bronchitis, pneumonia, otitis media and sinusitis are considered 
secondary illnesses of influenza and should be recorded as adverse events. 
Other adverse events to be expected in the transplant population such as rejection and 
graft versus host disease (in HSCT subjects) will also be collected as adverse events.  
5.4 
Laboratory Assessments 
The laboratory assessments include those for efficacy and safety. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 28 


Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described in 
the Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR and 
viral cultures.  Influenza virus shedding will be assessed.  Baseline samples will be 
assessed for the presence of oseltamivir-resistance mutations.   
During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza.  At the end of treatment 
(day 11), a rapid diagnostic test is permitted for the diagnosis of ongoing influenza.  
Safety 
The safety laboratory assessments in this study, including the assessment of serum 
chemistry and hematology will be done at the central laboratory.  Serum chemistry 
assessments comprise AST, ALT, total bilirubin, urea and creatinine.  Hematology 
assessments include CBC and differential count.  The total volume of blood loss for 
laboratory assessments will be approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section 16) will extend to any data generated from 
the assaying of these samples.  Biological samples taken from all patients may be 
infectious and will be classified as “diagnostic specimens” for dispatch purposes. 
The Principal Investigator may draw blood for serum creatinine to be assessed at the local 
laboratory when clinically indicated during the study to calculate creatinine clearance. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/ml) or 75 mg capsules and matching placebo. 
The Investigational Medicinal Products will be supplied, packaged individually for each 
subject and labeled in accordance with Roche Standard and local regulation by Roche 
Clinical Trial Supply, Basel, Switzerland.  
6.1 
Dose and Schedule of Study Drug 
Oseltamivir will be given twice daily over 10 days for a total of 20 doses.  The doses 
need to be taken at 12 hourly intervals.  Under no circumstances is a subject allowed to 
take two doses within 7 hours of each other.  
Patients will be randomized to receive either conventional or high dose of study drug. 
Conventional dose: 
Children ages 1 - 12 years: Oseltamivir syrup 
≤ 15 kg  
 
 
30 mg twice daily 
> 15 – 23 kg   
 
45 mg twice daily 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 29 


> 23 – 40 kg  
 
60 mg twice daily 
> 40 kg 
 
 
75 mg twice daily 
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules  
75 mg twice daily 
Subjects randomized to the conventional dose will simultaneously receive matching 
placebo so as to blind them and the investigator from the high dose arm.  
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg  
 
 
60 mg twice daily 
> 15 – 23 kg   
 
90 mg twice daily 
> 23 – 40 kg  
 
120 mg twice daily 
> 40 kg 
 
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years): Oseltamivir capsules  
150 mg twice daily  
6.1.1 
Dose Modifications 
No dose modifications will be allowed on study. 
6.2 
Preparation and Administration of Study Drug 
Oseltamivir will be provided in two forms:  
1. Capsules containing 75 mg of active drug and packaging material consisting of 
pregelatinized starch, povidone, talc and sodium stearyl fumarate.  All participants 13 
years and older will receive this dosage form.  Oseltamivir capsules should be stored 
at 25ºC.  
2. A pediatric suspension containing 12 mg oseltamivir per ml of reconstituted solution 
and the following excipients: sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor).  All participants 12 years and under will receive this dosage form.  
Oseltamivir dry powder for suspension [pediatric syrup] should be stored at 25ºC.  
After reconstitution, the suspension should not be used for longer than 10 days.  Store 
constituted suspension under refrigeration at 2º to 8ºC.  Do not freeze. 
 
Matching placebo will be available as capsules and suspension.  Subjects in the 
conventional dose arm will get the conventional dose and matching placebo so that they 
are blinded from the high dose arm.  
Each subject will be dispensed a medication pack that will provide enough medication to 
cover 20 doses.  For subjects randomized to the conventional dose arm, the medication 
pack will contain a bottle of oseltamivir dry powder or a blister wallet with oseltamivir 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 30 


capsules and matching placebo.  For subjects randomized to the high dose arm, the 
medication pack will contain two bottles of oseltamivir dry powder or two blister wallets 
with oseltamivir capsules.  Irrespective of the treatment group the subject is randomized 
to, for each dose the subject will take the same amount from both bottles or blister wallets 
provided in the medication pack such that the sum of the amounts from each immediate 
container constitutes one dose. 
One dose is to be administered twice per day at approximately 12-hour intervals with a 
light snack or glass of milk or fruit juice.  The first dose of study medication will be 
administered in the clinic at the time of randomization. 
6.3 
Blinding and Unblinding 
Randomization will be administered by a central randomization center.  
The Randomization List will not be available at the study center, to the study monitors, 
project statisticians or to the project team at Roche.  Emergency codes, or another 
adequate method of unblinding, will be implemented before study start, if the identity of 
the test medication is necessary for patient management in the case of a serious adverse 
event.  Emergency codes should not be broken except in the case of emergency 
situations.  Any request from the investigator for information about the treatment 
administered to study subjects for another purpose must be discussed with 
Roche/designee.  
As per regulatory reporting requirement, Roche/designee will unblind the identity of the 
study medication for all unexpected [as per IB] serious adverse events that are considered 
by the investigator to be related to study drug.  Details of patients who are unblinded 
during the study will be included in the Clinical Study Report. 
All other individuals directly involved in this study will remain blinded until the final 
analysis of the primary parameter.  
The randomization will be stratified by transplant status, duration of symptoms, 
influenza vaccination status and age and will be provided by the Roche randomization 
group for the IVRS vendor.   
6.4 
Assessment of Compliance 
Accountability and subject compliance will be assessed by maintaining adequate “drug 
dispensing” and return records.  
Subjects will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  
A Drug Dispensing Log must be kept current and should contain the following 
information: 
• the identification of the subject [randomization and medication numbers] to whom the 
study medication was dispensed 
• the date[s], quantity of the study medication dispensed to the subject 
• the date[s] and quantity of the study medication returned by the subject 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 31 


This inventory must be available for inspection by the Monitor. All supplies, including 
partially used or empty containers and the dispensing logs, must be returned to the 
monitor at the end of the study. 
6.5 
Destruction of Study Drug 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons.  In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned and destroyed.  Written authorization must be obtained from the sponsor or 
designee at study start up before destruction. 
Written documentation of destruction must contain the following: 
– Identity [batch numbers or subject numbers] of investigational product[s] destroyed 
– Quantity of investigational product[s] destroyed 
– Date of destruction 
– Method of destruction 
– Name and signature of responsible person [or company] who destroyed 
investigational products[s] 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
Adverse Events (AEs) and Laboratory Abnormalities 
7.1.1 
Clinical AEs 
Per the International Conference of Harmonization [ICH], an AE is any untoward 
medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign [including 
an abnormal laboratory finding], symptom, or disease temporally associated with the use 
of a medicinal [investigational] product, whether or not considered related to the 
medicinal [investigational] product.  Pre-existing conditions which worsen during a study 
are to be reported as AEs.  Influenza signs and symptoms reported on the patient diary 
will be summarized as efficacy end points and need not be captured as adverse events.  
However, secondary illnesses due to influenza must be reported as adverse events.  
7.1.1.1 
Intensity  
All clinical AEs encountered during the clinical study will be reported on the AE page of 
the CRF.   
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 32 


Intensity of AEs will be graded on a four -point scale [mild, moderate, severe, 
life-threatening] and reported in detail on the CRF.   
Mild 
discomfort noticed but no disruption of normal daily activity. 
Moderate 
discomfort sufficient to reduce or affect daily activity. 
Severe 
inability to work or perform normal daily activity 
Life Threatening 
represents an immediate threat to life   
7.1.1.2 
Drug - Adverse Event Relationship 
Relationship of the AE to the treatment should always be assessed by the investigator.  
Description of scales can be found in Appendix 4. 
7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
A Serious Adverse Event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfils at least 
one of the following criteria: 
– is fatal; [results in death; NOTE: death is an outcome, not an event].  
– is Life-Threatening [NOTE: the term "Life-Threatening" refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– required in-patient hospitalization or prolongation of existing hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to 
(Appendix 5). 
7.1.2 
Treatment and Follow-up of AEs  
AEs, especially those for which the relationship to test “drug” is not “unrelated”, should 
be followed up until they have returned to baseline status or stabilized.  If a clear 
explanation is established it should be recorded on the CRF.   
7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will appear printed on laboratory reports provided to the site from 
the central laboratory.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] 
should be reported as such, in addition to being recorded as an AE in the CRF. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 33 


Any treatment-emergent abnormal laboratory result which is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE page in the CRF: 
• Accompanied by clinical symptoms. 
• Leading to a change in study medication [e.g. dose modification, interruption or 
permanent discontinuation]. 
• Requiring a change in concomitant therapy [e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment]. 
 
7.1.4 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  If a clear explanation is 
established it should be recorded on the CRF.  
7.2 
Handling of Safety Parameters 
7.2.1 
Reporting of Serious Adverse Events [immediately reportable] 
Any clinical AE or abnormal laboratory test value that is serious [as defined in 
Section 7.1.1.3 above] and which occurs during the course of the study, regardless of 
the treatment arm, occurring from the enrollment visit (start of study screening 
procedures), must be reported to Roche or designee within one working day of the 
investigator becoming aware of the event [expedited reporting]. 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and up 
until the follow-up visit.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to (Appendix 5). 
7.2.2 
Pregnancy  
A female subject must be instructed to stop taking the test “drug” and immediately 
inform the investigator if she becomes pregnant during the study.  The investigator 
should report all pregnancies within 24 hours to the sponsor or designee.  The 
investigator should counsel the subject, and discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Pregnancies occurring within 28 days of 
treatment completion should be reported to Roche.  
7.3 
Warnings and Precautions  
Events such as convulsions and delirium (including symptoms such as altered level of 
consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 34 


anxiety, nightmares) have been reported during oseltamivir use in patients with influenza, 
predominately in children and adolescents.  In rare cases, these events resulted in 
accidental injury.  The contribution of oseltamivir to those events is unknown.  Such 
events have also been reported in patients with influenza who were not taking 
oseltamivir.  Patients, especially children and adolescents, should be closely monitored 
for signs of abnormal behavior. 
Please refer to the attached Investigator’s Brochure for additional warnings, precautions, 
and other reported adverse events. 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN   
Full details of all planned analyses will be specified in a separate Statistical Analysis 
Plan (SAP) for the safety and efficacy variables and in the Resistance Plan for the 
development of resistance.  The methods described below are an outline of the main 
planned analyses. 
8.1 
Primary and Secondary Study Endpoints 
8.1.1 
Primary Endpoints 
The primary endpoints for safety will be assessments of adverse events, physical 
exams, vital signs and clinical laboratory evaluations.  The primary endpoint of 
development of resistance will be determined from the genotypic and phenotypic 
variables measured post baseline and is described further in the Resistance Plan. 
8.1.2 
Secondary Endpoints 
The following are secondary endpoints which measure efficacy, the primary of which 
is time to alleviation of all clinical symptoms.  With the exception of this variable, 
viral load and time to resolution of fever, they are defined as either the occurrence or 
non-occurrence of the specified events or the presence or absence of the specified 
symptoms. 
The time (hours) to alleviation of all clinical influenza symptoms (recorded in 
the patient diary)  
Shedding virus by culture at day 1, 2, 6, 8, 11, 15 and 40 
Shedding virus by RT-PCR at day 1, 2, 6, 8, 11, 15, and 40 
Viral load by culture (log10TCID50/mL) at Day 1, 2, 6, 8, 11, 15, and 40  
Viral load by quantitative RT-PCR at day 1, 2, 6, 8, 11, 15 and 40 
The time (hours) from first dose of study medication until resolution of fever  
Fever  
Cough   
Coryza   
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 35 


Development of secondary illnesses (otitis media, bronchitis, pneumonia, or 
sinusitis) at any time during the study 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or 
sinusitis) at any time during the study that are treated with antibiotics 
Initiation of treatment with antibiotics after randomization  
Hospitalization, and for those who are hospitalized, the duration of hospitalization 
Development of rejection or GVHD 
8.1.3 
Safety 
Safety of the treatment will be evaluated by AEs, physical exams, clinical laboratory 
tests, and vital signs. 
In addition to routine safety assessments, the proportion of subjects experiencing a 
rejection and/or graft versus host disease will be summarized by treatment group.  
8.2 
Statistical and Analytical Methods  
8.2.1 
Statistical Model  
8.2.1.1 
Time to Event Variables 
A non-parametric model will be assumed with estimation of medians based on Kaplan-
Meier methods. Subjects without alleviation of symptoms will have their time censored at 
the last available observation that a complete assessment was made. 
For the purpose of comparing treatment groups, it will be assumed that their respective 
distributions for the primary endpoint differ only by a shift in location. 
8.2.1.2 
Dichotomous Variables and Viral Load  
For the endpoints defined dichotomously in terms of events or symptoms including the 
development of resistance, it will be assumed that the number of patients experiencing 
the event or exhibiting the symptom will have a binomial distribution. 
For the continuous endpoints of viral load at Day 1, 2, 6, 8, 11, 15, and 40 no model will 
be assumed.  
8.2.2 
Sample Size 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 
90% of enrolled patients will have laboratory-confirmed influenza, there will be 75 
patients in each treatment arm in the population evaluable for the development of 
resistance.  The following table shows the 95% Pearson-Clopper confidence 
intervals that would result with a sample size of 75 patients in a treatment arm if 
certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of 
development resistance will be monitored in a blinded fashion, in order to ensure a 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 36 


reasonable precision for the estimation.  An additional number of patients may be 
enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the 
assessment of safety.  This number of patients would provide estimates of adverse 
event rates with similar precision. 
8.2.3 
Hypothesis Testing  
Formal hypothesis testing will be not performed, instead inferences will be based on 
comparison of confidence intervals.  
8.2.4 
Analysis Populations 
Three main patient populations will be used for the analysis of data from this study; the 
Safety Population, the Intent-to treat Population and the Intent-to-Treat Infected 
Population.  Detailed definitions of these populations will be given in the SAP.  
8.2.4.1 
Intent to Treat Population 
All patients randomized will be included in the intent to treat population [Patients will be 
assigned to treatment groups as randomized for analysis purposes]. 
8.2.4.2 
Intent to Treat Infected Population 
All patients randomized and with laboratory confirmation of influenza infection, 
excluding patients infected with oseltamivir-resistant influenza at baseline, will be 
included in the intent to treat influenza infected population [Patients will be assigned to 
treatment groups as randomized for analysis purposes]. 
The ITTI Population will be the primary population for the summary and analysis of the 
development of resistance and the efficacy variables. 
8.2.4.3 
Subpopulations 
A subpopulation of the ITTI population will be defined comprising patients who 
received their first dose of study medication within 48 hours of influenza symptom 
onset for the comparison of efficacy endpoints with the age appropriate placebo 
treated patients (pediatric or adult) from the registration trials. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 37 


In order to evaluate the potential for relapse, the following two subpopulations of the 
ITTI population will be evaluated:  
• patients not shedding virus as assessed by culture on Day 11 
• patients not shedding virus as assessed by RT-PCR on Day 11 
 
Viral shedding and RT-PCR at days 15 and 40 will be evaluated in these subpopulations. 
Based on the proportion of subjects hospitalized, an additional subpopulation may be 
defined to evaluate the length of hospitalization for hospitalized subjects. 
Likewise, based on the proportion of children enrolled additional subpopulations of 
children and adults will be created to evaluate the course of influenza in children and 
adults.  
8.2.5 
Efficacy Analysis 
For the analysis of time to alleviation of all clinical symptoms, the following two 
assessments will be made independently of each other and without regard to the 
outcomes in each case. 
• Comparison to placebo control from pivotal registration trials  
 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is 
comparable to the subpopulation of patients in the current study whose first dose 
of study medication was within 48 hours of symptom onset.  For this population, a 
median time to resolution of all clinical influenza symptoms will be determined along 
with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.  These confidence intervals 
will be compared individually to the placebo control confidence interval described 
above as a potential means of establishing treatment effects. 
• Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval.  
This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences. For example, if it does not contain 
the value zero a difference will have been established.   
For the dichotomous endpoints, the proportion experiencing the event or symptom, and 
its associated 95% confidence interval will be derived for each treatment group.  Where 
possible, the corresponding confidence intervals from the placebo control population will 
be presented for comparison to those derived for the active treatment groups in this trial. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 38 


The continuous secondary endpoint time to resolution of fever will be analyzed as for the 
primary efficacy endpoint.  
For the continuous endpoints of viral load (log10TCID50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, standard deviation, median, minimum and 
maximum) will be derived for each treatment group. 
8.2.6 
Safety Data Analysis 
The safety analysis population will include all subjects who receive at least one dose and 
had a safety assessment performed post randomization.  All safety variables will be 
summarized and presented in tables based on this safety population. 
8.2.7 
Analysis of Resistance 
For the summary of the development of resistance for each treatment arm, 95% 
confidence intervals will be provided with the estimated rates.  Further details are 
available in the Resistance Plan for NV20234.  These data will be summarized in a 
report separate from the final study report. 
8.2.7.1 
Exclusion of Data from Analysis 
Efficacy data collected from any patient who begins treatment with another antiviral for 
influenza (for example, amantadine, rimantadine, laninamivir, peramivir, or 
zanamavir), after the other antiviral treatment commences, will be excluded from the 
primary and secondary efficacy analyses.  Such patients will be considered failures to 
oseltamivir treatment in the analyses.  Further details will be provided in the SAP. 
8.2.7.2 
Interim Analysis 
No interim analyses are planned.  
8.2.8 
Other Analyses 
Further exploratory analysis, (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the SAP. 
9. 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs against the investigator’s records by the study monitor [source document 
verification], and the maintenance of a drug–dispensing log by the investigator.  
The data collected will be entered into the study database from the working copy of the 
CRF faxed from the site. 
A comprehensive validation check program will verify the data and discrepancy reports 
will be generated accordingly for resolution by the investigator.  As patients complete the 
study [or prematurely withdraw] and their signed CRFs become available, a second data 
entry will be performed from the original, signed CRF.  A comparison check will be run 
to identify and resolve any discrepancies between the first and second data entry. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 39 


Throughout the study the Study Management Team [SMT] will review data according to 
the SMT Data Review Plan as described in the Data Quality Plan.  
9.1 
Assignment of Preferred Terms and Original Terminology 
For classification purposes, preferred terms will be assigned by the sponsor to the original 
terms entered on the CRF, using the current version of MedDRA (Medical Dictionary for 
Regulatory Activities terminology) for adverse events and diseases and the INN 
(International Non-Proprietary name) drug terms and procedures dictionary for 
treatments and surgical and medical procedures. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 40 


10. 
REFERENCES 
1. 
Murphy B.G and Webster R.G.  Orthomyxoviruses. Chapter 46.  Fields 
Virology 3rd Edition, Eds:  Fields B.N, Knipe D.M, Howley P.M et al. Pub 
Lippincott.Raven.  1996.  p1397 – 1445.  
2. 
World Health Organization. Influenza. Fact Sheet No. 211. March, 2003. 
3. 
Ison Michael, G., P. Mishin Vasiliy, J. Braciale Thomas, G. Hayden-
Frederick, and V. Gubareva Larisa., Comparative activities of oseltamivir and 
A-322278 in immunocompetent and immunocompromised murine models of 
influenza virus infection. The Journal of infectious diseases, 2006. 193(6): p. 
765-72 . 
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5. 
Vilchez Regis, A., K. McCurry, J. Dauber, A. Lacono, B. Griffith, et al., 
Influenza virus infection in adult solid organ transplant recipients. American 
journal of transplantation : official journal of the American Society of 
Transplantation and the American Society of Transplant Surgeons, 2002. 
2(3): p. 287-91. 
6. 
Ljungman, P., K.N. Ward, B.N. Crooks, A. Parker, R. Martino, et al., 
Respiratory virus infections after stem cell transplantation: a prospective 
study from the Infectious Diseases Working Party of the European Group for 
Blood and Marrow Transplantation. Bone marrow transplantation, 2001. 
28(5): p. 479-84. 
7. 
Nichols, W.G., A. Guthrie Katherine, L. Corey, and M. Boeckh, Influenza 
infections after hematopoietic stem cell transplantation: risk factors, mortality, 
and the effect of antiviral therapy. Clinical infectious diseases : an  official 
publication of the Infectious Diseases Society of America, 2004. 39(9): p. 
1300-6. 
8. 
Investigator Brochure for Tamiflu® (oseltamivir phosphate) 11th version 
June 2010.  
9. 
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10. 
January 14, 2006 CDC Health Alert Notice. CDC Recommends against the 
use of amantadine and rimantadine for the treatment or prophylaxis of 
influenza in the United States during the 2005 – 2006 Influenza season. As 
assessed on April 3, 2006 at http://www.cdc.gov/flu/han011406.htm.  
11. 
Kaiser, L., C. Wat, T. Mills, P. Mahoney, P. Ward, et al., Impact of 
oseltamivir 
treatment 
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influenza-related 
lower 
respiratory 
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complications and hospitalizations. Archives of internal medicine, 2003. 
163(14): p. 1667-72.  
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12. 
Whitley, R.J., F.G. Hayden, K.S. Reisinger, N. Young, R. Dutkowski, D. Ipe, 
R.G. Mills, and P. Ward, Oral oseltamivir treatment of influenza in children. 
The Pediatric infectious disease journal, Feb 2001, vol. 20, no. 2, p. 127 33, 
ISSN: 0891 3668., 2001. 
13. 
Machado, C.M., L.S.V. Boas, A.V.A. Mendes, I.F. da Rocha, D. Sturaro, et 
al., Use of Oseltamivir to control influenza complications after bone marrow 
transplantation. Bone marrow transplantation, 2004. 34(2): p. 111-4.   
14. 
Dutkowski, R., B. Thakrar, E. Froehlich, P. Suter, C. Oo, et al., Safety and 
pharmacology of oseltamivir in clinical use. Drug safety : an international 
journal of medical toxicology and drug experience, 2003. 26(11): p. 787-801. 
15. 
He, G., J. Massarella, and P. Ward, Clinical pharmacokinetics of the prodrug 
oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinetics. 
1999 Dec. 37(6):471-84. Review.  
16. 
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17. 
Levey Andrew, S., J. Coresh, E. Balk, T. Kausz Annamaria, A. Levin, et al., 
National Kidney Foundation practice guidelines for chronic kidney disease: 
evaluation, classification, and stratification. Annals of internal medicine, 
2003. 139 (2): p. 137-47. 
18. 
Hogg Ronald, J., S. Furth, V. Lemley Kevin, R. Portman, J. Schwartz- 
George, et al., National Kidney Foundation's Kidney Disease Outcomes 
Quality Initiative clinical practice guidelines for chronic kidney disease in 
children and adolescents: evaluation, classification, and stratification. 
Pediatrics, 2003. 111(6 Pt 1): p. 1416-21. 
19. 
Ferrara, J.L. and H.J. Deeg, Graft-versus-host disease. The New England 
journal of medicine, 1991. 324(10): p. 667-74. 
20. 
Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. 
Harrison's Principles of Internal Medicine. 17th ed. The McGraw Hill 
companies, Inc; 2008.  
21. 
CDC http://www.cdc.gov/flu/protect/hiv-flu.htm as assessed on 27 
October 2010. 
22. 
Caselli D , Carraro F, Castagnola E, Ziino O, Frenos S, et al. Morbidity 
of pandemic H1N1 influenza in children with cancer. Pediatr Blood 
Cancer. 2010;55:226–28. 
23. 
Tramontana AR , George B, Hurt AC, Doyle JS, Langan K, et al. 
Oseltamivir resistance in adult oncology and hematology patients 
infected with pandemic (H1N1) 2009 virus, Australia. Emerging 
Infectious Diseases. 2010;16(7):1068-75. 
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24. 
Chironna M, Tafuri S, Santoro N, Prato R, Quarto M, et al. A 
nosocomial outbreak of 2009 pandemic influenza A (H1N1) in a pediatric 
oncology ward in Italy (October-November 2009), Eurosurveillance. 7 
Jan 2010;15(1). 
25. 
Launes C, Rives S, Catala A, Berrueco R, Toll T , et al. pandemic 
influenza A (2009 H1N1) in children with acute lymphoblastic leukemia. 
Br J Haematol. Jun 2010;149(6):874-8. 
26. 
Clinical Study Report Protocol NV20235 Research Report No. 
 
27. 
AIDS 2010, DOI:10.1097/QAD.0b013e32833d2096. 
28. 
Akyuz S, Yilmaz A, Bulbul M, Erdogan O, Renda R, et al. Do 
immunosupressive patients really have a severe outcome with H1N1 
virus infection? Journal of Tropical Pediatrics. 2010. 
29. 
Mellouli F, Ouederni M, Dhouib N, Hajkacem MA, Slim A, et al. 
Successful treatment of influenza A virus by oseltamivir in bone marrow 
transplant recipients. Pediatr Transplantation. 2010;14:178–181. 
30. 
Kumar D, Michaels MG, Morris MI, Green M, Avery RK, et al on behalf 
of the American Society of Transplant H1N1 Collaborative Study Group. 
Lancet. 2010 Aug;10;pg 521 -6. 
31. 
Fox BD, Raviv Y, Rozengarten D, Rusanov V, Bakal I, et al. Pandemic 
influenza (H1N1): Impact on lung transplant recipients and candidates. J 
Heart Lung Transplant. 2010. 
32. 
Ng BJH, Glanville AR, D’Costa J, Snell G, Musk M, et al. The combined 
Australian experience with human swine influenza H1N1 in lung 
transplant recipients. S141 (abstract). 
33. 
Ison MG, Sharma A, Shepard JO, Wain JC, Ginns LC. Outcome of 
Influenza Infection Managed With Oseltamivir in Lung Transplant 
Recipients. J Heart Lung Transplant 2008;27:282-88. 
34. 
Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza 
virus: January 2010. Wkly Epidemiol Rec 2009b; 85(6): 37-40. 
35. 
Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of 
drug-resistant influenza virus from immunocompromised patients: a 
case series. J Infect Dis 2006; 193(6): 760-764. 
36. 
Hayden FG. Antiviral resistance in influenza viruses: clinical and 
epidemiological aspects. In: Antimicrobial drug resistance: clinical and 
epidemiological aspects, Vol 2 (Infectious Diseases). (Ed. Mayers DL). 
Humana Press, 2009; 1st: 1011-1034. 
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37. 
Klein, Marina B., Ying Lu, Lina DelBalso, Stephanie Cote´ and Guy 
Boivin. Influenza virus Infection Is a Primary Cause of Febrile 
Respiratory Illness in HIV Infected Adults, Despite Vaccination. Clinical 
Infectious Diseases 2007; 45:234–40. 
38. 
Lee N, Chan PK, Hui DS, Rainer TH, Wong E, Choi KW, Lui GC, Wong 
BC, Wong RY, Lam WY, Chu IM, Lai RW, Cockram CS, Sung JJ. Viral 
loads and duration of viral shedding in adult patients hospitalized with 
influenza. J Infect Dis. 2009 Aug 15;200(4):492-500. 
39. 
Quick Facts for Clinicians on Antiviral Treatments for H1N1 Influenza. 
2009 
Nov. 
From 
http://www.cdc.gov/H1N1flu/antivirals/facts_clinicians.htm accessed on 
May 14th, 2010. 
40. 
Allen U, Blumberg EA, Fischer SA, Green M, Ison MG, Kotton CN, et al. 
American Society of Transplantation (AST) Infectious Diseases 
Community of Practice / Transplant Infectious Disease Section of The 
Transplantation Society (TTS) Guidance On Novel Influenza A/H1N1. 
[cited 2010 Oct 28]. 2009 Dec 03. Available from: www.a-s-
t.org/files/pdf/ast_h1n1_guidance.pdf. 
41. 
Katzung BG, Masters SB, Trevor AJ (ed). Basic and clinical 
pharmacology. 11th edition. Tata McGraw-Hill Companies, Inc., New 
York: 2009: 971-80.  
42. 
Salvana EMT, Salata RA. Infectious complications associated with 
monoclonal antibodies and related small molecules. Clin Microbiol Rev. 
2009 Apr;22(2): 274-90. 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 44 


PART II: 
ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
Local Regulations/Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the subject.  For studies conducted in the EU/EEA countries, the 
investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].  
For studies conducted in the USA or under US IND, the investigator will additionally 
ensure that the basic principles of “Good Clinical Practice” as outlined in the current 
version of 21 CFR, subchapter D, part 312, “Responsibilities of Sponsors and 
Investigators”, part 50, “Protection of Human Subjects”, and part 56, “Institutional 
Review Boards”, are adhered to. 
In other countries where “Guideline for Good Clinical Practice” exist Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
Informed Consent  
It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain written informed consent from each subject 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study.  For subjects not qualified or incapable of 
giving legal consent, written consent must be obtained from the legally acceptable 
representative.  In the case where both the subject and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the entire 
informed consent discussion.  After the subject and representative have orally consented 
to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood.  The 
investigator or designee must also explain that the subjects are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason.  The Case Report 
Forms [CRFs] for this study contain a section for documenting informed subject consent, 
and this must be completed appropriately.  If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and updated 
if necessary.  All subjects [including those already being treated] should be informed of 
the new information, given a copy of the revised form and give their consent to continue 
in the study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written consent. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 45 


11.3 
Independent Ethics Committees/Institutional Review Board  
Independent Ethics Committees [non-US]:  This protocol and any accompanying 
material provided to the subject [such as subject information sheets or descriptions of the 
study used to obtain informed consent] as well as any advertising or compensation given 
to the patient, will be submitted by the investigator to an Independent Ethics Committee.  
Approval from the committee must be obtained before starting the study, and should be 
documented in a letter to the investigator specifying the date on which the committee met 
and granted the approval. 
Any modifications made to the protocol after receipt of the Independent Ethics 
Committee approval must also be submitted by the investigator to the Committee in 
accordance with local procedures and regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee. 
Institutional Review Board [US]:  It is the understanding of the sponsor that this 
protocol [and any modifications] as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board.  This board must operate in 
accordance with the current Federal Regulations.  A letter or certificate of approval will 
be sent by the investigator to the  sponsor or designee prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between 
an appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial].  Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Clinical Science Leader/Clinical Pharmacologist and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required.  Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial subjects, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g. change in monitor[s], change of telephone 
number[s]. 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 46 


14. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
14.1 
Investigator's Files / Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] subject clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence etc.  
Subject clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and subject screening and enrollment logs.  
The Investigator must keep these two categories of documents on file for at least 15 years 
after completion or discontinuation of the study.  After that period of time the documents 
may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them to 
another location, Roche must be notified in advance. 
If the Investigator can not guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
14.2 
Source Documents and Background Data 
The investigator shall supply the sponsor or designee on request with any required 
background data from the study documentation or clinic records.  This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected.  In 
case of special problems and/or governmental queries or requests for audit inspections, it 
is also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. 
14.3 
Audits and Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees, or to health authority inspectors after appropriate 
notification.  The verification of the CRF data must be by direct inspection of source 
documents. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 47 


14.4 
Case Report Forms 
For each patient enrolled, a CRF must be completed and signed by the principal 
investigator or authorized delegate from the study staff.  This also applies to records for 
those patients who fail to complete the study [even during a pre-randomization screening 
period if a CRF was initiated].  If a patient withdraws from the study, the reason must be 
noted on the CRF.  If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
All forms should be typed or filled out using indelible ink, and must be legible.  Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed 
and dated by the investigator or his/her authorized delegate.  The investigator should 
ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
sponsor or designee in the CRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the CRF.  
The investigator [or his/her deputy] agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On CRFs or other documents 
submitted to the sponsor or designee, subjects should not be identified by their names, but 
by an identification code.  The investigator should keep a subject enrollment log showing 
codes, names and addresses.  The investigator should maintain documents not for 
submission to Roche, e.g., subjects’ written consent forms, in strict confidence. 
17. 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  This allows the sponsor or designee to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the investigator. 
In accord with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator will be designated by mutual agreement. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 48 


Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel.  Authorship will be determined by mutual agreement. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 49 


Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD  
Calculation of Creatinine Clearance 
Conversion Factor for Serum Creatinine: 
Conventional Units (mg/dL) = SI Units (µmol/L) ÷ 88.4   
Age = number of years (12 years 11 months = 12 years) 
 
Estimated Creatinine Clearance according to Cockcroft-Gault [17] 
 (for patients ≥ 18 years): 
¾ Males 
Creatinine  
Clearance (mL/min) = 
 
[(140 – age) X Body Weight (kg)] ÷ [72 X Serum Creatinine (mg/dL)] 
 
¾ Females  
Creatinine Clearance = above equation X 0.85 
 
Estimated Creatinine Clearance according to Schwartz equation [18]  
(for patients < 18 years): 
Creatinine Clearance 
(mL/min/1.73 M2) = 
 
k X Height (cms) ÷  Serum Creatinine (mg/dL) 
 
Value for k:  
k 
Age (years) 
0.45 
< 2 
0.55 
≥ 2 to < 13 
0.7 
≥ 13 to < 18 (males) 
0.55 
≥ 13 to < 18 
(females) 
 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 50 


Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD (Cont.) 
Grading of Chronic GVHD [19] 
Type of Disease 
Extent of Disease 
Limited 
Localized 
skin 
involvement, 
liver 
dysfunction or both 
Extensive 
Generalized skin involvement 
 
Localized 
skin 
involvement 
or 
liver 
dysfunction plus any one of the following: 
   1. Chronic aggressive hepatitis, bridging 
necrosis or cirrhosis 
   2. Eye involvement (Schirmer’s test, 
< 5 mm) 
   3. Involvement of mucosalivary glands 
   4. Mucosal involvement (on lip biopsy) 
   5. Involvement of other target organs  
 
 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 51 


Appendix 2 
Adult Patient Diary Data and Symptom Record  
The purpose of the electronic diary is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study. Temperature and date 
and time of drug administration will also be recorded on the electronic patient diary. 
Scoring of Symptoms. 
Please answer All of the questions yourself by checking one box for each row. 
The information you provide is very important and will remain strictly confidential. 
 
 
 
 
    absent 
 mild 
        moderate 
      severe 
 
 
 
 
        0                  1 
 
2 
         3 
 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 52 


Appendix 3 
Diary Data for Children  
Temperature and date and time of drug administration will also be recorded on the 
electronic patient diary. 
 
Temperature:  
 
 
.  
C/F 
 
Symptoms of influenza-like illness 
Please mark one box only per question 
Item 
 
No 
Problem 
0 
 
Minor 
Problem 
1 
 
Moderate 
Problem 
2 
 
Major 
Problem 
3 
Don’t Know 
or not 
Applicable 
1. 
Poor appetite........................................
 
 
 
 
 
2. 
Not sleeping well.................................
 
 
 
 
 
3. 
Irritable, cranky, fussy.........................
 
 
 
 
 
4. 
Feels unwell.........................................
 
 
 
 
 
5. 
Low energy, tired.................................
 
 
 
 
 
6. 
Not playing well ..................................
 
 
 
 
 
7. 
Crying more than usual........................
 
 
 
 
 
8. 
Needing extra care...............................
 
 
 
 
 
9. 
Clinginess............................................
 
 
 
 
 
10. Headache .............................................
 
 
 
 
 
11. Sore throat ...........................................
 
 
 
 
 
12.   Muscle aches or pains..........................
 
 
 
 
 
13. Fever....................................................
 
 
 
 
 
14. Cough ..................................................
 
 
 
 
 
15. Nasal congestion, runny nose ..............
 
 
 
 
 
16. Vomiting..............................................
 
 
 
 
 
17. Not interested in what’s going on 
 
 
 
 
 
18. Unable to get to get out of bed 
 
 
 
 
 
 
This form was filled out by:          
                                                        1. 
 Parent 
 
2. 
 Other relative 
 
3. 
Nanny 
 
4. 
Subject 
 
5. 
 Other     specify______________________________________________ 
 
Date of Assessment 
 
 
 
 
 
 
 
dd 
mm 
yy 
Time of Assessment 
 
 
 
 
 
h 
min 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 53 


Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug 
PROBABLE [must have first three] 
This category applies to those AEs which are considered, with a high degree of certainty, 
to be related to the test drug.  An AE may be considered probable, if: 
1. It follows a reasonable temporal sequence from administration of the drug. 
2. It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the subject. 
3. It disappears or decreases on cessation or reduction in dose.  [There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., [1] bone marrow depression, [2] tardive 
dyskinesias]. 
4. It follows a known pattern of response to the suspected drug. 
5. It reappears upon rechallenge. 
 
POSSIBLE [must have first two] 
1. This category applies to those AEs in which the connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty. An AE may be 
considered possible if, or when: 
2. It follows a reasonable temporal sequence from administration of the drug. 
3. It may have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
4. It follows a known pattern of response to the suspected drug. 
 
REMOTE [must have first two] 
1. In general, this category is applicable to an AE which meets the following criteria: 
2. It does not follow a reasonable temporal sequence from administration of the drug. 
3. It may readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
4. It does not follow a known pattern of response to the suspected drug. 
5. It does not reappear or worsen when the drug is readministered. 
 
UNRELATED 
This category is applicable to those AEs which are judged to be clearly and 
incontrovertibly due only to extraneous causes [disease, environment, etc.] and do not 
meet the criteria for drug relationship listed under remote, possible, or probable. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 54 


Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug (Cont.) 
 
Probable 
Possible 
Remote 
Unrelated 
Clearly due to extraneous causes 
– 
– 
– 
+ 
 
 
 
 
 
Reasonable temporal association with drug 
administration 
+ 
+ 
– 
– 
 
 
 
 
 
May be produced by subject clinical state, 
etc. 
– 
+ 
+ 
+ 
 
 
 
 
 
Known response pattern to suspected drug 
+ 
+ 
– 
– 
 
 
 
 
 
Disappears or decreases on cessation or 
reduction in dose 
+ 
– 
– 
– 
 
 
 
 
 
Reappears on rechallenge 
+ 
– 
– 
– 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 55 


Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– is fatal; [results in death] [NOTE: death is an outcome, not an event]. 
– is Life-Threatening    [NOTE: the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer to 
an event which could hypothetically have caused a death had it been more severe]. 
– required in-patient hospitalization or prolongation of existing hospitalization; 
– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor or designee is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definitions above. These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator. For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply)  
– Pre-existing/Underlying disease - specify  
– Study treatment – specify the drug(s) related to the event 
– Other treatment (concomitant or previous) – specify 
– Protocol-related procedure 
– Other (e.g. accident, new or intercurrent illness) - specify 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious. For 
example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 56 


Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
[Cont.] 
A serious adverse event occurring during the study or which comes to the attention of the 
investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will 
include copies of hospital case reports, autopsy reports and other documents when 
requested and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs page 
of the CRF: intensity, relationship to test substance, action taken, and outcome to date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor  
ROCHE HEADQUARTERS CONTACT for SAEs: Clinical Operations/Clinical Science  
Within the US, weekends, holidays and after 5:00 pm, call 
 and ask for 
the physician on call.  Outside the US, call the local emergency contact number provided 
by the Monitor. 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 57 


Appendix 6 
Primary Immunodeficiency Conditions 
Category 
Conditions 
Adenosine deaminse (ADA) deficiency 
Artemis deficiency (SCIDA) 
CD45 deficiency 
Cernunnos deficiency 
DNA ligase IV (LIG4) deficiency 
Interleukin receptor γ chain deficiency (X-linked SCID) 
Janus-associated kinase 3 (JAK3) deficiency 
Recombinase activating gene (RAG 1 / 2) deficiency  
Reticular dysgenesis 
Severe Combined 
Immunodeficiency (SCID) 
TAP- 1 or TAP- 2 deficiency (MHC class I deficiency) 
CD8 deficiency 
diGeorge syndrome  
Interleukin 7 receptor α (IL7RA) deficiency 
MHC class II deficiency 
LCK deficiency 
Orai 1 deficiency 
Nude syndrome (wing helix nude deficiency) 
Purine nucleotide phosphorylase (PNP) deficiency 
T cell receptor deficiency (CD 3γ, δ, ε, and ζ 
deficiencies) 
Primary T cell Deficiency 
Zap 70 tyrosine kinase deficiency 
X-Linked CD40 ligand deficiency 
X- Linked IKK-γ (NEMO) deficiency 
Predominantly Antibody 
Deficiency 
CD40 deficiency 
Interferon γ receptor deficiency 
Other Well-Defined 
immunodeficiency Syndromes 
X-Linked lymphoproliferative syndrome 
Adapted from Table 310-2: p2056 reference 20. 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 58 


Appendix 7 
Hematologic Malignancies and their Effect on the Immune 
System 
Malignancy 
Effect on immunity 
ALL, lymphomas 
suppression of hematopoiesis, neutropenia, 
lymphocyte dysfunction 
CLL, small lymphocytic lymphoma 
hypogammaglobulinemia, increased susceptibility 
to infections, autoimmune anemia or 
thrombocytopenia 
Hairy cell leukemia, myelodysplastic syndromes 
pancytopenia 
peripheral T cell and NK neoplasms 
lymphocyte dysfunction, increase in immature 
cells 
Hodgkin’s disease  
suppression of cell-mediated immunity 
AML 
neutropenia, anemia, thrombocytopenia, 
predisposed to infections, lymphocyte dysfunction
CML 
anemia, granulocyte dysfunction in some patients 
in early phase and in most patients in blast phase
Adapted from reference 20. 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 59 


Appendix 8 
Immunosuppressive Medications 
Class 
Category 
Drugs 
Corticosteroids 
- 
Glucocorticoids (oral, sc, im, iv) 
Alkylating agents 
cyclophosphamide, busulfan, 
mechlorethamine, chlorambucil, 
melphalan, carmustine, lomustine, 
ifosfamide, procarbazine, dacarbazine, 
temozolomide, cisplatin, carboplatin, 
oxaliplatin 
Anti-metabolites 
methotrexate, 6-mercaptopurine, 
azathioprine 
Anti-tumor antibiotics 
bleomycin, actinomycin D, mitomycin 
C, etoposide, topotecan, irinotecan, 
doxorubicin, daunorubicin, idarubicin, 
epirubicin, mitoxantrone 
Anti-mitotic agents 
vincristine, vinblastine, vinorelbine, 
paclitaxel, docetaxel, estramustine 
phosphate, NAB-paclitaxel 
Cytotoxic agents[20] 
Molecularly targeted 
agents 
imatinib, tretinoin,  bexarotene, 
denileukin,  diftitox, gefitinib, 
erlotinib, dasatinib, sorafenib, 
sunitinib 
Calcineurin inhibitors 
- 
cyclosporine, tacrolimus 
mTOR inhibitors 
(proliferation-signal 
inhibitors) 
- 
sirolimus, everolimus 
Immunosuppressive 
antibodies 
- 
anti lymphocyte and antithymocyte 
globulins (ALG and ATG) 
Adalimumab 
Infliximab 
Cetrolizumab 
Etarnecept 
Basiliximab 
Inhibitors of  pro 
inflammatory cytokines 
Daclizumab 
Adhesion cell modulators Natalizumab 
Abatacept 
Alefacept 
T-cell inhibitors 
Muromonab 
Rituximab 
90Y-Ibritumomab 
B-cell inhibitors 
131I-Tositumomab 
Anti-CD33 
Gemtuzumab 
Monoclonal antibodies [41, 42] 
Anti- CD52 
Alemtuzumab 
Others 
- 
mycophenolate mofetil, thalidomide 
Compiled from Table 81-2: p521-24 reference 20 and references 41, 42. 
 
CONFIDENTIAL  Roche Protocol NV20234C  (Ro 64-0796)  - Page 60 


 
Title
28-Sep-2012 14:52:40
Date and Time (UTC)
Clinical Science Leader
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL STATEMENT 
 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board.  It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Oseltamivir—F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version D 
PROTOCOL 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, MULTI-CENTER 
TRIAL EVALUATING CONVENTIONAL AND HIGH DOSE 
OSELTAMIVIR IN THE TREATMENT OF IMMUNOCOMPROMISED 
PATIENTS WITH INFLUENZA 
PROTOCOL NUMBER: NV20234 
VERSION NUMBER: D 
EUDRACT NUMBER: 
2006-002468-24 IND NUMBER: 
53,093 
TEST PRODUCT: 
oseltamivir (Tamiflu® RO 64-0796) 
MEDICAL MONITOR: 
, M.D.  
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version A:  14 June 2007 
DATES AMENDED: 
Version B:  21 July 2008 
Version C:  28 March 2011 
Version D:  See electronic date stamp below 


PROTOCOL AMENDMENT, VERSION D:  
RATIONALE 
Protocol NV20234 has been amended to include the Southern Hemisphere and allow 
global enrollment into this clinical trial.  In order to further facilitate enrollment, inclusion 
and exclusion criteria have been amended to include as much of the 
immunocompromised patient population as possible. 
Additional changes to the protocol are as follows: 
• 
Update to the safety reporting section to include SAE reporting timeline changes 
from within one working day to within 24 hours of the knowledge of its occurrence; 
this change is in line with new E.U. legislation. 
• 
Allowance for self-swabbing at home when there is a home visit planned, thereby 
allowing the sample to be shipped in an expedited manner. 
• 
Reintroduction of the pharmacokinetic (PK) study component that was present in 
Version A of this protocol.  However, for this protocol version, a sparse PK sampling 
schedule will be used in which blood samples are not required to be collected on 
multiple days.  This is possible due to the additional data available on Tamiflu®.  
This component of the study will only be applicable to patients who provide 
additional consent, thereby avoiding recruitment issues should a patient not want to 
take part in the PK sampling aspect of this study.  
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
Oseltamivir—F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version D 
2 


 
PROTOCOL AMENDMENT, VERSION D: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
References have been updated throughout the document 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The list of abbreviations and definitions of terms has been updated to reflect the 
changes to the protocol, where applicable. 
SECTION 1.1:  BACKGROUND
The neuraminidase (NA) protein is proteins are the second major surface protein proteins 
in the virion and plays play a role in enhancing virus penetration of the mucus layer 
around the target cell and in release of virus from the cell surface.  The matrix proteins, 
M1 and M2 appear to trigger the disintegration of the M1 complex during virus fusion 
with the cell and may also be involved in the maturation of the HA prior to assembly of 
new virus particles.  The M2 protein triggers the disintegration of the virion during virus entry 
into the cell and may also be involved in protecting the HA prior to assembly of new virus 
particles. 
SECTION 1.1.1:  Influenza in the Immunodeficient Population 
. . . 
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T cell count of < 200/μL (AIDS defining) are highly 
susceptible to opportunistic disease [16].  However, CD4 counts < 500/μL are considered 
abnormal in HIV-infected individuals, and therefore these individuals are also more susceptible to 
infection.   
SECTION 1.2:  RATIONALE FOR THE STUDY 
Because of the increasing body of evidence (Section 1.1.2), oseltamivir is now 
recommended in national guidelines as an option for the treatment of influenza in the 
transplant population [37].  As the transplant population is considered representative, 
which comprises a significant portion of the immunocompromised population, the.  However, 
there is limited data on safety and efficacy of oseltamivir use in this population.  The primary 
objective of this study is to evaluate safety and resistance, while evaluating efficacy as a 
secondary objective, in the broader immunocompromised patient population, who are 
considered at increased risk of viral infection. 
SECTION 2.2:  SECONDARY OBJECTIVES 
• 
The time to resolution of influenza symptoms. 
Oseltamivir—F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version D 
3 


 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis).  
• 
The virologic course of influenza (proportion shedding and viral loads at different 
time points). 
• 
To estimate the population pharmacokinetics of oseltamivir and oseltamivir carboxylate (e.g., 
clearance, volume of distribution) in immunocompromised patients with confirmed 
influenza infection, through the application of established population pharmacokinetic (PK) 
models to the sparse plasma concentration data generated.  
SECTION 3.1.1.3:  Rational for Sparse PK Sampling 
Limited PK sampling will be done in this protocol, in patients who have provided additional 
consent, and is justifiable in this study for the following two reasons: 
• 
There are already tested and qualified population PK models available [36] that will be used 
to estimate exposure in the immunocompromised population on the basis of the data collected 
in this study, meaning extensive PK sampling over a steady-state dosing interval is not 
required.  
• 
The patient population in this study is likely to be very ill with a complex clinical picture 
and significant additional burden of treatment and monitoring due to their primary 
condition.  In this context, it makes ethical sense to minimize blood draws and assessments 
to only those absolutely essential to meet the objectives of the study and to ensure patient 
safety. 
 
SECTION 3.3:  CENTERS 
This will be a multicenter study with approximately 100 110 centers taking place in the 
Northern and Southern Hemispheres at approximately 125 centers. 
SECTION 4.2:  INCLUSION CRITERIA 
• 
Rapid diagnostic test, PCR, or viral culture positive for influenza in the 96 hours 
prior to first dose 
• 
Immunocompromised subject defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in Appendix 6) OR 
o Secondary immunodeficiency 
 
SOT with ongoing immunosuppression OR 
 
Allogenic HSCT with ongoing immunosuppression OR 
 
HIV with CD4 count < 200 < 500/mm3 and, in the investigator’s 
opinion, considered immunocompromised OR 
 
Hematologic malignancies (representative examples in 
Appendix 7) OR 
 
Systemic (e.g. enteric, sc, im or iv) immunosuppressive therapy, 
irrespective of medical indication, started at least 12 weeks prior 
to, and ongoing at the time of first dose of study drug 
(representative examples in Appendix 8) 
Oseltamivir—F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version D 
4 


 
 
SECTION 4.3:  EXCLUSION CRITERIA 
• 
SOT within 6 months of the time of randomization. 
• 
Have in the investigator’s opinion experienced acute rejection in the 4 weeks prior to 
randomization. 
• 
HSCT patients with no evidence of engraftment (engraftment is defined as the point 
at which a patient can maintain a sustained absolute neutrophil count (ANC) of 
> 500/mm3 and sustained platelet count of  ≥ 20,000/mm3, lasting  ≥ 3 consecutive 
days without transfusions). 
• 
HSCT subjects not discharged from hospital after their initial hospitalization for 
transplantation 
• 
Have clinical evidence for hepatic decompensation at the time of randomization 
(clinical icterus, ascites, hepatic encephalopathy, coagulopathy). 
• 
Have cirrhosis of the liver at the time of randomization. 
• 
Clinical evidence of severe hepatic impairment, defined as Child-Pugh grade C (score > 9) or 
decompensated cirrhosis. 
• 
Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration. 
• 
Have evidence of a serious secondary respiratory or disseminated infection that may 
confound or overlay the diagnosis and/or symptomatology of influenza. 
• 
Have evidence of active or uncontrolled opportunistic infections (bacterial, fungal, or 
viral including cytomegalovirus [CMV] or polyoma virus [BKV]) at the time of 
randomization.  Patients with HCV or HBV are not excluded.   
• 
Patients with co morbid conditions which are uncontrolled.  Uncontrolled is defined 
as disease requiring change of therapy or hospitalization in the 4 weeks preceding 
randomization.  Change of therapy is defined as dose increase or change of 
medication prior to onset of present influenza like illness. 
• 
Patients with gastrointestinal disorders which might interfere with their ability to 
absorb oral medication.  
• 
Allergy to the test medication. 
• 
Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation). 
• 
Influenza vaccination with live attenuated vaccine in the 2 weeks prior to 
randomization. 
• 
Antiviral treatment (example:  amantadine, rimantadine, oseltamivir, laninamivir, 
peramivir, zanamivir and ribavirin) for influenza in the 2 weeks prior to 
randomization. 
• 
Patients taking probenecid medication. 
• 
Patients who are pregnant or breast-feeding.   
Oseltamivir—F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version D 
5 


 
• 
Participation Participated in a clinical trial or expanded access trial with an 
investigational drug suspected/demonstrated to impact pathways important for the 
metabolism and excretion of oseltamivir in the 4 weeks prior to randomization or 
concomitantly with this study.   
 
TABLE 1:  SCHEDULE OF ASSESSMENTS AND PROCEDURES
Table 1 has been revised to reintroduce the PK sampling (blood assessment) that was 
present in Version A of this protocol, as well as allow for self-swabbing at home when 
there is a home visit planned.. 
SECTION 5.3:  CLINICAL ASSESSMENTS AND PROCEDURES 
At all visits subjects will receive the routine care for their primary illness.  Routine patient 
care (including the adjustment of doses of any of the immunosuppressive drugs) will be 
dictated by tests performed locally at the trial site.  For subjects unable to attend the clinic, 
provision will be made for swabbing to be conducted at home, when there is a home visit 
scheduled.  Training will be provided to site staff on how to perform this.  All safety labs will be 
sent to a central laboratory.  Results for these laboratory parameters will be used by the 
sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 1).  Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
Blood samples will be collected from patients who provide additional consent for PK sampling, as 
outlined in Section 5.5. 
SECTION 5.5:  PHARMACOKINETIC ASSESSMENTS 
/PHARMACODYNAMIC ASSESSMENTS 
Participation in PK assessments is not compulsory for this study.  Blood samples for the 
characterization of oseltamivir and oseltamivir carboxylate pharmacokinetics using a sparse 
sampling strategy will be collected from all patients who provide additional consent to participate 
in the PK assessments. 
Blood samples will be collected according to the Schedule of Assessments (Table 1) and as 
described below.  If these blood samples are collected at a home visit, site staff should ensure the 
PK blood sample handling processing is not compromised.  The time and date of the dose and 
blood samples should be captured.  Further details on pharmacokinetics/pharmacodynamics can 
be found in Sections 8.3.1 and 8.3.2.  
5.5.1 
Pharmacokinetic Assessments 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be collected at 
the following timepoints on Day 6, or any day after the 11th dose, using the following sampling 
approach: 
Oseltamivir—F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version D 
6 


 
• 
Within 30 minutes prior to the dose administration (e.g., 08:30 a.m.) 
• 
1.5 hours ± 30 minutes post-dose (e.g., 10:30 a.m. ± 30 min) 
• 
4 hours ± 60 minutes post dose (e.g., 1:00 p.m. ± 60 min) 
• 
8 hours ± 1.5 hours post dose (e.g., 5:00 p.m. ± 1.5 hr) 
 
For adults and adolescents, approximately 2 mL of blood will be taken at each timepoint; therefore, 
the total volume blood loss for PK assessments will be approximately 8 mL.  For pediatric subjects, 
not less than approximately 0.6 mL of blood will be taken at each timepoint; therefore, the total 
volume blood loss for PK assessments will be approximately 3.6 mL. 
The samples from this study are classified as Biological Substance, Category B.  
Plasma concentrations of oseltamivir and oseltamivir carboxylate will be measured by a specific 
and validated method.  Details on sampling procedures, sample storage, and shipment are 
provided in the Sampling Manual. 
5.5.2 Pharmacodynamic Assessments 
Nasal and throat swabs will be collected from individuals on the days specified in the schedule of 
assessments.  Specimens will be analyzed at a central laboratory.  The proportion of patients with 
viral shedding at each visit will be summarized. 
SECTION 6.2:  PREPARATION AND ADMINISTRATION OF STUDY DRUG 
Oseltamivir will be provided in two forms:  
1. 
Oseltamivir capsules containing 75 mg of active drug and packaging material 
consisting of pregelatinized starch, povidone, talc and sodium stearyl fumarate.  All 
participants 13 years and older will receive this dosage form.  Oseltamivir capsules 
should be stored at 25ºC. 
2. 
A pediatric suspension containing 12 mg oseltamivir per ml of reconstituted solution 
and the following excipients:  sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor).  All participants 12 years and under will receive this dosage form.  
Oseltamivir dry powder for oral suspension [pediatric syrup] should be stored at 
25ºC.  After reconstitutionbelow 30°C [86°F]).  Once reconstituted, the suspension 
should not be used for longer than 10 days.  Store constituted suspension  if stored 
under room temperature conditions (below 25°C) or for 17 days if stored under refrigeration 
at 2°C to 8ºC.  Do8°C (36°F to 46°F).  The suspension is not freeze suitable for freezing. 
For further details, refer to the Tamiflu® Investigator’s Brochure. 
SECTION 7.1.1.3:  Serious Adverse Events [Immediately Reportable to 
Roche] 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial.  The investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 24 hours 
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after the investigator learns of the event.  The following is a list of events that the investigator 
must report to the Sponsor within 24 hours after learning of the event, regardless of relationship 
to study drug: 
• 
Serious adverse events 
• 
Pregnancies 
 
SECTION 7.2.1:  Reporting of Serious Adverse Events [immediately 
reportable] 
Any clinical AE or abnormal laboratory test value that is serious [as defined in 
Section 7.1.1.3 above] and which occurs during the course of the study, regardless of 
the treatment arm, occurring from the enrollment visit (start of study screening 
procedures), must be reported to Roche or designee within one working day 
ofimmediately (i.e., no more than 24 hours after the investigator becomes aware of the event 
[expedited reporting]). 
SECTION 7.2.2:  Pregnancy 
A female subject must be instructed to stop taking the test “drug” and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should 
report all pregnancies within immediately (i.e., no more than 24 hours after the investigator 
becomes aware of the pregnancy) to the Sponsor or designee.  The investigator should 
counsel the subject, and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion 
of the pregnancy.  Pregnancies occurring within 28 days of treatment completion should 
be reported to Roche.  
SECTION 8.1.2:  Secondary Endpoints 
The following are the model-predicted PK secondary endpoints for both oseltamivir and 
oseltamivir carboxylate: 
• 
Steady-state area under the concentration–time curve from 0 to 12 hours (AUC0-12) 
) for both oseltamivir and oseltamivir carboxylate 
• 
Maximum plasma concentration (Cmax
) for both oseltamivir and oseltamivir carboxylate 
• 
Trough plasma concentration (Ctrough
 
The following model-predicted PK endpoints may be included, if appropriate:  
• 
Elimination half-life (t1/2) 
) 
• 
Time to maximum concentration (tmax
) 
• 
Elimination constant (ke
• 
Apparent clearance (CL/F) 
• 
Apparent volume of distribution (Vc/F) 
• 
Apparent total clearance of metabolite (CLm) 
• 
Last measurable concentration (Clast) and time to last measurable concentration (tlast)  
 
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SECTION 8.2.4.3:  Pharmacokinetic Evaluable Patient Population (PKEP) 
The PKEP population comprises all patients in the ITT population who have at least one post-
dose drug concentration measurement at a scheduled visit timepoint.  Patients may be excluded 
from the PKEP population if they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or have unavailable or incomplete data that may influence the PK 
analysis.  
Decisions on patient exclusion from the PK analysis will be made prior to database closure by the 
clinical pharmacologist.  Excluded patients will be documented along with the reason for 
exclusion. 
SECTION 8.3:  PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSIS 
8.3.1 
Pharmacokinetic Analysis 
The primary study variables are the model-predicted PK parameters:  steady-state AUC0-12, Cmax, 
and Ctrough of oseltamivir and oseltamivir carboxylate. 
Secondary model-predicted PK variables may be included for both oseltamivir and oseltamivir 
carboxylate, if appropriate:  t1/2, tmax, k , CL/F, Vc/F, CL
e
m, Clast and tlast. 
Individual and mean plasma concentrations at each sampling timepoint for oseltamivir and 
oseltamivir carboxylate will be presented by listings and descriptive summary statistics, 
including means, geometric means, medians, ranges, standard deviations, and coefficients of 
variation.  Individual and mean concentration-versus-time profiles will be plotted on linear and 
semi-logarithmic scales. 
Plasma concentration data from sparse sampling will be analyzed using an established population 
PK model to determine key exposure parameters (e.g., Cmax, Ctrough, and AUC).  For 
immunocompromised children aged 1 to 18 years, plasma oseltamivir and oseltamivir carboxylate 
concentrations will be modeled in NONMEM using a structure similar to a comprehensive 
population PK model, which was previously developed using plasma data of 
non-immunocompromised children and adults (ages 1 to 80 years) [36].  The basic structure 
consists of a 2-compartment model with first-order absorption and direct conversion of 
oseltamivir to oseltamivir carboxylate, while a 1-compartment model is used to account for the 
renal elimination of oseltamivir carboxylate from the plasma.  Body weight, evaluated using a 
power function and centered around 70 kg, is a statistically significant predictor of the CL/F for 
oseltamivir, and both CL/F and central volume of distribution (Vc/F) for oseltamivir carboxylate.  
For oseltamivir carboxylate, CrCl is also a significant predictor of CL/F, while Vc/F decreases 
linearly with age. 
8.3.2 
Pharmacodynamic Analysis 
If feasible, the relationship between PK exposure of oseltamivir carboxylate and viral shedding 
response data will be characterized using nonlinear mixed effects modeling (using software 
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NONMEM).  Relevant population pharmacodynamic (PD) parameters will be derived, and the 
influence of covariates will be investigated.  If deemed appropriate and necessary, data may be 
pooled with data from previous studies investigating oseltamivir and oseltamivir carboxylate in 
order to improve the model stability. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND AND RATIONALE............................................................. 20 
1.1 
Background ........................................................................... 20 
1.1.1 
Influenza in the Immunodeficient Population ......................... 20 
1.1.2 
Oseltamivir............................................................................. 22 
1.2 
Rationale for the Study .......................................................... 25 
2. 
OBJECTIVES.............................................................................................. 25 
2.1 
Primary Objective .................................................................. 25 
2.2 
Secondary Objectives............................................................ 25 
3. 
STUDY DESIGN ......................................................................................... 25 
3.1 
Overview of Study Design and Dosing Regimen................... 25 
3.1.1 
Rationale for Study Design.................................................... 26 
3.1.1.1 
Choice of Treatment Arms..................................................... 26 
3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours ................ 27 
3.1.1.3 
Rational for Sparse PK Sampling .......................................... 27 
3.1.1.4 
Interpretation of Study Results .............................................. 27 
3.1.2 
Rationale for Dose Selection and Adjustment ....................... 28 
3.1.3 
End of Study.......................................................................... 29 
3.2 
Number of Subjects/ Assignment to Treatment 
Groups................................................................................... 29 
3.3 
Centers.................................................................................. 29 
4. 
STUDY POPULATION................................................................................ 30 
4.1 
Overview................................................................................ 30 
4.2 
Inclusion Criteria.................................................................... 30 
4.3 
Exclusion Criteria................................................................... 31 
4.4 
Concomitant Medication and Treatment................................ 31 
4.5 
Criteria for Premature Withdrawal ......................................... 32 
4.6 
Replacement Policy [Ensuring Adequate 
Numbers of Evaluable Subjects]............................................ 32 
4.6.1 
For Subjects .......................................................................... 32 
4.6.2 
For Centers............................................................................ 33 
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5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES............................ 33 
5.1 
Screening Examination and Eligibility Screening 
Form ...................................................................................... 34 
5.2 
Procedures for Enrollment of Eligible Subjects...................... 35 
5.3 
Clinical Assessments and Procedures .................................. 35 
5.3.1 
Efficacy Assessments............................................................ 37 
5.3.2 
Safety .................................................................................... 37 
5.4 
Laboratory Assessments ....................................................... 37 
5.5 
Pharmacokinetic Assessments 
/Pharmacodynamic Assessments.......................................... 38 
5.5.1 
Pharmacokinetic Assessments.............................................. 38 
5.5.2 
Pharmacodynamic Assessments........................................... 39 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT............................................. 39 
6.1 
Dose and Schedule of Study Drug ........................................ 39 
6.1.1 
Dose Modifications ................................................................ 40 
6.2 
Preparation and Administration of Study Drug....................... 40 
6.3 
Blinding and Unblinding......................................................... 41 
6.4 
Assessment of Compliance ................................................... 41 
6.5 
Destruction of Study Drug...................................................... 42 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE.............................................. 42 
7.1 
Adverse Events (AEs) and Laboratory 
Abnormalities......................................................................... 42 
7.1.1 
Clinical AEs ........................................................................... 42 
7.1.1.1 
Intensity ................................................................................. 43 
7.1.1.2 
Drug - Adverse Event Relationship........................................ 43 
7.1.1.3 
Serious Adverse Events [Immediately Reportable 
to Roche] ............................................................................... 43 
7.1.2 
Treatment and Follow-up of AEs ........................................... 44 
7.1.3 
Laboratory Test Abnormalities............................................... 44 
7.1.4 
Follow-up of Abnormal Laboratory Test Values..................... 44 
7.2 
Handling of Safety Parameters.............................................. 44 
7.2.1 
Reporting of Serious Adverse Events 
[immediately reportable] ........................................................ 44 
7.2.2 
Pregnancy ............................................................................. 45 
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7.3 
Warnings and Precautions..................................................... 45 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................. 45 
8.1 
Primary and Secondary Study Endpoints .............................. 45 
8.1.1 
Primary Endpoints ................................................................. 45 
8.1.2 
Secondary Endpoints ............................................................ 46 
8.1.3 
Safety .................................................................................... 47 
8.2 
Statistical and Analytical Methods ......................................... 47 
8.2.1 
Statistical Model .................................................................... 47 
8.2.1.1 
Time to Event Variables......................................................... 47 
8.2.1.2 
Dichotomous Variables and Viral Load.................................. 47 
8.2.2 
Sample Size .......................................................................... 47 
8.2.3 
Hypothesis Testing ................................................................ 48 
8.2.4 
Analysis Populations ............................................................. 48 
8.2.4.1 
Intent to Treat Population ...................................................... 48 
8.2.4.2 
Intent to Treat Infected Population......................................... 48 
8.2.4.3 
Pharmacokinetic Evaluable Patient Population 
(PKEP)................................................................................... 48 
8.2.4.4 
Subpopulations...................................................................... 49 
8.2.5 
Efficacy Analysis.................................................................... 49 
8.2.6 
Safety Data Analysis ............................................................. 50 
8.2.7 
Analysis of Resistance........................................................... 50 
8.2.7.1 
Exclusion of Data from Analysis ............................................ 50 
8.2.7.2 
Interim Analysis ..................................................................... 50 
8.2.8 
Other Analyses...................................................................... 50 
8.3 
Pharmacokinetic and Pharmacodynamic Analysis ................ 51 
8.3.1 
Pharmacokinetic Analysis...................................................... 51 
8.3.2 
Pharmacodynamic Analysis................................................... 51 
9. 
DATA QUALITY ASSURANCE................................................................... 51 
9.1 
Assignment of Preferred Terms and Original 
Terminology........................................................................... 52 
10. REFERENCES ........................................................................................... 53 
11. ETHICAL ASPECTS ................................................................................... 56 
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11.1 
Local Regulations/Declaration of Helsinki.............................. 56 
11.2 
Informed Consent .................................................................. 56 
11.3 
Independent Ethics Committees/Institutional 
Review Board ........................................................................ 57 
12. CONDITIONS FOR MODIFYING THE PROTOCOL................................... 57 
13. CONDITIONS FOR TERMINATING THE STUDY ...................................... 57 
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING.................. 58 
14.1 
Investigator's Files / Retention of Documents........................ 58 
14.2 
Source Documents and Background Data............................. 58 
14.3 
Audits and Inspections .......................................................... 59 
14.4 
Case Report Forms ............................................................... 59 
15. MONITORING THE STUDY ....................................................................... 59 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS.................................................................................................. 59 
17. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS................................................................................................... 60 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments........................................................... 33 
 
 
LIST OF APPENDICES 
Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD......................................................................... 61 
Appendix 2 
Adult Patient Diary Data and Symptom Record .......................... 63 
Appendix 3 
Diary Data for Children ............................................................... 64 
Appendix 4 
Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug............................................................ 65 
Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 .... 67 
Appendix 6 
Primary Immunodeficiency Conditions........................................ 69 
Appendix 7 
Hematologic Malignancies and their Effect on the Immune 
System........................................................................................ 70 
Appendix 8 
Immunosuppressive Medications................................................ 71 
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PROTOCOL SYNOPSIS 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, MULTI-CENTER 
TRIAL EVALUATING CONVENTIONAL AND HIGH DOSE 
OSELTAMIVIR IN THE TREATMENT OF IMMUNOCOMPROMISED 
PATIENTS WITH INFLUENZA 
PROTOCOL NUMBER: 
NV20234 
VERSION NUMBER: 
D 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
® 
TEST PRODUCT: 
oseltamivir (Tamiflu RO 64-0796) 
PHASE: 
IIIb
INDICATION: 
Treatment of influenza in immunocompromised patients 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary 
To evaluate prospectively the safety and tolerability of oseltamivir for the treatment of influenza 
in immunocompromised patients and characterize the effects of oseltamivir in 
immunocompromised patients on the development of resistant influenza virus 
Secondary 
To evaluate the effects of conventional and high dose oseltamivir in immunocompromised 
patients on: 
• 
The time to resolution of influenza symptoms 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced by 
otitis media, bronchitis, pneumonia, or sinusitis)  
• 
The virologic course of influenza (proportion shedding and viral loads at different time points) 
• 
To estimate the population pharmacokinetics of oseltamivir and oseltamivir carboxylate (e.g., 
clearance, volume of distribution) in immunocompromised patients with confirmed influenza 
infection, through the application of established population pharmacokinetic (PK) models to the 
sparse plasma concentration data generated. 
 
Study Design 
Description of Study 
This is a double-blind, randomized, multi-center trial of twice daily, conventional and high dose 
oseltamivir for the treatment of influenza in immunocompromised patients.  Subjects will be 
stratified by age ( ≤ 12, > 12 years), transplant status (yes, no), time since onset of flu symptoms 
and treatment start (up to 96 hours) ( ≤ 48 or > 48 hours) and vaccination status (yes, no) 
Number of Patients 
A minimum of 166 (83 per arm) to allow an adequate number of influenza A patients per arm; 
including 50 transplant recipients.   
Number of Centers 
Approximately 125 centers in the Northern and Southern Hemispheres 
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Target Population 
Patients immunocompromised due to a primary or secondary immunodeficiency, 1 year of age 
and older.  The subjects will be positive for influenza by a rapid diagnostic test, PCR or virus 
culture at baseline. 
Length of Study 
10 days of treatment, 30 days of follow up.   
Procedures (summary) 
The key procedures are: 
• 
Blood draws for serum chemistry, hematology, serology, and PK assessments (for those 
patients who provide additional consent to participate in the PK assessments). 
• 
Nasal and throat swabs for viral culture and RT-PCR. 
 
Assessments of: 
Safety 
Adverse events, physical exams, vital signs, clinical laboratory evaluations 
Resistance 
Development of resistance 
Efficacy 
Time to resolution of all clinical influenza symptoms as recorded in the patient diary. 
Investigational Medicinal Products 
Test Product: 
Oseltamivir/placebo dry powder (to be reconstituted to a concentration of 12 mg/ml) and 75 mg 
capsules.  The duration of dosing in both adults and children is 10 days. 
 
Conventional dose: 
Children ages 1 − 12 years:  Oseltamivir syrup 
 ≤ 15 kg   
 
30 mg twice daily 
 > 15 – 23 kg   
45 mg twice daily 
 > 23 – 40 kg  
60 mg twice daily 
 > 40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules 75 mg twice daily 
 
Subjects randomized to the conventional dose will simultaneously receive matching placebo so 
as to blind them and the investigator from the high dose arm.  
 
High dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
 ≤ 15 kg   
 
60 mg twice daily 
 > 15 – 23 kg   
90 mg twice daily 
 > 23 – 40 kg  
120 mg twice daily 
 > 40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Comparator: 
Placebo (from pivotal registration trials in otherwise healthy adults) 
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Statistical Methods 
The sample size has been chosen to provide an adequate number of patients to estimate the 
development of resistance with reasonable precision.  Assuming that 90% of enrolled patients 
will have laboratory-confirmed influenza, there will be 75 patients in each treatment arm in the 
population evaluable for the development of resistance.  The following table shows the 95% 
Pearson-Clopper confidence intervals that would result with a sample size of 75 patients in a 
treatment arm if certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of development 
of resistance will be monitored in a blinded fashion, in order to ensure a reasonable precision 
for the estimation is maintained.  Additional patients may be enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of safety.  
This number of patients would provide estimates of adverse event rates with similar precision. 
For the primary objective of evaluating the safety of oseltamivir conventional and high dose 
treatments, AEs, laboratory tests, and vital signs will be summarized and compared with the 
known safety profile of the drug.  For the summary of the development of resistance for each 
treatment arm, 95% confidence intervals will be provided with the estimated rates.   
For the secondary objective of evaluating the efficacy of oseltamivir as measured by the time to 
resolution of influenza symptoms, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment approval, a 
population of placebo treated patients will be established that is comparable to patients in 
the current study.  For this population, a median time to resolution of all clinical influenza 
symptoms will be determined along with its 95% confidence interval. 
 
• 
Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence 
interval.  
 
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GLOSSARY OF ABBREVIATIONS
AIDS 
Acquired immunodeficiency syndrome 
ALT [SGPT] 
Alanine aminotransferase 
ALL 
Acute lymphocytic leukemia 
AML 
Acute myeloid leukemia 
ANOVA 
Analysis of variance 
AST [SGOT] 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC
Steady-state area under the concentration–time curve from 0 to 12 
hours 
0-12
b.i.d. 
Bis in die (twice daily) 
BP 
Blood pressure 
CARIFS 
Canadian acute respiratory infections scale 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CL/F 
Apparent clearance 
C
Last measurable concentration 
last
CL
Apparent total clearance of metabolite 
m
C
Maximum plasma concentration 
max
CML 
Chronic myeloid leukemia 
Cr Cl 
Creatinine clearance 
CRF 
Case report form[s] 
C
Trough plasma concentration 
trough
ESF 
Eligibility screening form 
GVHD 
Graft versus host disease 
hrs 
Hours 
HA 
Hemagglutinin 
HIV 
Human immunodeficiency virus 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ITT 
Intent to treat 
ITTI 
Intent to treat influenza infected 
IVRS 
Interactive voice response system 
k
Elimination constant 
e
mg 
Milligram 
mL 
Milliliter 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
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GLOSSARY OF ABBREVIATIONS
PKEP 
Pharmacokinetic Evaluable Patient Population 
p.o. 
Per os (by mouth) 
QD 
Once per day 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCID 
Severe combined immunodeficiency 
SOT 
Solid organ transplant 
TCID50 
50% tissue culture infectious dose 
Time to last measurable concentration 
tlast
Time to maximum plasma concentration 
tmax
t
Elimination half-life 
1/2
μg 
Microgram 
Vc/F 
Apparent volume of distribution 
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PART I: STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
Influenza is an acute respiratory infection caused by a virus of the orthomyxovirus family 
which occurs in three forms, influenza A, B and C.  Influenza virus types A and B cause 
an acute febrile infection of the respiratory tract characterized by the sudden onset of 
fever, malaise, headaches, myalgias and cough.  Influenza causes numerous deaths 
each year [1].  Although difficult to assess, annual influenza epidemics are thought to 
result in between three and five million cases of severe illness, and between 250,000 
and 500,000 deaths every year around the world [2]. 
The influenza viruses are segmented, negative sense, single stranded, lipid 
encapsulated, RNA viruses between 80 and 100 nm in size.  Subtypes are defined 
according to glycoproteins present in the viral lipid coat.  The haemagglutinin complex 
(HA) is the major surface protein of the virus.  The neuraminidase (NA) proteins are the 
second major surface proteins in the virion and play a role in enhancing virus penetration 
of the mucus layer around the target cell and in release of virus from the cell surface.  
The M2 protein triggers the disintegration of the virion during virus entry into the cell and may 
also be involved in protecting the HA prior to assembly of new virus particles.  
1.1.1 
Influenza in the Immunodeficient Population 
Influenza infection is usually a self limiting condition.  However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus may 
cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death [3].   
Conditions that compromise immunity may be classified based on etiology into primary 
(genetic) and secondary (acquired) immunodeficiency.  Of the immunodeficient 
conditions, the ones that affect cell mediated immunity are likely to have adverse 
outcomes following viral infections [16]. 
Primary immunodeficiency  
Primary immunodeficiencies are relatively common, may be either congenital or manifest 
later in life and are classified according to whether the genetic defect affects T or B cells 
or both [16].  There are four groups of disorders:  severe combined immunodeficiency 
(SCID), primary T cell deficiency (e.g. CD8 deficiency, DiGeorge syndrome), 
predominantly B-cell-related antibody deficiency (e.g. common variable immunodeficiency, 
selective IgA deficiency) and other well-defined immunodeficiency syndromes (e.g. 
Wiskott Aldrich syndrome) [16].  
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Of the primary immunodeficiencies, antibody deficiencies are the most frequent.  
However, some of the more common antibody deficiency conditions (isolated IgA 
deficiency, IgG subclass deficiency and common variable immunodeficiency) have intact 
cell-mediated immunity and therefore the clinical course of viral infections (unless 
complicated by bacterial infections) does not differ significantly from that in the normal 
host [16].  A list of primary immunodeficiency disorders at risk for viral infections is 
provided in Appendix 6.  The incidence of some of these conditions has been estimated.  
The incidence of SCID is 1 in 100,000 to 1 in 1,000,000 [16].  The more severe forms of 
primary immunodeficiency are relatively rare, have their onset early in life, and all too 
frequently result in death during childhood [16].  
Secondary Immunodeficiency 
Secondary immunodeficiencies are not caused by intrinsic abnormalities in development 
of T and B cells [16].  Secondary immunodeficiency may result from diseases (human 
immunodeficiency virus [HIV], hematologic malignancy) or immunosuppressive and 
cytotoxic drugs (such as those used for treatment of transplant recipients, collagen 
vascular disease, malignancies).  
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T cell count of < 200/μL (AIDS defining) are highly 
susceptible to opportunistic disease [16].  However, CD4 counts < 500/μL are considered 
abnormal in HIV-infected individuals, and therefore these individuals are also more susceptible to 
infection.  Studies in HIV/AIDS subjects have shown an increased risk for heart and 
lung-related hospitalizations during the influenza season compared to other times of the 
year, prolonged duration of influenza symptoms, increased risk for influenza-related 
complications and a higher risk of influenza-related death [17]. 
Several hematologic malignancies affect the immune system (Appendix 7).  Several 
authors have reported influenza in children and adults with hematologic malignancies 
[18, 19, 20, 21].  
Secondary immunodeficiency due to drugs (e.g. transplant recipients, collagen 
vascular disease, malignancies) 
The enhanced survival of the transplant population following the availability of newer 
immunosuppressive drugs has made them representative of the immunocompromised 
population in general; and secondary immunodeficiency due to drugs, in particular. 
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality.  In a cohort study of influenza viral infection in solid organ 
transplant (SOT) subjects, 30 cases of influenza viral infection were identified.  
Secondary bacterial pneumonia was seen in 17% of subjects and three SOT recipients 
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(2 liver and one kidney) had myositis, myocarditis and bronchiolitis obliterans.  Biopsy of 
the transplanted organ was performed in 21 of 30 cases and revealed variable degrees 
of acute allograft rejection in 62% of subjects.  The study concluded that influenza was 
associated with significant morbidity in different groups of SOT recipients [4]. 
Among transplant recipients, subjects with hematopoietic stem cell transplant (HSCT) are 
at the greatest risk for morbidity.  In a prospective study from the Infectious Diseases 
Working Party of the European Group for Blood and Marrow Transplantation, 1973 
patients were evaluated for respiratory virus infections after stem cell transplantation.  
The overall mortality was 23% from influenza A infection and the direct influenza A-
associated mortality was 15.3% in this study [5].  A large retrospective study 
(4797 subjects undergoing HSCT over a 13-year period) identified 62 patients with 
influenza of whom as many as 29% (18 of 62 patients) developed pneumonia.  Ten 
percent of the subjects with influenza died [6].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects.  In otherwise healthy adults, elderly 
subjects and children, the median duration of viral shedding in untreated subjects was 
70, 96 and 118 hours respectively [7].  In contrast, in the retrospective HSCT study, 
influenza virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a 
median duration of 168 hours (7 days, range 2 to 37 days) [6]. 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir).  
1.1.2 
Oseltamivir 
Oseltamivir (Tamiflu®, Ro 64-0796) is an ethyl ester prodrug which is rapidly absorbed 
from the gastrointestinal tract after oral administration and metabolized in the liver by 
high capacity carboxylesterases to form oseltamivir carboxylate (Ro 64-0802), a potent, 
stable and selective inhibitor of influenza A and B neuraminidase enzymes.  The active 
form, oseltamivir carboxylate is excreted unchanged by the kidney via glomerular 
filtration and active tubular secretion by the organic anion transport system.  The efficacy 
and safety of oseltamivir in influenza treatment and prevention has been established in 
an extensive series of clinical studies in man. 
Oseltamivir has been approved for the treatment of influenza in Europe, the United 
States and most other countries around the world.  In adults and adolescents, the 
recommended dose is 75 mg twice daily for five days.  In children 1 year of age and 
older recommended doses are 30, 45 or 60 mg bid based on body weight.  In all age 
groups the recommended dose is administered bid for 5 days.   
The approval of oseltamivir for the treatment of influenza is based on several controlled 
clinical trials.  In the pooled population from these clinical trials encompassing adults 
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aged from 13-97 years, many with significant co-morbidity, 1325 subjects were treated 
with oseltamivir (75 mg bid) and 1056 subjects received placebo.  A total of seven 
influenza symptoms (both respiratory and constitutional) were captured on the diary card 
for adults.  The time to resolution of all symptoms (on the diary card) decreased by 
24 hours; from 124.5 hours in the placebo arm to 100.6 hours with oseltamivir 75 mg bid 
(p < 0.0001) [7].  Further, in adults and adolescents with a proven influenza illness, 
oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% and the 
incidence of influenza-related lower respiratory tract complications resulting in antibiotic 
therapy by 55%.  The study concluded that oseltamivir treatment of influenza reduces 
lower respiratory tract complications, antibiotic use and hospitalizations in healthy and ‘at 
risk’ subjects [8].   
Likewise, in the influenza-infected pediatric population (1 to 12 years of age), oseltamivir 
treatment (n = 217) was compared with placebo (n = 235).  There was a reduction  in  the 
median duration of illness (defined based on resolution of temperature, cough, coryza 
and return to pre-illness health and activity) of 36 hours; from 137 hours with placebo to 
101 hours in the oseltamivir treatment arm (p ≤ 0.0001).  The Canadian Acute 
Respiratory Infections Scale (CARIFS), validated for use in children, was used to collect 
symptom data on the pediatric diary card.  The CARIFS scale comprised a total of 18 
symptoms which were evaluated twice daily by the parent or guardian.  There was a 
similar reduction in the time to alleviation of all CARIFS symptoms of 36 hours; from 100 
hours in the placebo group to 63 hours in the oseltamivir group (p < 0.0001) [9].  
Thus in both adults and children, the time to resolution of all symptoms was significantly 
reduced in the oseltamivir treatment arm compared with placebo.   
Oseltamivir was well-tolerated in clinical trials.  Approximately 11,000 subjects have 
received oseltamivir in the development program.  The most common adverse events 
reported by adults, the elderly, and children were nausea and vomiting.  Serious adverse 
events (SAEs) were reported with a low and equal frequency by subjects taking active 
drug and placebo.  Full details are given in the Investigator Brochure [7]. 
The safety profile of oseltamivir has been well characterized for the prophylaxis 
indication in a prospective randomized placebo controlled trial conducted in the adult 
and pediatric immunocompromised (HSCT and SOT) population.  In the oseltamivir 
group, the indications for transplant included hematologic malignancies (acute and 
chronic leukemias, multiple myeloma and myelodysplastic syndrome), lymphoid 
malignancies (Hodgkins or non-Hodgkins lymphomas), primary immunodeficiencies 
(Wiskott-Aldrich syndrome, X-linked lymphoproliferative disease and severe combined 
immunodeficiency).  Other rare indications included bone marrow aplasia, paroxysmal 
nocturnal hemoglobinuria, myelofibrosis and multiple sclerosis.  In the safety population, 
there were 239 subjects randomized to the conventional dose of oseltamivir and 238 to 
placebo.  The total number of adverse events reported in the placebo group (361 events) 
was generally similar to that in the oseltamivir group (323 events).  Diarrhea was the 
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most frequently reported adverse event (placebo, 8%; oseltamivir, 6%).  There were no 
deaths in the oseltamivir group.  Oseltamivir was found to be safe in immunosuppressed 
transplant recipients [22]. 
Limited safety and/or efficacy of oseltamivir for the treatment indication is available from 
several case reports in children and adolescents.  Oseltamivir was shown to be safe 
and/or effective in HIV infected children (n = 10) [23], children (age 3 to 12 years) with 
acute lymphocytic leukemia (ALL) (n = 10) [21], in a nosocomial H1N1 outbreak in a 
pediatric (children aged 10 months to 13 years) oncology ward (n = 8) [20], in children 
and adolescents (age 2 to 19 years) with malignancies (ALL, neuroblastoma, brain 
tumor, non-Hodgkin’s lymphoma, osteosarcoma, Ewing sarcoma, myelodysplasia, acute 
myeloid leukemia (AML), Wilms tumor, aplastic anemia, chronic myeloid leukemia (CML) 
and acute promyelocytic leukemia) (n = 51) [18], in children aged 4 to 14 years on 
immunosuppressive drugs (n = 5) [24] and in children (aged 5 months to 5 years) with 
bone marrow transplant (n = 3) [25].  
Oseltamivir has also been shown to be safe and/or effective in mixed populations of 
children and adults (62 patients) with HSCT [6], and in a large epidemiologic study 
(n = 221) with SOT [26].  
Finally, oseltamivir has been shown to be safe and/or effective in immunocompromised 
adults with HSCT [10] and adults with lung transplant [27, 28, 29].  
The dose of oseltamivir was the same as the conventional dose in a majority of these 
reports.  In one report as many as 25 adult patients received twice the conventional dose 
[26] while in another report, three of nine adult patients received twice the conventional 
dose [29].  Treatment with oseltamivir generally ranged from 5 to 10 days [28, 29, 26] 
and occasionally until the patient was symptom free [28, 29].  In exceptional cases 
treatment was given for as long as 20 days [18] or for as long as the patient was positive 
by RT-PCR [21]. 
There is some concern about the development of resistance in the immunocompromised 
population.  During the pandemic influenza season, more than 23,000 clinical isolates of 
novel H1N1 pandemic virus were tested for resistance in the 6 international WHO 
regions.  A total of 225 isolates (from 225 subjects) were resistant (H275Y mutation in 
the neuraminidase coding sequence) to oseltamivir for an approximate incidence of 1%.  
Information on immune status was available for 142 of 225 patients.  Among the 142 
patients, 56 (40%) were immunocompromised [30].  Prolonged viral replication and lack 
of immune-mediated virus clearance in immunosuppressed patients treated with 
antivirals can result in a higher incidence of selection of drug-resistant viruses, a 
phenomenon that has been documented previously [31, 32].  
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1.2 
RATIONALE FOR THE STUDY  
Because of the increasing body of evidence (Section 1.1.2), oseltamivir is recommended 
in national guidelines as an option for the treatment of influenza in the transplant 
population [37], which comprises a significant portion of the immunocompromised population.  
However, there is limited data on safety and efficacy of oseltamivir use in this population.  The 
primary objective of this study is to evaluate safety and resistance, while evaluating 
efficacy as a secondary objective, in the broader immunocompromised patient population, 
who are considered at increased risk of viral infection. 
2. 
OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate prospectively the safety and tolerability 
of oseltamivir for the treatment of influenza in immunocompromised patients and 
characterize the effects of oseltamivir in immunocompromised patients on the 
development of resistant influenza virus. 
2.2 
SECONDARY OBJECTIVES   
The secondary objectives of the study are:  
To evaluate the effects of conventional and high dose oseltamivir in 
immunocompromised patients on: 
• 
The time to resolution of influenza symptoms. 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis).  
• 
The virologic course of influenza (proportion shedding and viral loads at different 
time points). 
• 
To estimate the population pharmacokinetics of oseltamivir and oseltamivir carboxylate (e.g., 
clearance, volume of distribution) in immunocompromised patients with confirmed 
influenza infection, through the application of established population pharmacokinetic (PK) 
models to the sparse plasma concentration data generated.  
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN   
This is a double blind, randomized, stratified, multi-center trial of conventional and high 
dose oseltamivir for the treatment of influenza in immunocompromised patients.  
Immunocompromised patients who develop an influenza-like illness with a positive rapid 
diagnostic test, PCR, or viral culture for influenza, will be enrolled during the influenza 
season.  Patients will be stratified by transplant status [yes, no], the time between onset 
of influenza symptoms and treatment start (up to 96 hours) [ ≤ 48 hours; > 48 hours], 
influenza vaccination status for current influenza season [Yes; No] and by age [ ≤ 12 
years; > 12 years].  Eligible patients will be consented and randomized to receive 
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oseltamivir twice daily for 10 days in one of two treatment arms:  conventional dose or 
high dose (double the conventional dose).  
3.1.1 
Rationale for Study Design 
This study incorporates several features that distinguish it from classic placebo 
controlled trials.  
There is no placebo control arm in this study as it was considered unethical for this high 
risk population.  The development of resistance following treatment with oseltamivir (one 
of the primary objectives of the study) is an objective assessment (determined by 
laboratory tests) and is unlikely to be impacted by the absence of a placebo arm.  
As a placebo control arm was considered unethical in this population, an alternative 
control arm had to be identified for efficacy end points.  The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial.  In order to do this, the 
end points were designed to be similar to that in the pivotal registration trials.  
The following sections provide rationale and justification for specific aspects of the study 
design which differ from the currently approved dosing for influenza or from previous 
pivotal registration trials.  They also provide information on how the results will be used 
to make recommendations on dose and duration of treatment. 
3.1.1.1 
Choice of Treatment Arms 
The currently approved dose of oseltamivir for the treatment indication is the 
conventional dose with a duration of five days.  In this study a conventional and high 
dose (twice the conventional dose) are being evaluated.  The pivotal registration trials for 
oseltamivir in healthy adults with influenza had three treatment arms, two active (75 mg 
and 150 mg) and one placebo.  Both treatment arms were found to be significantly better 
than placebo.  No statistical comparisons were made between the two active treatment 
arms.  Evaluation of the results in the two active treatment arms did not reveal any 
clinically meaningful difference.  However, the proportion of subjects shedding virus on 
day 4 (3 days after the start of treatment), suggested a possible dose response 
relationship (36%, 28% and 23% in the placebo, 75 mg and 150 mg dose arms 
respectively).  Because defective immune-mediated virus clearance in 
immunosuppressed patients treated with antivirals can result in a higher incidence of 
selection of drug-resistant viruses, it was decided to use both the conventional and high 
dose arm for this study.  A longer duration of treatment was chosen because a large 
retrospective study has shown that the median duration of viral shedding of 7 days [6] 
was greater for HSCT recipients than that seen in the healthy children, adult and elderly 
population with influenza (Section 1.1.1) [7].  
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3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours 
In immunocompromised patients, time from onset of symptoms to seeking medical 
attention (presentation at the clinic) of  > 48 hours has been shown in several case 
reports [33, 27, 28, 29] including two instances of nosocomial outbreaks in children [25, 
20].  This notwithstanding, oseltamivir has been shown to be effective in 
immunocompromised populations that included patients treated with oseltamivir beyond 
48 hours of presentation; patients with lung transplant (median time to presentation 3 
days) [27], bone marrow transplant (treatment started more than 48 hours after onset of 
symptoms in all three patients) [25], organ transplant (62 out of 221 patients started 
treatment after 96 hours) [26] and children with ALL (one child presented after 3 days 
and two children after 5 days of symptoms) [21]. 
In a prospective, observational study involving adults hospitalized with influenza, the 
study authors concluded that ‘Weakened host defenses slow viral clearance, whereas 
antivirals started within the first four days of illness enhance viral clearance’ [34].  
Additionally, in November 2009, in a communication for clinicians on antiviral treatments 
for H1N1, the US Centers for Disease Control and Prevention (CDC) stated that while 
antiviral treatment is most effective when started early; both outpatients with risk factors 
and hospitalized patients still benefit when treatment with oseltamivir is started more 
than 48 hours after illness onset [35].   
3.1.1.3 
Rational for Sparse PK Sampling 
Limited PK sampling will be done in this protocol, in patients who have provided additional 
consent, and is justifiable in this study for the following two reasons: 
• 
There are already tested and qualified population PK models available [36] that will be used 
to estimate exposure in the immunocompromised population on the basis of the data collected 
in this study, meaning extensive PK sampling over a steady-state dosing interval is not 
required.  
• 
The patient population in this study is likely to be very ill with a complex clinical picture 
and significant additional burden of treatment and monitoring due to their primary 
condition.  In this context, it makes ethical sense to minimize blood draws and assessments 
to only those absolutely essential to meet the objectives of the study and to ensure patient 
safety. 
 
3.1.1.4 
Interpretation of Study Results  
Safety and tolerability and the development of resistance are the primary objectives of 
this study.  These will be characterized descriptively.  For the secondary objective of 
efficacy, the subset of the population enrolled in the first 48 hours will be compared with 
placebo patients from pivotal registration trials (where patients were enrolled in the first 
two days of illness).  Sections 8.2.5, 8.2.6, and 8.2.7 provide details on the statistical 
considerations and their rationale associated with these comparisons. 
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Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials.  However, in order to evaluate a dose response relationship between the two 
active treatment arms in this trial, stratification remains essential.  
Patients will be stratified by transplant status (yes, no) because transplant patients form 
a relatively large homogenous group in this study and might influence outcome.  
Patients will be stratified by time between onset of symptoms and treatment start 
( < 48 hours or ≥ 48 hours) because previous experience in otherwise healthy adults and 
children has shown that patients treated early in their illness respond to treatment better 
than those who are treated later.  Patients will also be stratified by age ( ≤ 12 years 
and > 12 years) because otherwise healthy children shed virus longer than otherwise 
healthy adults.  It is expected that a similar difference in the duration of viral shedding 
would exist between immunocompromised children and adults.  As vaccinated subjects 
may respond faster to therapy, the study is also stratified based on influenza vaccination 
status for the current influenza season (Yes; No).  
3.1.2 
Rationale for Dose Selection and Adjustment 
Dose Selection 
The dose of oseltamivir to be used in this study is the conventional, approved dose for 
children and adults in the treatment of influenza.  There will be a second higher dose for 
comparison which is two times the conventional dose.  This higher dose is used based 
on theoretical considerations which suggest that the higher dose may be associated with 
improved efficacy and decreased emergence of resistance.  
The anticipated pro-drug and metabolite exposures from this higher dose are not 
expected to exceed maximum exposures seen previously in the oseltamivir development 
program.  The safety and tolerability of the higher dose regimen has already been 
demonstrated in treatment studies of immunocompetent adult subjects (n = 447) [11].  In 
a study to demonstrate cardiac safety, in the highest dose group treated with 450 mg 
b.i.d. for 5 days [n = 99], no subject had a serious adverse event, nor withdrew 
prematurely.  In Phase I studies in adults, oseltamivir has been administered in multiple 
doses of up to 500 mg b.i.d.  Doses of 200 mg b.i.d. and greater have been associated 
with increased gastrointestinal adverse effects (nausea and vomiting) [7].  In adult 
subjects with creatinine clearances of ≤ 30 mL/min, doses of 100 mg b.i.d. for 6 days 
were well tolerated, despite steady-state oseltamivir carboxylate exposures 
approximately 10-fold higher than those achieved with standard dosing in renally 
competent individuals [12].  No other adverse effects were reported more frequently with 
higher doses and no serious adverse events have been reported within the volunteer 
studies.  Co-administration of oseltamivir with food has been demonstrated to 
substantially reduce the frequency and severity of gastrointestinal side effects.  
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Thus, the rationale for the higher dose arm in this study is to explore the possibility of 
improved efficacy and decreased emergence of resistance without an undue increase in 
risk.  
Drug interactions with immunosuppressive medications have also been evaluated.  The 
pharmacokinetics of oseltamivir and oseltamivir carboxylate after administration of 
75 mg oseltamivir (conventional adult dose) in subjects with a well-functioning, stable 
renal allograft who were being maintained on immunosuppressive therapy were studied.  
These were similar to those described in the literature for adults with comparable 
degrees of renal function.  Oseltamivir was well tolerated and had no clinically relevant 
effect on the steady-state pharmacokinetics of cyclosporine A, tacrolimus, or 
mycophenolate mofetil [7]. 
Duration of Dosing 
The duration of dosing chosen for this population (10 days) is longer than that in the 
healthy adult and pediatric populations (5 days).  This is based on observations that the 
viral shedding and illness are typically longer in immunocompromised patients than it is 
in healthy adults [6, 10]. 
Dose Adjustments 
In this study, patients whose CrCl decreases to  < 60mL/min/1.73M2 will be discontinued 
from treatment. 
3.1.3 
End of Study 
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 
days later as shown in the schedule of assessments.  A rapid diagnostic test for 
influenza will be performed at the end of the 10 days of treatment.  Subjects still having 
influenza based on the rapid diagnostic test will be treated per the local standard of care 
by the principal investigator.  
3.2 
NUMBER OF SUBJECTS/ ASSIGNMENT TO TREATMENT 
GROUPS 
A minimum of 166 patients (approximately 83 per arm) to allow an adequate number of 
influenza A patients, including 50 transplant recipients will be enrolled in this study.  After 
screening, patients will be randomly assigned to one of the two active treatment groups. 
3.3 
CENTERS 
This will be a multicenter study taking place in the Northern and Southern Hemispheres at 
approximately 125 centers.  
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4. 
STUDY POPULATION 
4.1 
OVERVIEW 
The study population comprises immunocompromised adults (including adolescents) 
and children who have influenza.  Additionally, the subjects must not have other medical 
conditions that will preclude the assessment of efficacy or safety.  Influenza vaccinated 
and non-vaccinated subjects are eligible to participate in this study.  Principal 
investigators will review oseltamivir resistance patterns of strains circulating in the area 
and weigh the risk versus the benefit before enrolling patients with a potentially resistant 
strain. 
Under no circumstances are patients who enroll in this study permitted to be re-
randomized to this study and enrolled for a second course of treatment. 
4.2 
INCLUSION CRITERIA 
• 
Age greater than or equal to 1 year 
• 
Rapid diagnostic test, PCR, or viral culture positive for influenza 
• 
Immunocompromised subject defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in Appendix 6) OR 
o Secondary immunodeficiency 
 
SOT with ongoing immunosuppression OR 
 
Allogenic HSCT with ongoing immunosuppression OR 
 
HIV with CD4 count < 500/mm3 and, in the investigator’s opinion, 
considered immunocompromised OR 
 
Hematologic malignancies (representative examples in 
Appendix 7) OR 
 
Systemic (e.g. enteric, sc, im or iv) immunosuppressive therapy, 
irrespective of medical indication, started at least 12 weeks prior 
to, and ongoing at the time of first dose of study drug 
(representative examples in Appendix 8) 
 
• 
Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza 
• 
In patients with history or clinical presentation at randomization suggestive of renal 
failure; a CrCl > 60 ml/min/1.73M2 
• 
Less than or equal to 96 hours between onset of influenza like illness and first dose 
of study drug 
• 
Parent/guardian willing and able to comply with study requirements and give 
consent, (country specific age cut off) 
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• 
Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• 
For adult patients, willing and able to comprehend and give written informed consent  
• 
Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for females for one reproductive 
cycle following cessation of study therapy 
• 
Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study medication 
 
4.3 
EXCLUSION CRITERIA 
• 
Clinical evidence of severe hepatic impairment, defined as Child-Pugh grade C (score > 9) or 
decompensated cirrhosis. 
• 
Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration. 
• 
Have evidence of a serious secondary respiratory or disseminated infection that may 
confound or overlay the diagnosis and/or symptomatology of influenza. 
• 
Patients with gastrointestinal disorders which might interfere with their ability to 
absorb oral medication.  
• 
Allergy to the test medication. 
• 
Patients with hereditary fructose intolerance (for subjects who will be taking the 
liquid formulation). 
• 
Influenza vaccination with live attenuated vaccine in the 2 weeks prior to 
randomization. 
• 
Antiviral treatment (example:  amantadine, rimantadine, oseltamivir, laninamivir, 
peramivir, zanamivir and ribavirin) for influenza in the 2 weeks prior to 
randomization. 
• 
Patients taking probenecid medication. 
• 
Patients who are pregnant or breast-feeding.   
• 
Participated in a clinical trial or expanded access trial with an investigational drug 
suspected/demonstrated to impact pathways important for the metabolism and excretion of 
oseltamivir in the 4 weeks prior to randomization or concomitantly with this study.   
 
4.4 
CONCOMITANT MEDICATION AND TREATMENT 
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, laninamivir, peramivir, and additional oseltamivir above that 
specified for this study) are not allowed during the 10-day treatment phase of the study.  
Concomitant use of an investigational drug during the study is also excluded.  Live 
attenuated vaccines may not be advisable for this population.  It is possible that 
concurrent use with oseltamivir may render live vaccines ineffective.  
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Medications required for the routine care of the patient may be continued during the 
study.  Concomitant use of probenecid (irrespective of the indication) is not allowed 
during the study. 
4.5 
CRITERIA FOR PREMATURE WITHDRAWAL  
The investigator must discontinue treatment if the creatinine clearance is  < 60 ml/min in 
adults or < 60 ml/min/1.73 M2 in children.  The investigator must also discontinue 
treatment from all subjects with intercurrent illnesses or adverse events suggestive of 
hepatic decompensation.  The investigator also has the right to discontinue treatment in 
the event of intercurrent illness, adverse events, treatment failure, protocol violations, 
administrative reasons or other reasons. 
The investigator must discontinue treatment with study drug if the patient is to be treated 
concomitantly with another antiviral for influenza, for example, amantadine, rimantadine, 
laninamivir, peramivir, or zanamavir.  However, all patients, including those who 
discontinue study drug prematurely and/or are treated with another antiviral, will be 
required to return for follow up approximately 5 and 30 days after the last dose of study 
medication (day 15 and day 40 assessments). 
Subjects have the right to withdraw from the study at any time for any reason.  
An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
The investigator should contact the subject or a responsible relative either by telephone 
or through a personal visit to establish as completely as possible the reason for the 
withdrawal.  A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the subject is withdrawing from the study.  If the reason 
for removal of a subject from the study is an Adverse Event, the principal specific event 
will be recorded on the CRF. 
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further 
information.  The outcome of that discussion should be documented in both the medical 
records and in the CRF.  
4.6 
REPLACEMENT POLICY [ENSURING ADEQUATE NUMBERS 
OF EVALUABLE SUBJECTS] 
4.6.1 
For Subjects 
No subject prematurely discontinued from the study for any reason will be replaced. 
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Table 1 
Schedule of Assessments (cont.)  
f  A home visit may be made on day 2 or 3 (for patients who are too ill to come into the clinic) 
and/or, day 6, and/or day 8; however, it is recommended that the PK blood draw be performed at the 
clinic. 
g. Day 2/3 visit window = +1 day.  Day 6 visit window = +/- 1 day; Day 8 visit window = +1 day.  
Day 11 visit window = ± 1 day.  Day 15 and day 40 visit occur approximately 5 and 30 days 
after the last dose respectively.  Day 15 window = ± 1 day.  Day 40 window ± 2 days.  
h. Only weight to be assessed.  Height is not necessary at this visit.  Study drug is taken on day 
11, only if the first dose was taken after 4 PM on Day 1 [5.3] Subjects who are rapid diagnostic 
positive can be treated per standard of care.  They will be required to come for their follow-up 
visits on day 15 and day 40.  
i. 
Subjects who discontinue treatment prematurely will have an end of treatment (day 11) 
assessment at the time of treatment discontinuation or the following day.  They will be 
required to attend their follow up visits approximately 5 and 30 days after the last dose (day 15 
and day 40 assessments).  
j. 
Subjects who discontinue during follow-up will have an end of follow-up (day 40) assessment.  
This visit must occur within 30 days of the last dose.   
k. For subjects who are unable to attend the clinic, swabs may be taken at home on those days where there 
is a home visit by site personnel. 
l. Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be collected from 
patients who give additional consent to participate in PK sampling using a sparse PK sampling 
approach (Section 5.5).  
m. Serial PK samples taken at steady-state no earlier than day 6 (i.e., not before the 11th dose) consisting of 
as many of the four timepoints as possible:  within 30 minutes prior to the dose administration, 1.5 
hours ± 30 minutes post dose, 4 hours ± 60 minutes post dose, and 8 hours ± 1.5 hours post dose (for 
patients who have given additional consent). 
  
5.1 
SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM  
All subjects must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed.  Screening will take place at 
the baseline visit prior to first dose.  However, if necessary, screening may take place 
the day before the baseline visit, as long as the patient is randomized and receives 
his/her first dose of study medication within 96 hours of influenza symptom onset. 
Subjects will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  
An Eligibility Screening Form [ESF] documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.  
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5.2 
PROCEDURES FOR ENROLLMENT OF ELIGIBLE SUBJECTS  
Once a subject has fulfilled the entry criteria, he/she will be randomized to one of two 
treatment groups.  The subject randomization numbers will be generated by Roche or its 
designee and incorporated into double-blind labeling. 
The investigator or designee will use the CRF pre-printed with the assigned subject 
number and enter the randomization number provided by IVRS for allocation to the 
treatment groups in the appropriate place on each subject’s CRF. 
Randomization will be stratified by transplant status (Yes; No); time between onset of 
symptoms and treatment start ( ≤ 48 hrs or  > 48 hrs), influenza vaccination status (Yes; 
No) and patient’s age ( ≤ 12 years or  > 12 years).  
5.3 
CLINICAL ASSESSMENTS AND PROCEDURES 
At all visits subjects will receive the routine care for their primary illness.  Routine patient 
care (including the adjustment of doses of any of the immunosuppressive drugs) will be 
dictated by tests performed locally at the trial site.  For subjects unable to attend the clinic, 
provision will be made for swabbing to be conducted at home, when there is a home visit 
scheduled.  Training will be provided to site staff on how to perform this.  All safety labs will be 
sent to a central laboratory.  Results for these laboratory parameters will be used by the 
sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 1).  Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
Blood samples will be collected from patients who provide additional consent for PK sampling, as 
outlined in Section 5.5. 
Study Day 1 
The baseline and study day 1 assessment may be performed at the same visit. 
Study medication, electronic diaries, and thermometers will be dispensed.  Patients or 
guardians/parents will be instructed how to complete electronic symptom diaries 
(Appendix 2) (Appendix 3), temperature recording, and treatment administration details, 
including time of each oseltamivir dose.  The first diary entries will be made at the site 
before the first dose of study drug.  
Baseline nasal and throat swab samples will be assessed for the presence of 
oseltamivir-resistance mutations.   
The date of the first dose of study drug is defined as study day 1.  Once randomized, the 
first dose of study drug will be administered in the clinic.  Study day 2 will begin at 12 
midnight of the same calendar day.  If the first dose of study drug is taken after 4 pm on 
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day 1, the next dose of study drug will be taken in the morning of day 2.  In this case, the 
last dose of study drug will be taken on the morning of study day 11.   
If the first dose of study drug is taken prior to 4 pm on day 1, the next dose of study drug 
should be taken in the evening of the same day (i.e. prior to midnight on the same 
calendar day with a minimum of 7 hours between doses).  For these patients the last 
dose of study drug will be taken in the evening of study day 10.  More information on 
dosing is provided later (Section 6.1). 
Study Days 2 - 11 
Study day 2 will begin at 12 midnight of study day 1.  
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study.  The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is entering data into the electronic diary 
properly, and assess drug compliance.  During the dosing period, diary symptoms 
should be assessed and temperature should be recorded at the same time that the study 
drug is taken.  
End of Treatment Day 11 
The end of treatment visit for all subjects is on day 11 (irrespective of whether they took 
one or two doses on day 1).  Subjects who discontinue study medication prematurely will 
have all day 11 assessments completed at the time of discontinuation or the following 
day.  
After all day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit.  If the rapid diagnostic test is positive, the subject may be treated 
per standard of care at the discretion of the investigator.  
All subjects (including those who discontinue study medication prematurely and those 
who are positive for influenza on their rapid diagnostic test at the end of treatment visit) 
will be required to return for follow up approximately 5 and 30 days after the last dose 
(day 15 and day 40 assessments).    
Study Days 12 – 40 
Study day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  
End of Follow-Up Day 40  
All subjects must attend an end of follow-up visit on day 40.  
If the patient is withdrawn after completion of treatment (after the day 11 assessment), a 
termination visit should be arranged.  This visit should be the end of follow-up visit 
assessment [Day 40].  This visit must occur within 30 days of the last dose.  
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Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the electronic diary. 
5.3.1 
Efficacy Assessments 
The primary efficacy end point in this study is the time to resolution of all influenza 
symptoms as recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. 
Symptoms of influenza-like illness.  These are captured in the diary for both adults 
and children (Appendix 2) (Appendix 3).  Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem).  A 
score of zero is considered asymptomatic.  The primary efficacy end point, time to 
alleviation of all symptoms is comprised of all the symptoms captured in the diary.  
2. 
Temperature.  This is captured in the diary.  Temperature is used for assessment of 
the primary and several secondary efficacy end points.  
 
5.3.2 
Safety 
Safety parameters in this study include adverse events, vital signs, and clinical 
laboratory evaluations.  
Pre-defined symptoms of influenza captured in the adult and pediatric diaries are not to 
be reported as adverse events unless they can be further qualified.  Thus ‘headache due 
to stress at work’ is reported as an adverse event.  However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Adverse events such as bronchitis, pneumonia, otitis media and sinusitis are considered 
secondary illnesses of influenza and should be recorded as adverse events. 
Other adverse events to be expected in the transplant population such as rejection and 
graft versus host disease (in HSCT subjects) will also be collected as adverse events.  
5.4 
LABORATORY ASSESSMENTS 
The laboratory assessments include those for efficacy and safety. 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described 
in the Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR 
and viral cultures.  Influenza virus shedding will be assessed.  Baseline samples will be 
assessed for the presence of oseltamivir-resistance mutations.   
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During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza.  At the end of treatment 
(day 11), a rapid diagnostic test is permitted for the diagnosis of ongoing influenza.  
Safety 
The safety laboratory assessments in this study, including the assessment of serum 
chemistry and hematology will be done at the central laboratory.  Serum chemistry 
assessments comprise AST, ALT, total bilirubin, urea and creatinine.  Hematology 
assessments include CBC and differential count.  The total volume of blood loss for 
laboratory assessments will be approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section 16) will extend to any data generated from 
the assaying of these samples.  Biological samples taken from all patients may be 
infectious and will be classified as “diagnostic specimens” for dispatch purposes. 
The Principal Investigator may draw blood for serum creatinine to be assessed at the 
local laboratory when clinically indicated during the study to calculate creatinine 
clearance. 
5.5 
PHARMACOKINETIC ASSESSMENTS /PHARMACODYNAMIC 
ASSESSMENTS  
Participation in PK assessments is not compulsory for this study.  Blood samples for the 
characterization of oseltamivir and oseltamivir carboxylate pharmacokinetics using a sparse 
sampling strategy will be collected from all patients who provide additional consent to participate 
in the PK assessments. 
Blood samples will be collected according to the Schedule of Assessments (Table 1) and as 
described below.  If these blood samples are collected at a home visit, site staff should ensure the 
PK blood sample handling processing is not compromised.  The time and date of the dose and 
blood samples should be captured.  Further details on pharmacokinetics/pharmacodynamics can 
be found in Sections 8.3.1and 8.3.2.  
Pharmacokinetic Assessments
5.5.1 
 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be collected at 
the following timepoints on Day 6, or any day after the 11th dose, using the following sampling 
approach: 
• 
Within 30 minutes prior to the dose administration (e.g., 08:30 a.m.) 
• 
1.5 hours ± 30 minutes post-dose (e.g., 10:30 a.m. ± 30 min) 
• 
4 hours ± 60 minutes post dose (e.g., 1:00 p.m. ± 60 min) 
• 
8 hours ± 1.5 hours post dose (e.g., 5:00 p.m. ± 1.5 hr) 
 
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For adults and adolescents, approximately 2 mL of blood will be taken at each timepoint; therefore, 
the total volume blood loss for PK assessments will be approximately 8 mL.  For pediatric subjects, 
not less than approximately 0.6 mL of blood will be taken at each timepoint; therefore, the total 
volume blood loss for PK assessments will be approximately 3.6 mL. 
The samples from this study are classified as Biological Substance, Category B.  
Plasma concentrations of oseltamivir and oseltamivir carboxylate will be measured by a specific 
and validated method.  Details on sampling procedures, sample storage, and shipment are 
provided in the Sampling Manual. 
Pharmacodynamic Assessments
5.5.2 
 
Nasal and throat swabs will be collected from individuals on the days specified in the schedule of 
assessments.  Specimens will be analyzed at a central laboratory.  The proportion of patients with 
viral shedding at each visit will be summarized. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/ml) or 75 mg capsules and matching placebo. 
The Investigational Medicinal Products will be supplied, packaged individually for each 
subject and labeled in accordance with Roche Standard and local regulation by Roche 
Clinical Trial Supply, Basel, Switzerland.  
6.1 
DOSE AND SCHEDULE OF STUDY DRUG 
Oseltamivir will be given twice daily over 10 days for a total of 20 doses.  The doses 
need to be taken at 12 hourly intervals.  Under no circumstances is a subject allowed to 
take two doses within 7 hours of each other.  
Patients will be randomized to receive either conventional or high dose of study drug. 
Conventional dose: 
Children ages 1 − 12 years:  Oseltamivir syrup 
 ≤ 15 kg   
 
 
30 mg twice daily 
 > 15 − 23 kg   
 
45 mg twice daily 
 > 23 − 40 kg  
 
60 mg twice daily 
 > 40 kg  
 
 
75 mg twice daily 
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Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
75 mg twice daily 
Subjects randomized to the conventional dose will simultaneously receive matching 
placebo so as to blind them and the investigator from the high dose arm.  
High dose: 
Children ages 1 − 12 years:  Oseltamivir syrup  
 ≤ 15 kg   
 
 
60 mg twice daily 
 > 15 – 23 kg   
90 mg twice daily 
 > 23 – 40 kg  
 
120 mg twice daily 
 > 40 kg  
 
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
6.1.1 
Dose Modifications 
No dose modifications will be allowed on study. 
6.2 
PREPARATION AND ADMINISTRATION OF STUDY DRUG 
Oseltamivir will be provided in two forms:  
1. 
Oseltamivir capsules containing 75 mg of active drug and packaging material 
consisting of pregelatinized starch, povidone, talc and sodium stearyl fumarate.  All 
participants 13 years and older will receive this dosage form.  Oseltamivir capsules 
should be stored at 25ºC. 
2. 
A pediatric suspension containing 12 mg oseltamivir per ml of reconstituted solution 
and the following excipients:  sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor).  All participants 12 years and under will receive this dosage form.  
Oseltamivir dry powder for oral suspension [pediatric syrup] should be stored below 
30°C [86°F]).  Once reconstituted, the suspension should not be used for longer than 
10 days if stored under room temperature conditions (below 25°C) or for 17 days if stored 
under refrigeration at 2°C to 8°C (36°F to 46°F).  The suspension is not suitable for freezing. 
For further details, refer to the Tamiflu® Investigator’s Brochure. 
Matching placebo will be available as capsules and suspension.  Subjects in the 
conventional dose arm will get the conventional dose and matching placebo so that they 
are blinded from the high dose arm.  
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Each subject will be dispensed a medication pack that will provide enough medication to 
cover 20 doses.  For subjects randomized to the conventional dose arm, the medication 
pack will contain a bottle of oseltamivir dry powder or a blister wallet with oseltamivir 
capsules and matching placebo.  For subjects randomized to the high dose arm, the 
medication pack will contain two bottles of oseltamivir dry powder or two blister wallets 
with oseltamivir capsules.  Irrespective of the treatment group the subject is randomized 
to, for each dose the subject will take the same amount from both bottles or blister 
wallets provided in the medication pack such that the sum of the amounts from each 
immediate container constitutes one dose. 
One dose is to be administered twice per day at approximately 12-hour intervals with a 
light snack or glass of milk or fruit juice.  The first dose of study medication will be 
administered in the clinic at the time of randomization. 
6.3 
BLINDING AND UNBLINDING 
Randomization will be administered by a central randomization center.  
The Randomization List will not be available at the study center, to the study monitors, 
project statisticians or to the project team at Roche.  Emergency codes, or another 
adequate method of unblinding, will be implemented before study start, if the identity of 
the test medication is necessary for patient management in the case of a serious 
adverse event.  Emergency codes should not be broken except in the case of 
emergency situations.  Any request from the investigator for information about the 
treatment administered to study subjects for another purpose must be discussed with 
Roche/designee.  
As per regulatory reporting requirement, Roche/designee will unblind the identity of the 
study medication for all unexpected [as per IB] serious adverse events that are 
considered by the investigator to be related to study drug.  Details of patients who are 
unblinded during the study will be included in the Clinical Study Report. 
All other individuals directly involved in this study will remain blinded until the final 
analysis of the primary parameter.  
The randomization will be stratified by transplant status, duration of symptoms, influenza 
vaccination status and age and will be provided by the Roche randomization group for 
the IVRS vendor.   
6.4 
ASSESSMENT OF COMPLIANCE 
Accountability and subject compliance will be assessed by maintaining adequate “drug 
dispensing” and return records.  
Subjects will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  
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A Drug Dispensing Log must be kept current and should contain the following 
information: 
• 
the identification of the subject [randomization and medication numbers] to whom 
the study medication was dispensed 
• 
the date[s], quantity of the study medication dispensed to the subject 
• 
the date[s] and quantity of the study medication returned by the subject 
 
This inventory must be available for inspection by the Monitor.  All supplies, including 
partially used or empty containers and the dispensing logs, must be returned to the 
monitor at the end of the study. 
6.5 
DESTRUCTION OF STUDY DRUG 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons.  In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned and destroyed.  Written authorization must be obtained from the sponsor or 
designee at study start up before destruction. 
Written documentation of destruction must contain the following: 
– 
Identity [batch numbers or subject numbers] of investigational product[s] destroyed 
– 
Quantity of investigational product[s] destroyed 
– 
Date of destruction 
– 
Method of destruction 
– 
Name and signature of responsible person [or company] who destroyed 
investigational products[s] 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
ADVERSE EVENTS (AES) AND LABORATORY 
ABNORMALITIES 
7.1.1 
Clinical AEs 
Per the International Conference of Harmonization [ICH], an AE is any untoward medical 
occurrence in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign [including an abnormal 
laboratory finding], symptom, or disease temporally associated with the use of a 
medicinal [investigational] product, whether or not considered related to the medicinal 
[investigational] product.  Pre-existing conditions which worsen during a study are to be 
reported as AEs.  Influenza signs and symptoms reported on the patient diary will be 
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summarized as efficacy end points and need not be captured as adverse events.  
However, secondary illnesses due to influenza must be reported as adverse events.  
7.1.1.1 
Intensity  
All clinical AEs encountered during the clinical study will be reported on the AE page of 
the CRF.   
Intensity of AEs will be graded on a four -point scale [mild, moderate, severe, 
life-threatening] and reported in detail on the CRF.   
Mild 
discomfort noticed but no disruption of normal daily activity. 
Moderate 
discomfort sufficient to reduce or affect daily activity. 
Severe 
inability to work or perform normal daily activity 
Life Threatening 
represents an immediate threat to life   
 
7.1.1.2 
Drug - Adverse Event Relationship 
Relationship of the AE to the treatment should always be assessed by the investigator.  
Description of scales can be found in Appendix 4. 
7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
Certain events require immediate reporting to allow the Sponsor to take appropriate measures to 
address potential new risks in a clinical trial.  The investigator must report such events to the 
Sponsor immediately; under no circumstances should reporting take place more than 24 hours 
after the investigator learns of the event.  The following is a list of events that the investigator 
must report to the Sponsor within 24 hours after learning of the event, regardless of relationship 
to study drug: 
• 
Serious adverse events 
• 
Pregnancies 
 
A Serious Adverse Event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfils at least 
one of the following criteria: 
– 
is fatal; [results in death; NOTE:  death is an outcome, not an event].  
– 
is Life-Threatening [NOTE:  the term "Life-Threatening" refers to an event in which 
the subject was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
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– 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
 
The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to 
(Appendix 5). 
7.1.2 
Treatment and Follow-up of AEs  
AEs, especially those for which the relationship to test “drug” is not “unrelated”, should 
be followed up until they have returned to baseline status or stabilized.  If a clear 
explanation is established it should be recorded on the CRF.   
7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will appear printed on laboratory reports provided to the site from 
the central laboratory.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] 
should be reported as such, in addition to being recorded as an AE in the CRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE page in the CRF: 
• 
Accompanied by clinical symptoms. 
• 
Leading to a change in study medication [e.g. dose modification, interruption or 
permanent discontinuation]. 
• 
Requiring a change in concomitant therapy [e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment]. 
 
7.1.4 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  If a clear explanation is 
established it should be recorded on the CRF.  
7.2 
HANDLING OF SAFETY PARAMETERS 
Reporting of Serious Adverse Events [immediately reportable]
7.2.1 
 
Any clinical AE or abnormal laboratory test value that is serious [as defined in 
Section 7.1.1.3 above] and which occurs during the course of the study, regardless of 
the treatment arm, occurring from the enrollment visit (start of study screening 
procedures), must be reported to Roche or designee immediately (i.e., no more than 
24 hours after the investigator becomes aware of the event [expedited reporting]). 
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Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and 
up until the follow-up visit.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to (Appendix 5). 
7.2.2 
Pregnancy  
A female subject must be instructed to stop taking the test “drug” and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should 
report all pregnancies immediately (i.e., no more than 24 hours after the investigator becomes 
aware of the pregnancy) to the Sponsor or designee.  The investigator should counsel the 
subject, and discuss the risks of continuing with the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Pregnancies occurring within 28 days of treatment completion should be reported to 
Roche.  
7.3 
WARNINGS AND PRECAUTIONS  
Events such as convulsions and delirium (including symptoms such as altered level of 
consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, 
anxiety, nightmares) have been reported during oseltamivir use in patients with influenza, 
predominately in children and adolescents.  In rare cases, these events resulted in 
accidental injury.  The contribution of oseltamivir to those events is unknown.  Such 
events have also been reported in patients with influenza who were not taking 
oseltamivir.  Patients, especially children and adolescents, should be closely monitored 
for signs of abnormal behavior. 
Please refer to the attached Investigator’s Brochure for additional warnings, precautions, 
and other reported adverse events. 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN   
Full details of all planned analyses will be specified in a separate Statistical Analysis 
Plan (SAP) for the safety and efficacy variables and in the Resistance Plan for the 
development of resistance.  The methods described below are an outline of the main 
planned analyses. 
8.1 
PRIMARY AND SECONDARY STUDY ENDPOINTS 
8.1.1 
Primary Endpoints 
The primary endpoints for safety will be assessments of adverse events, physical exams, 
vital signs and clinical laboratory evaluations.  The primary endpoint of development of 
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resistance will be determined from the genotypic and phenotypic variables measured 
post baseline and is described further in the Resistance Plan. 
8.1.2 
Secondary Endpoints 
The following are secondary endpoints which measure efficacy, the primary of which is 
time to alleviation of all clinical symptoms.  With the exception of this variable, viral load 
and time to resolution of fever, they are defined as either the occurrence or non-
occurrence of the specified events or the presence or absence of the specified 
symptoms. 
• 
The time (hours) to alleviation of all clinical influenza symptoms (recorded in the 
patient diary)  
• 
Shedding virus by culture at day 1, 2, 6, 8, 11, 15 and 40 
• 
Shedding virus by RT-PCR at day 1, 2, 6, 8, 11, 15, and 40 
• 
Viral load by culture (log TCID /mL) at Day 1, 2, 6, 8, 11, 15, and 40  
10
50
• 
Viral load by quantitative RT-PCR at day 1, 2, 6, 8, 11, 15 and 40 
• 
The time (hours) from first dose of study medication until resolution of fever  
• 
Fever  
• 
Cough   
• 
Coryza   
• 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or sinusitis) 
at any time during the study 
• 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or sinusitis) 
at any time during the study that are treated with antibiotics 
• 
Initiation of treatment with antibiotics after randomization  
• 
Hospitalization, and for those who are hospitalized, the duration of hospitalization 
• 
Development of rejection or GVHD 
 
The following are the model-predicted PK secondary endpoints for both oseltamivir and 
oseltamivir carboxylate: 
• 
Steady-state area under the concentration–time curve from 0 to 12 hours (AUC0-12) 
) for both oseltamivir and oseltamivir carboxylate 
• 
Maximum plasma concentration (Cmax
) for both oseltamivir and oseltamivir carboxylate 
• 
Trough plasma concentration (Ctrough
 
The following model-predicted PK endpoints may be included, if appropriate:  
• 
Elimination half-life (t1/2) 
) 
• 
Time to maximum concentration (tmax
) 
• 
Elimination constant (ke
• 
Apparent clearance (CL/F) 
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• 
Apparent volume of distribution (Vc/F) 
• 
Apparent total clearance of metabolite (CLm) 
• 
Last measurable concentration (Clast) and time to last measurable concentration (tlast)  
 
8.1.3 
Safety 
Safety of the treatment will be evaluated by AEs, physical exams, clinical laboratory tests, 
and vital signs. 
In addition to routine safety assessments, the proportion of subjects experiencing a 
rejection and/or graft versus host disease will be summarized by treatment group.  
8.2 
STATISTICAL AND ANALYTICAL METHODS  
8.2.1 
Statistical Model  
8.2.1.1 
Time to Event Variables 
A non-parametric model will be assumed with estimation of medians based on Kaplan-
Meier methods.  Subjects without alleviation of symptoms will have their time censored 
at the last available observation that a complete assessment was made. 
For the purpose of comparing treatment groups, it will be assumed that their respective 
distributions for the primary endpoint differ only by a shift in location. 
8.2.1.2 
Dichotomous Variables and Viral Load  
For the endpoints defined dichotomously in terms of events or symptoms including the 
development of resistance, it will be assumed that the number of patients experiencing 
the event or exhibiting the symptom will have a binomial distribution. 
For the continuous endpoints of viral load at Day 1, 2, 6, 8, 11, 15, and 40 no model will 
be assumed.  
8.2.2 
Sample Size 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 90% 
of enrolled patients will have laboratory-confirmed influenza, there will be 75 patients in 
each treatment arm in the population evaluable for the development of resistance.  The 
following table shows the 95% Pearson-Clopper confidence intervals that would result 
with a sample size of 75 patients in a treatment arm if certain event rates are observed 
in the study. 
During the study the number of influenza A virus infected patients and the rate of 
development resistance will be monitored in a blinded fashion, in order to ensure a 
reasonable precision for the estimation.  An additional number of patients may be 
enrolled if necessary. 
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Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of 
safety.  This number of patients would provide estimates of adverse event rates with 
similar precision. 
8.2.3 
Hypothesis Testing  
Formal hypothesis testing will be not performed, instead inferences will be based on 
comparison of confidence intervals.  
8.2.4 
Analysis Populations 
Three main patient populations will be used for the analysis of data from this study; the 
Safety Population, the Intent-to treat Population and the Intent-to-Treat Infected 
Population.  Detailed definitions of these populations will be given in the SAP.  
8.2.4.1 
Intent to Treat Population 
All patients randomized will be included in the intent to treat population [Patients will be 
assigned to treatment groups as randomized for analysis purposes]. 
8.2.4.2 
Intent to Treat Infected Population 
All patients randomized and with laboratory confirmation of influenza infection, excluding 
patients infected with oseltamivir-resistant influenza at baseline, will be included in the 
intent to treat influenza infected population [Patients will be assigned to treatment groups 
as randomized for analysis purposes]. 
The ITTI Population will be the primary population for the summary and analysis of the 
development of resistance and the efficacy variables. 
8.2.4.3 
 Pharmacokinetic Evaluable Patient Population (PKEP) 
The PKEP population comprises all patients in the ITT population who have at least one post-
dose drug concentration measurement at a scheduled visit timepoint.  Patients may be excluded 
from the PKEP population if they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or have unavailable or incomplete data that may influence the PK 
analysis.  
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Decisions on patient exclusion from the PK analysis will be made prior to database closure by the 
clinical pharmacologist.  Excluded patients will be documented along with the reason for 
exclusion. 
8.2.4.4 
Subpopulations 
A subpopulation of the ITTI population will be defined comprising patients who received 
their first dose of study medication within 48 hours of influenza symptom onset for the 
comparison of efficacy endpoints with the age appropriate placebo treated patients 
(pediatric or adult) from the registration trials. 
In order to evaluate the potential for relapse, the following two subpopulations of the ITTI 
population will be evaluated:  
• 
patients not shedding virus as assessed by culture on Day 11 
• 
patients not shedding virus as assessed by RT-PCR on Day 11 
 
Viral shedding and RT-PCR at days 15 and 40 will be evaluated in these subpopulations. 
Based on the proportion of subjects hospitalized, an additional subpopulation may be 
defined to evaluate the length of hospitalization for hospitalized subjects. 
Likewise, based on the proportion of children enrolled additional subpopulations of 
children and adults will be created to evaluate the course of influenza in children and 
adults.  
8.2.5 
Efficacy Analysis 
For the analysis of time to alleviation of all clinical symptoms, the following two 
assessments will be made independently of each other and without regard to the 
outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials  
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is 
comparable to the subpopulation of patients in the current study whose first dose of 
study medication was within 48 hours of symptom onset.  For this population, a 
median time to resolution of all clinical influenza symptoms will be determined along 
with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.  These confidence intervals 
will be compared individually to the placebo control confidence interval described 
above as a potential means of establishing treatment effects. 
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• 
Assessment of relative efficacy 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 95% 
confidence interval.  
This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences.  For example, if it does not contain 
the value zero a difference will have been established.   
For the dichotomous endpoints, the proportion experiencing the event or symptom, and 
its associated 95% confidence interval will be derived for each treatment group.  Where 
possible, the corresponding confidence intervals from the placebo control population will 
be presented for comparison to those derived for the active treatment groups in this trial. 
The continuous secondary endpoint time to resolution of fever will be analyzed as for the 
primary efficacy endpoint.  
For the continuous endpoints of viral load (log TCID
10
50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, standard deviation, median, minimum and 
maximum) will be derived for each treatment group. 
8.2.6 
Safety Data Analysis 
The safety analysis population will include all subjects who receive at least one dose and 
had a safety assessment performed post randomization.  All safety variables will be 
summarized and presented in tables based on this safety population. 
8.2.7 
Analysis of Resistance 
For the summary of the development of resistance for each treatment arm, 95% 
confidence intervals will be provided with the estimated rates.  Further details are 
available in the Resistance Plan for NV20234.  These data will be summarized in a 
report separate from the final study report. 
8.2.7.1 
Exclusion of Data from Analysis 
Efficacy data collected from any patient who begins treatment with another antiviral for 
influenza (for example, amantadine, rimantadine, laninamivir, peramivir, or zanamavir), 
after the other antiviral treatment commences, will be excluded from the primary and 
secondary efficacy analyses.  Such patients will be considered failures to oseltamivir 
treatment in the analyses.  Further details will be provided in the SAP. 
8.2.7.2 
Interim Analysis 
No interim analyses are planned.  
8.2.8 
Other Analyses 
Further exploratory analysis (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the SAP. 
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8.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
Pharmacokinetic Analysis
8.3.1 
 
The primary study variables are the model-predicted PK parameters:  steady-state AUC0-12, Cmax, 
and Ctrough of oseltamivir and oseltamivir carboxylate. 
Secondary model-predicted PK variables may be included for both oseltamivir and oseltamivir 
carboxylate, if appropriate:  t1/2, tmax, k , CL/F, Vc/F, CL
e
m, Clast and tlast. 
Individual and mean plasma concentrations at each sampling timepoint for oseltamivir and 
oseltamivir carboxylate will be presented by listings and descriptive summary statistics, 
including means, geometric means, medians, ranges, standard deviations, and coefficients of 
variation.  Individual and mean concentration-versus-time profiles will be plotted on linear and 
semi-logarithmic scales. 
Plasma concentration data from sparse sampling will be analyzed using an established population 
PK model to determine key exposure parameters (e.g., Cmax, Ctrough, and AUC).  For 
immunocompromised children aged 1 to 18 years, plasma oseltamivir and oseltamivir carboxylate 
concentrations will be modeled in NONMEM using a structure similar to a comprehensive 
population PK model, which was previously developed using plasma data of 
non-immunocompromised children and adults (ages 1 to 80 years) [36].  The basic structure 
consists of a 2-compartment model with first-order absorption and direct conversion of 
oseltamivir to oseltamivir carboxylate, while a 1-compartment model is used to account for the 
renal elimination of oseltamivir carboxylate from the plasma.  Body weight, evaluated using a 
power function and centered around 70 kg, is a statistically significant predictor of the CL/F for 
oseltamivir, and both CL/F and central volume of distribution (Vc/F) for oseltamivir carboxylate.  
For oseltamivir carboxylate, CrCl is also a significant predictor of CL/F, while Vc/F decreases 
linearly with age. 
Pharmacodynamic Analysis  
8.3.2 
If feasible, the relationship between PK exposure of oseltamivir carboxylate and viral shedding 
response data will be characterized using nonlinear mixed effects modeling (using software 
NONMEM).  Relevant population pharmacodynamic (PD) parameters will be derived, and the 
influence of covariates will be investigated.  If deemed appropriate and necessary, data may be 
pooled with data from previous studies investigating oseltamivir and oseltamivir carboxylate in 
order to improve the model stability. 
9. 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs against the investigator’s records by the study monitor [source document 
verification], and the maintenance of a drug–dispensing log by the investigator.  
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The data collected will be entered into the study database from the working copy of the 
CRF faxed from the site. 
A comprehensive validation check program will verify the data and discrepancy reports 
will be generated accordingly for resolution by the investigator.  As patients complete the 
study [or prematurely withdraw] and their signed CRFs become available, a second data 
entry will be performed from the original, signed CRF.  A comparison check will be run to 
identify and resolve any discrepancies between the first and second data entry. 
Throughout the study the Study Management Team [SMT] will review data according to 
the SMT Data Review Plan as described in the Data Quality Plan.  
9.1 
ASSIGNMENT OF PREFERRED TERMS AND ORIGINAL 
TERMINOLOGY 
For classification purposes, preferred terms will be assigned by the sponsor to the 
original terms entered on the CRF, using the current version of MedDRA (Medical 
Dictionary for Regulatory Activities terminology) for adverse events and diseases and 
the INN (International Non-Proprietary name) drug terms and procedures dictionary for 
treatments and surgical and medical procedures. 
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10. 
REFERENCES 
rd
1. 
Murphy B.G and Webster R.G.  Orthomyxoviruses. Chapter 46.  Fields Virology 3  
Edition, Eds:  Fields B.N, Knipe D.M, Howley P.M et al. Pub Lippincott.Raven.  1996.  
p1397 – 1445.  
2. 
World Health Organization. Influenza. Fact Sheet No. 211. March, 2003. 
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Ison Michael, G., P. Mishin Vasiliy, J. Braciale Thomas, G. Hayden-Frederick, and V. 
Gubareva Larisa., Comparative activities of oseltamivir and A-322278 in 
immunocompetent and immunocompromised murine models of influenza virus 
infection. The Journal of infectious diseases, 2006. 193(6): p. 765-72 . 
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Vilchez Regis, A., K. McCurry, J. Dauber, A. Lacono, B. Griffith, et al., Influenza 
virus infection in adult solid organ transplant recipients. American journal of 
transplantation : official journal of the American Society of Transplantation and the 
American Society of Transplant Surgeons, 2002. 2(3): p. 287-91. 
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Ljungman, P., K.N. Ward, B.N. Crooks, A. Parker, R. Martino, et al., Respiratory 
virus infections after stem cell transplantation: a prospective study from the 
Infectious Diseases Working Party of the European Group for Blood and Marrow 
Transplantation. Bone marrow transplantation, 2001. 28(5): p. 479-84. 
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Nichols, W.G., A. Guthrie Katherine, L. Corey, and M. Boeckh, Influenza infections 
after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of 
antiviral therapy. Clinical infectious diseases : an  official publication of the Infectious 
Diseases Society of America, 2004. 39(9): p. 1300-6. 
7. 
Investigator Brochure for Tamiflu® (oseltamivir phosphate) 11th version June 2010.  
8. 
Kaiser, L., C. Wat, T. Mills, P. Mahoney, P. Ward, et al., Impact of oseltamivir 
treatment on influenza-related lower respiratory tract complications and 
hospitalizations. Archives of internal medicine, 2003. 163(14): p. 1667-72.  
9. 
Whitley, R.J., F.G. Hayden, K.S. Reisinger, N. Young, R. Dutkowski, D. Ipe, R.G. 
Mills, and P. Ward, Oral oseltamivir treatment of influenza in children. The Pediatric 
infectious disease journal, Feb 2001, vol. 20, no. 2, p. 127 33, ISSN: 0891 3668., 
2001. 
10. Machado, C.M., L.S.V. Boas, A.V.A. Mendes, I.F. da Rocha, D. Sturaro, et al., Use 
of Oseltamivir to control influenza complications after bone marrow transplantation. 
Bone marrow transplantation, 2004. 34(2): p. 111-4.   
11. Dutkowski, R., B. Thakrar, E. Froehlich, P. Suter, C. Oo, et al., Safety and 
pharmacology of oseltamivir in clinical use. Drug safety : an international journal of 
medical toxicology and drug experience, 2003. 26(11): p. 787-801. 
12. He, G., J. Massarella, and P. Ward, Clinical pharmacokinetics of the prodrug 
oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinetics. 1999 Dec. 
37(6):471-84. Review.  
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13. Levey Andrew, S., J. Coresh, E. Balk, T. Kausz Annamaria, A. Levin, et al., National 
Kidney Foundation practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification. Annals of internal medicine, 2003. 139 (2): p. 137-
47. 
14. Hogg Ronald, J., S. Furth, V. Lemley Kevin, R. Portman, J. Schwartz- George, et al., 
National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical 
practice guidelines for chronic kidney disease in children and adolescents: 
evaluation, classification, and stratification. Pediatrics, 2003. 111(6 Pt 1): p. 1416-21. 
15. Ferrara, J.L. and H.J. Deeg, Graft-versus-host disease. The New England journal of 
medicine, 1991. 324(10): p. 667-74. 
16. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. Harrison's 
Principles of Internal Medicine. 17th ed. The McGraw Hill companies, Inc; 2008.  
17. CDC http://www.cdc.gov/flu/protect/hiv-flu.htm as assessed on 27 October 2010. 
18. Caselli D , Carraro F, Castagnola E, Ziino O, Frenos S, et al. Morbidity of pandemic 
H1N1 influenza in children with cancer. Pediatr Blood Cancer. 2010;55:226–28. 
19. Tramontana AR , George B, Hurt AC, Doyle JS, Langan K, et al. Oseltamivir 
resistance in adult oncology and hematology patients infected with pandemic (H1N1) 
2009 virus, Australia. Emerging Infectious Diseases. 2010;16(7):1068-75. 
20. Chironna M, Tafuri S, Santoro N, Prato R, Quarto M, et al. A nosocomial outbreak of 
2009 pandemic influenza A (H1N1) in a pediatric oncology ward in Italy (October-
November 2009), Eurosurveillance. 7 Jan 2010;15(1). 
21. Launes C, Rives S, Catala A, Berrueco R, Toll T , et al. pandemic influenza A (2009 
H1N1) in children with acute lymphoblastic leukemia. Br J Haematol. Jun 
2010;149(6):874-8. 
22. Clinical Study Report Protocol NV20235 Research Report No. 
 
23. AIDS 2010, DOI:10.1097/QAD.0b013e32833d2096. 
24. Akyuz S, Yilmaz A, Bulbul M, Erdogan O, Renda R, et al. Do immunosupressive 
patients really have a severe outcome with H1N1 virus infection? Journal of Tropical 
Pediatrics. 2010. 
25. Mellouli F, Ouederni M, Dhouib N, Hajkacem MA, Slim A, et al. Successful 
treatment of influenza A virus by oseltamivir in bone marrow transplant recipients. 
Pediatr Transplantation. 2010;14:178–181. 
26. Kumar D, Michaels MG, Morris MI, Green M, Avery RK, et al on behalf of the 
American Society of Transplant H1N1 Collaborative Study Group. Lancet. 2010 
Aug;10;pg 521 -6. 
27. Fox BD, Raviv Y, Rozengarten D, Rusanov V, Bakal I, et al. Pandemic influenza 
(H1N1): Impact on lung transplant recipients and candidates. J Heart Lung 
Transplant. 2010. 
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28. Ng BJH, Glanville AR, D’Costa J, Snell G, Musk M, et al. The combined Australian 
experience with human swine influenza H1N1 in lung transplant recipients. S141 
(abstract). 
29. Ison MG, Sharma A, Shepard JO, Wain JC, Ginns LC. Outcome of Influenza 
Infection Managed With Oseltamivir in Lung Transplant Recipients. J Heart Lung 
Transplant 2008;27:282-88. 
30. Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: January 
2010. Wkly Epidemiol Rec 2009b; 85(6): 37-40. 
31. Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of drug-
resistant influenza virus from immunocompromised patients: a case series. J Infect 
Dis 2006; 193(6): 760-764. 
32. Hayden FG. Antiviral resistance in influenza viruses: clinical and epidemiological 
aspects. In: Antimicrobial drug resistance: clinical and epidemiological aspects, Vol 
2 (Infectious Diseases). (Ed. Mayers DL). Humana Press, 2009; 1st: 1011-1034. 
33. Klein, Marina B., Ying Lu, Lina DelBalso, Stephanie Cote´ and Guy Boivin. Influenza 
virus Infection Is a Primary Cause of Febrile Respiratory Illness in HIV Infected 
Adults, Despite Vaccination. Clinical Infectious Diseases 2007; 45:234–40. 
34. Lee N, Chan PK, Hui DS, Rainer TH, Wong E, Choi KW, Lui GC, Wong BC, Wong 
RY, Lam WY, Chu IM, Lai RW, Cockram CS, Sung JJ. Viral loads and duration of 
viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009 Aug 
15;200(4):492-500. 
35. Quick Facts for Clinicians on Antiviral Treatments for H1N1 Influenza. 2009 Nov. 
From http://www.cdc.gov/H1N1flu/antivirals/facts_clinicians.htm accessed on May 
14th, 2010. 
36. Kamal MA, Van Wart SA, Rayner CR, Subramoney V, Reynolds DK, Bulik CC, Smith PF, 
Bhavnani SM, Forrest A. Population pharmacokinetics of oseltamivir in pediatric and adult 
subjects. ICAAC 2012. 
37. Allen U, Blumberg EA, Fischer SA, Green M, Ison MG, Kotton CN, et al. American 
Society of Transplantation (AST) Infectious Diseases Community of Practice / 
Transplant Infectious Disease Section of The Transplantation Society (TTS) 
Guidance On Novel Influenza A/H1N1. [cited 2010 Oct 28]. 2009 Dec 03. Available 
from: www.a-s-t.org/files/pdf/ast_h1n1_guidance.pdf. 
38. Katzung BG, Masters SB, Trevor AJ (ed). Basic and clinical pharmacology. 11th 
edition. Tata McGraw-Hill Companies, Inc., New York: 2009: 971-80.  
39. Salvana EMT, Salata RA. Infectious complications associated with monoclonal 
antibodies and related small molecules. Clin Microbiol Rev. 2009 Apr;22(2): 274-90. 
 
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PART II: ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the subject.  For studies conducted in the EU/EEA countries, the 
investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].  For 
studies conducted in the USA or under US IND, the investigator will additionally ensure 
that the basic principles of “Good Clinical Practice” as outlined in the current version of 
21 CFR, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 
50, “Protection of Human Subjects”, and part 56, “Institutional Review Boards”, are 
adhered to. 
In other countries where “Guideline for Good Clinical Practice” exist Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
INFORMED CONSENT  
It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain written informed consent from each subject 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study.  For subjects not qualified or incapable of 
giving legal consent, written consent must be obtained from the legally acceptable 
representative.  In the case where both the subject and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the 
entire informed consent discussion.  After the subject and representative have orally 
consented to participation in the trial, the witness’ signature on the form will attest that 
the information in the consent form was accurately explained and understood.  The 
investigator or designee must also explain that the subjects are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason.  The Case Report 
Forms [CRFs] for this study contain a section for documenting informed subject consent, 
and this must be completed appropriately.  If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and 
updated if necessary.  All subjects [including those already being treated] should be 
informed of the new information, given a copy of the revised form and give their consent 
to continue in the study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written consent. 
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11.3 
INDEPENDENT ETHICS COMMITTEES/INSTITUTIONAL 
REVIEW BOARD  
Independent Ethics Committees [non-US]:  This protocol and any accompanying 
material provided to the subject [such as subject information sheets or descriptions of 
the study used to obtain informed consent] as well as any advertising or compensation 
given to the patient, will be submitted by the investigator to an Independent Ethics 
Committee.  Approval from the committee must be obtained before starting the study, 
and should be documented in a letter to the investigator specifying the date on which the 
committee met and granted the approval. 
Any modifications made to the protocol after receipt of the Independent Ethics 
Committee approval must also be submitted by the investigator to the Committee in 
accordance with local procedures and regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee. 
Institutional Review Board [US]:  It is the understanding of the sponsor that this 
protocol [and any modifications] as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board.  This board must operate in 
accordance with the current Federal Regulations.  A letter or certificate of approval will 
be sent by the investigator to the Sponsor or designee prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between 
an appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial].  Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Clinical Science Leader/Clinical Pharmacologist and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required.  Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial subjects, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g. change in monitor[s], change of telephone 
number[s]. 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
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basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
14. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
14.1 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] subject clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff curriculum vitae and authorization forms and other appropriate 
documents/correspondence etc.  
Subject clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and subject screening and enrollment logs.  
The Investigator must keep these two categories of documents on file for at least 15 
years after completion or discontinuation of the study.  After that period of time the 
documents may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
14.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
The investigator shall supply the sponsor or designee on request with any required 
background data from the study documentation or clinic records.  This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected.  In 
case of special problems and/or governmental queries or requests for audit inspections, 
it is also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. 
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14.3 
AUDITS AND INSPECTIONS 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees, or to health authority inspectors after 
appropriate notification.  The verification of the CRF data must be by direct inspection of 
source documents. 
14.4 
CASE REPORT FORMS 
For each patient enrolled, a CRF must be completed and signed by the principal 
investigator or authorized delegate from the study staff.  This also applies to records for 
those patients who fail to complete the study [even during a pre-randomization screening 
period if a CRF was initiated].  If a patient withdraws from the study, the reason must be 
noted on the CRF.  If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
All forms should be typed or filled out using indelible ink, and must be legible.  Errors 
should be crossed out but not obliterated, the correction inserted, and the change 
initialed and dated by the investigator or his/her authorized delegate.  The investigator 
should ensure the accuracy, completeness, legibility, and timeliness of the data reported 
to the sponsor or designee in the CRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the CRF.  
The investigator [or his/her deputy] agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On CRFs or other documents 
submitted to the sponsor or designee, subjects should not be identified by their names, 
but by an identification code.  The investigator should keep a subject enrollment log 
showing codes, names and addresses.  The investigator should maintain documents not 
for submission to Roche, e.g., subjects’ written consent forms, in strict confidence. 
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17. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  This allows the sponsor or designee to protect proprietary information and 
to provide comments based on information from other studies that may not yet be 
available to the investigator. 
In accord with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator will be designated by mutual agreement. 
Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel.  Authorship will be determined by mutual agreement. 
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Appendix 1 Calculation of Creatinine Clearance and Grading of 
Chronic Extensive GVHD  
Calculation of Creatinine Clearance 
Conversion Factor for Serum Creatinine: 
Conventional Units (mg/dL) = SI Units (μmol/L) ÷ 88.4   
Age = number of years (12 years 11 months = 12 years) 
Estimated Creatinine Clearance according to Cockcroft-Gault [13] 
 (for patients ≥ 18 years): 
¾ Males 
 
Creatinine 
Clearance (mL/min)  =  
[(140 − age) × Body Weight (kg)] ÷ [72 × Serum Creatinine 
(mg/dL)] 
 
¾ Females  
Creatinine Clearance = above equation × 0.85 
 
Estimated Creatinine Clearance according to Schwartz equation [14]  
(for patients < 18 years): 
 
k × Height (cms) ÷  Serum Creatinine (mg/dL) 
Creatinine Clearance 
(mL/min/1.73 M2) =  
Value for k:  
k 
Age (years) 
0.45 
 < 2 
0.55 
 ≥ 2 to < 13 
0.7 
 ≥ 13 to < 18 (males) 
 ≥ 13 to < 18 
(females) 
0.55 
 
 
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Appendix 1 Calculation of Creatinine Clearance and Grading of 
Chronic Extensive GVHD (cont.)  
Grading of Chronic GVHD [15] 
Type of Disease 
Extent of Disease 
Limited 
Localized skin involvement, liver 
dysfunction or both 
Extensive 
Generalized skin involvement 
 
Localized skin involvement or liver 
dysfunction plus any one of the following: 
   1. Chronic aggressive hepatitis, bridging 
necrosis or cirrhosis 
   2. Eye involvement (Schirmer’s 
test,  < 5 mm) 
   3. Involvement of mucosalivary glands 
   4. Mucosal involvement (on lip biopsy) 
   5. Involvement of other target organs  
 
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Appendix 2 Adult Patient Diary Data and Symptom Record 
 
The purpose of the electronic diary is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study.  Temperature and date 
and time of drug administration will also be recorded on the electronic patient diary. 
Scoring of Symptoms. 
Please answer All of the questions yourself by checking one box for each row. 
The information you provide is very important and will remain strictly confidential. 
 
 
 
 
   
 
 
  absent  mild 
   moderate    severe 
 
 
 
 
      
   0       1 
 
     2         3 
 
 
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Appendix 3 Diary Data for Children  
Temperature and date and time of drug administration will also be recorded on the 
electronic patient diary. 
 
Temperature
: 
 
 
 
.  
ºC/F 
 
Symptoms of influenza-like illness 
Please mark one box only per question 
Item 
 
No 
Problem 
0 
 
Minor 
Problem 
1 
 
Moderate
Problem 
2 
 
Major 
Problem 
3 
Don’t Know 
or not 
Applicable 
1. 
Poor appetite..................................
 
 
 
 
 
2. 
Not sleeping well ............................
 
 
 
 
 
3. 
Irritable, cranky, fussy ....................
 
 
 
 
 
4. 
Feels unwell ...................................
 
 
 
 
 
5. 
Low energy, tired............................
 
 
 
 
 
6. 
Not playing well ..............................
 
 
 
 
 
7. 
Crying more than usual ..................
 
 
 
 
 
8. 
Needing extra care.........................
 
 
 
 
 
9. 
Clinginess.......................................
 
 
 
 
 
10. Headache.......................................
 
 
 
 
 
11. Sore throat .....................................
 
 
 
 
 
12.   Muscle aches or pains...................
 
 
 
 
 
13. Fever..............................................
 
 
 
 
 
14. Cough.............................................
 
 
 
 
 
15. Nasal congestion, runny nose ........
 
 
 
 
 
16. Vomiting .........................................
 
 
 
 
 
17. Not interested in what’s going on 
 
 
 
 
 
18. Unable to get to get out of bed 
 
 
 
 
 
 
This form was filled out by:          
                            1. 
 Parent 
 
 
 
 
 
    2. 
 Other relative 
 
 
 
 
 
    3. 
Nanny 
 
 
 
 
 
    4. 
Subject 
 
 
 
 
 
    5. 
 Other     
specify______________________________________________ 
Date of Assessment 
 
 
 
 
 
 
 
 
 
 
Time of Assessment 
 
dd 
mm 
yy 
 
h 
min 
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Appendix 4 Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug 
PROBABLE [must have first three] 
This category applies to those AEs which are considered, with a high degree of certainty, 
to be related to the test drug.  An AE may be considered probable, if: 
3. 
It follows a reasonable temporal sequence from administration of the drug. 
4. 
It cannot be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the subject. 
5. 
It disappears or decreases on cessation or reduction in dose.  [There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., [1] bone marrow depression, [2] tardive 
dyskinesias]. 
6. 
It follows a known pattern of response to the suspected drug. 
7. 
It reappears upon rechallenge. 
 
POSSIBLE [must have first two] 
1. 
This category applies to those AEs in which the connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty.  An AE may 
be considered possible if, or when: 
2. 
It follows a reasonable temporal sequence from administration of the drug. 
3. 
It may have been produced by the subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the subject. 
4. 
It follows a known pattern of response to the suspected drug. 
 
REMOTE [must have first two] 
1. 
In general, this category is applicable to an AE which meets the following criteria: 
2. 
It does not follow a reasonable temporal sequence from administration of the drug. 
3. 
It may readily have been produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the subject. 
4. 
It does not follow a known pattern of response to the suspected drug. 
5. 
It does not reappear or worsen when the drug is readministered. 
 
UNRELATED 
This category is applicable to those AEs which are judged to be clearly and 
incontrovertibly due only to extraneous causes [disease, environment, etc.] and do not 
meet the criteria for drug relationship listed under remote, possible, or probable. 
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Appendix 4 Adverse Event [AEs] Categories for Determining 
Relationship to Test Drug (cont.) 
 
 
Probable 
Possible 
Remote 
Unrelated 
Clearly due to extraneous causes 
– 
– 
– 
+ 
 
 
 
 
 
Reasonable temporal association with 
drug administration 
+ 
+ 
– 
– 
 
 
 
 
 
May be produced by subject clinical 
state, etc. 
– 
+ 
+ 
+ 
 
 
 
 
 
Known response pattern to suspected 
drug 
+ 
+ 
– 
– 
 
 
 
 
 
Disappears or decreases on cessation 
or reduction in dose 
+ 
– 
– 
– 
 
 
 
 
 
Reappears on rechallenge 
+ 
– 
– 
– 
 
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Appendix 5 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– 
is fatal; [results in death] [NOTE:  death is an outcome, not an event]. 
– 
is Life-Threatening    [NOTE:  the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
– 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor or designee is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definitions above.  These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator.  For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply)  
– 
Pre-existing/Underlying disease - specify  
– 
Study treatment – specify the drug(s) related to the event 
– 
Other treatment (concomitant or previous) – specify 
– 
Protocol-related procedure 
– 
Other (e.g. accident, new or intercurrent illness) - specify 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious.  
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
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Appendix 5 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
(cont.) 
A serious adverse event occurring during the study or which comes to the attention of 
the investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
page of the CRF:  intensity, relationship to test substance, action taken, and outcome to 
date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs:  Local Monitor  
ROCHE HEADQUARTERS CONTACT for SAEs:  Clinical Operations/Clinical Science  
Within the US, weekends, holidays and after 5:00 pm, call 
 and ask for 
the physician on call.  Outside the US, call the local emergency contact number provided 
by the Monitor. 
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Appendix 6 Primary Immunodeficiency Conditions 
Category 
Conditions 
Adenosine deaminse (ADA) deficiency 
Artemis deficiency (SCIDA) 
CD45 deficiency 
Cernunnos deficiency 
DNA ligase IV (LIG4) deficiency 
Severe Combined 
Immunodeficiency (SCID) 
Interleukin receptor γ chain deficiency (X-linked SCID) 
Janus-associated kinase 3 (JAK3) deficiency 
Recombinase activating gene (RAG 1 / 2) deficiency  
Reticular dysgenesis 
TAP- 1 or TAP- 2 deficiency (MHC class I deficiency) 
CD8 deficiency 
diGeorge syndrome  
Interleukin 7 receptor α (IL7RA) deficiency 
MHC class II deficiency 
LCK deficiency 
Primary T cell Deficiency 
Orai 1 deficiency 
Nude syndrome (wing helix nude deficiency) 
Purine nucleotide phosphorylase (PNP) deficiency 
T cell receptor deficiency (CD 3γ, δ, ε, and ζ 
deficiencies) 
Zap 70 tyrosine kinase deficiency 
X-Linked CD40 ligand deficiency 
Predominantly Antibody 
Deficiency 
X- Linked IKK-γ (NEMO) deficiency 
CD40 deficiency 
Interferon γ receptor deficiency 
Other Well-Defined 
immunodeficiency Syndromes 
X-Linked lymphoproliferative syndrome 
Adapted from Table 310-2:  p2056 reference 16. 
 
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Appendix 7 Hematologic Malignancies and their Effect on the 
Immune System 
Malignancy 
Effect on immunity 
suppression of hematopoiesis, neutropenia, 
lymphocyte dysfunction 
ALL, lymphomas 
hypogammaglobulinemia, increased 
susceptibility to infections, autoimmune anemia 
or thrombocytopenia 
CLL, small lymphocytic lymphoma 
Hairy cell leukemia, myelodysplastic syndromes
pancytopenia 
lymphocyte dysfunction, increase in immature 
cells 
peripheral T cell and NK neoplasms 
Hodgkin’s disease  
suppression of cell-mediated immunity 
neutropenia, anemia, thrombocytopenia, 
predisposed to infections, lymphocyte 
dysfunction 
AML 
anemia, granulocyte dysfunction in some 
patients in early phase and in most patients in 
blast phase 
CML 
Adapted from reference 16. 
 
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Appendix 8 Immunosuppressive Medications 
Class 
Category 
Drugs 
Corticosteroids 
- 
Glucocorticoids (oral, sc, im, iv) 
cyclophosphamide, busulfan, mechlorethamine, 
chlorambucil, melphalan, carmustine, lomustine, 
ifosfamide, procarbazine, dacarbazine, 
temozolomide, cisplatin, carboplatin, oxaliplatin 
Alkylating agents 
Anti-metabolites 
methotrexate, 6-mercaptopurine, azathioprine 
bleomycin, actinomycin D, mitomycin C, etoposide, 
topotecan, irinotecan, doxorubicin, daunorubicin, 
idarubicin, epirubicin, mitoxantrone 
Anti-tumor 
antibiotics 
Anti-mitotic agents 
vincristine, vinblastine, vinorelbine, paclitaxel, 
docetaxel, estramustine phosphate, NAB-
paclitaxel 
Cytotoxic agents[
]
16
Molecularly 
targeted agents 
imatinib, tretinoin,  bexarotene, denileukin,  diftitox, 
gefitinib, erlotinib, dasatinib, sorafenib, sunitinib 
Calcineurin inhibitors 
- 
cyclosporine, tacrolimus 
mTOR inhibitors 
(proliferation-signal 
inhibitors) 
sirolimus, everolimus 
- 
Immunosuppressive 
antibodies 
anti lymphocyte and antithymocyte globulins (ALG 
and ATG) 
- 
Adalimumab 
Infliximab 
Cetrolizumab 
Etarnecept 
Basiliximab 
Inhibitors of pro 
inflammatory 
cytokines 
Daclizumab 
Adhesion cell 
modulators 
Natalizumab 
Monoclonal 
antibodies 
Abatacept 
[
, 
]
38 39
Alefacept 
T-cell inhibitors 
Muromonab 
Rituximab 
90Y-Ibritumomab 
B-cell inhibitors 
131I-Tositumomab 
Anti-CD33 
Gemtuzumab 
Anti- CD52 
Alemtuzumab 
Others 
- 
mycophenolate mofetil, thalidomide 
Compiled from Table 81-2:  p521-24 reference 16 and references 38, 39. 
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Title
30-Oct-2013 16:46:29
Date and Time (UTC)
Clinical Science Leader
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL STATEMENT 
 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board.  It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Oseltamivir ⎯  F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version E 
PROTOCOL 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, 
MULTI-CENTER TRIAL EVALUATING 
CONVENTIONAL AND DOUBLE DOSE 
OSELTAMIVIR IN THE TREATMENT OF 
IMMUNOCOMPROMISED PATIENTS WITH 
INFLUENZA 
PROTOCOL NUMBER: NV20234 
VERSION NUMBER: 
E 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
TEST PRODUCT: 
Oseltamivir (Tamiflu® RO 64-0796) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version A:  14 June 2007 
DATES AMENDED: 
Version B:  31 July 2008 
Version C:  28 March 2011 
Version D:  28 September 2012 
Version E: see electronic stamp below 


PROTOCOL AMENDMENT, VERSION E 
RATIONALE 
Protocol NV20234 has been amended to provide clarity and additional guidance on the 
inclusion criteria regarding  CD4 counts for patients with HIV and on the discontinuation 
of patients with a creatinine clearance (CrCl) value of  < 60 mL/min. 
Additional changes to the protocol are as follows: 
• 
The statistical methods section was updated to include an overview of planned 
pharmacokinetic analysis 
• 
CD4  + T − cell percentage values that will be used for patients  ≤ 5 years with HIV 
were added  
• 
The exclusion criterion ‘have evidence of a serious secondary respiratory or 
disseminated infection that may confound or overlay the diagnosis and/or 
symptomatology of influenza’ was removed.  This was removed to prevent 
ambiguity around which patients should not be enrolled into this clinical protocol, 
since patients on antibiotics or with other secondary infections are not allowed to be 
enrolled.  Removal of this criterion is not expected to impact the benefit-risk profile 
of NV20234 as high-risk patients suspected of having influenza would receive 
oseltamivir as part of their clinical care (as per WHO guidance) and these data are 
available through various publications. 
• 
Reference to patient electronic diary cards and to all uses of paper diaries in 
emergency situations were removed 
• 
The total PK blood volume for pediatric patients was corrected from 3.6 mL to 
2.4 mL 
• 
Appendices 2 and 3 have been updated to include an example of the current patient 
diary text 
• 
Updated emergency medical call-in information in Appendix 5 
• 
Added  Child-Pugh Classification  
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
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PROTOCOL AMENDMENT, VERSION E 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
Throughout the protocol high dose was changed to double dose to more accurately 
reflect the  dose amount.  Pharmacokinetic assessment reference to oseltamivir was 
removed as only oseltamivir carboxylate is evaluated in plasma samples.  The term 
medication was changed to drug to better identify which medication and all references to 
electronic diary were changed to patient diary.  References were added as appropriate 
from newly added text. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The list of abbreviations and definitions of terms has been updated to reflect the 
changes to the protocol, where applicable. 
SECTION 1.1.1:  Influenza in the Immunodeficient Population
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T-cell count of  < 200/mm μ
3 L (AIDS defining) are 
highly susceptible to opportunistic disease [16].  However, CD4 counts < 500/mm μ
3 L are 
considered abnormal in HIV-infected individuals, and therefore these individuals are also 
more susceptible to infection.  CD4+T cell counts are higher in infants and young 
children than in adults and decline over the first few years of life [40, 41].  because of 
this age-dependent variation in absolute CD4+ T cell count, calculation of CD4 
percentage is used as a measure for young children because it has shown less variability.  
HIV-infected children (12 months to 5 years old) with < 15% CD4+ T cells are classed 
as severely immunosuppressed and highly susceptible to opportunistic disease, although 
antiretroviral therapy is recommended in children with  < 25% CD4+ T cells as they are 
still classified as immunosuppressed [42].  Studies in patients with HIV/AIDS  have 
shown an increased risk for heart and lung-related hospitalizations during the influenza 
season compared with other times of the year, prolonged duration of influenza 
symptoms, increased risk for influenza-related complications and a higher risk of 
influenza-related death [17]. 
SECTION 2.2:  SECONDARY OBJECTIVES
To evaluate the effects of conventional and high double dose oseltamivir in 
immunocompromised patients on: 
• 
The population pharmacokinetics of oseltamivir and oseltamivir carboxylate (e.g., clearance, 
volume of distribution) in immunocompromised patients with confirmed influenza infection, 
through the application of established population pharmacokinetic (PK) models to the sparse 
plasma concentration data generated  
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• 
The virologic course of influenza (proportion shedding and viral loads at different time 
points) 
• 
The virologic course of influenza (proportion shedding and viral loads at different 
time points). 
• 
To estimate the population pharmacokinetics of oseltamivir and oseltamivir 
carboxylate (e.g., clearance, volume of dstribution) in immunocompromised patients 
with confirmed influenza infection, through the application of established population 
pharmacokinetic (PK) models to the sparse plasma concentration data generated. 
• 
To explore the relationship of metrics of exposure (e.g. AUC, Cmin) to relevant 
pharmacodynamic  (PD) endpoints 
 
SECTION 3.1.1.1:  Choice of Treatment Arms
The currently approved dose of oseltamivir for the treatment indication is the 
conventional dose with a duration of 5 days.  In this study a conventional and high double 
dose (twice the conventional dose) are being evaluated.  The pivotal registration trials for 
oseltamivir in healthy adults with influenza had three treatment arms, two active (75 mg 
and 150 mg) and one placebo.  Both treatment arms were found to be significantly better 
than placebo.  No statistical comparisons were made between the two active treatment 
arms.  Evaluation of the results in the two active treatment arms did not reveal any 
clinically meaningful difference.  However, the proportion of patients shedding virus on 
Day 4 (3 days after the start of treatment), suggested a possible dose-response 
relationship (36%, 28% and 23% in the placebo, 75 mg and 150 mg dose arms 
respectively).  Because defective immune-mediated virus clearance in 
immunosuppressed patients treated with antivirals can result in a higher incidence of 
selection of drug-resistant viruses, it was decided to use both the conventional and high 
double dose arm for this study. 
SECTION 3.1.1.2:  Inclusion of Patients Symptomatic up to 96 Hours
In immunocompromised patients, time from onset of symptoms to seeking medical 
attention (presentation at the clinic) of  > 48 hours has been shown in several case 
reports [33, 27, 28,29] including two instances of nosocomial outbreaks in children 
[25,20].  This notwithstanding, oseltamivir has been shown to offer benefitbe effective in 
immunocompromised populations that included patients treated with oseltamivir beyond 
48 hours of presentation; patients with lung transplant (median time to presentation 3 
days) [27], bone marrow transplant (treatment started more than 48 hours after onset of 
symptoms in all 3 patients) [25], organ transplant (62 of 221 patients started treatment 
after 96 hours) [26] and children with ALLacute lymphocytic leukemia (one child 
presented after 3 days and two children presented after 5 days of symptoms) [21]. 
SECTION 3.1.1.4:  Interpretation of Study Results
Safety and tolerability and the development of resistance are the primary objectives of 
this study.  These will be characterized descriptively.  For the secondary objective of 
efficacy, the subset of the population enrolled in the first 48 hours will be compared with 
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placebo patients from pivotal registration trials (where patients were enrolled in the first 
2 days of illness).  Sections 8.2.5, 8.2.6, and 8.2.7 provide details on the statistical 
considerations and their rationale associated with these comparisons. 
SECTION 3.1.2:  Rationale for Dose Selection and Adjustment 
Dose Selection 
Thus, the rationale for the double higher dose arm in this study is to explore the 
possibility of improved efficacy and decreased emergence of resistance without an 
undue increase in risk.  For patients with a creatinine clearance level of 45 mL/min or above, 
oseltamivir carboxylate exposures for both the 75-mg and 150-mg doses are not expected to exceed 
exposures previously tested.  Patients with a creatinine clearance as low as 45 ml/min, who 
receive the 150-mg BID dose, will have exposures of oseltamivir carboxylate that are within 
(albeit in the upper end) the established safety margin. This corresponds to an AUC produced by 
the 450 mg BID dose in adults with normal renal function (AUC 0-12 hrs of  approximately 15,000 
ng • hr/mL). 
Dose Adjustments 
As this is a double blind In this study, patients whose creatinine clearance (CrCl) decreases 
to  < 60mL45mL/min (adults) using the Cockcroft-Gault method or <45mL/min/1.73m2 (<18 
years old) using the Schwartz equation will be discontinued from study treatment.  A lower 
limit of 45 mL/min for creatinine clearance will be used to allow for patients with a mild to 
moderate renal impairment.  
 
SECTION 3.1.3:  End of Study
The study comprises 10 days of treatment with follow-up visits approximately 5 and 30 
days later as shown in the schedule of assessments.  Study medication will be 
administered twice daily over 10 days for a total of 20 doses.  A rapid diagnostic test for 
influenza will be performed at the end of the 10 days of treatment.  Patients still having 
influenza based on the rapid diagnostic test will be treated per the local standard of care 
by the principal investigator, and any medication provided during the follow-up period should 
be captured in the CRF. 
SECTION 4.2:   INCLUSION CRITERIA
• 
Immunocompromised patient defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in Appendix 6) OR 
o Secondary immunodeficiency 
 
SOT with ongoing immunosuppression OR 
 
Allogenic HSCT with ongoing immunosuppression OR 
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3
 
HIV with a most recent CD4 count < 500/mm  (or  < 25% in 
children  ≤   5 years old) within the last 6 months and, in the 
investigator’s opinion, considered immunocompromised OR 
 In patients with history or clinical presentation at randomization suggestive of renal 
failure; a CrCl > 60 mL/min ( > 18 years old) or >60mL/min/1.73m2( < 18 years old) 
within the last 3 months 
• 
 
SECTION 4.3:  EXCLUSION CRITERIA
• 
Have evidence of a serious secondary respiratory or disseminated infection that 
may confound or overlay the diagnosis and/or symptomatology of influenza. 
• 
Participatedion in a clinical trial or expanded access trial with an investigational 
drug suspected/demonstrated to impact pathways important for the metabolism and 
excretion of oseltamivir in the 4 weeks prior to randomization or concomitantly with 
this study 
SECTION 4.4:  CONCOMITANT MEDICATION AND TREATMENT
Antiviral treatments with activity against influenza (e.g. amantadine, rimantadine, 
zanamivir, ribavirin, laninamivir, peramivir, and additional oseltamivir above that 
specified for this study) are not allowed during the 10-day treatment phase of the study.  
Concomitant use of an investigational drug during the study is also excluded. if 
suspected/demonstrated to impact pathways important for the metabolism and excretion 
of oseltamivir.   
SECTION 4.5:  CRITERIA FOR PREMATURE WITHDRAWAL
The investigator must discontinue treatment if the creatinine clearance is  < 60 45 mL/min 
in adults using the Cockcroft-Gault method or < 60 45 mL/min/1.73 m2 using the 
Schwartz equation in children.  A lower limit of 45 mL/min for creatinine clearance will be 
used to allow for patients with a mild to moderate renal impairment.   
SECTION 5.1: SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM
Patients will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  Influenza 
Rapid Diagnostic test, PCR, or viral culture for the purposes of inclusion criteria 
fulfillment will be done by the site or the local laboratory.  Historical CrCl values 
within 3 months and CD4+ T-cell counts (where applicable) within 6 months before 
randomization are acceptable for inclusion into the study.  
SECTION 5.3:  CLINICAL ASSESSMENTS AND PROCEDURES
Study Day 1 
The baseline and study Day 1 assessment may be performed at the same visit.  
Laboratory assessments (safety labs and nasal and throat swabs for virology) should be performed 
after randomization but prior to the patient receiving first dose of study drug. 
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Study medication, electronic drug, patient diaries, and thermometers will be dispensed.  
Patients or guardians/parents will be instructed on how to complete electronic symptom 
the patient diaries (Appendix 2 andAppendix 3), temperature recording, and treatment  
End of Treatment Day 11 
The end of treatment visit for all patients is on Day 11 (irrespective of whether they took 
one or two doses on Day 1).  Study medication will be administered twice daily over 10 days 
for a total of 20 doses.  Patients who discontinue study medicationdrug prematurely will 
have all Day 11 assessments completed at the time of discontinuation or the following 
day.  
After all Day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit.  If the rapid diagnostic test is positive, the patient may be treated 
per standard of care at the discretion of the investigator.  If treatment is provided, this 
should be captured in the CRF.  
Study Days 12 – 40 
Study Day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  It is therefore important that this visit is completed.  
 
SECTION 5.3.1:  Efficacy Assessments
The primary efficacy end point in this study is the time to resolution of all influenza 
symptoms as recorded in the patient diary.  
The clinical efficacy parameters in this study are: 
1. 
Symptoms of influenza like illness.  These are captured in the patient diary for both 
adults and children (Appendix 2) (Appendix 3).  Influenza symptoms are graded on 
a nominal scale from zero (absent/no problem) to 3 (severe or major problem).  A 
score of zero is considered asymptomatic.  The primary efficacy end point, time to 
alleviation of all symptoms is comprised of all the symptoms captured in the patient 
diary.  
2. 
Temperature.  This is captured in the patient diary.  Temperature is used for 
assessment of the primary and several secondary efficacy end points.  
 
SECTION 5.3.1:  Safety
Safety is one of the primary end-points of this study. Safety parameters in this study include 
adverse events, vital signs, and clinical laboratory evaluations. 
Nasal and throat swab samples will be assessed from each study visit for the presence of 
oseltamivir-resistant mutations. 
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SECTION 5.3.2:  Efficacy Assessments
The clinical efficacy parameters in this study are: 
1. Symptoms of influenza-like illness.  These are captured in the patient diary for both 
adults and children (Appendix 2and Appendix 3).  Influenza symptoms are graded on a 
nominal scale from zero (absent/no problem) to 3 (severe or major problem).  A score of 
zero is considered asymptomatic.  The efficacy end point, time to alleviation of all 
symptoms is comprised of all the symptoms captured in the patient diary.  
2. Temperature.  This is captured in the patient diary.  Temperature is used for assessment 
of several efficacy endpoints. 
SECTION 5.4:  LABORATORY ASSESSMENTS
The laboratory assessments include those for efficacy and safety, resistance, and efficacy. 
Safety 
The safety laboratory assessments in this study, including the assessment of serum chemistry and 
hematology, will be carried out at a central laboratory.  Serum chemistry assessments comprise 
AST, ALT, total bilirubin, urea and creatinine.  Hematology assessments include CBC and 
differential count.  The total volume of blood loss for laboratory assessments will be 
approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section16) will extend to any data generated from the assay 
of these samples.  Biological samples collected from all patients may be infectious and will be 
classified as “diagnostic specimens” for dispatch purposes. 
When clinically indicated, the investigator may draw blood for serum creatinine to be assessed at 
the local laboratory  during the study to calculate creatinine clearance. 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described 
in the Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR 
and viral cultures.  Influenza virus shedding will be assessed.  Baseline samples will be 
assessed for the presence of oseltamivir resistance mutations.   
During the course of treatment, neither the investigator nor the patient will know which 
participants have ongoing positive viral cultures for influenza.  At the end of treatment 
(dayDay 11), a rapid diagnostic test is permitted for the diagnosis of ongoing influenza.  
Safety 
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The safety laboratory assessments in this study, including the assessment of serum 
chemistry and hematology will be done at the central laboratory.  Serum chemistry 
assessments comprise AST, ALT, total bilirubin, urea and creatinine.  Hematology 
assessments include CBC and differential count.  The total volume of blood loss for 
laboratory assessments will be approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section16) will extend to any data generated from 
the assaying of these samples.  Biological samples taken from all patients may be 
infectious and will be classified as “diagnostic specimens” for dispatch purposes. 
The Principal Investigator may draw blood for serum creatinine to be assessed at the 
local laboratory when clinically indicated during the study to calculate creatinine 
clearance. 
SECTION 5.5.1:  Pharmacokinetic Assessments
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected at the following timepoints on Day 6, or any day after the 11th dose, using the 
following sampling approach: 
• 
Within 30 minutes prior to the dose administration (e.g., 8:30 a.m.). dose 09:00 am) 
For adults and adolescents, approximately 2 mL of blood will be collected at each 
timepoint; therefore, the total volume blood loss for PK assessments will be 
approximately 8 mL.  For pediatric patients, not less than approximately 0.6 mL of blood 
will be collected at each timepoint; therefore, the total volume blood loss for PK 
assessments will be approximately 3.62.4 mL 
SECTION 5.5.2:  Pharmacodynamic Assessments
Nasal and throat swabs will be collected from individuals on the days specified in the 
schedule of assessments.  Specimens will be analyzed at a central laboratory.  As 
immunocompromised patients are expected to shed virus for a longer duration, viral samples will 
be collected at all visits.  The proportion of patients with viral shedding at each visit will be 
summarized 
SECTION 6.2:  PREPARATION AND ADMINISTRATION OF STUDY DRUG
1. 
Oseltamivir capsules containing 75 mg of active drug and packaging material 
consisting of pregelatinized starch, povidone, talc and sodium stearyl fumarate.  All 
participants 13 years and older will receive this dosage form.  Oseltamivir capsules 
should be stored atbetween 2-25ºC. 
2. 
A pediatric suspension containing 12 mg oseltamivir per mL of reconstituted solution 
and the following excipients:  sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor).  All participants 12 years and under will receive this dosage form.  
Oseltamivir dry powder for oral suspension [pediatric syrup] should be stored below 
30°C [86°F]).  Once reconstituted, the suspension should not be used for longer 
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than 10 days if stored underat room temperature conditions (below 25°C) or for 17 
days if).  If  stored under refrigerationrefrigerated conditions at 2−8 °C (36−46 °F) 
the suspension should not be used for longer than 17 days. 
SECTION 6.3:  BLINDING AND UNBLINDING
Emergency codes should not be broken except in the case of emergency situations.  
Any request from the investigator for information about the treatment administered to 
study patients for another purpose must be discussed with Roche/designee.  
SECTION 7.2.1:  Reporting of Serious Adverse Events [immediately 
reportable]
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to (Appendix 5).  The serious adverse events should be reported in the most 
up -to-date version of the SAE form. 
SECTION 7.2.2:  Pregnancy
A female patient must be instructed to stop taking the test “drug” and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should 
report all pregnancies immediately (i.e., no more than 24 hours after the investigator 
becomes aware of the pregnancy) to the Sponsor or designee, using the most up -to-
date version of the pregnancy form. 
SECTION 8:  STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
For continuous endpoints summary statistics including mean, standard deviation, median, 
minimum and maximum will be derived for each treatment group. For categorical data the 
number and percentage of events and/or patients for each treatment group will be presented. 
SECTION 8.1.1:  Primary Endpoints
The primary endpoints for safety will be descriptive assessments of:  
• 
Adverse events 
• 
Physical examinations,  
• 
Vital signs and  
• 
Clinical laboratory evaluations  
• 
Tissue rejection and/or graft versus host disease in transplant patients 
• 
 
SECTION 8.1.2:  Secondary Endpoints
The following endpoints will be analyzed descriptively at relevant timepoints The following are 
secondary endpoints which measure efficacy, the primary of which is time to alleviation 
of all clinical symptoms.  With the exception of this variable, viral load and time to 
resolution of fever, they are defined as either the occurrence or non occurrence of the 
specified events or the presence or absence of the specified symptoms. 
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The time (hours) to alleviation of all clinical influenza symptoms (recorded in the patient 
diary)  
• 
Shedding virus by culture and RT-PCR at dayDay 1, 2, 6, 8, 11, 15 and 40 
• 
Shedding virus by RT PCR at dayDay 1, 2, 6, 8, 11, 15, and 40 
/mL) and quantitative RT-PCR 
TCID
• 
Viral load by culture (log10
50
• 
Individual symptom scores  at Day 1, 2, 6, 8, 11, 15, and 40  
• 
Viral load by quantitative RT PCR at dayDay 1, 2, 6, 8, 11, 15 and 40 
• 
The time (hours) from first dose of study medicationdrug until resolution of fever  
• 
Fever  
• 
Cough   
• 
Coryza   
 
SECTION 8.1.3:  Safety
Safety of the treatment will be evaluated by AEs, physical exams, clinical laboratory 
tests, and vital signs. 
In addition to routine safety assessments, the proportion of subjects experiencing a 
rejection and/or graft versus host disease will be summarized by treatment group.
SECTION 8.2.1.1:  Time to Event Variables
For the purpose of comparing treatment groups, it will be assumed that their respective 
distributions for the primary endpoint differ only by a shift in location. 
SECTION 8.2.3:  Hypothesis Testing
Formal hypothesis testing will be not performed, any comparisons between groups instead 
inferences will be based on comparison of confidence intervals.  
SECTION 8.2.4.4:   Subpopulations
In order to evaluate the potential for relapse, the following two subpopulations of the ITTI 
population will be evaluated: 
• 
patients not shedding virus as assessed by culture on Day 11 
• 
patients not shedding virus as assessed by RT PCR on Day 11 
 
Viral shedding and RT PCR at daysDays 15 and 40 will be evaluated in these 
subpopulations. 
Based on the proportion of subjects hospitalized, an additional subpopulation may be 
defined to evaluate the length of hospitalization for hospitalized subjects. 
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Likewise, based on the proportion of children enrolled additional subpopulations of 
children and adults will be created to evaluate the course of influenza in children and 
adults.  
Efficacy Analysis 
For the analysis of time to alleviation of all clinical symptoms, the following two 
assessments will be made independently of each other and without regard to the 
outcomes in each case. 
Comparison to placebo control from pivotal registration trials  
From the integrated efficacy database associated with the oseltamivir treatment approval, 
a population of placebo treated patients will be established that is comparable to the 
subpopulation of patients in the current study whose first dose of study medicationdrug 
was within 48 hours of symptom onset.  For this population, a median time to resolution 
of all clinical influenza symptoms will be determined along with its 95% confidence 
interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.  These confidence intervals will 
be compared individually to the placebo control confidence interval described above as a 
potential means of establishing treatment effects. 
Assessment of relative efficacy 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence 
interval.  
This confidence interval will provide lower and upper limits for the treatment difference 
and can be used as the basis for potential inferences.  For example, if it does not contain 
the value zero a difference will have been established.   
For the dichotomous endpoints, the proportion experiencing the event or symptom, and 
its associated 95% confidence interval will be derived for each treatment group.  Where 
possible, the corresponding confidence intervals from the placebo control population will 
be presented for comparison to those derived for the active treatment groups in this trial. 
The continuous secondary endpoint time to resolution of fever will be analyzed as for the 
primary efficacy endpoint.  
For the continuous endpoints of viral load (log10TCID50/mL) at Day 1, 6, 8, 11, 15, and 40, 
summary statistics (including mean, standard deviation, median, minimum and 
maximum) will be derived for each treatment group. 
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SECTION 8.2.5:  Safety Data Analysis
The safety analysis population will include all patients who receive at least one dose of 
study medicationdrug and had a safety assessment performed post randomization.  All 
safety variables will be summarized and presented in tables based on this safety 
population: 
• 
Adverse events 
• 
Physical examination 
• 
Vital signs 
• 
Clinical laboratory evaluations 
• 
Rejection and/or graft versus host disease 
SECTION 8.2.7:  Efficacy Analysis
For the analysis of time to alleviation of all clinical symptoms, the following two assessments 
will be made independently of each other and without regard to the outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials  
From the integrated efficacy database associated with the oseltamivir treatment approval, a 
population of placebo treated patients will be established that is comparable to the 
subpopulation of patients in the current study whose first dose of study drug was within 48 
hours of symptom onset.  For this population, a median time to resolution of all clinical 
influenza symptoms will be determined along with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.   
• 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence interval.  
For the dichotomous endpoints, the proportion of patients experiencing the event or symptom, 
and its associated 95% confidence interval will be derived for each treatment group.  Where 
possible, the corresponding confidence intervals from the placebo control population will be 
presented for comparison to those derived for the active treatment groups in this trial. 
The continuous secondary endpoint time to resolution of fever will be analyzed as for the time to 
alleviation of all symptoms. 
SECTION 8.2.8:  Other Analyses
Further exploratory analyses (including assessments of the rapid diagnostic test, sub 
group analysis) will be detailed in the SAP 
SECTION 8.3.1:  Pharmacokinetic Analysis
The primary study variables are the model-predicted derived PK parameters:  steady-
state AUC0-12, Cmax, and Ctrough of oseltamivir and oseltamivir carboxylate. 
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Secondary model predicted PK variables may be included for both oseltamivir and 
oseltamivir carboxylate, if appropriate:  t1/2, tmax, ke, CL/F, Vc/F, CLm, Clast and tlast. 
Plasma concentration data from sparse sampling will be analyzed using an established 
population PK model to determine key exposure parameters (e.g., Cmax, Ctrough, and 
AUC).  For immunocompromised children aged 1 to 18 years, plasma oseltamivir and 
oseltamivir carboxylate concentrations will be modeled in NONMEM using a structure 
similar to a comprehensive population PK model, which was previously developed using 
plasma data from non-immunocompromised children and adults (ages 1 to 80 years) 
[36].  The basic structure consists of a 2-compartment model with first-order absorption 
and direct conversion of oseltamivir to oseltamivir carboxylate, while a 1-compartment 
model is used to account for the renal elimination of oseltamivir carboxylate from the 
plasma.  Body weight, evaluated using a power function and centered around 70 kg, is a 
statistically significant predictor of the CL/F for oseltamivir, and both CL/F and central 
volume of distribution (Vc/F) for oseltamivir carboxylate.  For oseltamivir carboxylate, 
CrCl is also a significant predictor of CL/F, while Vc/F decreases linearly with age. 
SECTION 8.3.2:  Pharmacokinetic/Pharmacodynamic Analysis
If feasible, exposure-response relationships [43]will be evaluated between independent variables 
of exposure (e.g., AUC, Cmin) and  dependent variables including continuous (area under the 
viral titer curve, and peak viral titer) and time-to-event (cessation of viral shedding) virologic 
endpoints. Exploratory PK/PD analyses will be performed using appropriate methodologies. In 
order to account for potential non-linearity and non-monotonicity, each continuous independent 
variable (e.g., AUC) will be evaluated in its original form, as a categorical variable based on 
quartiles, as two- and three-group categorical variables.the relationship between PK exposure 
of oseltamivir carboxylate and viral shedding response data will be characterized using 
nonlinear mixed effects modeling (using software NONMEM).  Relevant population 
pharmacodynamic (PD) parameters will be derived, and the influence of covariates will 
be investigated.  If deemed appropriate and necessary, data may be pooled with data 
from previous studies investigating oseltamivir and oseltamivir carboxylate in order to 
improve the model stability
TABLE 1:  Schedule of Assessments 
Table 1 has been revised to remove reference to the electronic patient diary and testing 
by RIDT PCR/ Culture for confirmation of influenza virus was added. 
APPENDIX 2:  Patient Diary Data and Symptom Record for Adults 
Appendix 2 has been revised to reflect the changes to the protocol. 
APPENDIX 3:  Patient Diary Data and Symptom Record for Children 
Appendix 3 has been revised to reflect the changes to the protocol. 
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APPENDIX 5:  ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
Appendix 5 has been updated to remove the call number and information regarding the 
Emergency Medical Call Center Help Desk were added. 
APPENDIX 9:  Child-Pugh Classification of Severity of Liver Disease 
Appendix 9 has been added. 
SAMPLE INFORMED CONSENT FORMS 
The sample Informed Consent Forms have been revised to reflect the changes to the 
protocol. 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 21 
PROTOCOL SYNOPSIS .................................................................................... 22 
1. 
BACKGROUND AND RATIONALE............................................................. 28 
1.1 
Background ........................................................................... 28 
1.1.1 
Influenza in the Immunodeficient Population ......................... 28 
1.1.2 
Oseltamivir............................................................................. 30 
1.2 
Rationale for the Study .......................................................... 33 
2. 
OBJECTIVES.............................................................................................. 33 
2.1 
Primary Objective .................................................................. 33 
2.2 
Secondary Objectives............................................................ 33 
3. 
STUDY DESIGN ......................................................................................... 34 
3.1 
Overview of Study Design and Dosing Regimen................... 34 
3.1.1 
Rationale for Study Design.................................................... 34 
3.1.1.1 
Choice of Treatment Arms..................................................... 34 
3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours ................ 35 
3.1.1.3 
Rational for Sparse PK Sampling .......................................... 35 
3.1.1.4 
Interpretation of Study Results .............................................. 36 
3.1.2 
Rationale for Dose Selection and Adjustment ....................... 36 
3.1.3 
End of Study.......................................................................... 38 
3.2 
Number of patients/ Assignment to Treatment 
Groups................................................................................... 38 
3.3 
Centers.................................................................................. 38 
4. 
STUDY POPULATION................................................................................ 38 
4.1 
Overview................................................................................ 38 
4.2 
Inclusion Criteria.................................................................... 38 
4.3 
Exclusion Criteria................................................................... 39 
4.4 
Concomitant Medication and Treatment................................ 40 
4.5 
Criteria for Premature Withdrawal ......................................... 40 
4.6 
Replacement Policy [Ensuring Adequate 
Numbers of Evaluable Patients] ............................................ 41 
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4.6.1 
For Patients ........................................................................... 41 
4.6.2 
For Centers............................................................................ 41 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES............................ 42 
5.1 
Screening Examination and Eligibility Screening 
Form ...................................................................................... 43 
5.2 
Procedures for Enrollment of Eligible Patients....................... 44 
5.3 
Clinical Assessments and Procedures .................................. 44 
5.3.1 
Safety .................................................................................... 46 
5.3.2 
Efficacy Assessments............................................................ 46 
5.4 
Laboratory Assessments ....................................................... 46 
5.5 
Pharmacokinetic Assessments 
/Pharmacodynamic Assessments.......................................... 47 
5.5.1 
Pharmacokinetic Assessments.............................................. 48 
5.5.2 
Pharmacodynamic Assessments........................................... 48 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT............................................. 48 
6.1 
Dose and Schedule of Study Drug ........................................ 48 
6.1.1 
Dose Modifications ................................................................ 49 
6.2 
Preparation and Administration of Study Drug....................... 49 
6.3 
Blinding and Unblinding......................................................... 50 
6.4 
Assessment of Compliance ................................................... 51 
6.5 
Destruction of Study Drug...................................................... 51 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE.............................................. 52 
7.1 
Adverse Events and Laboratory Abnormalities...................... 52 
7.1.1 
Clinical AEs ........................................................................... 52 
7.1.1.1 
Intensity ................................................................................. 52 
7.1.1.2 
Drug - Adverse Event Relationship........................................ 52 
7.1.1.3 
Serious Adverse Events [Immediately Reportable 
to Roche] ............................................................................... 52 
7.1.2 
Treatment and Follow-up of AEs ........................................... 53 
7.1.3 
Laboratory Test Abnormalities............................................... 53 
7.1.4 
Follow-up of Abnormal Laboratory Test Values..................... 54 
7.2 
Handling of Safety Parameters.............................................. 54 
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7.2.1 
Reporting of Serious Adverse Events 
[immediately reportable] ........................................................ 54 
7.2.2 
Pregnancy ............................................................................. 54 
7.3 
Warnings and Precautions..................................................... 54 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................. 55 
8.1 
Primary and Secondary Study Endpoints .............................. 55 
8.1.1 
Primary Endpoints ................................................................. 55 
8.1.2 
Secondary Endpoints ............................................................ 55 
8.2 
Statistical and Analytical Methods ......................................... 56 
8.2.1 
Statistical Model .................................................................... 56 
8.2.1.1 
Time to Event Variables......................................................... 56 
8.2.1.2 
Dichotomous Variables and Viral Load.................................. 56 
8.2.2 
Sample Size .......................................................................... 56 
8.2.3 
Hypothesis Testing ................................................................ 57 
8.2.4 
Analysis Populations ............................................................. 57 
8.2.4.1 
Intent to Treat Population ...................................................... 57 
8.2.4.2 
Intent to Treat Infected Population......................................... 57 
8.2.4.3 
Pharmacokinetic Evaluable Patient Population ..................... 58 
8.2.4.4 
Subpopulations...................................................................... 58 
8.2.5 
Safety Data Analysis ............................................................. 58 
8.2.6 
Analysis of Resistance........................................................... 58 
8.2.7 
Efficacy Analysis.................................................................... 58 
8.2.7.1 
Exclusion of Data from Analysis ............................................ 59 
8.2.7.2 
Interim Analysis ..................................................................... 59 
8.2.8 
Other Analyses...................................................................... 59 
8.3 
Pharmacokinetic and Pharmacodynamic Analysis ................ 59 
8.3.1 
Pharmacokinetic Analysis...................................................... 59 
8.3.2 
Pharmacokinetic/Pharmacodynamic Analysis ....................... 60 
9. 
DATA QUALITY ASSURANCE................................................................... 60 
9.1 
Assignment of Preferred Terms and Original 
Terminology........................................................................... 61 
10. REFERENCES ........................................................................................... 62 
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11. ETHICAL ASPECTS ................................................................................... 65 
11.1 
Local Regulations/Declaration of Helsinki.............................. 65 
11.2 
Informed Consent .................................................................. 65 
11.3 
Independent Ethics Committees/Institutional 
Review Board ........................................................................ 66 
12. CONDITIONS FOR MODIFYING THE PROTOCOL................................... 66 
13. CONDITIONS FOR TERMINATING THE STUDY ...................................... 66 
14. STUDY DOCUMENTATION, CRFS AND RECORD KEEPING.................. 67 
14.1 
Investigator's Files / Retention of Documents........................ 67 
14.2 
Source Documents and Background Data............................. 67 
14.3 
Audits and Inspections .......................................................... 68 
14.4 
Case Report Forms ............................................................... 68 
15. MONITORING THE STUDY ....................................................................... 68 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS.................................................................................................. 68 
17. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS................................................................................................... 69 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments........................................................... 42 
 
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LIST OF APPENDICES 
Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD......................................................................... 70 
Appendix 2 
Patient Diary Data and Symptom Record for Adults ................... 72 
Appendix 3 
Patient Diary Data and Symptom Record for Children................ 73 
Appendix 4 
Adverse Event [AE] Categories for Determining Relationship 
to Test Drug ................................................................................ 74 
Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 .... 76 
Appendix 6 
Primary Immunodeficiency Conditions........................................ 78 
Appendix 7 
Hematologic Malignancies and their Effect on the Immune 
System........................................................................................ 79 
Appendix 8 
Immunosuppressive Medications................................................ 80 
Appendix 9 
Child-Pugh Classification of Severity of Liver Disease................ 81 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, 
MULTI-CENTER TRIAL EVALUATING 
CONVENTIONAL AND DOUBLE DOSE 
OSELTAMIVIR IN THE TREATMENT OF 
IMMUNOCOMPROMISED PATIENTS WITH 
INFLUENZA 
PROTOCOL NUMBER: NV20234 
VERSION NUMBER: 
E 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
® 
TEST PRODUCT: 
Oseltamivir (Tamiflu RO 64-0796) 
MEDICAL MONITOR: 
Vedran Pavlovic, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form as instructed by your local study monitor. .  
Please retain a copy for your study files. 
 
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PROTOCOL SYNOPSIS 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, MULTI-CENTER 
TRIAL EVALUATING CONVENTIONAL AND DOUBLE DOSE 
OSELTAMIVIR IN THE TREATMENT OF IMMUNOCOMPROMISED 
PATIENTS WITH INFLUENZA 
PROTOCOL NUMBER: 
NV20234 
VERSION NUMBER: 
E 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
® 
TEST PRODUCT: 
oseltamivir (Tamiflu RO 64-0796) 
PHASE: 
IIIb
INDICATION: 
Treatment of influenza in immunocompromised patients 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary 
To evaluate prospectively the safety and tolerability of oseltamivir for the treatment of influenza 
in immunocompromised patients and characterize the effects of oseltamivir in 
immunocompromised patients on the development of resistant influenza virus 
Secondary 
To evaluate the effects of conventional and double dose oseltamivir in immunocompromised 
patients on: 
• 
The population pharmacokinetics of oseltamivir carboxylate (e.g., clearance, volume of distribution) 
in immunocompromised patients with confirmed influenza infection, through the application of 
established population pharmacokinetic (PK) models to the sparse plasma concentration data 
generated. 
• 
The virologic course of influenza (proportion shedding and viral loads at different time points) 
• 
The time to resolution of influenza symptoms 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced by 
otitis media, bronchitis, pneumonia, or sinusitis)  
• 
To explore the relationship of metrics of exposure (e.g. AUC, Cmin) to relevant pharmacodynamic  
endpoints 
 
Study Design 
Description of Study 
This is a double-blind, randomized, multi-center trial of twice daily, conventional and double dose 
oseltamivir for the treatment of influenza in immunocompromised patients.  Patientss will be 
stratified by age ( ≤ 12, > 12 years), transplant status (yes, no), time since onset of flu symptoms 
and treatment start (up to 96 hours) ( ≤ 48 or > 48 hours) and vaccination status (yes, no) 
Number of Patients 
A minimum of 166 (83 per arm) to allow an adequate number of influenza A patients per arm; 
including 50 transplant recipients.   
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Number of Centers 
Approximately 125 centers in the Northern and Southern Hemispheres 
Target Population 
Patients immunocompromised due to a primary or secondary immunodeficiency, 1 year of age 
and older.  The patientss will be positive for influenza by a rapid diagnostic test, PCR or virus 
culture at baseline. 
Length of Study 
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 days 
later as shown in the schedule of assessments.  Study medication will be administered twice daily 
over 10 days for a total of 20 doses.  A rapid diagnostic test for influenza will be performed at the 
end of the 10 days of treatment.  Patients still having influenza based on the rapid diagnostic 
test will be treated per the local standard of care by the principal investigator, and any medication 
provided during the follow-up period should be captured in the CRF.   
Procedures (summary) 
The key procedures are: 
• 
Blood draws for serum chemistry, hematology, serology, and PK assessments (for those 
patients who provide additional consent to participate in the PK assessments). 
• 
Nasal and throat swabs for viral culture and RT-PCR. 
 
Assessments of: 
Safety 
The safety laboratory assessments in this study, including the assessment of serum chemistry and 
hematology will be carried out at a central laboratory.  Serum chemistry assessments comprise AST, ALT, 
total bilirubin, urea and creatinine.  Hematology assessments include CBC and differential count.  The 
total volume of blood loss for laboratory assessments will be approximately 20 mL for the entire duration of 
the study.  
Protection of patient confidentiality (Section16) will extend to any data generated from the assaying of 
these samples.  Biological samples taken from all patients may be infectious and will be classified as 
“diagnostic specimens” for dispatch purposes. 
When clinically indicated, the investigator may draw blood for serum creatinine to be assessed at the local 
laboratory during the study to calculate creatinine clearance 
Resistance 
Development of resistance 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. These 
are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described in the 
Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR and viral 
cultures.  Influenza virus shedding will be assessed.   
At the end of treatment (Day 11), a rapid diagnostic test is permitted for the diagnosis of 
ongoing influenza. 
Investigational Medicinal Products 
Test Product: 
Oseltamivir/placebo dry powder (to be reconstituted to a concentration of 12 mg/ml) and 75 mg 
capsules.  The duration of dosing in both adults and children is 10 days. 
 
Conventional dose: 
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Children ages 1 − 12 years:  Oseltamivir syrup 
 ≤ 15 kg   
 
30 mg twice daily 
 > 15 – 23 kg   
45 mg twice daily 
 > 23 – 40 kg  
60 mg twice daily 
 > 40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules 75 mg twice daily 
 
Patients randomized to the conventional dose will simultaneously receive matching placebo so 
as to blind them and the investigator from the double dose arm.  
 
Double dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
 ≤ 15 kg   
 
60 mg twice daily 
 > 15 – 23 kg   
90 mg twice daily 
 > 23 – 40 kg  
120 mg twice daily 
 > 40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Comparator: 
Placebo (from pivotal registration trials in otherwise healthy adults) 
Statistical Methods 
The sample size has been chosen to provide an adequate number of patients to estimate the 
development of resistance with reasonable precision.  Assuming that 90% of enrolled patients 
will have laboratory-confirmed influenza, there will be 75 patients in each treatment arm in the 
population evaluable for the development of resistance.  The following table shows the 95% 
Pearson-Clopper confidence intervals that would result with a sample size of 75 patients in a 
treatment arm if certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of development 
of resistance will be monitored in a blinded fashion, in order to ensure a reasonable precision 
for the estimation is maintained.  Additional patients may be enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of safety.  
This number of patients would provide estimates of adverse event rates with similar precision. 
For the primary objective of evaluating the safety of oseltamivir conventional and double dose 
treatments, AEs, physical examinations, tissue rejection and/or graft versus host disease in transplant 
patients, laboratory tests, and vital signs will be summarized and compared with the known 
safety profile of the drug.  For the summary of the development of resistance for each treatment 
arm, 95% confidence intervals will be provided with the estimated rates.   
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For the secondary objective of evaluating the efficacy of oseltamivir as measured by the time to 
resolution of influenza symptoms, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials 
 
From the integrated efficacy database associated with the oseltamivir treatment approval, a 
population of placebo treated patients will be established that is comparable to patients in 
the current study whose first dose of study drug was within 48 hours of symptom onset.  For this 
population, a median time to resolution of all clinical influenza symptoms will be determined 
along with its 95% confidence interval. 
 
• 
Assessment of relative efficacy 
 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence 
interval. 
The following are the model-derived PK secondary endpoints for oseltamivir carboxylate: steady-state 
AUC, Cmax, and C
. 
trough
 
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GLOSSARY OF ABBREVIATIONS 
AIDS 
Acquired immunodeficiency syndrome 
ALT [SGPT] 
Alanine aminotransferase 
ALL 
Acute lymphocytic leukemia 
AML 
Acute myeloid leukemia 
ANOVA 
Analysis of variance 
AST [SGOT] 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC
Steady-state area under the concentration–time curve from 0 to 
12 hours 
0-12
BID. 
Bis in die (twice daily) 
BP 
Blood pressure 
CARIFS 
Canadian Acute Respiratory Infections Scale 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CL/F 
Apparent clearance 
C
Last measurable concentration 
last
CL
Apparent total clearance of metabolite 
m
C
Maximum plasma concentration 
max
CML 
Chronic myeloid leukemia 
CrCl 
Creatinine clearance 
CRF 
Case report form[s] 
C
Trough plasma concentration 
trough
ESF 
Eligibility screening form 
GVHD 
Graft versus host disease 
HA 
Hemagglutinin 
HIV 
Human immunodeficiency virus 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ITT 
Intent to treat 
ITTI 
Intent to treat influenza infected 
IVRS 
Interactive voice response system 
k
Elimination constant 
e
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PKEP 
Pharmacokinetic Evaluable Patient Population 
p.o. 
Per os (by mouth) 
QD 
Once per day 
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GLOSSARY OF ABBREVIATIONS 
RIDT 
Rapid Influenza Diagnostic Test 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCID 
Severe combined immunodeficiency 
SOT 
Solid organ transplant 
TCID50 
50% tissue culture infectious dose 
Time to last measurable concentration 
tlast
Time to maximum plasma concentration 
tmax
t
Elimination half-life 
1/2
Vc/F 
Apparent volume of distribution 
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PART I: STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
Influenza is an acute respiratory infection caused by a virus of the orthomyxovirus family 
which occurs in three forms, influenza A, B and C.  Influenza virus types A and B cause 
an acute febrile infection of the respiratory tract characterized by the sudden onset of 
fever, malaise, headaches, myalgias and cough.  Influenza causes numerous deaths 
each year [1].  Although difficult to assess, annual influenza epidemics are thought to 
result in between three and five million cases of severe illness, and between 250,000 
and 500,000 deaths every year around the world [2]. 
The influenza viruses are segmented, negative sense, single stranded, lipid 
encapsulated, RNA viruses between 80 and 100 nm in size.  Subtypes are defined 
according to glycoproteins present in the viral lipid coat.  The haemagglutinin complex 
(HA) is the major surface protein of the virus.  The neuraminidase (NA) proteins are the 
second major surface proteins in the virion and play a role in enhancing virus penetration 
of the mucus layer around the target cell and in release of virus from the cell surface.  
The M2 protein triggers the disintegration of the virion during virus entry into the cell and 
may also be involved in protecting the HA prior to assembly of new virus particles.  
1.1.1 
Influenza in the Immunodeficient Population 
Influenza infection is usually a self−limiting condition.  However, in children, the elderly 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus may 
cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis and death [3].   
Conditions that compromise immunity may be classified based on etiology into primary 
(genetic) and secondary (acquired) immunodeficiency.  Of the immunodeficient 
conditions, the ones that affect cell mediated immunity are likely to have adverse 
outcomes following viral infections [16]. 
Primary immunodeficiency  
Primary immunodeficiencies are relatively common, may be either congenital or manifest 
later in life and are classified according to whether the genetic defect affects T or B cells 
or both [16].  There are four groups of disorders: severe combined immunodeficiency 
(SCID), primary T cell deficiency (e.g. CD8 deficiency, DiGeorge syndrome), 
predominantly B-cell-related antibody deficiency (e.g. common variable 
immunodeficiency, selective IgA deficiency) and other well-defined immunodeficiency 
syndromes (e.g., Wiskott Aldrich syndrome) [16].  
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Of the primary immunodeficiencies, antibody deficiencies are the most frequent.  
However, some of the more common antibody deficiency conditions (isolated IgA 
deficiency, IgG subclass deficiency and common variable immunodeficiency) have intact 
cell-mediated immunity and therefore the clinical course of viral infections (unless 
complicated by bacterial infections) does not differ significantly from that in the normal 
host [16].  A list of primary immunodeficiency disorders at risk for viral infections is 
provided in Appendix 6.  The incidence of some of these conditions has been estimated.  
The incidence of SCID is 1 in 100,000 to 1 in 1,000,000 [16].  The more severe forms of 
primary immunodeficiency are relatively rare, have their onset early in life, and all too 
frequently result in death during childhood [16].  
Secondary Immunodeficiency 
Secondary immunodeficiencies are not caused by intrinsic abnormalities in development 
of T and B cells [16].  Secondary immunodeficiency may result from diseases (human 
immunodeficiency virus [HIV], hematologic malignancy) or immunosuppressive and 
cytotoxic drugs (such as those used for treatment of transplant recipients, collagen 
vascular disease, malignancies).  
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T-cell count of  < 200/mm3 (AIDS defining) are 
highly susceptible to opportunistic disease [
].  However, CD4 counts < 500/mm
16
3 are 
considered abnormal in HIV-infected individuals, and therefore these individuals are also 
more susceptible to infection.  CD4+T cell counts are higher in infants and young 
children than in adults and decline over the first few years of life [40 ,41].  Because of 
this age-dependent variation in absolute CD4+ T cell count, calculation of CD4 
percentage is used as a measure for young children because it has shown less variability.  
HIV-infected children (12 months to 5 years old) with < 15% CD4+ T cells are classed 
as severely immunosuppressed and highly susceptible to opportunistic disease, although 
antiretroviral therapy is recommended in children with  < 25% CD4+ T cells as they are 
still classified as immunosuppressed [42].  Studies in patients with HIV/AIDS have 
shown an increased risk for heart and lung-related hospitalizations during the influenza 
season compared with other times of the year, prolonged duration of influenza 
symptoms, increased risk for influenza-related complications and a higher risk of 
influenza-related death [17]. 
Several hematologic malignancies affect the immune system (Appendix 7).  Several 
authors have reported influenza in children and adults with hematologic malignancies 
[18, 19, 20, 21].  
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Secondary immunodeficiency due to drugs (e.g. transplant recipients, collagen 
vascular disease, malignancies) 
The enhanced survival of the transplant population following the availability of newer 
immunosuppressive drugs has made them representative of the immunocompromised 
population in general; and secondary immunodeficiency due to drugs, in particular. 
In transplant recipients influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations and an increased risk of graft dysfunction 
and high attributable mortality.  In a cohort study of influenza viral infection in solid organ 
transplant (SOT) patients, 30 cases of influenza viral infection were identified.  
Secondary bacterial pneumonia was seen in 17% of patients and three SOT recipients 
(2 liver and one kidney) had myositis, myocarditis and bronchiolitis obliterans.  Biopsy of 
the transplanted organ was performed in 21 of 30 cases and revealed variable degrees 
of acute allograft rejection in 62% of patients.  The study concluded that influenza was 
associated with significant morbidity in different groups of SOT recipients [4]. 
Among transplant recipients, patients with hematopoietic stem cell transplant (HSCT) 
are at the greatest risk for morbidity.  In a prospective study from the Infectious Diseases 
Working Party of the European Group for Blood and Marrow Transplantation, 1973 
patients were evaluated for respiratory virus infections after stem cell transplantation.  
The overall mortality was 23% from influenza A infection and the direct influenza A-
associated mortality was 15.3% in this study [5].  A large retrospective study 
(4797 patients undergoing HSCT over a 13-year period) identified 62 patients with 
influenza of whom as many as 29% (18 of 62 patients) developed pneumonia.  Ten 
percent of the patients with influenza died [6].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects.  In otherwise healthy adults, elderly 
patients and children, the median duration of viral shedding in untreated patients was 70, 
96 and 118 hours respectively [7].  In contrast, in the retrospective HSCT study, 
influenza virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a 
median duration of 168 hours (7 days, range 2 to 37 days) [6]. 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g. amantadine, rimantadine) and the neuraminidase inhibitors (e.g. oseltamivir, 
zanamivir).  
1.1.2 
Oseltamivir 
Oseltamivir (Tamiflu®, Ro 64-0796) is an ethyl ester prodrug which is rapidly absorbed 
from the gastrointestinal tract after oral administration and metabolized in the liver by 
high capacity carboxylesterases to form oseltamivir carboxylate (Ro 64-0802), a potent, 
stable and selective inhibitor of influenza A and B neuraminidase enzymes.  The active 
form, oseltamivir carboxylate is excreted unchanged by the kidney via glomerular 
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filtration and active tubular secretion by the organic anion transport system.  The efficacy 
and safety of oseltamivir in influenza treatment and prevention has been established in 
an extensive series of clinical studies in man. 
Oseltamivir has been approved for the treatment of influenza in Europe, the United 
States and most other countries around the world.  In adults and adolescents, the 
recommended dose is 75 mg twice daily for five days.  In children 1 year of age and 
older recommended doses are 30, 45 or 60 mg bid based on body weight.  In all age 
groups the recommended dose is administered bid for 5 days.   
The approval of oseltamivir for the treatment of influenza is based on several controlled 
clinical trials.  In the pooled population from these clinical trials encompassing adults 
aged from 13-97 years, many with significant co-morbidity, 1325 patients were treated 
with oseltamivir (75 mg bid) and 1056 patients received placebo.  A total of seven 
influenza symptoms (both respiratory and constitutional) were captured on the diary card 
for adults.  The time to resolution of all symptoms (on the diary card) decreased by 
24 hours; from 124.5 hours in the placebo arm to 100.6 hours with oseltamivir 75 mg bid 
(p  < 0.0001) [7].  Further, in adults and adolescents with a proven influenza illness, 
oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% and the 
incidence of influenza-related lower respiratory tract complications resulting in antibiotic 
therapy by 55%.  The study concluded that oseltamivir treatment of influenza reduces 
lower respiratory tract complications, antibiotic use and hospitalizations in healthy and ‘at 
risk’ patients [8].   
Likewise, in the influenza-infected pediatric population (1 to 12 years of age), oseltamivir 
treatment (n = 217) was compared with placebo (n = 235).  There was a reduction in the 
median duration of illness (defined based on resolution of temperature, cough, coryza 
and return to pre-illness health and activity) of 36 hours; from 137 hours with placebo to 
101 hours in the oseltamivir treatment arm (p ≤ 0.0001).  The Canadian Acute 
Respiratory Infections Scale (CARIFS), validated for use in children, was used to collect 
symptom data on the pediatric diary card.  The CARIFS scale comprised a total of 18 
symptoms which were evaluated twice daily by the parent or guardian.  There was a 
similar reduction in the time to alleviation of all CARIFS symptoms of 36 hours; from 100 
hours in the placebo group to 63 hours in the oseltamivir group (p < 0.0001) [9].  
Thus in both adults and children, the time to resolution of all symptoms was significantly 
reduced in the oseltamivir treatment arm compared with placebo.   
Oseltamivir was well-tolerated in clinical trials.  Approximately 11,000 patients have 
received oseltamivir in the development program.  The most common adverse events 
reported by adults, the elderly, and children were nausea and vomiting.  Serious adverse 
events (SAEs) were reported with a low and equal frequency by patients taking active 
drug and placebo.  Full details are given in the Investigator Brochure [7]. 
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The safety profile of oseltamivir has been well characterized for the prophylaxis 
indication in a prospective randomized placebo controlled trial conducted in the adult 
and pediatric immunocompromised (HSCT and SOT) population.  In the oseltamivir 
group, the indications for transplant included hematologic malignancies (acute and 
chronic leukemias, multiple myeloma and myelodysplastic syndrome), lymphoid 
malignancies (Hodgkins or non-Hodgkins lymphomas), primary immunodeficiencies 
(Wiskott-Aldrich syndrome, X-linked lymphoproliferative disease and severe combined 
immunodeficiency).  Other rare indications included bone marrow aplasia, paroxysmal 
nocturnal hemoglobinuria, myelofibrosis and multiple sclerosis.  In the safety population, 
there were 239 patients randomized to the conventional dose of oseltamivir and 238 to 
placebo.  The total number of adverse events reported in the placebo group (361 events) 
was generally similar to that in the oseltamivir group (323 events).  Diarrhea was the 
most frequently reported adverse event (placebo, 8%; oseltamivir, 6%).  There were no 
deaths in the oseltamivir group.  Oseltamivir was found to be safe in immunosuppressed 
transplant recipients [22]. 
Limited safety and/or efficacy of oseltamivir for the treatment indication is available from 
several case reports in children and adolescents.  Oseltamivir was shown to be safe 
and/or effective in HIV infected children (n = 10) [23], children (age 3 to 12 years) with 
acute lymphocytic leukemia (ALL) (n = 10) [21], in a nosocomial H1N1 outbreak in a 
pediatric (children aged 10 months to 13 years) oncology ward (n = 8) [20], in children 
and adolescents (age 2 to 19 years) with malignancies (ALL, neuroblastoma, brain 
tumor, non-Hodgkin’s lymphoma, osteosarcoma, Ewing sarcoma, myelodysplasia, acute 
myeloid leukemia (AML), Wilms tumor, aplastic anemia, chronic myeloid leukemia (CML) 
and acute promyelocytic leukemia) (n = 51) [18], in children aged 4 to 14 years on 
immunosuppressive drugs (n = 5) [24] and in children (aged 5 months to 5 years) with 
bone marrow transplant (n = 3) [25].  
Oseltamivir has also been shown to be safe and/or effective in mixed populations of 
children and adults (62 patients) with HSCT [6], and in a large epidemiologic study 
(n = 221) with SOT [26].  
Finally, oseltamivir has been shown to be safe and/or effective in immunocompromised 
adults with HSCT [10] and adults with lung transplant [27, 28, 29].  
The dose of oseltamivir was the same as the conventional dose in a majority of these 
reports.  In one report as many as 25 adult patients received twice the conventional dose 
[26] while in another report, three of nine adult patients received twice the conventional 
dose [29].  Treatment with oseltamivir generally ranged from 5 to 10 days [28, 29, 26] 
and occasionally until the patient was symptom free [28, 29].  In exceptional cases 
treatment was given for as long as 20 days [18] or for as long as the patient was positive 
by RT-PCR [21]. 
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There is some concern about the development of resistance in the immunocompromised 
population.  During the pandemic influenza season, more than 23,000 clinical isolates of 
novel H1N1 pandemic virus were tested for resistance in the 6 international WHO 
regions.  A total of 225 isolates (from 225 patients) were resistant (H275Y mutation in 
the neuraminidase coding sequence) to oseltamivir for an approximate incidence of 1%.  
Information on immune status was available for 142 of 225 patients.  Among the 142 
patients, 56 (40%) were immunocompromised [30].  Prolonged viral replication and lack 
of immune-mediated virus clearance in immunosuppressed patients treated with 
antivirals can result in a higher incidence of selection of drug-resistant viruses, a 
phenomenon that has been documented previously [31, 32].  
1.2 
RATIONALE FOR THE STUDY  
Because of the increasing body of evidence (Section 1.1.2), oseltamivir is recommended 
in national guidelines as an option for the treatment of influenza in the transplant 
population [37], which comprises a significant portion of the immunocompromised 
population.  However, there is limited data on safety and efficacy of oseltamivir use in 
this population.  The primary objective of this study is to evaluate safety and resistance, 
while evaluating efficacy as a secondary objective, in the broader immunocompromised 
patient population, who are considered at increased risk of viral infection. 
2. 
OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate prospectively the safety and tolerability 
of oseltamivir for the treatment of influenza in immunocompromised patients and 
characterize the effects of oseltamivir in immunocompromised patients on the 
development of resistant influenza virus. 
2.2 
SECONDARY OBJECTIVES   
The secondary objectives of the study are:  
To evaluate the effects of conventional and double dose oseltamivir in 
immunocompromised patients on: 
• 
The population pharmacokinetics of oseltamivir carboxylate (e.g., clearance, volume of 
distribution) in immunocompromised patients with confirmed influenza infection, through 
the application of established population pharmacokinetic (PK) models to the sparse plasma 
concentration data generated  
• 
The virologic course of influenza (proportion shedding and viral loads at different time 
points) 
• 
The time to resolution of influenza symptoms 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
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• 
To explore the relationship of metrics of exposure (e.g., AUC, Cmin) to relevant 
pharmacodynamic (PD) endpoints 
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN   
This is a double blind, randomized, stratified, multi-center trial of conventional and double 
dose oseltamivir for the treatment of influenza in immunocompromised patients.  
Immunocompromised patients, who develop an influenza-like illness with a positive rapid 
diagnostic test, PCR, or viral culture for influenza, will be enrolled during the influenza 
season.  Patients will be stratified by transplant status [yes, no], the time between onset 
of influenza symptoms and treatment start (up to 96 hours) [ ≤ 48 hours; > 48 hours], 
influenza vaccination status for current influenza season [Yes; No] and by age 
[ ≤ 12 years; > 12 years].  Eligible patients will be consented and randomized to receive 
oseltamivir twice daily for 10 days in one of two treatment arms:  conventional dose or 
double dose (double the conventional dose).  
3.1.1 
Rationale for Study Design 
This study incorporates several features that distinguish it from classic placebo 
controlled trials.  
There is no placebo control arm in this study as it was considered unethical for this high 
risk population.  The development of resistance following treatment with oseltamivir (one 
of the primary objectives of the study) is an objective assessment (determined by 
laboratory tests) and is unlikely to be impacted by the absence of a placebo arm.  
As a placebo control arm was considered unethical in this population, an alternative 
control arm had to be identified for efficacy end points.  The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial.  In order to do this, the 
end points were designed to be similar to that in the pivotal registration trials.  
The following sections provide rationale and justification for specific aspects of the study 
design which differ from the currently approved dosing for influenza or from previous 
pivotal registration trials.  They also provide information on how the results will be used 
to make recommendations on dose and duration of treatment. 
3.1.1.1 
Choice of Treatment Arms 
The currently approved dose of oseltamivir for the treatment indication is the 
conventional dose with a duration of 5 days.  In this study a conventional and double 
dose are being evaluated.  The pivotal registration trials for oseltamivir in healthy adults 
with influenza had three treatment arms; two active (75 mg and 150 mg) and one 
placebo.  Both treatment arms were found to be significantly better than placebo.  No 
statistical comparisons were made between the two active treatment arms.  Evaluation 
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of the results in the two active treatment arms did not reveal any clinically meaningful 
difference.  However, the proportion of patients shedding virus on Day 4 (3 days after 
the start of treatment), suggested a possible dose-response relationship (36%, 28% and 
23% in the placebo, 75 mg and 150 mg dose arms respectively).  Because defective 
immune-mediated virus clearance in immunosuppressed patients treated with antivirals 
can result in a higher incidence of selection of drug-resistant viruses, it was decided to 
use both the conventional and double dose arm for this study.  A longer duration of 
treatment was chosen because a large retrospective study has shown that the median 
duration of viral shedding of 7 days [6] was greater for HSCT recipients than that seen in 
the healthy children, adult and elderly population with influenza (Section 1.1.1) [7].  
3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours 
In immunocompromised patients, time from onset of symptoms to seeking medical 
attention (presentation at the clinic) of  > 48 hours has been shown in several case 
reports [33, 27, 28, 29] including two instances of nosocomial outbreaks in children [25, 
20].  This notwithstanding, oseltamivir has been shown to offer benefit in 
immunocompromised populations that included patients treated with oseltamivir beyond 
48 hours of presentation; patients with lung transplant (median time to presentation 3 
days) [27], bone marrow transplant (treatment started more than 48 hours after onset of 
symptoms in all 3 patients) [25], organ transplant (62 of 221 patients started treatment 
after 96 hours) [26] and children with acute lymphocytic leukemia (one child presented 
after 3 days and two children presented after 5 days of symptoms) [21]. 
In a prospective, observational study involving adults hospitalized with influenza, the 
study authors concluded that ‘Weakened host defenses slow viral clearance, whereas 
antivirals started within the first four days of illness enhance viral clearance’ [34].  
Additionally, in November 2009, in a communication for clinicians on antiviral treatments 
for H1N1, the US Centers for Disease Control and Prevention (CDC) stated that while 
antiviral treatment is most effective when started early; both outpatients with risk factors 
and hospitalized patients still benefit when treatment with oseltamivir is started more 
than 48 hours after illness onset [35].   
3.1.1.3 
Rational for Sparse PK Sampling 
Limited PK sampling will be done in this protocol, in patients who have provided 
additional consent, and is justifiable in this study for the following two reasons: 
36
• 
There are already tested and qualified population PK models available [
] that will 
be used to estimate exposure in the immunocompromised population on the basis 
of the data collected in this study, meaning extensive PK sampling over a steady-
state dosing interval is not required.  
• 
The patient population in this study is likely to be very ill with a complex clinical 
picture and significant additional burden of treatment and monitoring due to their 
primary condition.  In this context, it makes ethical sense to minimize blood draws 
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and assessments to only those absolutely essential to meet the objectives of the 
study and to ensure patient safety. 
 
3.1.1.4 
Interpretation of Study Results  
Safety and tolerability and the development of resistance are the primary objectives of 
this study.  These will be characterized descriptively.  For the secondary objective of 
efficacy, the subset of the population enrolled in the first 48 hours will be compared with 
placebo patients from pivotal registration trials (where patients were enrolled in the first 
2 days of illness).  Section 8.2.5 , Section 8.2.6 , and Section 8.2.7  provide details on 
the statistical considerations. 
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials.  However, in order to evaluate a dose response relationship between the two 
active treatment arms in this trial, stratification remains essential.  
Patients will be stratified by transplant status (yes, no) because transplant patients form 
a relatively large homogenous group in this study and might influence outcome.  
Patients will be stratified by time between onset of symptoms and treatment start 
( < 48 hours or ≥ 48 hours) because previous experience in otherwise healthy adults and 
children has shown that patients treated early in their illness respond to treatment better 
than those who are treated later.  Patients will also be stratified by age ( ≤ 12 years 
and > 12 years) because otherwise healthy children shed virus longer than otherwise 
healthy adults.  It is expected that a similar difference in the duration of viral shedding 
would exist between immunocompromised children and adults.  As vaccinated patients 
may respond faster to therapy, the study is also stratified based on influenza vaccination 
status for the current influenza season (Yes; No).  
3.1.2 
Rationale for Dose Selection and Adjustment 
Dose Selection 
The dose of oseltamivir to be used in this study is the conventional, approved dose for 
children and adults in the treatment of influenza.  There will be a second higher dose for 
comparison which is two times the conventional dose.  This higher dose is used based 
on theoretical considerations which suggest that the higher dose may be associated with 
improved efficacy and decreased emergence of resistance.  
The anticipated pro-drug and metabolite exposures from this higher dose are not 
expected to exceed maximum exposures seen previously in the oseltamivir development 
program.  The safety and tolerability of the higher dose regimen has already been 
demonstrated in treatment studies of immunocompetent adult subjects (n =  447) [11].  In 
a study to demonstrate cardiac safety, in the highest dose group treated with 450 mg 
BID. for 5 days [n =  99], no subject had a serious adverse event, nor withdrew 
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prematurely.  In Phase I studies in adults, oseltamivir has been administered in multiple 
doses of up to 500 mg BID.  Doses of 200 mg BID. and greater have been associated 
with increased gastrointestinal adverse effects (nausea and vomiting) [7].  In adult 
subjects with creatinine clearances of ≤ 30 mL/min, doses of 100 mg BID for 6 days 
were well tolerated, despite steady-state oseltamivir carboxylate exposures 
approximately 10-fold higher than those achieved with standard dosing in renally 
competent individuals [12].  No other adverse effects were reported more frequently with 
higher doses and no serious adverse events have been reported within the volunteer 
studies.  Co-administration of oseltamivir with food has been demonstrated to 
substantially reduce the frequency and severity of gastrointestinal side effects.  
Thus, the rationale for the double dose arm in this study is to explore the possibility of 
improved efficacy and decreased emergence of resistance without an undue increase in 
risk.  For patients with a creatinine clearance level of 45 mL/min or above, oseltamivir 
carboxylate exposures for both the 75-mg and 150-mg doses are not expected to exceed exposures 
previously tested.  Patients with a creatinine clearance as low as 45 mL/min, who receive the 
150-mg BID dose, will have exposures of oseltamivir carboxylate that are within (albeit in the 
upper end) the established safety margin. This corresponds to an AUC produced by the 450-mg 
BID dose in adults with normal renal function (AUC 0-12 hrs of approximately 15,000 ng • hr/mL).  
Drug interactions with immunosuppressive medications have also been evaluated.  The 
pharmacokinetics of oseltamivir and oseltamivir carboxylate after administration of 
75 mg oseltamivir (conventional adult dose) in patients with a well-functioning, stable 
renal allograft who were being maintained on immunosuppressive therapy were studied.  
These were similar to those described in the literature for adults with comparable 
degrees of renal function.  Oseltamivir was well tolerated and had no clinically relevant 
effect on the steady-state pharmacokinetics of cyclosporine A, tacrolimus, or 
mycophenolate mofetil [7]. 
Duration of Dosing 
The duration of dosing chosen for this population (10 days) is longer than that in the 
healthy adult and pediatric populations (5 days).  This is based on observations that the 
viral shedding and illness are typically longer in immunocompromised patients than it is 
in healthy adults [6, 10]. 
Dose Adjustments 
As this is a double blind study, patients whose creatinine clearance (CrCl) decreases 
to  < 45mL/min (adults) using the Cockcroft-Gault method or <45 mL/min/1.73m2 (<18 years 
old) using the Schwartz equation will be discontinued from study treatment.  A lower limit of 
45 mL/min for CrCl will be used to allow for patients with a mild to moderate renal impairment.  
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3.1.3 
End of Study 
The study comprises 10 days of treatment with follow-up visits approximately 5 and 
30 days later as shown in the schedule of assessments.  Study medication will be 
administered BID over 10 days for a total of 20 doses.  A rapid diagnostic test for influenza will 
be performed at the end of the 10 days of treatment.  Patients still having influenza 
based on the rapid diagnostic test will be treated per the local standard of care by the 
principal investigator, and any medication provided during the follow-up period should be 
captured in the CRF.  
3.2 
NUMBER OF PATIENTS/ ASSIGNMENT TO TREATMENT 
GROUPS 
A minimum of 166 patients (approximately 83 per arm) to allow an adequate number of 
influenza A patients, including 50 transplant recipients will be enrolled in this study.  After 
screening, patients will be randomly assigned to one of the two active treatment groups. 
3.3 
CENTERS 
This will be a multicenter study taking place in the Northern and Southern Hemispheres 
at approximately 125 centers.  
4. 
STUDY POPULATION 
4.1 
OVERVIEW 
The study population comprises immunocompromised adults (including adolescents) 
and children who have influenza.  Additionally, the patients must not have other medical 
conditions that will preclude the assessment of efficacy or safety.  Influenza vaccinated 
and non-vaccinated patients are eligible to participate in this study.  Principal 
investigators will review oseltamivir resistance patterns of strains circulating in the area 
and weigh the risk versus the benefit before enrolling patients with a potentially resistant 
strain. 
Under no circumstances are patients who enroll in this study permitted to be re-
randomized to this study and enrolled for a second course of treatment. 
4.2 
INCLUSION CRITERIA 
• 
Age greater than or equal to 1 year 
• 
Rapid diagnostic test, PCR, or viral culture positive for influenza 
• 
Immunocompromised patient defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in Appendix 6) OR 
o Secondary immunodeficiency 
 
SOT with ongoing immunosuppression OR 
 
Allogenic HSCT with ongoing immunosuppression OR 
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3
 
HIV with a most recent CD4 count < 500/mm  (or <25% in children 
≤  5 years old) within the last 6 months and, in the investigator’s 
opinion, considered immunocompromised OR 
 
Hematologic malignancies (representative examples in 
Appendix 7) OR 
 
Systemic (e.g. enteric, sc, im or iv) immunosuppressive therapy, 
irrespective of medical indication, started at least 12 weeks prior 
to, and ongoing at the time of first dose of study drug 
(representative examples in Appendix 8) 
 
• 
Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza 
• 
In patients with history or clinical presentation at randomization suggestive of renal 
failure; a CrCl > 60 mL/min (>18 years old) or >60mL/min/1.73m2(<18 years old) 
within the last 3 months 
• 
Less than or equal to 96 hours between onset of influenza like illness and first dose 
of study drug 
• 
Parent/guardian willing and able to comply with study requirements and give 
consent, (country specific age cut off) 
• 
Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• 
For adult patients, willing and able to comprehend and give written informed consent  
• 
Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for females for one reproductive 
cycle following cessation of study therapy 
• 
Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study drug 
 
4.3 
EXCLUSION CRITERIA 
• 
Clinical evidence of severe hepatic impairment, defined as Child-Pugh grade C 
(score > 9) or decompensated cirrhosis (see Appendix 9). 
• 
Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration. 
• 
Patients with gastrointestinal disorders which might interfere with their ability to 
absorb oral medication.  
• 
Allergy to the test medication. 
• 
Patients with hereditary fructose intolerance (for patients who will be taking the 
liquid formulation). 
• 
Influenza vaccination with live attenuated vaccine in the 2 weeks prior to 
randomization. 
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• 
Antiviral treatment (example:  amantadine, rimantadine, oseltamivir, laninamivir, 
peramivir, zanamivir and ribavirin) for influenza in the 2 weeks prior to 
randomization. 
• 
Patients taking probenecid medication. 
• 
Patients who are pregnant or breast-feeding.   
• 
Participation in a clinical trial or expanded access trial with an investigational drug 
suspected/demonstrated to impact pathways important for the metabolism and 
excretion of oseltamivir in the 4 weeks prior to randomization or concomitantly with 
this study.   
 
4.4 
CONCOMITANT MEDICATION AND TREATMENT 
Antiviral treatments with activity against influenza (e.g., amantadine, rimantadine, 
zanamivir, ribavirin, laninamivir, peramivir, and additional oseltamivir above that 
specified for this study) are not allowed during the 10-day treatment phase of the study.  
Concomitant use of an investigational drug during the study is also excluded if 
suspected/demonstrated to impact pathways important for the metabolism and excretion 
of oseltamivir.  Live attenuated vaccines may not be advisable for this population.  It is 
possible that concurrent use with oseltamivir may render live vaccines ineffective.  
Medications required for the routine care of the patient may be continued during the 
study.  Concomitant use of probenecid (irrespective of the indication) is not allowed 
during the study. 
4.5 
CRITERIA FOR PREMATURE WITHDRAWAL  
The investigator must discontinue treatment if the creatinine clearance is  < 45 mL/min in 
adults using the Cockcroft-Gault method or < 45 mL/min/1.73 m2 using the Schwartz 
equation in children.  A lower limit of 45 mL/min for creatinine clearance will be used to allow 
for patients with a mild to moderate renal impairment.  The investigator must also 
discontinue treatment from all patients with intercurrent illnesses or adverse events 
suggestive of hepatic decompensation.  The investigator also has the right to 
discontinue treatment in the event of intercurrent illness, adverse events, treatment 
failure, protocol violations, administrative reasons or other reasons. 
The investigator must discontinue treatment with study drug if the patient is to be treated 
concomitantly with another antiviral for influenza, for example, amantadine, rimantadine, 
laninamivir, peramivir, or zanamavir.  However, all patients, including those who 
discontinue study drug prematurely and/or are treated with another antiviral, will be 
required to return for follow up approximately 5 and 30 days after the last dose of study 
drug (Day 15 and Day 40 assessments). 
Patients have the right to withdraw from the study at any time for any reason.  
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An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a patient decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
The investigator should contact the patient or a responsible relative either by telephone 
or through a personal visit to establish as completely as possible the reason for the 
withdrawal.  A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the patient is withdrawing from the study.  If the reason 
for removal of a patient from the study is an Adverse Event, the principal specific event 
will be recorded on the CRF. 
In the case that the patient decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further 
information.  The outcome of that discussion should be documented in both the medical 
records and in the CRF.  
4.6 
REPLACEMENT POLICY [ENSURING ADEQUATE NUMBERS 
OF EVALUABLE PATIENTS] 
4.6.1 
For Patients 
No patient prematurely discontinued from the study for any reason will be replaced. 
4.6.2 
For Centers 
A center may be replaced for the following administrative reasons:   
– 
Excessively slow recruitment. 
– 
Poor protocol adherence. 
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Table 1 
Schedule of Assessments (cont.)  
f. A home visit may be made on Day 2 or 3 (for patients who are too ill to come into the clinic) 
and/or, Day 6, and/or Day 8; however, it is recommended that the PK blood draw be 
performed at the clinic. 
g. Day 2/3 visit window = +1 day.  Day 6 visit window = ± 1 day; Day 8 visit window = +1 day.  
Day 11 visit window = ± 1 day.  Day 15 and Day 40 visit occur approximately 5 and 30 days 
after the last dose respectively.  Day 15 window = ± 1 day.  Day 40 window ± 2 days.  
h. Only weight to be assessed.  Height is not necessary at this visit.  Study drug is taken on 
Day 11, only if the first dose was taken after 4 PM on Day 1 [5.3] Patients who are rapid 
diagnostic positive can be treated per standard of care.  They will be required to come for their 
follow-up visits on Day 15 and Day 40.  
i. 
Patients who discontinue treatment prematurely will have an end of treatment (Day 11) 
assessment at the time of treatment discontinuation or the following day.  They will be 
required to attend their follow up visits approximately 5 and 30 days after the last dose 
(Day 15 and Day 40 assessments).  
j. 
Patients who discontinue during follow-up will have an end of follow-up (Day 40) assessment.  
This visit must occur within 30 days of the last dose.   
k. For patients who are unable to attend the clinic, swabs may be taken at home on those days 
where there is a home visit by site personnel. 
l. 
Plasma PK samples for assessment of oseltamivir carboxylate will be collected from patients 
who give additional consent to participate in PK sampling using a sparse PK sampling 
approach (Section 5.4).  
m. Serial PK samples taken at steady-state no earlier than Day 6 (i.e., not before the 11th dose) 
consisting of as many of the four timepoints as possible:  within 30 minutes prior to the dose 
administration, 1.5 hours ± 30 minutes post dose, 4 hours ± 60 minutes post dose, and 
8 hours ± 1.5 hours post dose (for patients who have given additional consent). 
  
5.1 
SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM  
All patients must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed.  Screening will take place at 
the baseline visit prior to first dose.  However, if necessary, screening may take place 
the day before the baseline visit, as long as the patient is randomized and receives 
his/her first dose of study drug within 96 hours of influenza symptom onset. 
Patients will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  Influenza 
Rapid Diagnostic test, PCR, or viral culture for the purposes of inclusion criteria 
fulfillment will be done by the site or the local laboratory.  Historical CrCl values 
within 3 months and CD4+ T-cell counts (where applicable) within 6 months before 
randomization are acceptable for inclusion into the study.  
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An Eligibility Screening Form [ESF] documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.  
5.2 
PROCEDURES FOR ENROLLMENT OF ELIGIBLE PATIENTS  
Once a patient has fulfilled the entry criteria, he/she will be randomized to one of two 
treatment groups.  The patient randomization numbers will be generated by Roche or its 
designee and incorporated into double-blind labeling. 
The investigator or designee will use the CRF pre-printed with the assigned patient 
number and enter the randomization number provided by IVRS for allocation to the 
treatment groups in the appropriate place on each patient’s CRF. 
Randomization will be stratified by transplant status (Yes; No); time between onset of 
symptoms and treatment start ( ≤ 48 hrs or  > 48 hrs), influenza vaccination status 
(Yes; No) and patient’s age ( ≤ 12 years or  > 12 years).  
5.3 
CLINICAL ASSESSMENTS AND PROCEDURES 
At all visits patients will receive the routine care for their primary illness.  Routine patient 
care (including the adjustment of doses of any of the immunosuppressive drugs) will be 
dictated by tests performed locally at the trial site.  For patients unable to attend the 
clinic, provision will be made for swabbing to be conducted at home, when there is a 
home visit scheduled.  Training will be provided to site staff on how to perform this.  All 
safety labs will be sent to a central laboratory.  Results for these laboratory parameters 
will be used by the sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 1).  Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
Blood samples will be collected from patients who provide additional consent for PK 
sampling, as outlined in Section 5.5 . 
Study Day 1 
The baseline and study Day 1 assessment may be performed at the same visit.  
Laboratory assessments (safety labs and nasal and throat swabs for virology) should be performed  
after randomization but prior to the patient receiving first dose of study drug. 
Study drug, patient diaries, and thermometers will be dispensed.  Patients or 
guardians/parents will be instructed on how to complete the patient diaries (Appendix 2) 
and(Appendix 3), temperature recording, and treatment administration details, including 
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time of each oseltamivir dose.  The first diary entries will be made at the site before the 
first dose of study drug.  
Baseline nasal and throat swab samples will be assessed for the presence of 
oseltamivir-resistance mutations.   
The date of the first dose of study drug is defined as study Day 1.  Once randomized, 
the first dose of study drug will be administered in the clinic.  Study Day 2 will begin at 
12 midnight of the same calendar day.  If the first dose of study drug is taken after 4 pm 
on Day 1, the next dose of study drug will be taken in the morning of Day 2.  In this case, 
the last dose of study drug will be taken on the morning of study Day 11.   
If the first dose of study drug is taken prior to 4 pm on Day 1, the next dose of study drug 
should be taken in the evening of the same day (i.e. prior to midnight on the same 
calendar day with a minimum of 7 hours between doses).  For these patients the last 
dose of study drug will be taken in the evening of study Day 10.  More information on 
dosing is provided later (Section 6.1). 
Study Days 2 - 11 
Study Day 2 will begin at 12 midnight of study Day 1.  
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study.  The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is entering data into the patient diary properly, 
and assess drug compliance.  During the dosing period, diary symptoms should be 
assessed and temperature should be recorded at the same time that the study drug is 
taken.  
End of Treatment Day 11 
The end-of-treatment visit for all patients is on Day 11 (irrespective of whether they took 
one or two doses on Day 1).  Study medication will be administered twice daily over 10 days 
for a total of 20 doses.  Patients who discontinue study drug prematurely will have all 
Day 11 assessments completed at the time of discontinuation or the following day.  
After all Day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit.  If the rapid diagnostic test is positive, the patient may be treated 
per standard of care at the discretion of the investigator.  If treatment is provided, this 
should be captured in the CRF.  
All patients (including those who discontinue study drug prematurely and those who are 
positive for influenza on their rapid diagnostic test at the end of treatment visit) will be 
required to return for follow up approximately 5 and 30 days after the last dose (Day 15 
and Day 40 assessments).    
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Study Days 12 – 40 
Study Day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  It is therefore important that this visit is completed.  
End of Follow-Up Day 40  
All patients must attend an end of follow-up visit on Day 40.  
If the patient is withdrawn after completion of treatment (after the Day 11 assessment), a 
termination visit should be arranged.  This visit should be the end of follow-up visit 
assessment [Day 40].  This visit must occur within 30 days of the last dose.  
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status, or that of their child’s, record information on 
adverse events, and to ask that they return the patient diary. 
5.3.1 
Safety 
Safety is one of the primary end-points of this study. Safety parameters include adverse 
events, vital signs, and clinical laboratory evaluations.  
Pre-defined symptoms of influenza captured in the adult and pediatric diaries are not to 
be reported as adverse events unless they can be further qualified.  Thus ‘headache due 
to stress at work’ is reported as an adverse event.  However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Adverse events such as bronchitis, pneumonia, otitis media and sinusitis are considered 
secondary illnesses of influenza and should be recorded as adverse events. 
Other adverse events to be expected in the transplant population such as rejection and 
graft versus host disease (in patients with HSCT) will also be collected as adverse 
events. Nasal and throat swab samples will be assessed from each study visit for the presence of 
oseltamivir-resistant mutations. 
5.3.2 
Efficacy Assessments 
The clinical efficacy parameters in this study are: 
1. 
Symptoms of influenza-like illness.  These are captured in the patient diary for both adults 
and children (Appendix 2) and (Appendix 3).  Influenza symptoms are graded on a nominal 
scale from zero (absent/no problem) to 3 (severe or major problem).  A score of zero is 
considered asymptomatic.  The efficacy end point, time to alleviation of all symptoms is 
comprised of all the symptoms captured in the patient diary.  
2. 
Temperature.  This is captured in the patient diary.  Temperature is used for assessment of 
several efficacy endpoints.  
 
5.4 
LABORATORY ASSESSMENTS 
The laboratory assessments include those for safety, resistance, and efficacy. 
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Safety 
The safety laboratory assessments in this study, including the assessment of serum chemistry and 
hematology, will be carried out at a central laboratory.  Serum chemistry assessments comprise 
AST, ALT, total bilirubin, urea and creatinine.  Hematology assessments include CBC and 
differential count.  The total volume of blood loss for laboratory assessments will be 
approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section 16) will extend to any data generated from the assay 
of these samples.  Biological samples collected from all patients may be infectious and will be 
classified as “diagnostic specimens” for dispatch purposes. 
When clinically indicated, the investigator may draw blood for serum creatinine to be assessed at 
the local laboratory during the study to calculate creatinine clearance. 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described 
in the Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR 
and viral cultures.  Influenza virus shedding will be assessed.   
At the end of treatment (Day 11), a rapid diagnostic test is permitted for the diagnosis of 
ongoing influenza.  
5.5 
PHARMACOKINETIC ASSESSMENTS /PHARMACODYNAMIC 
ASSESSMENTS  
Participation in PK assessments is not compulsory for this study.  Blood samples for the 
characterization of oseltamivir carboxylate pharmacokinetics using a sparse sampling 
strategy will be collected from all patients who provide additional consent to participate in 
the PK assessments. 
Blood samples will be collected according to the Schedule of Assessments (Table 1) and 
as described below.  If these blood samples are collected at a home visit, site staff 
should ensure the PK blood sample handling processing is not compromised.  The time 
and date of the dose and blood samples should be captured.  Further details on 
pharmacokinetics/pharmacodynamics can be found in Sections 8.3.1and 8.3.2.  
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5.5.1 
Pharmacokinetic Assessments 
Plasma PK samples for assessment of oseltamivir carboxylate will be collected at the 
following timepoints on Day 6, or any day after the 11th dose, using the following 
sampling approach: 
• 
Within 30 minutes prior to the dose administration (e.g., 8:30 a.m. dose 9:00 a.m.) 
• 
1.5 hours ± 30 minutes post-dose (e.g., 10:30 a.m. ± 30 min) 
• 
4 hours ± 60 minutes post dose (e.g., 1:00 p.m. ± 60 min) 
• 
8 hours ± 1.5 hours post dose (e.g., 5:00 p.m. ± 1.5 hr) 
 
For adults and adolescents, approximately 2 mL of blood will be collected at each 
timepoint; therefore, the total volume blood loss for PK assessments will be 
approximately 8 mL.  For pediatric patients, not less than approximately 0.6 mL of blood 
will be tcollected at each timepoint; therefore, the total volume blood loss for PK 
assessments will be approximately 2.4 mL. 
The samples from this study are classified as Biological Substance, Category B.  
Plasma concentrations of oseltamivir carboxylate will be measured by a specific and 
validated method.  Details on sampling procedures, sample storage, and shipment are 
provided in the Sampling Manual. 
5.5.2 
Pharmacodynamic Assessments 
Nasal and throat swabs will be collected from individuals on the days specified in the 
schedule of assessments.  Specimens will be analyzed at a central laboratory.  As 
immunocompromised patients are expected to shed virus for a longer duration, viral samples will 
be collected at all visits.  The proportion of patients with viral shedding at each visit will be 
summarized. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/mL) or 75 mg capsules and matching placebo. 
The Investigational Medicinal Products will be supplied, packaged individually for each 
subject and labeled in accordance with Roche Standard and local regulation by Roche 
Clinical Trial Supply, Basel, Switzerland.  
6.1 
DOSE AND SCHEDULE OF STUDY DRUG 
Oseltamivir will be given twice daily over 10 days for a total of 20 doses.  The doses 
need to be taken at 12 hourly intervals.  Under no circumstances is a patient allowed to 
take two doses within 7 hours of each other.  
Patients will be randomized to receive either conventional or double dose of study drug. 
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Conventional dose: 
Children ages 1 − 12 years:  Oseltamivir syrup 
 ≤ 15 kg   
 
 
30 mg twice daily 
 > 15 − 23 kg   
 
45 mg twice daily 
 > 23 − 40 kg  
 
60 mg twice daily 
 > 40 kg  
 
 
75 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
75 mg twice daily 
Patients randomized to the conventional dose will simultaneously receive matching 
placebo so as to blind them and the investigator from the double dose arm.  
Double dose: 
Children ages 1 − 12 years:  Oseltamivir syrup  
 ≤ 15 kg   
 
 
60 mg twice daily 
 > 15 – 23 kg   
 
90 mg twice daily 
 > 23 – 40 kg  
 
120 mg twice daily 
 > 40 kg  
 
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
6.1.1 
Dose Modifications 
No dose modifications will be allowed on study. 
6.2 
PREPARATION AND ADMINISTRATION OF STUDY DRUG 
Oseltamivir will be provided in two forms:  
1. 
Oseltamivir capsules containing 75 mg of active drug and packaging material 
consisting of pregelatinized starch, povidone, talc and sodium stearyl fumarate.  All 
participants 13 years and older will receive this dosage form.  Oseltamivir capsules 
should be stored between 2-25ºC. 
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2. 
A pediatric suspension containing 12 mg oseltamivir per ml of reconstituted solution 
and the following excipients:  sorbitol, titanium dioxide, sodium benzoate, xanthan 
gum, monosodium citrate, saccharin sodium and Permaseal11900-31 Tutti Frutti 
(flavor).  All participants 12 years and under will receive this dosage form.  
Oseltamivir dry powder for oral suspension [pediatric syrup] should be stored below 
30°C [86°F]).  Once reconstituted, the suspension should not be used for longer 
than 10 days if stored at room temperature conditions (below 25°C).  If  stored 
under refrigerated conditions at 2−8 °C (36−46 °F) the suspension should not be 
used for longer than 17 days.  The suspension is not suitable for freezing. 
®
For further details, refer to the Tamiflu  Investigator’s Brochure. 
Matching placebo will be available as capsules and suspension.  Patients in the 
conventional dose arm will get the conventional dose and matching placebo so that they 
are blinded from the double dose arm.  
Each patient will be dispensed a medication pack that will provide enough medication to 
cover 20 doses.  For patients randomized to the conventional dose arm, the medication 
pack will contain a bottle of oseltamivir dry powder or a blister wallet with oseltamivir 
capsules and matching placebo.  For patients randomized to the double dose arm, the 
medication pack will contain two bottles of oseltamivir dry powder or two blister wallets 
with oseltamivir capsules.  Irrespective of the treatment group the patient is randomized 
to, for each dose the patient will take the same amount from both bottles or blister 
wallets provided in the medication pack such that the sum of the amounts from each 
immediate container constitutes one dose. 
One dose is to be administered twice per day at approximately 12-hour intervals with a 
light snack or glass of milk or fruit juice.  The first dose of study drug will be administered 
in the clinic at the time of randomization. 
6.3 
BLINDING AND UNBLINDING 
Randomization will be administered by a central randomization center.  
The Randomization List will not be available at the study center, to the study monitors, 
project statisticians or to the project team at Roche.  Emergency codes, or another 
adequate method of unblinding, will be implemented before study start, if the identity of 
the test medication is necessary for patient management in the case of a serious 
adverse event.  Any request from the investigator for information about the treatment 
administered to study patients for another purpose must be discussed with 
Roche/designee.  
As per regulatory reporting requirement, Roche/designee will unblind the identity of the 
study drug for all unexpected [as per IB] serious adverse events that are considered by 
the investigator to be related to study drug.  Details of patients who are unblinded during 
the study will be included in the Clinical Study Report. 
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All other individuals directly involved in this study will remain blinded until the final 
analysis of the primary parameter.  
The randomization will be stratified by transplant status, duration of symptoms, influenza 
vaccination status and age and will be provided by the Roche randomization group for 
the IVRS vendor.   
6.4 
ASSESSMENT OF COMPLIANCE 
Accountability and patient compliance will be assessed by maintaining adequate “drug 
dispensing” and return records.  
Patients will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  
A Drug Dispensing Log must be kept current and should contain the following 
information: 
• 
the identification of the patient [randomization and medication numbers] to whom 
the study drug was dispensed 
• 
the date[s], quantity of the study drug dispensed to the patient 
• 
the date[s] and quantity of the study drug returned by the patient 
 
This inventory must be available for inspection by the Monitor.  All supplies, including 
partially used or empty containers and the dispensing logs, must be returned to the 
monitor at the end of the study. 
6.5 
DESTRUCTION OF STUDY DRUG 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons.  In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned and destroyed.  Written authorization must be obtained from the sponsor or 
designee at study start up before destruction. 
Written documentation of destruction must contain the following: 
– 
Identity [batch numbers or patient numbers] of investigational product[s] destroyed 
– 
Quantity of investigational product[s] destroyed 
– 
Date of destruction 
– 
Method of destruction 
– 
Name and signature of responsible person [or company] who destroyed 
investigational products[s] 
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7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
7.1.1 
Clinical AEs 
Per the International Conference of Harmonization [ICH], an Adverse Event (AE) is any 
untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign [including 
an abnormal laboratory finding], symptom, or disease temporally associated with the use 
of a medicinal [investigational] product, whether or not considered related to the 
medicinal [investigational] product.  Pre-existing conditions which worsen during a study 
are to be reported as AEs.  Influenza signs and symptoms reported on the patient diary 
will be summarized as efficacy end points and need not be captured as adverse events.  
However, secondary illnesses due to influenza must be reported as adverse events.  
7.1.1.1 
Intensity  
All clinical AEs encountered during the clinical study will be reported on the AE page of 
the CRF.   
Intensity of AEs will be graded on a four -point scale [mild, moderate, severe, 
life-threatening] and reported in detail on the CRF.   
Mild 
discomfort noticed but no disruption of normal daily activity. 
Moderate 
discomfort sufficient to reduce or affect daily activity. 
Severe 
inability to work or perform normal daily activity 
Life Threatening 
represents an immediate threat to life   
 
7.1.1.2 
Drug - Adverse Event Relationship 
Relationship of the AE to the treatment should always be assessed by the investigator.  
Description of scales can be found in Appendix 4. 
7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Pregnancies 
 
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A Serious Adverse Event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfils at least 
one of the following criteria: 
– 
is fatal; [results in death; NOTE:  death is an outcome, not an event].  
– 
is Life-Threatening [NOTE:  the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
– 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
 
The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to 
(Appendix 5). 
7.1.2 
Treatment and Follow-up of AEs  
AEs, especially those for which the relationship to test “drug” is not “unrelated”, should 
be followed up until they have returned to baseline status or stabilized.  If a clear 
explanation is established it should be recorded on the CRF.   
7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will appear printed on laboratory reports provided to the site from 
the central laboratory.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] 
should be reported as such, in addition to being recorded as an AE in the CRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE page in the CRF: 
• 
Accompanied by clinical symptoms. 
• 
Leading to a change in study drug [e.g. dose modification, interruption or 
permanent discontinuation]. 
• 
Requiring a change in concomitant therapy [e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment]. 
 
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7.1.4 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  If a clear explanation is 
established it should be recorded on the CRF.  
7.2 
HANDLING OF SAFETY PARAMETERS 
7.2.1 
Reporting of Serious Adverse Events [immediately reportable] 
Any clinical AE or abnormal laboratory test value that is serious [as defined in 
Section 7.1.1.3 above] and which occurs during the course of the study, regardless of 
the treatment arm, occurring from the enrollment visit (start of study screening 
procedures), must be reported to Roche or designee immediately (i.e., no more than 
24 hours after the investigator becomes aware of the event [expedited reporting]). 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and 
up until the follow-up visit.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to (Appendix 5).  The serious adverse events should be reported in the most 
up -to-date version of the SAE form. 
7.2.2 
Pregnancy  
A female patient must be instructed to stop taking the test “drug” and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should 
report all pregnancies immediately (i.e., no more than 24 hours after the investigator 
becomes aware of the pregnancy) to the Sponsor or designee, using the most 
up-to-date version of the pregnancy form.  The investigator should counsel the patient, 
and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Pregnancies occurring within 28 days of treatment completion should be reported to 
Roche.  
7.3 
WARNINGS AND PRECAUTIONS  
Events such as convulsions and delirium (including symptoms such as altered level of 
consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, 
anxiety, nightmares) have been reported during oseltamivir use in patients with influenza, 
predominately in children and adolescents.  In rare cases, these events resulted in 
accidental injury.  The contribution of oseltamivir to those events is unknown.  Such 
events have also been reported in patients with influenza who were not taking 
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oseltamivir.  Patients, especially children and adolescents, should be closely monitored 
for signs of abnormal behavior. 
Please refer to the attached Investigator’s Brochure for additional warnings, precautions, 
and other reported adverse events. 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN   
Full details of all planned analyses will be specified in a separate Statistical Analysis 
Plan (SAP) for the safety and efficacy variables and in the Resistance Plan for the 
development of resistance.  The methods described below are an outline of the main 
planned analyses. For continuous endpoints summary statistics including mean, standard 
deviation, median, minimum, and maximum will be derived for each treatment group.  For 
categorical data, the number and percentage of events and/or patients for each treatment group 
will be presented. 
8.1 
PRIMARY AND SECONDARY STUDY ENDPOINTS 
8.1.1 
Primary Endpoints 
The primary endpoints for safety will be descriptive assessments of:  
• 
Adverse events 
• 
Physical examinations  
• 
Vital signs 
• 
Clinical laboratory evaluations  
• 
Tissue rejection and/or graft versus host disease in transplant patients 
 
The primary endpoint of development of resistance will be determined from the 
genotypic and phenotypic variables measured post baseline and is described further in 
the Resistance Plan. 
8.1.2 
Secondary Endpoints 
The following endpoints will be analyzed descriptively at relevant timepoints:  
• 
Shedding virus by culture and RT-PCR  
/mL) and quantitative RT-PCR 
TCID
• 
Viral load by culture (log10
50
• 
Individual symptom scores  
• 
The time (hours) from first dose of study drug until resolution of fever  
• 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or sinusitis) 
at any time during the study 
• 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or sinusitis) 
at any time during the study that are treated with antibiotics 
• 
Initiation of treatment with antibiotics after randomization  
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• 
Hospitalization, and for those who are hospitalized, the duration of hospitalization 
• 
Development of rejection or GVHD 
 
The following are the model-predicted PK secondary endpoints for oseltamivir 
carboxylate: 
• 
Steady-state area under the concentration–time curve from 0 to 12 hours (AUC
) 
0-12
• 
Maximum plasma concentration (Cmax) for oseltamivir carboxylate 
• 
Trough plasma concentration (Ctrough) for oseltamivir carboxylate 
 
The following model-predicted PK endpoints may be included, if appropriate:  
• 
Elimination half-life (t1/2) 
• 
Time to maximum concentration (tmax) 
• 
Elimination constant (ke) 
• 
Apparent clearance (CL/F) 
• 
Apparent volume of distribution (Vc/F) 
• 
Apparent total clearance of metabolite (CLm) 
• 
Last measurable concentration (C
) and time to last measurable concentration (t
last
last)  
 
8.2 
STATISTICAL AND ANALYTICAL METHODS  
8.2.1 
Statistical Model  
8.2.1.1 
Time to Event Variables 
A non-parametric model will be assumed with estimation of medians based on Kaplan-
Meier methods.  Patients without alleviation of symptoms will have their time censored at 
the last available observation that a complete assessment was made. 
8.2.1.2 
Dichotomous Variables and Viral Load  
For the endpoints defined dichotomously in terms of events or symptoms including the 
development of resistance, it will be assumed that the number of patients experiencing 
the event or exhibiting the symptom will have a binomial distribution. 
For the continuous endpoints of viral load at Day 1, 2, 6, 8, 11, 15, and 40 no model will 
be assumed.  
8.2.2 
Sample Size 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 90% 
of enrolled patients will have laboratory-confirmed influenza, there will be 75 patients in 
each treatment arm in the population evaluable for the development of resistance.  The 
following table shows the 95% Pearson-Clopper confidence intervals that would result 
with a sample size of 75 patients in a treatment arm if certain event rates are observed 
in the study. 
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During the study the number of influenza A virus infected patients and the rate of 
development resistance will be monitored in a blinded fashion, in order to ensure a 
reasonable precision for the estimation.  An additional number of patients may be 
enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
  0%  - 4.8% 
1.3 
0.0% - 7.2% 
2.7  
0.3% - 9.3% 
5.3 
1.5% - 13.1% 
10.7 
4.7%-19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of 
safety.  This number of patients would provide estimates of adverse event rates with 
similar precision. 
8.2.3 
Hypothesis Testing  
Formal hypothesis testing will be not performed; any comparisons between groups will be 
based on comparison of confidence intervals.  
8.2.4 
Analysis Populations 
Three main patient populations will be used for the analysis of data from this study; the 
Safety Population, the Intent-to treat Population and the Intent-to-Treat Infected 
Population.  Detailed definitions of these populations will be given in the SAP.  
8.2.4.1 
Intent to Treat Population 
All patients randomized will be included in the intent to treat population [Patients will be 
assigned to treatment groups as randomized for analysis purposes]. 
8.2.4.2 
Intent to Treat Infected Population 
All patients randomized and with laboratory confirmation of influenza infection, excluding 
patients infected with oseltamivir-resistant influenza at baseline, will be included in the 
intent to treat influenza infected population [Patients will be assigned to treatment groups 
as randomized for analysis purposes]. 
The ITTI Population will be the primary population for the summary and analysis of the 
development of resistance and the efficacy variables. 
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8.2.4.3 
 Pharmacokinetic Evaluable Patient Population 
The Pharmacokinetic evaluable patient population (PKEP) population comprises all 
patients in the ITT population who have at least one post-dose drug concentration 
measurement at a scheduled visit timepoint.  Patients may be excluded from the PKEP 
population if they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or have unavailable or incomplete data that may influence 
the PK analysis.  
Decisions on patient exclusion from the PK analysis will be made prior to database 
closure by the clinical pharmacologist.  Excluded patients will be documented along with 
the reason for exclusion. 
8.2.4.4 
Subpopulations 
A subpopulation of the ITTI population will be defined comprising patients who received 
their first dose of study drug within 48 hours of influenza symptom onset for the 
comparison of efficacy endpoints with the age appropriate placebo treated patients 
(pediatric or adult) from the registration trials. 
8.2.5 
Safety Data Analysis 
The safety analysis population will include all patients who receive at least one dose of 
study drug and had a safety assessment performed post randomization.  All safety 
variables will be summarized and presented in tables based on this safety population: 
• 
Adverse events 
• 
Physical examination 
• 
Vital signs 
• 
Clinical laboratory evaluations 
• 
Rejection and/or graft versus host disease 
 
8.2.6 
Analysis of Resistance 
For the summary of the development of resistance for each treatment arm, 95% 
confidence intervals will be provided with the estimated rates.  Further details are 
available in the Resistance Plan for NV20234.  These data will be summarized in a 
report separate from the final study report. 
8.2.7 
Efficacy Analysis 
For the analysis of time to alleviation of all clinical symptoms, the following two assessments will 
be made independently of each other and without regard to the outcomes in each case. 
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• 
Comparison to placebo control from pivotal registration trials  
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo-treated patients will be established that is 
comparable to the subpopulation of patients in the current study whose first dose of 
study drug was within 48 hours of symptom onset.  For this population, a median 
time to resolution of all clinical influenza symptoms will be determined along with its 
95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for each 
treatment group, along with its 95% confidence interval.   
• 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence interval. 
  
For the dichotomous endpoints, the proportion of patients experiencing the event or symptom, 
and its associated 95% confidence interval will be derived for each treatment group.  Where 
possible, the corresponding confidence intervals from the placebo control population will be 
presented for comparison to those derived for the active treatment groups in this trial. 
The continuous secondary endpoint time to resolution of fever will be analyzed as for the time to 
alleviation of all symptoms.  
8.2.7.1 
Exclusion of Data from Analysis 
Efficacy data collected from any patient who begins treatment with another antiviral for 
influenza (for example, amantadine, rimantadine, laninamivir, peramivir, or zanamavir), 
after the other antiviral treatment commences, will be excluded from the primary and 
secondary efficacy analyses.  Such patients will be considered failures to oseltamivir 
treatment in the analyses.  Further details will be provided in the SAP. 
8.2.7.2 
Interim Analysis 
No interim analyses are planned.  
8.2.8 
Other Analyses 
Further exploratory analyses will be detailed in the SAP. 
8.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
8.3.1 
Pharmacokinetic Analysis 
The primary study variables are the model-derived PK parameters:  steady-state AUC, 
Cmax, and C
 of oseltamivir carboxylate. 
trough
Individual and mean plasma concentrations at each sampling timepoint for oseltamivir 
carboxylate will be presented by listings and descriptive summary statistics, including 
means, geometric means, medians, ranges, standard deviations, and coefficients of 
variation.  Individual and mean concentration-versus-time profiles will be plotted on 
linear and semi-logarithmic scales. 
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Plasma concentration data from sparse sampling will be analyzed using an established 
population PK model to determine key exposure parameters (e.g., Cmax, Ctrough, and 
AUC).  For immunocompromised children aged 1 to 18 years, plasma oseltamivir 
carboxylate concentration will be modeled in NONMEM using a structure similar to a 
comprehensive population PK model, which was previously developed using plasma 
data from non-immunocompromised children and adults (ages 1 to 80 years) [36].  The 
basic structure consists of a 2-compartment model with first-order absorption and direct 
conversion of oseltamivir to oseltamivir carboxylate, while a 1-compartment model is 
used to account for the renal elimination of oseltamivir carboxylate from the plasma.  
Body weight, evaluated using a power function and centered around 70 kg, is a 
statistically significant predictor of both CL/F and central volume of distribution (Vc/F) for 
oseltamivir carboxylate.  For oseltamivir carboxylate, CrCl is also a significant predictor 
of CL/F, while Vc/F decreases linearly with age. 
8.3.2 
Pharmacokinetic/Pharmacodynamic Analysis  
If feasible, exposure-response relationships [43]will be evaluated between independent variables 
of exposure (e.g., AUC, Cmin) and  dependent variables including continuous (area under the 
viral titer curve, and peak viral titer) and time-to-event (cessation of viral shedding) virologic 
endpoints. Exploratory PK/PD analyses will be performed using appropriate methodologies. In 
order to account for potential non-linearity and non-monotonicity, each continuous independent 
variable (e.g., AUC) will be evaluated in its original form, as a categorical variable based on 
quartiles, as two- and three-group categorical variables. 
9. 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs against the investigator’s records by the study monitor [source document 
verification], and the maintenance of a drug–dispensing log by the investigator.  
The data collected will be entered into the study database from the working copy of the 
CRF faxed from the site. 
A comprehensive validation check program will verify the data and discrepancy reports 
will be generated accordingly for resolution by the investigator.  As patients complete the 
study [or prematurely withdraw] and their signed CRFs become available, a second data 
entry will be performed from the original, signed CRF.  A comparison check will be run to 
identify and resolve any discrepancies between the first and second data entry. 
Throughout the study the Study Management Team [SMT] will review data according to 
the SMT Data Review Plan as described in the Data Quality Plan.  
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9.1 
ASSIGNMENT OF PREFERRED TERMS AND ORIGINAL 
TERMINOLOGY 
For classification purposes, preferred terms will be assigned by the sponsor to the 
original terms entered on the CRF, using the current version of MedDRA (Medical 
Dictionary for Regulatory Activities terminology) for adverse events and diseases and 
the INN (International Non-Proprietary name) drug terms and procedures dictionary for 
treatments and surgical and medical procedures. 
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10. 
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rd
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32. Hayden FG. Antiviral resistance in influenza viruses: clinical and epidemiological 
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14th, 2010. 
36. Kamal MA, Van Wart SA, Rayner CR, et al.,Population pharmacokinetics of 
oseltamivir in pediatric through geriatrics. Antimicrob Agents Chemother 2013; 
57:3470−7. 
37. Allen U, Blumberg EA, Fischer SA, et al. American Society of Transplantation (AST) 
Infectious Diseases Community of Practice / Transplant Infectious Disease Section 
of The Transplantation Society (TTS) Guidance On Novel Influenza A/H1N1. [cited 
2010 Oct 28]. 2009 Dec 03. Available from: www.a-s-
t.org/files/pdf/ast_h1n1_guidance.pdf. 
38. Katzung BG, Masters SB, Trevor AJ (ed). Basic and clinical pharmacology. 11th 
edition. Tata McGraw-Hill Companies, Inc., New York: 2009: 971−80.  
39. Salvana EM, Salata RA. Infectious complications associated with monoclonal 
antibodies and related small molecules. Clin Microbiol Rev. 2009;22(2):274−90. 
40. Erkeller-Yuksel FM, Deneys V, Yuksel B, et al. Age-related changes in human 
blood lymphocyte subpopulations. J Pediatr 1992;120:216−22 
41. Denny T, Yogev R, Gelman R, et al. Lymphocyte subsets in healthy children 
during the first 5 years of life. JAMA 1992;267:1484−8. 
42. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. 
[resource on the internet]. Available from: http://aidsinfo.nih.gov/guidelines 
43. Rayner CR, Bulik CC, Kamal MA et al., Pharmacokinetic-pharmacodynamic 
determinants of oseltamivir efficacy using data from phase 2 inoculation studies. 
Antimicrob Agents Chemother 2013; 57:3478−87 
 
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PART II: ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the patient.  For studies conducted in the European 
Union/European Economic Areacountries, the investigator will ensure compliance with 
the EU Clinical Trial Directive [2001/20/EC].  For studies conducted in the United States 
or under US IND, the investigator will additionally ensure that the basic principles of 
“Good Clinical Practice” as outlined in the current version of 21 CFR, subchapter D, part 
312, “Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Subjects”, and part 56, “Institutional Review Boards”, are adhered to. 
In other countries where “Guideline for Good Clinical Practice” exist Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
INFORMED CONSENT  
It is the responsibility of the investigator, or a person designated by the investigator [if 
acceptable by local regulations], to obtain written informed consent from each patient 
participating in this study, after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study.  For patients not qualified or incapable of 
giving legal consent, written consent must be obtained from the legally acceptable 
representative.  In the case where both the patient and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the 
entire informed consent discussion.  After the patient and representative have orally 
consented to participation in the trial, the witness’ signature on the form will attest that 
the information in the consent form was accurately explained and understood.  The 
investigator or designee must also explain that the patients are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason.  The Case Report 
Forms [CRFs] for this study contain a section for documenting informed patient consent, 
and this must be completed appropriately.  If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and 
updated if necessary.  All patients [including those already being treated] should be 
informed of the new information, given a copy of the revised form and give their consent 
to continue in the study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written consent. 
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11.3 
INDEPENDENT ETHICS COMMITTEES/INSTITUTIONAL 
REVIEW BOARD  
Independent Ethics Committees [non-US]:  This protocol and any accompanying 
material provided to the patient [such as patient information sheets or descriptions of the 
study used to obtain informed consent] as well as any advertising or compensation given 
to the patient, will be submitted by the investigator to an Independent Ethics Committee.  
Approval from the committee must be obtained before starting the study, and should be 
documented in a letter to the investigator specifying the date on which the committee 
met and granted the approval. 
Any modifications made to the protocol after receipt of the Independent Ethics 
Committee approval must also be submitted by the investigator to the Committee in 
accordance with local procedures and regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee. 
Institutional Review Board [US]:  It is the understanding of the sponsor that this 
protocol [and any modifications] as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board.  This board must operate in 
accordance with the current Federal Regulations.  A letter or certificate of approval will 
be sent by the investigator to the Sponsor or designee prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between 
an appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial].  Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Clinical Science Leader/Clinical Pharmacologist and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required.  Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial patients, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g. change in monitor[s], change of telephone 
number[s]. 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
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basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
14. 
STUDY DOCUMENTATION, CRFS AND RECORD KEEPING 
14.1 
INVESTIGATOR'S FILES / RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] patient clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff curriculum vitae and authorization forms and other appropriate 
documents/correspondence etc.  
Patient clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and patient screening and enrollment logs.  
The Investigator must keep these two categories of documents on file for at least 15 
years after completion or discontinuation of the study.  After that period of time the 
documents may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
14.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
The investigator shall supply the sponsor or designee on request with any required 
background data from the study documentation or clinic records.  This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected.  In 
case of special problems and/or governmental queries or requests for audit inspections, 
it is also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. 
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14.3 
AUDITS AND INSPECTIONS 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees, or to health authority inspectors after 
appropriate notification.  The verification of the CRF data must be by direct inspection of 
source documents. 
14.4 
CASE REPORT FORMS 
For each patient enrolled, a CRF must be completed and signed by the principal 
investigator or authorized delegate from the study staff.  This also applies to records for 
those patients who fail to complete the study [even during a pre-randomization screening 
period if a CRF was initiated].  If a patient withdraws from the study, the reason must be 
noted on the CRF.  If a patient is withdrawn from the study because of a treatment-
limiting AE, thorough efforts should be made to clearly document the outcome. 
All forms should be typed or filled out using indelible ink, and must be legible.  Errors 
should be crossed out but not obliterated, the correction inserted, and the change 
initialed and dated by the investigator or his/her authorized delegate.  The investigator 
should ensure the accuracy, completeness, legibility, and timeliness of the data reported 
to the sponsor or designee in the CRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the CRF.  
The investigator [or his/her deputy] agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On CRFs or other documents 
submitted to the sponsor or designee, patients should not be identified by their names, 
but by an identification code.  The investigator should keep a patient enrollment log 
showing codes, names and addresses.  The investigator should maintain documents not 
for submission to Roche, e.g., patients’ written consent forms, in strict confidence. 
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17. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  This allows the sponsor or designee to protect proprietary information and 
to provide comments based on information from other studies that may not yet be 
available to the investigator. 
In accord with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator will be designated by mutual agreement. 
Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel.  Authorship will be determined by mutual agreement. 
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Appendix 1 Calculation of Creatinine Clearance and Grading of 
Chronic Extensive GVHD  
Calculation of Creatinine Clearance 
Conversion Factor for Serum Creatinine: 
Conventional Units (mg/dL) = SI Units (μmol/L) ÷ 88.4   
Age = number of years (12 years 11 months = 12 years) 
Estimated Creatinine Clearance according to Cockcroft-Gault [13] 
 (for patients ≥ 18 years): 
¾ Males 
 
Creatinine 
Clearance (mL/min)  =  
[(140 − age) × Body Weight (kg)] ÷ [72 × Serum Creatinine 
(mg/dL)] 
 
¾ Females  
Creatinine Clearance = above equation × 0.85 
 
Estimated Creatinine Clearance according to Schwartz equation [14]  
(for patients < 18 years): 
 
k × Height (cms) ÷  Serum Creatinine (mg/dL) 
Creatinine Clearance 
(mL/min/1.73 M2) =  
Value for k:  
k 
Age (years) 
0.45 
 < 2 
0.55 
 ≥ 2 to < 13 
0.7 
 ≥ 13 to < 18 (males) 
 ≥ 13 to < 18 
(females) 
0.55 
 
 
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Appendix 1 Calculation of Creatinine Clearance and Grading of 
Chronic Extensive GVHD  (cont.) 
 
Grading of Chronic GVHD [15] 
Type of Disease 
Extent of Disease 
Limited 
Localized skin involvement, liver 
dysfunction or both 
Extensive 
Generalized skin involvement 
 
Localized skin involvement or liver 
dysfunction plus any one of the following: 
   1. Chronic aggressive hepatitis, bridging 
necrosis or cirrhosis 
   2. Eye involvement (Schirmer’s 
test,  < 5 mm) 
   3. Involvement of mucosalivary glands 
   4. Mucosal involvement (on lip biopsy) 
   5. Involvement of other target organs  
 
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Appendix 2 Patient Diary Data and Symptom Record for Adults
 
 
The purpose of the patient diary is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study.  Temperature and date 
and time of drug administration should also be recorded on the patient diary. 
 
 
 
 
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Appendix 3 Patient Diary Data and Symptom Record for 
Children  
Temperature and date and time of drug administration will also be recorded on the 
patient diary. 
 
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Appendix 4 Adverse Event [AE] Categories for Determining 
Relationship to Test Drug 
PROBABLE [must have first three] 
This category applies to those AEs which are considered, with a high degree of certainty, 
to be related to the test drug.  An AE may be considered probable, if: 
1. 
It follows a reasonable temporal sequence from administration of the drug. 
2. 
It cannot be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the patient. 
3. 
It disappears or decreases on cessation or reduction in dose.  [There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., [1] bone marrow depression, [2] tardive 
dyskinesias]. 
4. 
It follows a known pattern of response to the suspected drug. 
5. 
It reappears upon rechallenge. 
 
POSSIBLE [must have first two] 
1. 
This category applies to those AEs in which the connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty.  An AE may 
be considered possible if, or when: 
2. 
It follows a reasonable temporal sequence from administration of the drug. 
3. 
It may have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
4. 
It follows a known pattern of response to the suspected drug. 
 
REMOTE [must have first two] 
1. 
In general, this category is applicable to an AE which meets the following criteria: 
2. 
It does not follow a reasonable temporal sequence from administration of the drug. 
3. 
It may readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient. 
4. 
It does not follow a known pattern of response to the suspected drug. 
5. 
It does not reappear or worsen when the drug is readministered. 
 
UNRELATED 
This category is applicable to those AEs which are judged to be clearly and 
incontrovertibly due only to extraneous causes [disease, environment, etc.] and do not 
meet the criteria for drug relationship listed under remote, possible, or probable. 
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Appendix 4 Adverse Event [AE] Categories for Determining 
Relationship to Test Drug (cont.) 
 
 
Probable 
Possible 
Remote 
Unrelated 
Clearly due to extraneous causes 
– 
– 
– 
+ 
 
 
 
 
 
Reasonable temporal association with 
drug administration 
+ 
+ 
– 
– 
 
 
 
 
 
May be produced by patient clinical 
state, etc. 
– 
+ 
+ 
+ 
 
 
 
 
 
Known response pattern to suspected 
drug 
+ 
+ 
– 
– 
 
 
 
 
 
Disappears or decreases on cessation 
or reduction in dose 
+ 
– 
– 
– 
 
 
 
 
 
Reappears on rechallenge 
+ 
– 
– 
– 
 
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Appendix 5 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– 
is fatal; [results in death] [NOTE:  death is an outcome, not an event]. 
– 
is Life-Threatening    [NOTE:  the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
– 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor or designee is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definitions above.  These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator.  For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply)  
– 
Pre-existing/Underlying disease - specify  
– 
Study treatment – specify the drug(s) related to the event 
– 
Other treatment (concomitant or previous) – specify 
– 
Protocol-related procedure 
– 
Other (e.g. accident, new or intercurrent illness) - specify 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious.  
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
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Appendix 5 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
(cont.) 
A serious adverse event occurring during the study or which comes to the attention of 
the investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later which will include 
copies of hospital case reports, autopsy reports and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
page of the CRF:  intensity, relationship to test substance, action taken, and outcome to 
date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs:  Local Monitor  
ROCHE HEADQUARTERS CONTACT for SAEs:  Clinical Operations/Clinical Science  
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls, 
provide medical translation service (if necessary), connect the investigator with a Roche 
Medical Monitor, and track all calls.  The Emergency Medical Call Center Help Desk 
will be available 24 hours per day, 7 days per week.  Toll-free numbers for the Help 
Desk and Medical Monitor contact information will be distributed to all investigators. 
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Appendix 6 Primary Immunodeficiency Conditions 
Category 
Conditions 
Adenosine deaminse (ADA) deficiency 
Artemis deficiency (SCIDA) 
CD45 deficiency 
Cernunnos deficiency 
DNA ligase IV (LIG4) deficiency 
Severe Combined 
Immunodeficiency (SCID) 
Interleukin receptor γ chain deficiency (X-linked SCID) 
Janus-associated kinase 3 (JAK3) deficiency 
Recombinase activating gene (RAG 1 / 2) deficiency  
Reticular dysgenesis 
TAP- 1 or TAP- 2 deficiency (MHC class I deficiency) 
CD8 deficiency 
diGeorge syndrome  
Interleukin 7 receptor α (IL7RA) deficiency 
MHC class II deficiency 
LCK deficiency 
Primary T cell Deficiency 
Orai 1 deficiency 
Nude syndrome (wing helix nude deficiency) 
Purine nucleotide phosphorylase (PNP) deficiency 
T cell receptor deficiency (CD 3γ, δ, ε, and ζ 
deficiencies) 
Zap 70 tyrosine kinase deficiency 
X-Linked CD40 ligand deficiency 
Predominantly Antibody 
Deficiency 
X- Linked IKK-γ (NEMO) deficiency 
CD40 deficiency 
Interferon γ receptor deficiency 
Other Well-Defined 
immunodeficiency Syndromes 
X-Linked lymphoproliferative syndrome 
Adapted from Table 310-2:  p2056 reference 16. 
 
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Appendix 7 Hematologic Malignancies and their Effect on the 
Immune System 
Malignancy 
Effect on immunity 
suppression of hematopoiesis, neutropenia, 
lymphocyte dysfunction 
ALL, lymphomas 
hypogammaglobulinemia, increased 
susceptibility to infections, autoimmune anemia 
or thrombocytopenia 
CLL, small lymphocytic lymphoma 
Hairy cell leukemia, myelodysplastic syndromes
pancytopenia 
lymphocyte dysfunction, increase in immature 
cells 
peripheral T cell and NK neoplasms 
Hodgkin’s disease  
suppression of cell-mediated immunity 
neutropenia, anemia, thrombocytopenia, 
predisposed to infections, lymphocyte 
dysfunction 
AML 
anemia, granulocyte dysfunction in some 
patients in early phase and in most patients in 
blast phase 
CML 
Adapted from reference 16. 
 
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Appendix 8 Immunosuppressive Medications 
Class 
Category 
Drugs 
Corticosteroids 
- 
Glucocorticoids (oral, sc, im, iv) 
cyclophosphamide, busulfan, mechlorethamine, 
chlorambucil, melphalan, carmustine, lomustine, 
ifosfamide, procarbazine, dacarbazine, 
temozolomide, cisplatin, carboplatin, oxaliplatin 
Alkylating agents 
Anti-metabolites 
methotrexate, 6-mercaptopurine, azathioprine 
bleomycin, actinomycin D, mitomycin C, etoposide, 
topotecan, irinotecan, doxorubicin, daunorubicin, 
idarubicin, epirubicin, mitoxantrone 
Anti-tumor 
antibiotics 
Anti-mitotic agents 
vincristine, vinblastine, vinorelbine, paclitaxel, 
docetaxel, estramustine phosphate, NAB-
paclitaxel 
Cytotoxic agents[
]
16
Molecularly 
targeted agents 
imatinib, tretinoin,  bexarotene, denileukin,  diftitox, 
gefitinib, erlotinib, dasatinib, sorafenib, sunitinib 
Calcineurin inhibitors 
- 
cyclosporine, tacrolimus 
mTOR inhibitors 
(proliferation-signal 
inhibitors) 
sirolimus, everolimus 
- 
Immunosuppressive 
antibodies 
anti lymphocyte and antithymocyte globulins (ALG 
and ATG) 
- 
Adalimumab 
Infliximab 
Cetrolizumab 
Etarnecept 
Basiliximab 
Inhibitors of pro 
inflammatory 
cytokines 
Daclizumab 
Adhesion cell 
modulators 
Natalizumab 
Monoclonal 
antibodies 
Abatacept 
[
, 
]
38 39
Alefacept 
T-cell inhibitors 
Muromonab 
Rituximab 
90Y-Ibritumomab 
B-cell inhibitors 
131I-Tositumomab 
Anti-CD33 
Gemtuzumab 
Anti- CD52 
Alemtuzumab 
Others 
- 
mycophenolate mofetil, thalidomide 
. 
Compiled from Table 81-2:  p521-24 reference 16 and references 38, 39
 
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Appendix 9 Child-Pugh Classification of Severity of Liver Disease 
Child–Pugh Scoring on Select Parameters 
Points Scored for Increasing 
Abnormality 
Clinical and biochemical measurements 
1 
2 
3 
Encephalopathy (grade) 
None 
1 or 2 
3 or 4 
a
Ascites 
Absent 
Slight 
Moderate 
b
Bilirubin (mg/100 mL) 
 < 2 
2–3 
 > 3 
Albumin (g/100 mL) 
 > 3.5 
2.8–3.5 
 < 2.8 
Prothrombin time (International Normalized 
Ratio) 
 < 1.7 
1.7–2.3 
 > 2.3 
c
Note:  With increasing abnormality of each of the five parameters measured, 1, 2, or 3 points are scored. Grade A:  5 
or 6 points. Grade B:  7–9 points. Grade C:  10–15 points. 
 According to grading of Trey, Burns, and Saunders (1966). 
a
 As determined by physical examination alone. 
b
 Prothrombin time results should be reported and used for calculations only as International Normalized Ratios 
because of variations in the methods used and reference ranges for controls (expressed in seconds). 
c
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Title
18-Jun-2014 10:08:43
Date and Time (UTC)
Clinical Science Leader
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
CONFIDENTIAL 
 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board.  It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Oseltamivir ⎯ F. Hoffmann-La Roche Ltd 
Protocol NV20234, Version F 
PROTOCOL 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, 
MULTI-CENTER TRIAL EVALUATING 
CONVENTIONAL AND DOUBLE DOSE 
OSELTAMIVIR IN THE TREATMENT OF 
IMMUNOCOMPROMISED PATIENTS WITH 
INFLUENZA 
PROTOCOL NUMBER: NV20234 
VERSION NUMBER: 
F 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
TEST PRODUCT: 
Oseltamivir (Tamiflu® RO 64-0796) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version A:  14 June 2007 
DATES AMENDED: 
Version B:  31 July 2008 
Version C:  28 March 2011 
Version D:  28 September 2012 
Version E:  30 October 2013 
Version F:  See electronic stamp below. 


PROTOCOL AMENDMENT, VERSION F 
RATIONALE 
Protocol NV20234 has been amended to reintroduce the oseltamivir parent compound to 
the pharmacokinetic analysis, as this was inadvertently removed in Protocol Version E. 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
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PROTOCOL AMENDMENT, VERSION F 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
Throughout the document, oseltamivir has been added back to all the pharmacokinetic 
analysis sections, as applicable, as both oseltamivir (parent) and oseltamivir carboxylate 
(metabolite) plasma concentrations will be determined from the blood samples. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 2.2:  SECONDARY OBJECTIVES: 
To evaluate the effects of conventional and double dose oseltamivir in 
immunocompromised patients on: 
• 
The population pharmacokinetics of oseltamivir and oseltamivir carboxylate (e.g., 
clearance, volume of distribution) in immunocompromised patients with confirmed 
influenza infection, through the application of established population 
pharmacokinetic (PK) models to the sparse plasma concentration data generated  
 
SECTION 3.2:  NUMBER OF PATIENTS/ASSIGNMENT TO TREATMENT 
GROUPS 
A minimum of 166 patients (approximately 83 per arm) to allow an adequate number of 
influenza A patients, including 50 transplant recipients and at least 15 pediatric patients, 
will be enrolled in this study.  After screening, patients will be randomly assigned to one 
of the two active treatment groups. 
SECTION 4.1:  OVERVIEW 
The study population comprises immunocompromised adults (including adolescents) 
and children (pediatric) who have influenza (the pediatric and adolescent patients will 
be defined as 1 year to less than 18 years of age at randomization).… 
SECTION 5.5.1:  Pharmacokinetic Assessments 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected at the following timepoints on Day 6, or any day after the 11th dose, using the 
following sampling approach: 
• 
Within 30 minutes prior to the dose administration (e.g., 8:30 a.m. if dosing is 
scheduled fordose 9:00 a.m.) 
• 
1.5 hours ± 30 minutes post-dose (e.g., 10:30 a.m. ± 30 min if dosing is scheduled 
for 9:00 a.m.) 
• 
4 hours ± 60 minutes post dose (e.g., 1:00 p.m. ± 60 min if dosing is scheduled for 
9:00 a.m.) 
• 
8 hours ± 1.5 hours post dose (e.g., 5:00 p.m. ± 1.5 hr if dosing is scheduled for 
9:00 a.m.) 
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SECTION 6:  INVESTIGATIONAL MEDICINAL PRODUCT 
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/mL or 6 mg/mL [the 6 mg/mL will only be 
used if applicable and not before 2015]) or 75 mg capsules and matching placebo. 
SECTION 6.2:  PREPARATION AND ADMINISTRATION OF STUDY DRUG 
Oseltamivir will be provided in two forms:  
1. 
Oseltamivir capsules containing 75 mg of active drug and packaging material 
consisting of pregelatinized starch, povidone, talc, and sodium stearyl fumarate.  All 
participants 13 years and older will receive this dosage form.  Oseltamivir capsules 
should be stored below between 2−25°C [77°F].  Do not store refrigerated. 
2. 
A pediatric suspension containing 12 mg oseltamivir per mL or 6 mg oseltamivir 
per mL (the 6 mg/mL will only be used if applicable and not before 2015), of 
reconstituted solution and the following excipients:  sorbitol, titanium dioxide, sodium 
benzoate, xanthan gum, monosodium citrate, saccharin sodium, and 
Permaseal11900-31 Tutti Frutti (flavor).  All participants 12 years and under will 
receive this dosage form.  Oseltamivir dry powder for oral suspension [pediatric 
syrup] should be stored below 30°C [86°F]).  Once reconstituted, the suspension 
should not be used for longer than 10 days if stored at room temperature conditions 
(below 25°C/77°F).  If stored under refrigerated conditions at 2−8°C (36−46°F) the 
suspension should not be used for longer than 17 days.  The suspension is not 
suitable for freezing. 
 
SECTION 8.1.2:  Secondary Endpoints 
The following endpoints will be analyzed descriptively at relevant timepoints:. 
The pharmacodynamics assessments based on nose and throat swabs, collected on the 
days specified in the schedule of assessments: 
The following are the model-predicted PK secondary endpoints for oseltamivir and 
oseltamivir carboxylate: 
• 
Steady-state area under the concentration–time curve from 0 to 12 hours (AUC0-12) 
• 
Maximum plasma concentration (Cmax) for oseltamivir carboxylate 
• 
Trough plasma concentration (Ctrough) for oseltamivir carboxylate 
 
SECTION 8.3.1:  Pharmacokinetic Analysis 
… Body weight, evaluated using a power function and centered around 70 kg, is a 
statistically significant predictor of both the CL/F for oseltamivir and both CL/F and 
apparent volume of distribution (Vc/F) for oseltamivir carboxylate.  For oseltamivir 
carboxylate, CrCl is also a significant predictor of CL/F, while Vc/F decreases linearly 
with age. 


 
SECTION 16:  CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On CRFs or other documents (both 
paper and electronic) submitted to the sponsor or designee, patients should not be 
identified by their names but by an identification code.… 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND AND RATIONALE............................................................. 17 
1.1 
Background ........................................................................... 17 
1.1.1 
Influenza in the Immunodeficient Population ......................... 17 
1.1.2 
Oseltamivir............................................................................. 19 
1.2 
Rationale for the Study .......................................................... 22 
2. 
OBJECTIVES.............................................................................................. 22 
2.1 
Primary Objective .................................................................. 22 
2.2 
Secondary Objectives............................................................ 22 
3. 
STUDY DESIGN ......................................................................................... 23 
3.1 
Overview of Study Design and Dosing Regimen................... 23 
3.1.1 
Rationale for Study Design.................................................... 23 
3.1.1.1 
Choice of Treatment Arms..................................................... 23 
3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours ................ 24 
3.1.1.3 
Rational for Sparse PK Sampling .......................................... 24 
3.1.1.4 
Interpretation of Study Results .............................................. 25 
3.1.2 
Rationale for Dose Selection and Adjustment ....................... 25 
3.1.3 
End of Study.......................................................................... 27 
3.2 
Number of patients/Assignment to Treatment 
Groups................................................................................... 27 
3.3 
Centers.................................................................................. 27 
4. 
STUDY POPULATION................................................................................ 27 
4.1 
Overview................................................................................ 27 
4.2 
Inclusion Criteria.................................................................... 27 
4.3 
Exclusion Criteria................................................................... 28 
4.4 
Concomitant Medication and Treatment................................ 29 
4.5 
Criteria for Premature Withdrawal ......................................... 29 
4.6 
Replacement Policy [Ensuring Adequate 
Numbers of Evaluable Patients] ............................................ 30 
4.6.1 
For Patients ........................................................................... 30 
4.6.2 
For Centers............................................................................ 30 
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TABLE OF CONTENTS (cont.) 
5. 
SCHEDULE OF ASSESSMENTS AND PROCEDURES............................ 31 
5.1 
Screening Examination and Eligibility Screening 
Form ...................................................................................... 32 
5.2 
Procedures for Enrollment of Eligible Patients....................... 33 
5.3 
Clinical Assessments and Procedures .................................. 33 
5.3.1 
Safety .................................................................................... 35 
5.3.2 
Efficacy Assessments............................................................ 35 
5.4 
Laboratory Assessments ....................................................... 36 
5.5 
Pharmacokinetic 
Assessments/Pharmacodynamic Assessments .................... 36 
5.5.1 
Pharmacokinetic Assessments.............................................. 37 
5.5.2 
Pharmacodynamic Assessments........................................... 37 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT............................................. 37 
6.1 
Dose and Schedule of Study Drug ........................................ 38 
6.1.1 
Dose Modifications ................................................................ 38 
6.2 
Preparation and Administration of Study Drug....................... 39 
6.3 
Blinding and Unblinding......................................................... 39 
6.4 
Assessment of Compliance ................................................... 40 
6.5 
Destruction of Study Drug...................................................... 40 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE.............................................. 41 
7.1 
Adverse Events and Laboratory Abnormalities...................... 41 
7.1.1 
Clinical AEs ........................................................................... 41 
7.1.1.1 
Intensity ................................................................................. 41 
7.1.1.2 
Drug - Adverse Event Relationship........................................ 41 
7.1.1.3 
Serious Adverse Events [Immediately Reportable 
to Roche] ............................................................................... 42 
7.1.2 
Treatment and Follow-up of AEs ........................................... 42 
7.1.3 
Laboratory Test Abnormalities............................................... 42 
7.1.4 
Follow-up of Abnormal Laboratory Test Values..................... 43 
7.2 
Handling of Safety Parameters.............................................. 43 
7.2.1 
Reporting of Serious Adverse Events 
[Immediately Reportable]....................................................... 43 
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TABLE OF CONTENTS (cont.) 
7.2.2 
Pregnancy ............................................................................. 43 
7.3 
Warnings and Precautions..................................................... 44 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................. 44 
8.1 
Primary and Secondary Study Endpoints .............................. 44 
8.1.1 
Primary Endpoints ................................................................. 44 
8.1.2 
Secondary Endpoints ............................................................ 44 
8.2 
Statistical and Analytical Methods ......................................... 45 
8.2.1 
Statistical Model .................................................................... 45 
8.2.1.1 
Time to Event Variables......................................................... 45 
8.2.1.2 
Dichotomous Variables and Viral Load.................................. 46 
8.2.2 
Sample Size .......................................................................... 46 
8.2.3 
Hypothesis Testing ................................................................ 46 
8.2.4 
Analysis Populations ............................................................. 46 
8.2.4.1 
Intent to Treat Population ...................................................... 47 
8.2.4.2 
Intent to Treat Infected Population......................................... 47 
8.2.4.3 
Pharmacokinetic Evaluable Patient Population ..................... 47 
8.2.4.4 
Subpopulations...................................................................... 47 
8.2.5 
Safety Data Analysis ............................................................. 47 
8.2.6 
Analysis of Resistance........................................................... 48 
8.2.7 
Efficacy Analysis.................................................................... 48 
8.2.7.1 
Exclusion of Data from Analysis ............................................ 48 
8.2.7.2 
Interim Analysis ..................................................................... 48 
8.2.8 
Other Analyses...................................................................... 49 
8.3 
Pharmacokinetic and Pharmacodynamic Analysis ................ 49 
8.3.1 
Pharmacokinetic Analysis...................................................... 49 
8.3.2 
Pharmacokinetic/Pharmacodynamic Analysis ....................... 49 
9. 
DATA QUALITY ASSURANCE................................................................... 49 
9.1 
Assignment of Preferred Terms and Original 
Terminology........................................................................... 50 
10. REFERENCES ........................................................................................... 51 
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TABLE OF CONTENTS (cont.) 
11. ETHICAL ASPECTS ................................................................................... 54 
11.1 
Local Regulations/Declaration of Helsinki.............................. 54 
11.2 
Informed Consent .................................................................. 54 
11.3 
Independent Ethics Committees/Institutional 
Review Board ........................................................................ 55 
12. CONDITIONS FOR MODIFYING THE PROTOCOL................................... 55 
13. CONDITIONS FOR TERMINATING THE STUDY ...................................... 55 
14. STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING................. 56 
14.1 
Investigator's Files/Retention of Documents.......................... 56 
14.2 
Source Documents and Background Data............................. 56 
14.3 
Audits and Inspections .......................................................... 57 
14.4 
Case Report Forms ............................................................... 57 
15. MONITORING THE STUDY ....................................................................... 57 
16. CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS.................................................................................................. 57 
17. PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS................................................................................................... 58 
 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments........................................................... 31 
 
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LIST OF APPENDICES 
Appendix 1 
Calculation of Creatinine Clearance and Grading of Chronic 
Extensive GVHD......................................................................... 59 
Appendix 2 
Patient Diary Data and Symptom Record for Adults ................... 61 
Appendix 3 
Patient Diary Data and Symptom Record for Children................ 62 
Appendix 4 
Adverse Event [AE] Categories for Determining Relationship 
to Test Drug ................................................................................ 63 
Appendix 5 
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 .... 65 
Appendix 6 
Primary Immunodeficiency Conditions........................................ 67 
Appendix 7 
Hematologic Malignancies and their Effect on the Immune 
System........................................................................................ 68 
Appendix 8 
Immunosuppressive Medications................................................ 69 
Appendix 9 
Child-Pugh Classification of Severity of Liver Disease................ 70 
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PROTOCOL SYNOPSIS 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, MULTI-CENTER 
TRIAL EVALUATING CONVENTIONAL AND DOUBLE DOSE 
OSELTAMIVIR IN THE TREATMENT OF IMMUNOCOMPROMISED 
PATIENTS WITH INFLUENZA 
PROTOCOL NUMBER: 
NV20234 
VERSION NUMBER: 
F 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
oseltamivir (Tamiflu® RO 64-0796) 
TEST PRODUCT: 
PHASE: 
IIIb 
INDICATION: 
Treatment of influenza in immunocompromised patients 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary 
To evaluate prospectively the safety and tolerability of oseltamivir for the treatment of influenza 
in immunocompromised patients and characterize the effects of oseltamivir in 
immunocompromised patients on the development of resistant influenza virus 
Secondary 
To evaluate the effects of conventional and double dose oseltamivir in immunocompromised 
patients on: 
• 
The population pharmacokinetics of both oseltamivir and oseltamivir carboxylate in 
immunocompromised patients with confirmed influenza infection, through the application of 
established population pharmacokinetic (PK) models to the sparse plasma concentration 
data generated. 
• 
The virologic course of influenza (proportion shedding and viral loads at different timepoints) 
• 
The time to resolution of influenza symptoms 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced by 
otitis media, bronchitis, pneumonia, or sinusitis)  
• 
To explore the relationship of metrics of exposure (e.g., AUC, Cmin) to relevant 
pharmacodynamic  endpoints 
 
Study Design 
Description of Study 
This is a double-blind, randomized, multi-center trial of twice daily, conventional and double 
dose oseltamivir for the treatment of influenza in immunocompromised patients.  Patients will be 
stratified by age (≤ 12, > 12 years), transplant status (yes, no), time since onset of flu symptoms 
and treatment start (up to 96 hours) (≤ 48 or > 48 hours) and vaccination status (yes, no) 
Number of Patients 
A minimum of 166 (83 per arm) to allow an adequate number of influenza A patients per arm; 
including 50 transplant recipients and at least 15 pediatric patients.   
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Number of Centers 
Approximately 125 centers in the Northern and Southern Hemispheres 
Target Population 
Patients immunocompromised due to a primary or secondary immunodeficiency, 1 year of age 
and older (the pediatric and adolescent patients will be defined as 1 year to less than 18 years 
of age).  The patients will be positive for influenza by a rapid diagnostic test, PCR or virus 
culture at baseline. 
Length of Study 
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 days 
later as shown in the schedule of assessments.  Study medication will be administered twice 
daily over 10 days for a total of 20 doses.  A rapid diagnostic test for influenza will be performed 
at the end of the 10 days of treatment.  Patients still having influenza based on the rapid 
diagnostic test will be treated per the local standard of care by the principal investigator, and 
any medication provided during the follow-up period should be captured in the CRF.   
Procedures (summary) 
The key procedures are: 
• 
Blood draws for serum chemistry, hematology, serology, and PK assessments (for those 
patients who provide additional consent to participate in the PK assessments). 
• 
Nasal and throat swabs for viral culture and RT-PCR. 
 
Assessments of: 
Safety 
The safety laboratory assessments in this study, including the assessment of serum chemistry 
and hematology will be carried out at a central laboratory.  Serum chemistry assessments 
comprise AST, ALT, total bilirubin, urea and creatinine.  Hematology assessments include CBC 
and differential count.  The total volume of blood loss for laboratory assessments will be 
approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section16) will extend to any data generated from the 
assaying of these samples.  Biological samples taken from all patients may be infectious and 
will be classified as “diagnostic specimens” for dispatch purposes. 
When clinically indicated, the investigator may draw blood for serum creatinine to be assessed 
at the local laboratory during the study to calculate creatinine clearance 
Resistance 
Development of resistance 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. These 
are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described in the 
Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR and viral 
cultures.  Influenza virus shedding will be assessed.   
At the end of treatment (Day 11), a rapid diagnostic test is permitted for the diagnosis of 
ongoing influenza. 
Investigational Medicinal Products 
Test Product: 
Oseltamivir/placebo dry powder (to be reconstituted to a concentration of 12 mg/mL or 6 mg/mL 
[the 6 mg/mL will only be used if applicable and not before 2015]) and 75 mg capsules.  The 
duration of dosing in both adults and children is 10 days. 
 


 
Conventional dose: 
Children ages 1 −12 years:  Oseltamivir syrup 
≤ 15 kg   
 
30 mg twice daily 
> 15–23 kg   
45 mg twice daily 
> 23–40 kg 
 
60 mg twice daily 
> 40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules 75 mg twice daily 
 
Patients randomized to the conventional dose will simultaneously receive matching placebo so 
as to blind them and the investigator from the double dose arm.  
 
Double dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg   
 
60 mg twice daily 
> 15–23 kg   
90 mg twice daily 
> 23–40 kg 
 
120 mg twice daily 
> 40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Comparator: 
Placebo (from pivotal registration trials in otherwise healthy adults) 
Statistical Methods 
The sample size has been chosen to provide an adequate number of patients to estimate the 
development of resistance with reasonable precision.  Assuming that 90% of enrolled patients 
will have laboratory-confirmed influenza, there will be 75 patients in each treatment arm in the 
population evaluable for the development of resistance.  The following table shows the 95% 
Pearson-Clopper confidence intervals that would result with a sample size of 75 patients in a 
treatment arm if certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of development 
of resistance will be monitored in a blinded fashion, in order to ensure a reasonable precision 
for the estimation is maintained.  Additional patients may be enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0%−4.8% 
0.0 
0.0%−7.2% 
1.3 
0.3%−9.3% 
2.7  
1.5%−13.1% 
5.3 
4.7%−19.9% 
10.7 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of safety.  
This number of patients would provide estimates of adverse event rates with similar precision. 
For the primary objective of evaluating the safety of oseltamivir conventional and double dose 
treatments, AEs, physical examinations, tissue rejection and/or graft versus host disease in 
transplant patients, laboratory tests, and vital signs will be summarized and compared with the 
known safety profile of the drug.  For the summary of the development of resistance for each 
treatment arm, 95% confidence intervals will be provided with the estimated rates.   
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For the secondary objective of evaluating the efficacy of oseltamivir as measured by the time to 
resolution of influenza symptoms, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is comparable 
to patients in the current study whose first dose of study drug was within 48 hours of 
symptom onset.  For this population, a median time to resolution of all clinical influenza 
symptoms will be determined along with its 95% confidence interval. 
 
• 
Assessment of relative efficacy 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence 
interval. 
The following are the model-derived PK secondary endpoints for oseltamivir and 
oseltamivir carboxylate: steady-state AUC, Cmax, and Ctrough. 
 
 
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GLOSSARY OF ABBREVIATIONS 
AIDS 
Acquired immunodeficiency syndrome 
ALT [SGPT] 
Alanine aminotransferase 
ALL 
Acute lymphocytic leukemia 
AML 
Acute myeloid leukemia 
ANOVA 
Analysis of variance 
AST [SGOT] 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUC0-12 
Steady-state area under the concentration–time curve from 0 to 
12 hours 
BID 
Bis in die (twice daily) 
BP 
Blood pressure 
CARIFS 
Canadian Acute Respiratory Infections Scale 
CDC 
Centers for Disease Control and Prevention 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Clast 
Last measurable concentration 
CLm 
Apparent total clearance of metabolite 
Cmax 
Maximum plasma concentration 
CML 
Chronic myeloid leukemia 
CrCl 
Creatinine clearance 
CRF 
Case report form[s] 
Ctrough 
Trough plasma concentration 
ESF 
Eligibility screening form 
GVHD 
Graft versus host disease 
HA 
Hemagglutinin 
HIV 
Human immunodeficiency virus 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ITT 
Intent to treat 
ITTI 
Intent to treat influenza infected 
IVRS 
Interactive voice response system 
ke 
Elimination constant 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PKEP 
Pharmacokinetic Evaluable Patient Population 
p.o. 
Per os (by mouth) 
QD 
Once per day 
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GLOSSARY OF ABBREVIATIONS 
RIDT 
Rapid Influenza Diagnostic Test 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCID 
Severe combined immunodeficiency 
SOT 
Solid organ transplant 
TCID50 
50% tissue culture infectious dose 
Time to last measurable concentration 
tlast 
tmax 
Time to maximum plasma concentration 
t1/2 
Elimination half-life 
Vc/F 
Apparent volume of distribution 
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PART I: STUDY DESIGN AND CONDUCT 
1. 
BACKGROUND AND RATIONALE 
1.1 
BACKGROUND 
Influenza is an acute respiratory infection caused by a virus of the orthomyxovirus family 
which occurs in three forms, influenza A, B, and C.  Influenza virus types A and B cause 
an acute febrile infection of the respiratory tract characterized by the sudden onset of 
fever, malaise, headaches, myalgias and cough.  Influenza causes numerous deaths 
each year [1].  Although difficult to assess, annual influenza epidemics are thought to 
result in between three and five million cases of severe illness and between 250,000 and 
500,000 deaths every year around the world [2]. 
The influenza viruses are segmented, negative sense, single stranded, lipid 
encapsulated, RNA viruses between 80 and 100 nm in size.  Subtypes are defined 
according to glycoproteins present in the viral lipid coat.  The hemagglutinin complex 
(HA) is the major surface protein of the virus.  The neuraminidase (NA) proteins are the 
second major surface proteins in the virion and play a role in enhancing virus penetration 
of the mucus layer around the target cell and in release of virus from the cell surface.  
The M2 protein triggers the disintegration of the virion during virus entry into the cell and 
may also be involved in protecting the HA prior to assembly of new virus particles.  
1.1.1 
Influenza in the Immunodeficient Population 
Influenza infection is usually a self−limiting condition.  However, in children, the elderly, 
and the immunocompromised, influenza infection can be associated with substantial 
morbidity and mortality [1].  In patients with compromised immunity, influenza virus may 
cause severe lower respiratory tract involvement; unusual syndromes, including 
encephalitis, myocarditis, and hepatitis; and death [3].   
Conditions that compromise immunity may be classified based on etiology into primary 
(genetic) and secondary (acquired) immunodeficiency.  Of the immunodeficient 
conditions, the ones that affect cell mediated immunity are likely to have adverse 
outcomes following viral infections [16]. 
Primary immunodeficiency  
Primary immunodeficiencies are relatively common, may be either congenital or manifest 
later in life, and are classified according to whether the genetic defect affects T or B cells 
or both [16].  There are four groups of disorders:  severe combined immunodeficiency 
(SCID), primary T cell deficiency (e.g., CD8 deficiency, DiGeorge syndrome), 
predominantly B-cell-related antibody deficiency (e.g., common variable 
immunodeficiency, selective IgA deficiency), and other well-defined immunodeficiency 
syndromes (e.g., Wiskott Aldrich syndrome) [16].  
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Of the primary immunodeficiencies, antibody deficiencies are the most frequent.  
However, some of the more common antibody deficiency conditions (isolated IgA 
deficiency, IgG subclass deficiency, and common variable immunodeficiency) have 
intact cell-mediated immunity and therefore the clinical course of viral infections (unless 
complicated by bacterial infections) does not differ significantly from that in the normal 
host [16].  A list of primary immunodeficiency disorders at risk for viral infections is 
provided in Appendix 6.  The incidence of some of these conditions has been estimated.  
The incidence of SCID is 1 in 100,000 to 1 in 1,000,000 [16].  The more severe forms of 
primary immunodeficiency are relatively rare, have their onset early in life, and all too 
frequently result in death during childhood [16].  
Secondary Immunodeficiency 
Secondary immunodeficiencies are not caused by intrinsic abnormalities in development 
of T and B cells [16].  Secondary immunodeficiency may result from diseases (human 
immunodeficiency virus [HIV], hematologic malignancy) or immunosuppressive and 
cytotoxic drugs (such as those used for treatment of transplant recipients, collagen 
vascular disease, malignancies).  
Secondary immunodeficiency due to disease 
HIV-infected individuals with a CD4+ T-cell count of < 200/mm3 (AIDS defining) are 
highly susceptible to opportunistic disease [16].  However, CD4 counts < 500/mm3 are 
considered abnormal in HIV-infected individuals, and therefore these individuals are 
also more susceptible to infection.  CD4+ T-cell counts are higher in infants and young 
children than in adults and decline over the first few years of life [40, 41].  Because of 
this age-dependent variation in absolute CD4+ T-cell count, calculation of CD4 
percentage is used as a measure for young children because it has shown less 
variability.  HIV-infected children (12 months to 5 years old) with < 15% CD4+ T cells are 
classed as severely immunosuppressed and highly susceptible to opportunistic disease, 
although antiretroviral therapy is recommended in children with < 25% CD4+ T cells as 
they are still classified as immunosuppressed [42].  Studies in patients with HIV/AIDS 
have shown an increased risk for heart and lung-related hospitalizations during the 
influenza season compared with other times of the year, prolonged duration of influenza 
symptoms, increased risk for influenza-related complications, and a higher risk of 
influenza-related death [17]. 
Several hematologic malignancies affect the immune system (Appendix 7).  Several 
authors have reported influenza in children and adults with hematologic malignancies 
[18, 19, 20, 21].  
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Secondary immunodeficiency due to drugs (e.g., transplant recipients, collagen 
vascular disease, malignancies) 
The enhanced survival of the transplant population following the availability of newer 
immunosuppressive drugs has made them representative of the immunocompromised 
population in general and secondary immunodeficiency due to drugs, in particular. 
In transplant recipients, influenza is associated with a higher rate of pulmonary 
complications, extrapulmonary manifestations, and an increased risk of graft dysfunction 
and high attributable mortality.  In a cohort study of influenza viral infection in solid organ 
transplant (SOT) patients, 30 cases of influenza viral infection were identified.  
Secondary bacterial pneumonia was seen in 17% of patients and three SOT recipients 
(2 liver and 1 kidney) had myositis, myocarditis, and bronchiolitis obliterans.  Biopsy of 
the transplanted organ was performed in 21 of 30 cases and revealed variable degrees 
of acute allograft rejection in 62% of patients.  The study concluded that influenza was 
associated with significant morbidity in different groups of SOT recipients [4]. 
Among transplant recipients, patients with hematopoietic stem cell transplant (HSCT) 
are at the greatest risk for morbidity.  In a prospective study from the Infectious Diseases 
Working Party of the European Group for Blood and Marrow Transplantation, 
1973 patients were evaluated for respiratory virus infections after stem cell 
transplantation.  The overall mortality was 23% from influenza A infection and the direct 
influenza A-associated mortality was 15.3% in this study [5].  A large retrospective study 
(4797 patients undergoing HSCT over a 13-year period) identified 62 patients with 
influenza of whom as many as 29% (18 of 62 patients) developed pneumonia.  Ten 
percent of the patients with influenza died [6].  
The increased morbidity in transplant patients is associated with increased duration of 
virus shedding compared to that in healthy subjects.  In otherwise healthy adults, elderly 
patients and children, the median duration of viral shedding in untreated patients was 70, 
96, and 118 hours, respectively [7].  In contrast, in the retrospective HSCT study, 
influenza virus was shed in nasopharyngeal secretions (evaluated at least weekly) for a 
median duration of 168 hours (7 days, range 2 to 37 days) [6]. 
Currently available treatments for influenza infection are the M2 ion channel inhibitors 
(e.g., amantadine, rimantadine) and the neuraminidase inhibitors (e.g., oseltamivir, 
zanamivir).  
1.1.2 
Oseltamivir 
Oseltamivir (Tamiflu®, Ro 64-0796) is an ethyl ester prodrug that is rapidly absorbed 
from the gastrointestinal tract after oral administration and metabolized in the liver by 
high capacity carboxylesterases to form oseltamivir carboxylate (Ro 64-0802), a potent, 
stable, and selective inhibitor of influenza A and B neuraminidase enzymes.  The active 
form, oseltamivir carboxylate is excreted unchanged by the kidney via glomerular 
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filtration and active tubular secretion by the organic anion transport system.  The efficacy 
and safety of oseltamivir in influenza treatment and prevention has been established in 
an extensive series of clinical studies in man. 
Oseltamivir has been approved for the treatment of influenza in Europe, the 
United States and most other countries around the world.  In adults and adolescents, the 
recommended dose is 75 mg twice daily for 5 days.  In children 1 year of age and older, 
recommended doses are 30, 45, or 60 mg BID based on body weight.  In all age groups, 
the recommended dose is administered BID for 5 days.   
The approval of oseltamivir for the treatment of influenza is based on several controlled 
clinical trials.  In the pooled population from these clinical trials encompassing adults 
aged from 13−97 years, many with significant co-morbidity, 1325 patients were treated 
with oseltamivir (75 mg BID) and 1056 patients received placebo.  A total of seven 
influenza symptoms (both respiratory and constitutional) were captured on the diary card 
for adults.  The time to resolution of all symptoms (on the diary card) decreased by 
24 hours; from 124.5 hours in the placebo arm to 100.6 hours with oseltamivir 
75 mg BID (p < 0.0001) [7].  Further, in adults and adolescents with a proven influenza 
illness, oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% and 
the incidence of influenza-related lower respiratory tract complications resulting in 
antibiotic therapy by 55%.  The study concluded that oseltamivir treatment of influenza 
reduces lower respiratory tract complications, antibiotic use, and hospitalizations in 
healthy and ‘at risk’ patients [8].   
Likewise, in the influenza-infected pediatric population (1−12 years of age), oseltamivir 
treatment (n = 217) was compared with placebo (n = 235).  There was a reduction in the 
median duration of illness (defined based on resolution of temperature, cough, coryza 
and return to pre-illness health and activity) of 36 hours; from 137 hours with placebo to 
101 hours in the oseltamivir treatment arm (p ≤ 0.0001).  The Canadian Acute 
Respiratory Infections Scale (CARIFS), validated for use in children, was used to collect 
symptom data on the pediatric diary card.  The CARIFS scale comprised a total of 
18 symptoms that were evaluated twice daily by the parent or guardian.  There was a 
similar reduction in the time to alleviation of all CARIFS symptoms of 36 hours; from 
100 hours in the placebo group to 63 hours in the oseltamivir group (p < 0.0001) [9].  
Thus in both adults and children, the time to resolution of all symptoms was significantly 
reduced in the oseltamivir treatment arm compared with placebo.   
Oseltamivir was well-tolerated in clinical trials.  Approximately 11,000 patients have 
received oseltamivir in the development program.  The most common adverse events 
reported by adults, the elderly, and children were nausea and vomiting.  Serious adverse 
events (SAEs) were reported with a low and equal frequency by patients taking active 
drug and placebo.  Full details are given in the Investigator Brochure [7]. 
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The safety profile of oseltamivir has been well characterized for the prophylaxis 
indication in a prospective randomized placebo controlled trial conducted in the adult 
and pediatric immunocompromised (HSCT and SOT) population.  In the oseltamivir 
group, the indications for transplant included hematologic malignancies (acute and 
chronic leukemias, multiple myeloma, and myelodysplastic syndrome), lymphoid 
malignancies (Hodgkin’s or non-Hodgkin’s lymphomas), primary immunodeficiencies 
(Wiskott-Aldrich syndrome, X-linked lymphoproliferative disease, and severe combined 
immunodeficiency).  Other rare indications included bone marrow aplasia, paroxysmal 
nocturnal hemoglobinuria, myelofibrosis, and multiple sclerosis.  In the safety population, 
there were 239 patients randomized to the conventional dose of oseltamivir and 238 to 
placebo.  The total number of adverse events reported in the placebo group (361 events) 
was generally similar to that in the oseltamivir group (323 events).  Diarrhea was the 
most frequently reported adverse event (placebo, 8%; oseltamivir, 6%).  There were no 
deaths in the oseltamivir group.  Oseltamivir was found to be safe in immunosuppressed 
transplant recipients [22]. 
Limited safety and/or efficacy of oseltamivir for the treatment indication is available from 
several case reports in children and adolescents.  Oseltamivir was shown to be safe 
and/or effective in HIV infected children (n = 10) [23], children (ages 3 to 12 years) with 
acute lymphocytic leukemia (ALL) (n = 10) [21], in a nosocomial H1N1 outbreak in a 
pediatric (children aged 10 months to 13 years) oncology ward (n = 8) [20], in children 
and adolescents (ages 2 to 19 years) with malignancies (ALL, neuroblastoma, brain 
tumor, non-Hodgkin’s lymphoma, osteosarcoma, Ewing sarcoma, myelodysplasia, acute 
myeloid leukemia (AML), Wilms tumor, aplastic anemia, chronic myeloid leukemia (CML), 
and acute promyelocytic leukemia) (n = 51) [18], in children aged 4 to 14 years on 
immunosuppressive drugs (n = 5) [24], and in children (aged 5 months to 5 years) with 
bone marrow transplant (n = 3) [25].  
Oseltamivir has also been shown to be safe and/or effective in mixed populations of 
children and adults (62 patients) with HSCT [6] and in a large epidemiologic study 
(n = 221) with SOT [26].  
Finally, oseltamivir has been shown to be safe and/or effective in immunocompromised 
adults with HSCT [10] and adults with lung transplant [27, 28, 29].  
The dose of oseltamivir was the same as the conventional dose in a majority of these 
reports.  In one report, as many as 25 adult patients received twice the conventional 
dose [26] while in another report three of nine adult patients received twice the 
conventional dose [29].  Treatment with oseltamivir generally ranged from 5 to 10 days 
[28, 29, 26] and occasionally until the patient was symptom free [28, 29].  In exceptional 
cases treatment was given for as long as 20 days [18] or for as long as the patient was 
positive by RT-PCR [21]. 
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There is some concern about the development of resistance in the immunocompromised 
population.  During the pandemic influenza season, more than 23,000 clinical isolates of 
novel H1N1 pandemic virus were tested for resistance in the 6 international WHO 
regions.  A total of 225 isolates (from 225 patients) were resistant (H275Y mutation in 
the neuraminidase coding sequence) to oseltamivir for an approximate incidence of 1%.  
Information on immune status was available for 142 of 225 patients.  Among the 
142 patients, 56 (40%) were immunocompromised [30].  Prolonged viral replication and 
lack of immune-mediated virus clearance in immunosuppressed patients treated with 
antivirals can result in a higher incidence of selection of drug-resistant viruses, a 
phenomenon that has been documented previously [31, 32].  
1.2 
RATIONALE FOR THE STUDY  
Because of the increasing body of evidence (Section 1.1.2), oseltamivir is recommended 
in national guidelines as an option for the treatment of influenza in the transplant 
population [37], which comprises a significant portion of the immunocompromised 
population.  However, there is limited data on safety and efficacy of oseltamivir use in 
this population.  The primary objective of this study is to evaluate safety and resistance, 
while evaluating efficacy as a secondary objective, in the broader immunocompromised 
patient population, who are considered at increased risk of viral infection. 
2. 
OBJECTIVES  
2.1 
PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate prospectively the safety and tolerability 
of oseltamivir for the treatment of influenza in immunocompromised patients and 
characterize the effects of oseltamivir in immunocompromised patients on the 
development of resistant influenza virus. 
2.2 
SECONDARY OBJECTIVES 
The secondary objectives of the study are:  
To evaluate the effects of conventional and double dose oseltamivir in 
immunocompromised patients on: 
• 
The population pharmacokinetics of oseltamivir and oseltamivir carboxylate in 
immunocompromised patients with confirmed influenza infection, through the 
application of established population pharmacokinetic (PK) models to the sparse 
plasma concentration data generated  
• 
The virologic course of influenza (proportion shedding and viral loads at different 
timepoints) 
• 
The time to resolution of influenza symptoms 
• 
The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced 
by otitis media, bronchitis, pneumonia, or sinusitis)  
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• 
To explore the relationship of metrics of exposure (e.g., AUC, Cmin) to relevant 
pharmacodynamic (PD) endpoints 
 
3. 
STUDY DESIGN 
3.1 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN 
This is a double blind, randomized, stratified, multi-center trial of conventional and 
double dose oseltamivir for the treatment of influenza in immunocompromised patients.  
Immunocompromised patients, who develop an influenza-like illness with a positive rapid 
diagnostic test, PCR, or viral culture for influenza, will be enrolled during the influenza 
season.  Patients will be stratified by transplant status [yes, no], the time between onset 
of influenza symptoms and treatment start (up to 96 hours) [≤ 48 hours; > 48 hours], 
influenza vaccination status for current influenza season [yes; no] and by age 
[≤ 12 years; > 12 years].  Eligible patients will be consented and randomized to receive 
oseltamivir twice daily for 10 days in one of two treatment arms:  conventional dose or 
double dose (double the conventional dose).  
3.1.1 
Rationale for Study Design 
This study incorporates several features that distinguish it from classic placebo 
controlled trials.  
There is no placebo control arm in this study as it was considered unethical for this high 
risk population.  The development of resistance following treatment with oseltamivir (one 
of the primary objectives of the study) is an objective assessment (determined by 
laboratory tests) and is unlikely to be impacted by the absence of a placebo arm.  
As a placebo control arm was considered unethical in this population, an alternative 
control arm had to be identified for efficacy endpoints.  The response to placebo in 
pivotal oseltamivir registration trials in the healthy adult population with influenza was 
chosen as a control in lieu of a placebo arm in the current trial.  In order to do this, the 
endpoints were designed to be similar to that in the pivotal registration trials.  
The following sections provide rationale and justification for specific aspects of the study 
design that differ from the currently approved dosing for influenza or from previous 
pivotal registration trials.  They also provide information on how the results will be used 
to make recommendations on dose and duration of treatment. 
3.1.1.1 
Choice of Treatment Arms 
The currently approved dose of oseltamivir for the treatment indication is the 
conventional dose with a duration of 5 days.  In this study a conventional and double 
dose are being evaluated.  The pivotal registration trials for oseltamivir in healthy adults 
with influenza had three treatment arms; two active (75 mg and 150 mg) and one 
placebo.  Both treatment arms were found to be significantly better than placebo.  No 
statistical comparisons were made between the two active treatment arms.  Evaluation 
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of the results in the two active treatment arms did not reveal any clinically meaningful 
difference.  However, the proportion of patients shedding virus on Day 4 (3 days after 
the start of treatment), suggested a possible dose-response relationship (36%, 28%, and 
23% in the placebo, 75 mg, and 150 mg dose arms, respectively).  Because defective 
immune-mediated virus clearance in immunosuppressed patients treated with antivirals 
can result in a higher incidence of selection of drug-resistant viruses, it was decided to 
use both the conventional and double dose arm for this study.  A longer duration of 
treatment was chosen because a large retrospective study has shown that the median 
duration of viral shedding of 7 days [6] was greater for HSCT recipients than that seen in 
the healthy children, adult, and elderly population with influenza (Section 1.1.1) [7].  
3.1.1.2 
Inclusion of Patients Symptomatic up to 96 Hours 
In immunocompromised patients, time from onset of symptoms to seeking medical 
attention (presentation at the clinic) of > 48 hours has been shown in several case 
reports [33, 27, 28, 29] including two instances of nosocomial outbreaks in children 
[25, 20].  This notwithstanding, oseltamivir has been shown to offer benefit in 
immunocompromised populations that included patients treated with oseltamivir beyond 
48 hours of presentation; patients with lung transplant (median time to presentation 
3 days) [27], bone marrow transplant (treatment started more than 48 hours after onset 
of symptoms in all 3 patients) [25], organ transplant (62 of 221 patients started treatment 
after 96 hours) [26], and children with acute lymphocytic leukemia (one child presented 
after 3 days and two children presented after 5 days of symptoms) [21]. 
In a prospective, observational study involving adults hospitalized with influenza, the 
study authors concluded that ‘Weakened host defenses slow viral clearance, whereas 
antivirals started within the first four days of illness enhance viral clearance’ [34].  
Additionally, in November 2009, in a communication for clinicians on antiviral treatments 
for H1N1, the U.S. Centers for Disease Control and Prevention (CDC) stated that while 
antiviral treatment is most effective when started early; both outpatients with risk factors 
and hospitalized patients still benefit when treatment with oseltamivir is started more 
than 48 hours after illness onset [35].   
3.1.1.3 
Rational for Sparse PK Sampling 
Limited PK sampling will be done in this protocol, in patients who have provided 
additional consent, and is justifiable in this study for the following two reasons: 
• 
There are already tested and qualified population PK models available [36] that 
will be used to estimate exposure in the immunocompromised population on the 
basis of the data collected in this study, meaning extensive PK sampling over a 
steady-state dosing interval is not required.  
• 
The patient population in this study is likely to be very ill with a complex clinical 
picture and significant additional burden of treatment and monitoring due to their 
primary condition.  In this context, it makes ethical sense to minimize blood draws 
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and assessments to only those absolutely essential to meet the objectives of the 
study and to ensure patient safety. 
 
3.1.1.4 
Interpretation of Study Results  
Safety and tolerability and the development of resistance are the primary objectives of 
this study.  These will be characterized descriptively.  For the secondary objective of 
efficacy, the subset of the population enrolled in the first 48 hours will be compared with 
placebo patients from pivotal registration trials (where patients were enrolled in the first 
2 days of illness).  Section 8.2.5 , Section 8.2.6 , and Section 8.2.7 provide details on the 
statistical considerations. 
Stratification 
Stratification in this study has no bearing on any comparisons with results from previous 
trials.  However, in order to evaluate a dose response relationship between the two 
active treatment arms in this trial, stratification remains essential.  
Patients will be stratified by transplant status (yes, no) because transplant patients form 
a relatively large homogenous group in this study and might influence outcome.  
Patients will be stratified by time between onset of symptoms and treatment start 
(< 48 hours or ≥ 48 hours) because previous experience in otherwise healthy adults and 
children has shown that patients treated early in their illness respond to treatment better 
than those who are treated later.  Patients will also be stratified by age (≤ 12 years 
and > 12 years) because otherwise healthy children shed virus longer than otherwise 
healthy adults.  It is expected that a similar difference in the duration of viral shedding 
would exist between immunocompromised children and adults.  As vaccinated patients 
may respond faster to therapy, the study is also stratified based on influenza vaccination 
status for the current influenza season (yes; no).  
3.1.2 
Rationale for Dose Selection and Adjustment 
Dose Selection 
The dose of oseltamivir to be used in this study is the conventional, approved dose for 
children and adults in the treatment of influenza.  There will be a second higher dose for 
comparison, which is two times the conventional dose.  This higher dose is used based 
on theoretical considerations, which suggest that the higher dose may be associated 
with improved efficacy and decreased emergence of resistance.  
The anticipated pro-drug and metabolite exposures from this higher dose are not 
expected to exceed maximum exposures seen previously in the oseltamivir development 
program.  The safety and tolerability of the higher dose regimen has already been 
demonstrated in treatment studies of immunocompetent adult subjects (n = 447) [11].  
In a study to demonstrate cardiac safety, in the highest dose group treated with 
450 mg BID for 5 days [n = 99], no subject had a serious adverse event, nor withdrew 
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prematurely.  In Phase I studies in adults, oseltamivir has been administered in multiple 
doses of up to 500 mg BID.  Doses of 200 mg BID and greater have been associated 
with increased gastrointestinal adverse effects (nausea and vomiting) [7].  In adult 
subjects with creatinine clearances of ≤ 30 mL/min, doses of 100 mg BID for 6 days 
were well tolerated, despite steady-state oseltamivir carboxylate exposures 
approximately 10-fold higher than those achieved with standard dosing in renally 
competent individuals [12].  No other adverse effects were reported more frequently 
with higher doses and no serious adverse events have been reported within the 
volunteer studies.  Co-administration of oseltamivir with food has been demonstrated 
to substantially reduce the frequency and severity of gastrointestinal side effects.  
Thus, the rationale for the double dose arm in this study is to explore the possibility of 
improved efficacy and decreased emergence of resistance without an undue increase 
in risk.  For patients with a creatinine clearance level of 45 mL/min or above, oseltamivir 
carboxylate exposures for both the 75-mg and 150-mg doses are not expected to 
exceed exposures previously tested.  Patients with a creatinine clearance as low as 
45 mL/min, who receive the 150-mg BID dose, will have exposures of oseltamivir 
carboxylate that are within (albeit in the upper end) the established safety margin. This 
corresponds to an AUC produced by the 450-mg BID dose in adults with normal renal 
function (AUC 0-12 hrs of approximately 15,000 ng • hr/mL).  
Drug interactions with immunosuppressive medications have also been evaluated.  
The pharmacokinetics of oseltamivir and oseltamivir carboxylate after administration of 
75 mg oseltamivir (conventional adult dose) in patients with a well-functioning, stable 
renal allograft who were being maintained on immunosuppressive therapy were studied.  
These were similar to those described in the literature for adults with comparable 
degrees of renal function.  Oseltamivir was well tolerated and had no clinically relevant 
effect on the steady-state pharmacokinetics of cyclosporine A, tacrolimus, or 
mycophenolate mofetil [7]. 
Duration of Dosing 
The duration of dosing chosen for this population (10 days) is longer than that in the 
healthy adult and pediatric populations (5 days).  This is based on observations that the 
viral shedding and illness are typically longer in immunocompromised patients than it is 
in healthy adults [6, 10]. 
Dose Adjustments 
As this is a double blind study, patients whose creatinine clearance (CrCl) decreases to 
< 45mL/min (adults) using the Cockcroft-Gault method or <45 mL/min/1.73m2 (<18 years 
old) using the Schwartz equation will be discontinued from study treatment.  A lower limit 
of 45 mL/min for CrCl will be used to allow for patients with a mild to moderate renal 
impairment.  
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3.1.3 
End of Study 
The study comprises 10 days of treatment with follow-up visits approximately 5 and 
30 days later as shown in the schedule of assessments.  Study medication will be 
administered BID over 10 days for a total of 20 doses.  A rapid diagnostic test for 
influenza will be performed at the end of the 10 days of treatment.  Patients still having 
influenza based on the rapid diagnostic test will be treated per the local standard of care 
by the principal investigator, and any medication provided during the follow-up period 
should be captured in the CRF.  
3.2 
NUMBER OF PATIENTS/ASSIGNMENT TO TREATMENT 
GROUPS 
A minimum of 166 patients (approximately 83 per arm) to allow an adequate number of 
influenza A patients, including 50 transplant recipients and at least 15 pediatric patients, 
will be enrolled in this study.  After screening, patients will be randomly assigned to one 
of the two active treatment groups. 
3.3 
CENTERS 
This will be a multicenter study taking place in the Northern and Southern Hemispheres 
at approximately 125 centers.  
4. 
STUDY POPULATION 
4.1 
OVERVIEW 
The study population comprises immunocompromised adults (including adolescents) 
and children (pediatric) who have influenza (the pediatric and adolescent patients will 
be defined as 1 year to less than 18 years of age at randomization).  Additionally, the 
patients must not have other medical conditions that will preclude the assessment of 
efficacy or safety.  Influenza vaccinated and non-vaccinated patients are eligible to 
participate in this study.  Principal investigators will review oseltamivir resistance 
patterns of strains circulating in the area and weigh the risk versus the benefit before 
enrolling patients with a potentially resistant strain. 
Under no circumstances are patients who enroll in this study permitted to be 
re-randomized to this study and enrolled for a second course of treatment. 
4.2 
INCLUSION CRITERIA 
• 
Age greater than or equal to 1 year 
• 
Rapid diagnostic test, PCR, or viral culture positive for influenza 
• 
Immunocompromised patient defined as one who meets any of the following: 
o Primary immunodeficiency at risk for viral infections (representative 
examples in Appendix 6) OR 
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o Secondary immunodeficiency 
 
SOT with ongoing immunosuppression OR 
 
Allogenic HSCT with ongoing immunosuppression OR 
 
HIV with a most recent CD4 count < 500/mm3 (or < 25% in children 
≤  5 years old) within the last 6 months and, in the investigator’s 
opinion, considered immunocompromised OR 
 
Hematologic malignancies (representative examples in 
Appendix 7) OR 
 
Systemic (e.g., enteric, sc, im or iv) immunosuppressive therapy, 
irrespective of medical indication, started at least 12 weeks prior 
to, and ongoing at the time of first dose of study drug 
(representative examples in Appendix 8) 
 
• 
Symptoms suggestive of influenza like illness including, but not limited to fever, 
cough, or coryza 
• 
In patients with history or clinical presentation at randomization suggestive of renal 
failure; a CrCl > 60 mL/min (> 18 years old) or > 60 mL/min/1.73m2(< 18 years old) 
within the last 3 months 
• 
Less than or equal to 96 hours between onset of influenza-like illness and first dose 
of study drug 
• 
Parent/guardian willing and able to comply with study requirements and give 
consent (country specific age cut off) 
• 
Patient able to comply with study requirements and willing to give assent, as 
appropriate (country specific age cut off) 
• 
For adult patients willing and able to comprehend and give written informed consent  
• 
Patients, in the reproductive age group, must agree to utilize an effective method of 
contraception throughout the study period and for females for one reproductive 
cycle following cessation of study therapy 
• 
Females of childbearing potential must have a negative urine pregnancy test prior to 
start of study drug 
 
4.3 
EXCLUSION CRITERIA 
• 
Clinical evidence of severe hepatic impairment, defined as Child-Pugh grade C 
(score > 9) or decompensated cirrhosis (see Appendix 9) 
• 
Patients currently receiving any form of renal replacement therapy including 
hemodialysis, peritoneal dialysis or hemofiltration 
• 
Patients with gastrointestinal disorders that might interfere with their ability to absorb 
oral medication  
• 
Allergy to the test medication 
• 
Patients with hereditary fructose intolerance (for patients who will be taking the 
liquid formulation) 
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• 
Influenza vaccination with live attenuated vaccine in the 2 weeks prior to 
randomization 
• 
Antiviral treatment (example:  amantadine, rimantadine, oseltamivir, laninamivir, 
peramivir, zanamivir, and ribavirin) for influenza in the 2 weeks prior to 
randomization 
• 
Patients taking probenecid medication 
• 
Patients who are pregnant or breast-feeding   
• 
Participation in a clinical trial or expanded access trial with an investigational drug 
suspected/demonstrated to impact pathways important for the metabolism and 
excretion of oseltamivir in the 4 weeks prior to randomization or concomitantly with 
this study   
 
4.4 
CONCOMITANT MEDICATION AND TREATMENT 
Antiviral treatments with activity against influenza (e.g., amantadine, rimantadine, 
zanamivir, ribavirin, laninamivir, peramivir, and additional oseltamivir above that 
specified for this study) are not allowed during the 10-day treatment phase of the study.  
Concomitant use of an investigational drug during the study is also excluded if 
suspected/demonstrated to impact pathways important for the metabolism and excretion 
of oseltamivir.  Live attenuated vaccines may not be advisable for this population.  It is 
possible that concurrent use with oseltamivir may render live vaccines ineffective.  
Medications required for the routine care of the patient may be continued during the 
study.  Concomitant use of probenecid (irrespective of the indication) is not allowed 
during the study. 
4.5 
CRITERIA FOR PREMATURE WITHDRAWAL  
The investigator must discontinue treatment if the creatinine clearance is < 45 mL/min in 
adults using the Cockcroft-Gault method or < 45 mL/min/1.73 m2 using the Schwartz 
equation in children.  A lower limit of 45 mL/min for creatinine clearance will be used to 
allow for patients with a mild to moderate renal impairment.  The investigator must also 
discontinue treatment from all patients with intercurrent illnesses or adverse events 
suggestive of hepatic decompensation.  The investigator also has the right to 
discontinue treatment in the event of intercurrent illness, adverse events, treatment 
failure, protocol violations, administrative reasons, or other reasons. 
The investigator must discontinue treatment with study drug if the patient is to be treated 
concomitantly with another antiviral for influenza, for example, amantadine, rimantadine, 
laninamivir, peramivir, or zanamavir.  However, all patients, including those who 
discontinue study drug prematurely and/or are treated with another antiviral, will be 
required to return for follow-up approximately 5 and 30 days after the last dose of study 
drug (Day 15 and Day 40 assessments). 
Patients have the right to withdraw from the study at any time for any reason.  
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An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a patient decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
The investigator should contact the patient or a responsible relative either by telephone 
or through a personal visit to establish as completely as possible the reason for the 
withdrawal.  A complete final evaluation at the time of the patient’s withdrawal should be 
made with an explanation of why the patient is withdrawing from the study.  If the reason 
for removal of a patient from the study is an Adverse Event, the principal specific event 
will be recorded on the CRF. 
In the case that the patient decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further 
information.  The outcome of that discussion should be documented in both the medical 
records and in the CRF.  
4.6 
REPLACEMENT POLICY [ENSURING ADEQUATE NUMBERS 
OF EVALUABLE PATIENTS] 
4.6.1 
For Patients 
No patient prematurely discontinued from the study for any reason will be replaced. 
4.6.2 
For Centers 
A center may be replaced for the following administrative reasons:   
– 
Excessively slow recruitment 
– 
Poor protocol adherence 
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Table 1 
Schedule of Assessments (cont.)  
f. A home visit may be made on Day 2 or 3 (for patients who are too ill to come into the clinic) 
and/or, Day 6, and/or Day 8; however, it is recommended that the PK blood draw be 
performed at the clinic. 
g. Day 2/3 visit window = +1 day.  Day 6 visit window = ± 1 day; Day 8 visit window = +1 day.  
Day 11 visit window = ± 1 day.  Day 15 and Day 40 visit occur approximately 5 and 30 days 
after the last dose respectively.  Day 15 window = ± 1 day.  Day 40 window ± 2 days.  
h. Only weight to be assessed.  Height is not necessary at this visit.  Study drug is taken on 
Day 11, only if the first dose was taken after 4 p.m. on Day 1 [5.3] Patients who are rapid 
diagnostic positive can be treated per standard of care.  They will be required to come for their 
follow-up visits on Day 15 and Day 40.  
i. 
Patients who discontinue treatment prematurely will have an end of treatment (Day 11) 
assessment at the time of treatment discontinuation or the following day.  They will be 
required to attend their follow up visits approximately 5 and 30 days after the last dose 
(Day 15 and Day 40 assessments).  
j. 
Patients who discontinue during follow-up will have an end of follow-up (Day 40) assessment.  
This visit must occur within 30 days of the last dose.   
k. For patients who are unable to attend the clinic, swabs may be taken at home on those days 
where there is a home visit by site personnel. 
l. 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected from patients who give additional consent to participate in PK sampling using a 
sparse PK sampling approach (Section 5.5).  
m. Serial PK samples taken at steady-state no earlier than Day 6 (i.e., not before the 11th dose) 
consisting of as many of the four timepoints as possible:  within 30 minutes prior to the dose 
administration, 1.5 hours ± 30 minutes post dose, 4 hours ± 60 minutes post dose, and 
8 hours ± 1.5 hours post dose (for patients who have given additional consent). 
 
5.1 
SCREENING EXAMINATION AND ELIGIBILITY SCREENING 
FORM  
All patients must provide written informed consent (assent where applicable) before any 
study specific assessments or procedures are performed.  Screening will take place at 
the baseline visit prior to first dose.  However, if necessary, screening may take place 
the day before the baseline visit, as long as the patient is randomized and receives 
his/her first dose of study drug within 96 hours of influenza symptom onset. 
Patients will be assessed for inclusion and exclusion criteria and those who fulfill all the 
inclusion and none of the exclusion criteria will be randomized into the study.  Influenza 
Rapid Diagnostic test, PCR, or viral culture for the purposes of inclusion criteria 
fulfillment will be done by the site or the local laboratory.  Historical CrCl values within 
3 months and CD4+ T-cell counts (where applicable) within 6 months before 
randomization are acceptable for inclusion into the study.  
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An Eligibility Screening Form [ESF] documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator. 
A screen failure log must be maintained by the investigator.  
5.2 
PROCEDURES FOR ENROLLMENT OF ELIGIBLE PATIENTS  
Once a patient has fulfilled the entry criteria, he/she will be randomized to one of two 
treatment groups.  The patient randomization numbers will be generated by Roche or its 
designee and incorporated into double-blind labeling. 
The investigator or designee will use the CRF pre-printed with the assigned patient 
number and enter the randomization number provided by IVRS for allocation to the 
treatment groups in the appropriate place on each patient’s CRF. 
Randomization will be stratified by transplant status (Yes; No); time between onset of 
symptoms and treatment start (≤ 48 hrs or > 48 hrs), influenza vaccination status 
(Yes; No) and patient’s age (≤ 12 years or > 12 years).  
5.3 
CLINICAL ASSESSMENTS AND PROCEDURES 
At all visits patients will receive the routine care for their primary illness.  Routine patient 
care (including the adjustment of doses of any of the immunosuppressive drugs) will be 
dictated by tests performed locally at the trial site.  For patients unable to attend the 
clinic, provision will be made for swabbing to be conducted at home when there is a 
home visit scheduled.  Training will be provided to site staff on how to perform this.  All 
safety labs will be sent to a central laboratory.  Results for these laboratory parameters 
will be used by the sponsor/designee to assess overall safety. 
All assessments and procedures will be performed according to the Schedule of 
Assessments (Table 1).  Additional information regarding these procedures not provided 
in the Schedule of Assessments is provided below. 
Blood samples will be collected from patients who provide additional consent for PK 
sampling, as outlined in Section 5.5. 
Study Day 1 
The baseline and study Day 1 assessment may be performed at the same visit.  
Laboratory assessments (safety labs and nasal and throat swabs for virology) should be 
performed after randomization but prior to the patient receiving first dose of study drug. 
Study drug, patient diaries, and thermometers will be dispensed.  Patients or 
guardians/parents will be instructed on how to complete the patient diaries (Appendix 2 
and Appendix 3), temperature recording, and treatment administration details, including 
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time of each oseltamivir dose.  The first diary entries will be made at the site before the 
first dose of study drug.  
Baseline nasal and throat swab samples will be assessed for the presence of 
oseltamivir-resistance mutations.   
The date of the first dose of study drug is defined as study Day 1.  Once randomized, the 
first dose of study drug will be administered in the clinic.  Study Day 2 will begin at 
12 midnight of the same calendar day.  If the first dose of study drug is taken after 4 p.m. 
on Day 1, the next dose of study drug will be taken in the morning of Day 2.  In this case, 
the last dose of study drug will be taken on the morning of study Day 11.   
If the first dose of study drug is taken prior to 4 p.m. on Day 1, the next dose of study 
drug should be taken in the evening of the same day (i.e., prior to midnight on the same 
calendar day with a minimum of 7 hours between doses).  For these patients, the last 
dose of study drug will be taken in the evening of study Day 10.  More information on 
dosing is provided later (Section 6.1). 
Study Days 2−11 
Study Day 2 will begin at 12 midnight of study Day 1.  
It is expected the study staff will maintain close contact with patients, especially during 
the first few days of the study.  The study staff should inquire about any adverse events, 
check that the patient or parent/guardian is entering data into the patient diary properly, 
and assess drug compliance.  During the dosing period, diary symptoms should be 
assessed and temperature should be recorded at the same time that the study drug is 
taken.  
End of Treatment Day 11 
The end-of-treatment visit for all patients is on Day 11 (irrespective of whether they took 
one or two doses on Day 1).  Study medication will be administered twice daily over 
10 days for a total of 20 doses.  Patients who discontinue study drug prematurely will 
have all Day 11 assessments completed at the time of discontinuation or the following 
day.  
After all Day 11 study assessments are completed, a rapid diagnostic test will be 
performed at this visit.  If the rapid diagnostic test is positive, the patient may be treated 
per standard of care at the discretion of the investigator.  If treatment is provided, this 
should be captured in the CRF.  
All patients (including those who discontinue study drug prematurely and those who are 
positive for influenza on their rapid diagnostic test at the end of treatment visit) will be 
required to return for follow-up approximately 5 and 30 days after the last dose (Day 15 
and Day 40 assessments).    
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Study Days 12−40 
Study Day 15 is an important visit as it is the first assessment of viral culture after 
cessation of treatment.  It is therefore important that this visit is completed.  
End of Follow-Up Day 40  
All patients must attend an end of follow-up visit on Day 40.  
If the patient is withdrawn after completion of treatment (after the Day 11 assessment), 
a termination visit should be arranged.  This visit should be the end of follow-up visit 
assessment [Day 40].  This visit must occur within 30 days of the last dose.  
Patients or parents/guardians who do not return to the clinic will be contacted by 
telephone to ascertain their health status or that of their child’s, record information on 
adverse events, and to ask that they return the patient diary. 
5.3.1 
Safety 
Safety is one of the primary endpoints of this study. Safety parameters include adverse 
events, vital signs, and clinical laboratory evaluations.  
Pre-defined symptoms of influenza captured in the adult and pediatric diaries are not to 
be reported as adverse events unless they can be further qualified.  Thus ‘headache due 
to stress at work’ is reported as an adverse event.  However, unexplained ‘headache’ is 
considered a predefined symptom related to influenza and not an adverse event.  
Adverse events such as bronchitis, pneumonia, otitis media, and sinusitis are considered 
secondary illnesses of influenza and should be recorded as adverse events. 
Other adverse events to be expected in the transplant population such as rejection and 
graft versus host disease (in patients with HSCT) will also be collected as adverse 
events.  Nasal and throat swab samples will be assessed from each study visit for the 
presence of oseltamivir-resistant mutations. 
5.3.2 
Efficacy Assessments 
The clinical efficacy parameters in this study are: 
1. 
Symptoms of influenza-like illness.  These are captured in the patient diary for both 
adults and children (Appendix 2) and (Appendix 3).  Influenza symptoms are graded 
on a nominal scale from zero (absent/no problem) to 3 (severe or major problem).  
A score of zero is considered asymptomatic.  The efficacy endpoint, time to 
alleviation of all symptoms is comprised of all the symptoms captured in the patient 
diary.  
2. 
Temperature.  This is captured in the patient diary.  Temperature is used for 
assessment of several efficacy endpoints.  
 
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5.4 
LABORATORY ASSESSMENTS 
The laboratory assessments include those for safety, resistance, and efficacy. 
Safety 
The safety laboratory assessments in this study, including the assessment of serum 
chemistry and hematology, will be carried out at a central laboratory.  Serum chemistry 
assessments comprise AST, ALT, total bilirubin, urea, and creatinine.  Hematology 
assessments include CBC and differential count.  The total volume of blood loss for 
laboratory assessments will be approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section 16) will extend to any data generated from 
the assay of these samples.  Biological samples collected from all patients may be 
infectious and will be classified as “diagnostic specimens” for dispatch purposes. 
When clinically indicated, the investigator may draw blood for serum creatinine to be 
assessed at the local laboratory during the study to calculate creatinine clearance. 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. 
These are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described 
in the Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR 
and viral cultures.  Influenza virus shedding will be assessed.   
At the end of treatment (Day 11), a rapid diagnostic test is permitted for the diagnosis of 
ongoing influenza.  
5.5 
PHARMACOKINETIC ASSESSMENTS/PHARMACODYNAMIC 
ASSESSMENTS  
Participation in PK assessments is not compulsory for this study.  Blood samples for the 
characterization of oseltamivir and oseltamivir carboxylate pharmacokinetics using a 
sparse sampling strategy will be collected from all patients who provide additional 
consent to participate in the PK assessments. 
Blood samples will be collected according to the Schedule of Assessments (Table 1) and 
as described below.  If these blood samples are collected at a home visit, site staff 
should ensure the PK blood sample handling processing is not compromised.  The time 
and date of the dose and blood samples should be captured.  Further details on 
pharmacokinetics/pharmacodynamics can be found in Sections 8.3.1 and 8.3.2.  
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5.5.1 
Pharmacokinetic Assessments 
Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected at the following timepoints on Day 6, or any day after the 11th dose, using the 
following sampling approach: 
• 
Within 30 minutes prior to the dose administration (e.g., 8:30 a.m. if dosing is 
scheduled for 9:00 a.m.) 
• 
1.5 hours ± 30 minutes post-dose (e.g., 10:30 a.m. ± 30 min if dosing is scheduled 
for 9:00 a.m.) 
• 
4 hours ± 60 minutes post dose (e.g., 1:00 p.m. ± 60 min if dosing is scheduled for 
9:00 a.m.) 
• 
8 hours ± 1.5 hours post dose (e.g., 5:00 p.m. ± 1.5 hr if dosing is scheduled for 
9:00 a.m.) 
 
For adults and adolescents, approximately 2 mL of blood will be collected at each 
timepoint; therefore, the total volume blood loss for PK assessments will be 
approximately 8 mL.  For pediatric patients, not less than approximately 0.6 mL of blood 
will be collected at each timepoint; therefore, the total volume blood loss for PK 
assessments will be approximately 2.4 mL. 
The samples from this study are classified as Biological Substance, Category B.  
Plasma concentrations of oseltamivir and oseltamivir carboxylate will be measured by 
a specific and validated method.  Details on sampling procedures, sample storage, and 
shipment are provided in the Sampling Manual. 
5.5.2 
Pharmacodynamic Assessments 
Nasal and throat swabs will be collected from individuals on the days specified in the 
schedule of assessments.  Specimens will be analyzed at a central laboratory.  As 
immunocompromised patients are expected to shed virus for a longer duration, viral 
samples will be collected at all visits.  The proportion of patients with viral shedding at 
each visit will be summarized. 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT  
The Investigational Medical Product in this study is oseltamivir dry powder (to be 
reconstituted to a concentration of 12 mg/mL or 6 mg/mL [the 6 mg/mL will only be 
used if applicable and not before 2015]) or 75 mg capsules and matching placebo. 
The Investigational Medicinal Products will be supplied, packaged individually for each 
subject and labeled in accordance with Roche Standard and local regulation by Roche 
Clinical Trial Supply, Basel, Switzerland.  


 
6.1 
DOSE AND SCHEDULE OF STUDY DRUG 
Oseltamivir will be given twice daily over 10 days for a total of 20 doses.  The doses 
need to be taken at 12 hourly intervals.  Under no circumstances is a patient allowed to 
take two doses within 7 hours of each other.  
Patients will be randomized to receive either conventional or double dose of study drug. 
Conventional dose: 
Children ages 1−12 years:  Oseltamivir syrup 
≤ 15 kg   
 
 
30 mg twice daily 
> 15−23 kg   
 
45 mg twice daily 
> 23−40 kg 
 
 
60 mg twice daily 
> 40 kg  
 
 
75 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
75 mg twice daily 
Patients randomized to the conventional dose will simultaneously receive matching 
placebo so as to blind them and the investigator from the double dose arm.  
Double dose: 
Children ages 1−12 years:  Oseltamivir syrup  
≤ 15 kg   
 
 
60 mg twice daily 
> 15−23 kg   
 
90 mg twice daily 
> 23−40 kg 
 
 
120 mg twice daily 
> 40 kg  
 
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
6.1.1 
Dose Modifications 
No dose modifications will be allowed on study. 
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6.2 
PREPARATION AND ADMINISTRATION OF STUDY DRUG 
Oseltamivir will be provided in two forms:  
1. 
Oseltamivir capsules containing 75 mg of active drug and packaging material 
consisting of pregelatinized starch, povidone, talc, and sodium stearyl fumarate.  All 
participants 13 years and older will receive this dosage form.  Oseltamivir capsules 
should be stored below 25°C [77°F].  Do not store refrigerated. 
2. 
A pediatric suspension containing 12 mg oseltamivir per mL or 6 mg oseltamivir 
per mL (the 6 mg/mL will only be used if applicable and not before 2015), of 
reconstituted solution and the following excipients:  sorbitol, titanium dioxide, sodium 
benzoate, xanthan gum, monosodium citrate, saccharin sodium, and 
Permaseal11900-31 Tutti Frutti (flavor).  All participants 12 years and under will 
receive this dosage form.  Oseltamivir dry powder for oral suspension [pediatric 
syrup] should be stored below 30°C [86°F]).  Once reconstituted, the suspension 
should not be used for longer than 10 days if stored at room temperature conditions 
(below 25°C/77°F).  If stored under refrigerated conditions at 2−8°C (36−46°F) the 
suspension should not be used for longer than 17 days.  The suspension is not 
suitable for freezing. 
For further details, refer to the Tamiflu® Investigator’s Brochure. 
Matching placebo will be available as capsules and suspension.  Patients in the 
conventional dose arm will get the conventional dose and matching placebo so that they 
are blinded from the double dose arm.  
Each patient will be dispensed a medication pack that will provide enough medication to 
cover 20 doses.  For patients randomized to the conventional dose arm, the medication 
pack will contain a bottle of oseltamivir dry powder or a blister wallet with oseltamivir 
capsules and matching placebo.  For patients randomized to the double dose arm, the 
medication pack will contain two bottles of oseltamivir dry powder or two blister wallets 
with oseltamivir capsules.  Irrespective of the treatment group the patient is randomized 
to, for each dose the patient will take the same amount from both bottles or blister 
wallets provided in the medication pack such that the sum of the amounts from each 
immediate container constitutes one dose. 
One dose is to be administered twice per day at approximately 12-hour intervals with a 
light snack or glass of milk or fruit juice.  The first dose of study drug will be administered 
in the clinic at the time of randomization. 
6.3 
BLINDING AND UNBLINDING 
Randomization will be administered by a central randomization center.  
The Randomization List will not be available at the study center, to the study monitors, 
project statisticians, or to the project team at Roche.  Emergency codes, or another 
adequate method of unblinding, will be implemented before study start, if the identity of 


 
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the test medication is necessary for patient management in the case of a serious 
adverse event.  Any request from the investigator for information about the treatment 
administered to study patients for another purpose must be discussed with 
Roche/designee.  
As per regulatory reporting requirement, Roche/designee will unblind the identity of the 
study drug for all unexpected [as per IB] serious adverse events that are considered by 
the investigator to be related to study drug.  Details of patients who are unblinded during 
the study will be included in the Clinical Study Report. 
All other individuals directly involved in this study will remain blinded until the final 
analysis of the primary parameter.  
The randomization will be stratified by transplant status, duration of symptoms, influenza 
vaccination status and age and will be provided by the Roche randomization group for 
the IVRS vendor.   
6.4 
ASSESSMENT OF COMPLIANCE 
Accountability and patient compliance will be assessed by maintaining adequate “drug 
dispensing” and return records.  
Patients will be asked to return all used and unused drug supply containers at the end of 
the treatment as a measure of compliance.  
A Drug Dispensing Log must be kept current and should contain the following 
information: 
• 
the identification of the patient [randomization and medication numbers] to whom 
the study drug was dispensed 
• 
the date[s], quantity of the study drug dispensed to the patient 
• 
the date[s] and quantity of the study drug returned by the patient 
 
This inventory must be available for inspection by the Monitor.  All supplies, including 
partially used or empty containers and the dispensing logs, must be returned to the 
monitor at the end of the study. 
6.5 
DESTRUCTION OF STUDY DRUG 
Local or institutional regulations may require immediate destruction of used 
investigational product for safety reasons.  In these cases, it may be acceptable for 
investigational site staff to destroy dispensed investigational product before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned, and destroyed.  Written authorization must be obtained from the sponsor or 
designee at study start up before destruction. 


 
Written documentation of destruction must contain the following: 
– 
Identity [batch numbers or patient numbers] of investigational product[s] destroyed 
– 
Quantity of investigational product[s] destroyed 
– 
Date of destruction 
– 
Method of destruction 
– 
Name and signature of responsible person [or company] who destroyed 
investigational products[s] 
 
7. 
SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES 
7.1.1 
Clinical AEs 
Per the International Conference of Harmonization [ICH], an Adverse Event (AE) is any 
untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavorable and unintended sign [including 
an abnormal laboratory finding], symptom, or disease temporally associated with the use 
of a medicinal [investigational] product, whether or not considered related to the 
medicinal [investigational] product.  Pre-existing conditions that worsen during a study 
are to be reported as AEs.  Influenza signs and symptoms reported on the patient diary 
will be summarized as efficacy endpoints and need not be captured as adverse events.  
However, secondary illnesses due to influenza must be reported as adverse events.  
7.1.1.1 
Intensity  
All clinical AEs encountered during the clinical study will be reported on the AE page of 
the CRF.   
Intensity of AEs will be graded on a four-point scale [mild, moderate, severe, 
life-threatening] and reported in detail on the CRF.   
Mild 
discomfort noticed but no disruption of normal daily activity. 
Moderate 
discomfort sufficient to reduce or affect daily activity. 
Severe 
inability to work or perform normal daily activity. 
Life Threatening 
represents an immediate threat to life.   
 
7.1.1.2 
Drug - Adverse Event Relationship 
Relationship of the AE to the treatment should always be assessed by the investigator.  
Description of scales can be found in Appendix 4. 
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7.1.1.3 
Serious Adverse Events [Immediately Reportable to Roche] 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events 
• 
Pregnancies 
 
A Serious Adverse Event is any experience that suggests a significant hazard, 
contraindication, side effect, or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– 
is fatal; [results in death; NOTE:  death is an outcome, not an event].  
– 
is Life-Threatening [NOTE:  the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
– 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
 
The full requirements of the ICH Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 will be adhered to 
(Appendix 5). 
7.1.2 
Treatment and Follow-up of AEs  
AEs, especially those for which the relationship to test “drug” is not “unrelated,” should 
be followed up until they have returned to baseline status or stabilized.  If a clear 
explanation is established it should be recorded on the CRF.   
7.1.3 
Laboratory Test Abnormalities 
Laboratory test results will appear printed on laboratory reports provided to the site from 
the central laboratory.  
Any laboratory result abnormality fulfilling the criteria for a serious adverse event [SAE] 
should be reported as such, in addition to being recorded as an AE in the CRF. 
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Any treatment-emergent abnormal laboratory result which is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE page in the CRF: 
• 
Accompanied by clinical symptoms. 
• 
Leading to a change in study drug [e.g., dose modification, interruption, or 
permanent discontinuation]. 
• 
Requiring a change in concomitant therapy [e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, or 
treatment]. 
 
7.1.4 
Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  If a clear explanation is 
established it should be recorded on the CRF.  
7.2 
HANDLING OF SAFETY PARAMETERS 
7.2.1 
Reporting of Serious Adverse Events [Immediately Reportable] 
Any clinical AE or abnormal laboratory test value that is serious [as defined in 
Section 7.1.1.3 above] and which occurs during the course of the study, regardless of 
the treatment arm, occurring from the enrollment visit (start of study screening 
procedures), must be reported to Roche or designee immediately (i.e., no more than 
24 hours after the investigator becomes aware of the event [expedited reporting]). 
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.  
Unrelated Serious Adverse Events must be collected and reported during the study and 
up until the follow-up visit.  
The definition and reporting requirements of ICH Guideline for Clinical Safety Data 
Management, Definitions and Standards for Expedited Reporting, Topic E2 will be 
adhered to (Appendix 5).  The serious adverse events should be reported in the most 
up-to-date version of the SAE form. 
7.2.2 
Pregnancy  
A female patient must be instructed to stop taking the test “drug” and immediately inform 
the investigator if she becomes pregnant during the study.  The investigator should 
report all pregnancies immediately (i.e., no more than 24 hours after the investigator 
becomes aware of the pregnancy) to the Sponsor or designee, using the most 
up-to-date version of the pregnancy form.  The investigator should counsel the patient, 
and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
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Pregnancies occurring within 28 days of treatment completion should be reported to 
Roche.  
7.3 
WARNINGS AND PRECAUTIONS  
Events such as convulsions and delirium (including symptoms such as altered level of 
consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, 
anxiety, nightmares) have been reported during oseltamivir use in patients with influenza, 
predominately in children and adolescents.  In rare cases, these events resulted in 
accidental injury.  The contribution of oseltamivir to those events is unknown.  Such 
events have also been reported in patients with influenza who were not taking 
oseltamivir.  Patients, especially children and adolescents, should be closely monitored 
for signs of abnormal behavior. 
Please refer to the attached Investigator’s Brochure for additional warnings, precautions, 
and other reported adverse events. 
8. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Full details of all planned analyses will be specified in a separate Statistical Analysis 
Plan (SAP) for the safety and efficacy variables and in the Resistance Plan for the 
development of resistance.  The methods described below are an outline of the main 
planned analyses.  For continuous endpoints summary statistics including mean, 
standard deviation, median, minimum, and maximum will be derived for each treatment 
group.  For categorical data, the number and percentage of events and/or patients for 
each treatment group will be presented. 
8.1 
PRIMARY AND SECONDARY STUDY ENDPOINTS 
8.1.1 
Primary Endpoints 
The primary endpoints for safety will be descriptive assessments of:  
• 
Adverse events 
• 
Physical examination  
• 
Vital signs 
• 
Clinical laboratory evaluations  
• 
Tissue rejection and/or graft versus host disease in transplant patients 
 
The primary endpoint of development of resistance will be determined from the 
genotypic and phenotypic variables measured post baseline and is described further in 
the Resistance Plan. 
8.1.2 
Secondary Endpoints 
The following endpoints will be analyzed descriptively at relevant timepoints. 
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The pharmacodynamics assessments based on nose and throat swabs, collected on the 
days specified in the schedule of assessments: 
• 
Shedding virus by culture and RT-PCR  
• 
Viral load by culture (log10TCID50/mL) and quantitative RT-PCR 
• 
Individual symptom scores  
• 
The time (hours) from first dose of study drug until resolution of fever  
• 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or sinusitis) 
at any time during the study 
• 
Development of secondary illnesses (otitis media, bronchitis, pneumonia, or sinusitis) 
at any time during the study that are treated with antibiotics 
• 
Initiation of treatment with antibiotics after randomization  
• 
Hospitalization, and for those who are hospitalized, the duration of hospitalization 
• 
Development of rejection or GVHD 
 
The following are the model-predicted PK secondary endpoints for oseltamivir and 
oseltamivir carboxylate: 
• 
Steady-state area under the concentration–time curve from 0 to 12 hours (AUC0-12) 
• 
Maximum plasma concentration (Cmax)  
• 
Trough plasma concentration (Ctrough)  
 
The following model-predicted PK endpoints may be included, if appropriate:  
• 
Elimination half-life (t1/2) 
• 
Time to maximum concentration (tmax) 
• 
Elimination constant (ke) 
• 
Apparent clearance (CL/F) 
• 
Apparent volume of distribution (Vc/F) 
• 
Apparent total clearance of metabolite (CLm) 
• 
Last measurable concentration (Clast) and time to last measurable concentration (tlast)  
 
8.2 
STATISTICAL AND ANALYTICAL METHODS  
8.2.1 
Statistical Model  
8.2.1.1 
Time to Event Variables 
A non-parametric model will be assumed with estimation of medians based on 
Kaplan-Meier methods.  Patients without alleviation of symptoms will have their time 
censored at the last available observation that a complete assessment was made. 
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8.2.1.2 
Dichotomous Variables and Viral Load  
For the endpoints defined dichotomously in terms of events or symptoms including the 
development of resistance, it will be assumed that the number of patients experiencing 
the event or exhibiting the symptom will have a binomial distribution. 
For the continuous endpoints of viral load at Days 1, 2, 6, 8, 11, 15, and 40, no model 
will be assumed.  
8.2.2 
Sample Size 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance with reasonable precision.  Assuming that 90% 
of enrolled patients will have laboratory-confirmed influenza, there will be 75 patients in 
each treatment arm in the population evaluable for the development of resistance.  The 
following table shows the 95% Pearson-Clopper confidence intervals that would result 
with a sample size of 75 patients in a treatment arm if certain event rates are observed 
in the study. 
During the study, the number of influenza A virus infected patients and the rate of 
development resistance will be monitored in a blinded fashion in order to ensure a 
reasonable precision for the estimation.  An additional number of patients may be 
enrolled if necessary. 
Observed Rate (%) 
95% Confidence Interval 
0.0 
0.0%−4.8% 
1.3 
0.0%−7.2% 
2.7 
0.3%−9.3% 
5.3 
1.5%−13.1% 
10.7 
4.7%−19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of 
safety.  This number of patients would provide estimates of adverse event rates with 
similar precision. 
8.2.3 
Hypothesis Testing  
Formal hypothesis testing will not be performed; any comparisons between groups will 
be based on comparison of confidence intervals.  
8.2.4 
Analysis Populations 
Three main patient populations will be used for the analysis of data from this study; the 
Safety Population, the Intent-to treat Population and the Intent-to-Treat Infected 
Population.  Detailed definitions of these populations will be given in the SAP.  
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8.2.4.1 
Intent to Treat Population 
All patients randomized will be included in the intent-to-treat population [Patients will be 
assigned to treatment groups as randomized for analysis purposes]. 
8.2.4.2 
Intent to Treat Infected Population 
All patients randomized and with laboratory confirmation of influenza infection, excluding 
patients infected with oseltamivir-resistant influenza at baseline, will be included in the 
intent-to-treat influenza infected population [Patients will be assigned to treatment 
groups as randomized for analysis purposes]. 
The ITTI Population will be the primary population for the summary and analysis of the 
development of resistance and the efficacy variables. 
8.2.4.3 
 Pharmacokinetic Evaluable Patient Population 
The Pharmacokinetic evaluable patient population (PKEP) population comprises all 
patients in the ITT population who have at least one post-dose drug concentration 
measurement at a scheduled visit timepoint.  Patients may be excluded from the PKEP 
population if they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or have unavailable or incomplete data that may influence 
the PK analysis.  
Decisions on patient exclusion from the PK analysis will be made prior to database 
closure by the clinical pharmacologist.  Excluded patients will be documented along with 
the reason for exclusion. 
8.2.4.4 
Subpopulations 
A subpopulation of the ITTI population will be defined comprising patients who received 
their first dose of study drug within 48 hours of influenza symptom onset for the 
comparison of efficacy endpoints with the age appropriate placebo treated patients 
(pediatric or adult) from the registration trials. 
8.2.5 
Safety Data Analysis 
The safety analysis population will include all patients who receive at least one dose of 
study drug and had a safety assessment performed post randomization.  All safety 
variables will be summarized and presented in tables based on this safety population: 
• 
Adverse events 
• 
Physical examination 
• 
Vital signs 
• 
Clinical laboratory evaluations 
• 
Rejection and/or graft versus host disease 
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8.2.6 
Analysis of Resistance 
For the summary of the development of resistance for each treatment arm, 
95% confidence intervals will be provided with the estimated rates.  Further details are 
available in the Resistance Plan for NV20234.  These data will be summarized in a 
report separate from the final study report. 
8.2.7 
Efficacy Analysis 
For the analysis of time to alleviation of all clinical symptoms, the following two 
assessments will be made independently of each other and without regard to the 
outcomes in each case. 
• 
Comparison to placebo control from pivotal registration trials  
From the integrated efficacy database associated with the oseltamivir 
treatment approval, a population of placebo-treated patients will be 
established that is comparable to the subpopulation of patients in the current 
study whose first dose of study drug was within 48 hours of symptom onset.  
For this population, a median time to resolution of all clinical influenza 
symptoms will be determined along with its 95% confidence interval. 
The median time to resolution of all influenza symptoms will be determined for 
each treatment group, along with its 95% confidence interval.   
• 
The two dose groups will be compared to each other by estimating the difference in 
the median times to alleviation of symptoms and deriving an associated 
95% confidence interval. 
  
For the dichotomous endpoints, the proportion of patients experiencing the event or 
symptom, and its associated 95% confidence interval will be derived for each treatment 
group.  Where possible, the corresponding confidence intervals from the placebo control 
population will be presented for comparison to those derived for the active treatment 
groups in this trial. 
The continuous secondary endpoint time to resolution of fever will be analyzed as for the 
time to alleviation of all symptoms.  
8.2.7.1 
Exclusion of Data from Analysis 
Efficacy data collected from any patient who begins treatment with another antiviral for 
influenza (for example, amantadine, rimantadine, laninamivir, peramivir, or zanamavir), 
after the other antiviral treatment commences, will be excluded from the primary and 
secondary efficacy analyses.  Such patients will be considered failures to oseltamivir 
treatment in the analyses.  Further details will be provided in the SAP. 
8.2.7.2 
Interim Analysis 
No interim analyses are planned.  
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8.2.8 
Other Analyses 
Further exploratory analyses will be detailed in the SAP. 
8.3 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
8.3.1 
Pharmacokinetic Analysis 
The primary study variables are the model-derived PK parameters:  steady-state AUC, 
Cmax, and Ctrough of oseltamivir and oseltamivir carboxylate. 
Individual and mean plasma concentrations at each sampling timepoint for oseltamivir 
and oseltamivir carboxylate will be presented by listings and descriptive summary 
statistics, including means, geometric means, medians, ranges, standard deviations, and 
coefficients of variation.  Individual and mean concentration-versus-time profiles will be 
plotted on linear and semi-logarithmic scales. 
Plasma concentration data from sparse sampling will be analyzed using an established 
population PK model to determine key exposure parameters (e.g., Cmax, Ctrough, and 
AUC).  For immunocompromised children aged 1 to 18 years, plasma oseltamivir and 
oseltamivir carboxylate concentration will be modeled in NONMEM using a structure 
similar to a comprehensive population PK model, which was previously developed using 
plasma data from non-immunocompromised children and adults (ages 1 to 80 years) 
[36].  The basic structure consists of a 2-compartment model with first-order absorption 
and direct conversion of oseltamivir to oseltamivir carboxylate, while a 1-compartment 
model is used to account for the renal elimination of oseltamivir carboxylate from the 
plasma.  Body weight, evaluated using a power function and centered around 70 kg, is a 
statistically significant predictor of the CL/F for oseltamivir and both CL/F and apparent 
volume of distribution (Vc/F) for oseltamivir carboxylate.  For oseltamivir carboxylate, 
CrCl is also a significant predictor of CL/F, while Vc/F decreases linearly with age. 
8.3.2 
Pharmacokinetic/Pharmacodynamic Analysis  
If feasible, exposure-response relationships [43] will be evaluated between independent 
variables of exposure (e.g., AUC, Cmin) and dependent variables including continuous 
(area under the viral titer curve, and peak viral titer) and time-to-event (cessation of viral 
shedding) virologic endpoints.  Exploratory PK/PD analyses will be performed using 
appropriate methodologies.  In order to account for potential non-linearity and 
non-monotonicity, each continuous independent variable (e.g., AUC) will be evaluated in 
its original form, as a categorical variable based on quartiles, as two- and three-group 
categorical variables. 
9. 
DATA QUALITY ASSURANCE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures. 
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Accurate and reliable data collection will be assured by verification and cross–check of 
the CRFs against the investigator’s records by the study monitor [source document 
verification] and the maintenance of a drug–dispensing log by the investigator.  
The data collected will be entered into the study database from the working copy of the 
CRF faxed from the site. 
A comprehensive validation check program will verify the data and discrepancy reports 
will be generated accordingly for resolution by the investigator.  As patients complete the 
study [or prematurely withdraw] and their signed CRFs become available, a second data 
entry will be performed from the original, signed CRF.  A comparison check will be run to 
identify and resolve any discrepancies between the first and second data entry. 
Throughout the study the Study Management Team [SMT] will review data according to 
the SMT Data Review Plan as described in the Data Quality Plan.  
9.1 
ASSIGNMENT OF PREFERRED TERMS AND ORIGINAL 
TERMINOLOGY 
For classification purposes, preferred terms will be assigned by the sponsor to the 
original terms entered on the CRF, using the current version of MedDRA (Medical 
Dictionary for Regulatory Activities terminology) for adverse events and diseases and 
the INN (International Non-Proprietary name) drug terms and procedures dictionary for 
treatments and surgical and medical procedures. 
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10. 
REFERENCES 
1. 
Murphy B.G and Webster R.G.  Orthomyxoviruses. Chapter 46.  Fields Virology 3rd 
Edition, Eds:  Fields B.N, Knipe D.M, Howley P.M et al. Pub Lippincott.Raven. 1996. 
p1397–1445.  
2. 
World Health Organization. Influenza. Fact Sheet No. 211. March, 2003. 
3. 
Ison MG., Mishin VP, Braciale TJ et al. Comparative activities of oseltamivir and 
A-322278 in immunocompetent and immunocompromised murine models of 
influenza virus infection. J Infect Dis, 2006; 193:765−72. 
4. 
Vilchez RA, McCurry K, Dauber J, et al. Influenza virus infection in adult solid organ 
transplant recipients. Am J Transplant 2002; 2:287−91. 
5. 
Ljungman P, Ward KN, Crooks BM, et al. Respiratory virus infections after stem cell 
transplantation: a prospective study from the Infectious Diseases Working Party of 
the European Group for Blood and Marrow Transplantation. Bone Marrow 
Transplant 2001;28:479−84. 
6. 
Nichols WG, Guthrie KA, Corey L, et al. Influenza infections after hematopoietic 
stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. 
Clin Infect Dis 2004;39:1300−6. 
7. 
Investigator Brochure for Tamiflu® (oseltamivir phosphate) 11th version June 2010.  
8. 
Kaiser L., Wat C,  Mills T, et al. Impact of oseltamivir treatment on influenza-related 
lower respiratory tract complications and hospitalizations. Arch Intern Med 
2003;163:1667−72.  
9. 
Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza 
in children. Pediatr Infect Dis J 2001;20:127−33. 
10. Machado CM, Boas LS, Mendes AV, et al. Use of Oseltamivir to control influenza 
complications after bone marrow transplantation. Bone Marrow Transplant 
2004;34:111−4.   
11. Dutkowski R, Thakrar B, Froehlich E,et al. Safety and pharmacology of oseltamivir 
in clinical use. Drug Saf 2003;26:787−801. 
12. He G, Massarella J, Ward P, Clinical pharmacokinetics of the prodrug oseltamivir 
and its active metabolite Ro 64-0802. Clin Pharmacokinetics 1999;37:471−84.  
13. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines 
for chronic kidney disease: evaluation, classification, and stratification. Ann Intern 
Med` 2003.;139:137−47. 
14. Hogg RJ, Furth S, Lemley KV, et al., National Kidney Foundation's Kidney Disease 
Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in 
children and adolescents: evaluation, classification, and stratification. Pediatrics 
2003;111(6 Pt 1):1416-21. 
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15. Ferrara JL  Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667−74. 
16. Kasper DL, Braunwald E, Fauci AS, et al. Harrison's Principles of Internal Medicine. 
17th ed. The McGraw Hill companies, Inc.; 2008.  
17. CDC http://www.cdc.gov/flu/protect/hiv-flu.htm as assessed on 27 October 2010. 
18. Caselli D , Carraro F, Castagnola E, et al. Morbidity of pandemic H1N1 influenza in 
children with cancer. Pediatr Blood Cancer. 2010;55:226–28. 
19. Tramontana AR , George B, Hurt AC, et al. Oseltamivir resistance in adult oncology 
and hematology patients infected with pandemic (H1N1) 2009 virus, Australia. 
Emerg Infect Dis 2010;16(7):1068−75. 
20. Chironna M, Tafuri S, Santoro N, et al. A nosocomial outbreak of 2009 pandemic 
influenza A (H1N1) in a pediatric oncology ward in Italy (October-November 2009), 
Euro Surveill 2010;15(1). 
21. Launes C, Rives S, Catalá A, et al. Pandemic influenza A (2009 H1N1) in children 
with acute lymphoblastic leukaemia. Br J Haematol 2010;149(6):874−8. 
22. Clinical Study Report Protocol NV20235 Research Report No. 
 
23. AIDS 2010, DOI:10.1097/QAD.0b013e32833d2096. 
24. Akyüz S, Yilmaz A, Bülbül M, et al. Do immunosupressive patients really have a 
severe outcome with H1N1 virus infection? J Trop Pediatr 2011; 57:129−31. 
25. Mellouli F, Ouederni M, Dhouib N, et al. Successful treatment of influenza A virus by 
oseltamivir in bone marrow transplant recipients. Pediatr Transplant 
2010;14:178−81. 
26. Kumar D, Michaels MG, Morris MI, et al. Outcomes from pandemic influenza A 
H1N1 infection in recipients of solid-organ transplants: a multicenter cohort study. 
Lancet Infect Dis 2010;2010;521−6. 
27. Fox BD, Raviv Y, Rozengarten D, et al. Pandemic influenza (H1N1): Impact on lung 
transplant recipients and candidates. J Heart Lung Transplant 2010;29:1034−8. 
28. Ng BJH, Glanville AR, D’Costa J, et al . The combined Australian experience with 
human swine influenza H1N1 in lung transplant recipients. S141 (abstract). 
29. Ison MG, Sharma A, Shepard JO, et al. Outcome of influenza infection managed 
with oseltamivir in lung transplant recipients. J Heart Lung Transplant 
2008;27:282−8. 
30. Update on oseltamivir-resistant pandemic A (H1N1) 2009 influenza virus: 
January 2010. Wkly Epidemiol Rec 2009b; 85(6):37−40. 
31. Ison MG, Gubareva LV, Atmar RL, et al. Recovery of drug-resistant influenza virus 
from immunocompromised patients: a case series. J Infect Dis 2006;193(6):760−4. 
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32. Hayden FG. Antiviral resistance in influenza viruses: clinical and epidemiological 
aspects. In: Antimicrobial drug resistance: clinical and epidemiological aspects, 
Vol 2 (Infectious Diseases). (Ed. Mayers DL). Humana Press, 2009; 1st: 1011−34. 
33. Klein MB, Lu Y, DelBalso L, et al. Influenza virus infection is a primary cause of 
febrile respiratory illness in HIV-infected adults, despite vaccination. Clin Infect Dis 
2007; 45:234−40. 
34. Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult 
patients hospitalized with influenza. J Infect Dis. 2009 ;200(4):492−500. 
35. Quick Facts for Clinicians on Antiviral Treatments for H1N1 Influenza. 2009 Nov. 
From http://www.cdc.gov/H1N1flu/antivirals/facts_clinicians.htm accessed on May 
14th, 2010. 
36. Kamal MA, Van Wart SA, Rayner CR, et al., Population pharmacokinetics of 
oseltamivir in pediatric through geriatrics. Antimicrob Agents Chemother 2013; 
57:3470−7. 
37. Allen U, Blumberg EA, Fischer SA, et al. American Society of Transplantation (AST) 
Infectious Diseases Community of Practice/Transplant Infectious Disease Section of 
The Transplantation Society (TTS) Guidance On Novel Influenza A/H1N1. [cited 
2010 Oct 28]. 2009 Dec 03. Available from: www.a-s-
t.org/files/pdf/ast_h1n1_guidance.pdf. 
38. Katzung BG, Masters SB, Trevor AJ (ed). Basic and clinical pharmacology. 11th 
edition. Tata McGraw-Hill Companies, Inc., New York: 2009: 971−80.  
39. Salvana EM, Salata RA. Infectious complications associated with monoclonal 
antibodies and related small molecules. Clin Microbiol Rev. 2009;22(2):274−90. 
40. Erkeller-Yuksel FM, Deneys V, Yuksel B, et al. Age-related changes in human blood 
lymphocyte subpopulations. J Pediatr 1992;120:216−22 
41. Denny T, Yogev R, Gelman R, et al. Lymphocyte subsets in healthy children during 
the first 5 years of life. JAMA 1992;267:1484−8. 
42. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. [resource 
on the internet]. Available from: http://aidsinfo.nih.gov/guidelines 
43. Rayner CR, Bulik CC, Kamal MA, et al. Pharmacokinetic-pharmacodynamic 
determinants of oseltamivir efficacy using data from phase 2 inoculation studies. 
Antimicrob Agents Chemother 2013; 57:3478−87 
 
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PART II: ETHICS AND GENERAL STUDY ADMINISTRATION 
11. 
ETHICAL ASPECTS 
11.1 
LOCAL REGULATIONS/DECLARATION OF HELSINKI 
The investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline [January 1997] or with local law if it affords 
greater protection to the patient.  For studies conducted in the European 
Union/European Economic Area countries, the investigator will ensure compliance with 
the EU Clinical Trial Directive [2001/20/EC].  For studies conducted in the United States 
or under U.S. IND, the investigator will additionally ensure that the basic principles of 
“Good Clinical Practice” as outlined in the current version of 21 CFR, subchapter D, 
part 312, “Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Subjects”, and part 56, “Institutional Review Boards”, are adhered to. 
In other countries where “Guideline for Good Clinical Practice” exists, Roche and the 
investigators will strictly ensure adherence to the stated provisions. 
11.2 
INFORMED CONSENT  
It is the responsibility of the investigator, or a person designated by the investigator 
[if acceptable by local regulations], to obtain written informed consent from each patient 
participating in this study after adequate explanation of the aims, methods, anticipated 
benefits, and the potential hazards of the study.  For patients not qualified or incapable 
of giving legal consent, written consent must be obtained from the legally acceptable 
representative.  In the case where both the patient and his/her legally acceptable 
representative are unable to read, an impartial witness should be present during the 
entire informed consent discussion.  After the patient and representative have orally 
consented to participation in the trial, the witness’ signature on the form will attest that 
the information in the consent form was accurately explained and understood.  The 
investigator or designee must also explain that the patients are completely free to refuse 
to enter the study or to withdraw from it at any time, for any reason.  The Case Report 
Forms [CRFs] for this study contain a section for documenting informed patient consent, 
and this must be completed appropriately.  If new safety information results in significant 
changes in the risk/benefit assessment, the consent form should be reviewed and 
updated if necessary.  All patients [including those already being treated] should be 
informed of the new information, given a copy of the revised form, and give their consent 
to continue in the study. 
If children are old enough to understand the risks and benefits of the study, they should 
also be informed and should also provide their written consent. 
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11.3 
INDEPENDENT ETHICS COMMITTEES/INSTITUTIONAL 
REVIEW BOARD  
Independent Ethics Committees [non-U.S.]:  This protocol and any accompanying 
material provided to the patient [such as patient information sheets or descriptions of the 
study used to obtain informed consent] as well as any advertising or compensation given 
to the patient, will be submitted by the investigator to an Independent Ethics Committee.  
Approval from the committee must be obtained before starting the study and should be 
documented in a letter to the investigator specifying the date on which the committee 
met and granted the approval. 
Any modifications made to the protocol after receipt of the Independent Ethics 
Committee approval must also be submitted by the investigator to the Committee in 
accordance with local procedures and regulatory requirements. 
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the investigator 
in submitting the protocol to the European Ethics Review Committee. 
Institutional Review Board [U.S.]:  It is the understanding of the sponsor that this 
protocol [and any modifications] as well as appropriate consent procedures, will be 
reviewed and approved by an Institutional Review Board.  This board must operate in 
accordance with the current Federal Regulations.  A letter or certificate of approval will 
be sent by the investigator to the Sponsor or designee prior to initiation of the study, and 
also whenever subsequent modifications to the protocol are made. 
12. 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications to ongoing studies must be made only after consultation between 
an appropriate representative of the sponsor and the investigator [investigator 
representative[s] in the case of a multicenter trial].  Protocol modifications must be 
prepared by a representative of the sponsor and initially reviewed and approved by the 
Clinical Science Leader/Clinical Pharmacologist and Biostatistician. 
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required.  Approval must be awaited 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial patients, or when the change[s] involves only logistical or 
administrative aspects of the trial [e.g., change in monitor[s], change of telephone 
number[s]. 
13. 
CONDITIONS FOR TERMINATING THE STUDY 
Both the sponsor and the investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
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basis after review and consultation.  In terminating the study, Roche and the investigator 
will assure that adequate consideration is given to the protection of the patient’s interests. 
14. 
STUDY DOCUMENTATION, CRFS, AND RECORD KEEPING 
14.1 
INVESTIGATOR'S FILES/RETENTION OF DOCUMENTS 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into two different separate categories [1] Investigator's 
Study File, and [2] patient clinical source documents. 
The Investigator's Study File will contain the protocol/amendments, Case Report and 
Query Forms, Independent Ethics Committee/Institutional Review Board and 
governmental approval with correspondence, sample informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate 
documents/correspondence, etc.  
Patient clinical source documents [usually defined by the project in advance to record 
key efficacy/safety parameters independent of the CRFs] would include patient 
hospital/clinic records, physician's and nurse's notes, appointment book, original 
laboratory reports, ECG, EEG, X-ray, pathology and special assessment reports, signed 
informed consent forms, consultant letters, and patient screening and enrollment logs.  
The Investigator must keep these two categories of documents on file for at least 
15 years after completion or discontinuation of the study.  After that period of time the 
documents may be destroyed, subject to local regulations.  
Should the Investigator wish to assign the study records to another party or move them 
to another location, Roche must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
14.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
The investigator shall supply the sponsor or designee on request with any required 
background data from the study documentation or clinic records.  This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected.  In 
case of special problems and/or governmental queries or requests for audit inspections, 
it is also necessary to have access to the complete study records, provided that patient 
confidentiality is protected. 
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14.3 
AUDITS AND INSPECTIONS 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 
Quality Assurance Unit or its designees or to health authority inspectors after 
appropriate notification.  The verification of the CRF data must be by direct inspection of 
source documents. 
14.4 
CASE REPORT FORMS 
For each patient enrolled, a CRF must be completed and signed by the principal 
investigator or authorized delegate from the study staff.  This also applies to records for 
those patients who fail to complete the study [even during a pre-randomization screening 
period if a CRF was initiated].  If a patient withdraws from the study, the reason must be 
noted on the CRF.  If a patient is withdrawn from the study because of a 
treatment-limiting AE, thorough efforts should be made to clearly document the outcome. 
All forms should be typed or filled out using indelible ink and must be legible.  Errors 
should be crossed out but not obliterated, the correction inserted, and the change 
initialed and dated by the investigator or his/her authorized delegate.  The investigator 
should ensure the accuracy, completeness, legibility, and timeliness of the data reported 
to the sponsor or designee in the CRFs and in all required reports. 
15. 
MONITORING THE STUDY 
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [CRFs and other pertinent data] provided that patient confidentiality is 
maintained in accord with local requirements. 
It will be the monitor's responsibility to inspect the CRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor should have access to 
laboratory test reports and other patient records needed to verify the entries on the CRF.  
The investigator [or his/her deputy] agrees to cooperate with the monitor to ensure that 
any problems detected in the course of these monitoring visits are resolved. 
16. 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT 
RECORDS 
The investigator must assure that patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On CRFs or other documents (both 
paper and electronic) submitted to the sponsor or designee, patients should not be 
identified by their names but by an identification code.  The investigator should keep a 
patient enrollment log showing codes, names, and addresses.  The investigator should 
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maintain documents not for submission to Roche, e.g., patients’ written consent forms, in 
strict confidence. 
17. 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  This allows the sponsor or designee to protect proprietary information and 
to provide comments based on information from other studies that may not yet be 
available to the investigator. 
In accord with standard editorial and ethical practice, Roche will generally support 
publication of multicenter trials only in their entirety and not as individual center data.  In 
this case, a coordinating investigator will be designated by mutual agreement. 
Any formal publication of the study in which input of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel.  Authorship will be determined by mutual agreement. 
Oseltamivir—F. Hoffmann-La Roche Ltd 
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Appendix 1 Calculation of Creatinine Clearance and Grading of 
Chronic Extensive GVHD  
Calculation of Creatinine Clearance 
Conversion Factor for Serum Creatinine: 
Conventional Units (mg/dL) = SI Units (μmol/L) ÷ 88.4   
Age = number of years (12 years 11 months = 12 years) 
Estimated Creatinine Clearance according to Cockcroft-Gault [13] 
 (for patients ≥ 18 years): 
¾ Males 
Creatinine 
Clearance (mL/min)  =  
 
[(140−age) × Body Weight (kg)] ÷ [72 × Serum Creatinine 
(mg/dL)] 
 
¾ Females  
Creatinine Clearance = above equation × 0.85 
 
Estimated Creatinine Clearance according to Schwartz equation [14]  
(for patients < 18 years): 
Creatinine Clearance 
(mL/min/1.73 M2) =  
 
k × Height (cms) ÷  Serum Creatinine (mg/dL) 
Value for k:  
k 
Age (years) 
0.45 
< 2 
0.55 
≥ 2 to < 13 
0.7 
≥ 13 to < 18 (males) 
0.55 
≥ 13 to < 18 
(females) 
 
 
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Appendix 1 Calculation of Creatinine Clearance and Grading of 
Chronic Extensive GVHD (cont.)  
Grading of Chronic GVHD [15] 
Type of Disease 
Extent of Disease 
Limited 
Localized skin involvement, liver 
dysfunction or both 
Extensive 
Generalized skin involvement 
 
Localized skin involvement or liver 
dysfunction plus any one of the following: 
   1. Chronic aggressive hepatitis, bridging 
necrosis or cirrhosis 
   2. Eye involvement (Schirmer’s 
test, < 5 mm) 
   3. Involvement of mucosalivary glands 
   4. Mucosal involvement (on lip biopsy) 
   5. Involvement of other target organs  
 
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Appendix 2 Patient Diary Data and Symptom Record for Adults
 
 
The purpose of the patient diary is for all adults (13 years and older) to record any 
symptoms of influenza-like illness for the duration of the study.  Temperature and date 
and time of drug administration should also be recorded on the patient diary. 
 
 
 
 
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Appendix 3 Patient Diary Data and Symptom Record for 
Children  
Temperature and date and time of drug administration will also be recorded on the 
patient diary. 
 
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Appendix 4 Adverse Event [AE] Categories for Determining 
Relationship to Test Drug 
PROBABLE [must have first three] 
This category applies to those AEs that are considered, with a high degree of certainty, 
to be related to the test drug.  An AE may be considered probable, if: 
1. 
It follows a reasonable temporal sequence from administration of the drug. 
2. 
It cannot be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered 
to the patient. 
3. 
It disappears or decreases on cessation or reduction in dose.  [There are important 
exceptions when an AE does not disappear upon discontinuation of the drug, yet 
drug-relatedness clearly exists; e.g., [1] bone marrow depression, [2] tardive 
dyskinesias]. 
4. 
It follows a known pattern of response to the suspected drug. 
5. 
It reappears upon rechallenge. 
 
POSSIBLE [must have first two] 
1. 
This category applies to those AEs in which the connection with the test drug 
administration appears unlikely but cannot be ruled out with certainty.  An AE may 
be considered possible if or when: 
1. 
It follows a reasonable temporal sequence from administration of the drug. 
2. 
It may have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
3. 
It follows a known pattern of response to the suspected drug. 
 
REMOTE [must have first two] 
1. 
In general, this category is applicable to an AE that meets the following criteria: 
2. 
It does not follow a reasonable temporal sequence from administration of the drug. 
3. 
It may readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient. 
4. 
It does not follow a known pattern of response to the suspected drug. 
5. 
It does not reappear or worsen when the drug is re-administered. 
 
UNRELATED 
This category is applicable to those AEs that are judged to be clearly and 
incontrovertibly due only to extraneous causes [disease, environment, etc.] and do not 
meet the criteria for drug relationship listed under remote, possible, or probable. 
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Appendix 4 Adverse Event [AE] Categories for Determining 
Relationship to Test Drug (cont.) 
 
 
Probable 
Possible 
Remote 
Unrelated 
Clearly due to extraneous causes 
– 
– 
– 
+ 
 
 
 
 
 
Reasonable temporal association with 
drug administration 
+ 
+ 
– 
– 
 
 
 
 
 
May be produced by patient clinical 
state, etc. 
– 
+ 
+ 
+ 
 
 
 
 
 
Known response pattern to suspected 
drug 
+ 
+ 
– 
– 
 
 
 
 
 
Disappears or decreases on cessation 
or reduction in dose 
+ 
– 
– 
– 
 
 
 
 
 
Reappears on rechallenge 
+ 
– 
– 
– 
 
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Appendix 5 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect, or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria: 
– 
is fatal; [results in death] [NOTE:  death is an outcome, not an event]. 
– 
is Life-Threatening    [NOTE:  the term "Life-Threatening" refers to an event in which 
the patient was at immediate risk of death at the time of the event; it does not refer 
to an event which could hypothetically have caused a death had it been more 
severe]. 
– 
required in-patient hospitalization or prolongation of existing hospitalization; 
– 
results in persistent or significant disability/incapacity; 
– 
is a congenital anomaly/birth defect; 
– 
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor or designee is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one 
of the outcomes listed in the definitions above.  These situations should also usually be 
considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
An unexpected AE is one, the nature or severity of which is not consistent with the 
applicable product information. 
Causality is initially assessed by the investigator.  For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply)  
– 
Pre-existing/Underlying disease - specify  
– 
Study treatment – specify the drug(s) related to the event 
– 
Other treatment (concomitant or previous) – specify 
– 
Protocol-related procedure 
– 
Other (e.g., accident, new or intercurrent illness) - specify 
The term severe is a measure of intensity, thus a severe AE is not necessarily serious.  
For example, nausea of several hours' duration may be rated as severe, but may not be 
clinically serious. 
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Appendix 5 ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
(cont.) 
A serious adverse event occurring during the study or which comes to the attention of 
the investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported. 
Such preliminary reports will be followed by detailed descriptions later, which will include 
copies of hospital case reports, autopsy reports, and other documents when requested 
and applicable. 
For serious adverse events, the following must be assessed and recorded on the AEs 
page of the CRF:  intensity, relationship to test substance, action taken, and outcome to 
date. 
The investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations. 
ROCHE LOCAL COUNTRY CONTACT for SAEs:  Local Monitor  
ROCHE HEADQUARTERS CONTACT for SAEs:  Clinical Operations/Clinical Science  
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all investigators. 
Oseltamivir—F. Hoffmann-La Roche Ltd 
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Appendix 6 Primary Immunodeficiency Conditions 
Category 
Conditions 
Adenosine deaminse (ADA) deficiency 
Artemis deficiency (SCIDA) 
CD45 deficiency 
Cernunnos deficiency 
DNA ligase IV (LIG4) deficiency 
Interleukin receptor γ chain deficiency (X-linked SCID) 
Janus-associated kinase 3 (JAK3) deficiency 
Recombinase activating gene (RAG 1/2) deficiency  
Reticular dysgenesis 
Severe Combined 
Immunodeficiency (SCID) 
TAP- 1 or TAP- 2 deficiency (MHC class I deficiency) 
CD8 deficiency 
diGeorge syndrome  
Interleukin 7 receptor α (IL7RA) deficiency 
MHC class II deficiency 
LCK deficiency 
Orai 1 deficiency 
Nude syndrome (wing helix nude deficiency) 
Purine nucleotide phosphorylase (PNP) deficiency 
T cell receptor deficiency (CD 3γ, δ, ε, and ζ 
deficiencies) 
Primary T cell Deficiency 
Zap 70 tyrosine kinase deficiency 
X-Linked CD40 ligand deficiency 
X- Linked IKK-γ (NEMO) deficiency 
Predominantly Antibody 
Deficiency 
CD40 deficiency 
Interferon γ receptor deficiency 
Other Well-Defined 
immunodeficiency Syndromes 
X-Linked lymphoproliferative syndrome 
Adapted from Table 310-2:  p2056 reference 16. 
 
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Appendix 7 Hematologic Malignancies and their Effect on the 
Immune System 
Malignancy 
Effect on immunity 
suppression of hematopoiesis, neutropenia, 
lymphocyte dysfunction 
ALL, lymphomas 
hypogammaglobulinemia, increased 
susceptibility to infections, autoimmune anemia 
or thrombocytopenia 
CLL, small lymphocytic lymphoma 
Hairy cell leukemia, myelodysplastic syndromes
pancytopenia 
lymphocyte dysfunction, increase in immature 
cells 
peripheral T cell and NK neoplasms 
Hodgkin’s disease  
suppression of cell-mediated immunity 
neutropenia, anemia, thrombocytopenia, 
predisposed to infections, lymphocyte 
dysfunction 
AML 
anemia, granulocyte dysfunction in some 
patients in early phase and in most patients in 
blast phase 
CML 
Adapted from reference 16. 
 
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Appendix 8 Immunosuppressive Medications 
Class 
Category 
Drugs 
Corticosteroids 
- 
Glucocorticoids (oral, sc, im, iv) 
cyclophosphamide, busulfan, mechlorethamine, 
chlorambucil, melphalan, carmustine, lomustine, 
ifosfamide, procarbazine, dacarbazine, 
temozolomide, cisplatin, carboplatin, oxaliplatin 
Alkylating agents 
Anti-metabolites 
methotrexate, 6-mercaptopurine, azathioprine 
bleomycin, actinomycin D, mitomycin C, etoposide, 
topotecan, irinotecan, doxorubicin, daunorubicin, 
idarubicin, epirubicin, mitoxantrone 
Anti-tumor 
antibiotics 
Cytotoxic agents[16] 
vincristine, vinblastine, vinorelbine, paclitaxel, 
docetaxel, estramustine phosphate, 
NAB-paclitaxel 
Anti-mitotic agents 
Molecularly 
targeted agents 
imatinib, tretinoin, bexarotene, denileukin, diftitox, 
gefitinib, erlotinib, dasatinib, sorafenib, sunitinib 
Calcineurin inhibitors 
- 
cyclosporine, tacrolimus 
mTOR inhibitors 
(proliferation-signal 
inhibitors) 
sirolimus, everolimus 
- 
Immunosuppressive 
antibodies 
anti lymphocyte and antithymocyte globulins (ALG 
and ATG) 
- 
Adalimumab 
Infliximab 
Cetrolizumab 
Etarnecept 
Basiliximab 
Inhibitors of pro 
inflammatory 
cytokines 
Daclizumab 
Adhesion cell 
modulators 
Natalizumab 
Monoclonal 
antibodies [
Abatacept 
38, 39] 
Alefacept 
T-cell inhibitors 
Muromonab 
Rituximab 
90Y-Ibritumomab 
B-cell inhibitors 
131I-Tositumomab 
Anti-CD33 
Gemtuzumab 
Anti- CD52 
Alemtuzumab 
Others 
- 
mycophenolate mofetil, thalidomide 
Compiled from Table 81-2:  p521-24 reference 16 and references 38, 39. 
 
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Appendix 9 Child-Pugh Classification of Severity of Liver 
Disease 
Child–Pugh Scoring on Select Parameters 
Points Scored for Increasing 
Abnormality 
Clinical and biochemical measurements 
1 
2 
3 
Encephalopathy (grade) a 
None 
1 or 2 
3 or 4 
Ascites b 
Absent 
Slight 
Moderate 
Bilirubin (mg/100 mL) 
< 2 
2–3 
> 3 
Albumin (g/100 mL) 
> 3.5 
2.8–3.5 
< 2.8 
Prothrombin time (International Normalized Ratio) c 
< 1.7 
1.7–2.3 
> 2.3 
Note:  With increasing abnormality of each of the five parameters measured, 1, 2, or 3 points are scored. Grade A:  5 or 6 
points. Grade B:  7–9 points. Grade C:  10–15 points. 
a According to grading of Trey, Burns, and Saunders (1966). 
b As determined by physical examination alone. 
c Prothrombin time results should be reported and used for calculations only as International Normalized Ratios 
because of variations in the methods used and reference ranges for controls (expressed in seconds). 
 
 
 
 
 
 
 
 
 
 
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SAP_001.pdf: 
 
Official Title: 
A Double Blind, Randomized, Stratified, Multi-Center Trial 
Evaluating Conventional and Double Dose Oseltamivir In The 
Treatment of Immunocompromised Patients with Influenza 
NCT Number: 
NCT00545532 
Document Date: 
Statistical Analysis Plan Version 1: 04-Aug-2017 
 
 
 
 


IDM Audit Trail Report
Report for document SAP NV20234 ((234)) Tamiflu v1, (Post marketing commitment Phase IIIb) 08-Dec-2017
Basic Object Properties:
Document Name:
SAP NV20234 ((234)) Tamiflu v1, (Post marketing commitment Phase IIIb) 08-Dec-2017
Title:
NV20234_SAP_Final.docx
Version number and label:
CURRENT, 1.0, Released
Group:
Statistical Analysis
SubGroup:
DAP
Artifact:
Statistical Analysis Plan
Content item:
SAP Study
Folder Locations:
Folder name
Folder Path
Folder last modified date (UTC)
SAPs
Audit Trail Entries:
User Acknowledgements
Version Number
Outcome Event Name
Activity
User role of signatory
User Name
Date and time of event (UTC)
0.5
Finalized
Acknowledgement
In Approval
Company Signatory (Clinical)
04-Aug-2017 09:27:21
Change Status
Original Status
New Status
Original Version
New Version
User Name
Date and time of event (UTC)
Reason
Finalized
Released
0.5
1.0
ccak
Initiated
0.1
Restricted Property Update
None
Reassign Work
None
Workflow Review Information
None
Terminate Workflow
None
Reclassify


None
Collaboration
Collaboration name
Collaboration
type
Participants
Completion date and
time (UTC)
Reviewing SAP NV20234 (Post marketing
commitment Phase IIb)
Review
03-Aug-2017 15:03:28
Retain Version Flag Update
None
Partner System Transfer
Target System
Document Version
Document Type
Date and time of event (UTC)




Oseltamivir (Tamiflu)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NV20234 
2 
ABBREVIATIONS 
AE 
Adverse Event 
AUC 
Area under the concentration-time curve 
AUE 
Area under the effect-time curve 
AST 
Aspartate transaminase 
ALT 
Alanine aminotransferase 
BID 
Bis In Die (Latin for Twice A Day) 
CARIFS 
Canadian Acute Respiratory Infections scale 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CRD 
Clinically Relevant Difference 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
Ctrough 
Minimum concentration of a molecule in serum before next dose 
EMA 
European Medicines Agency 
EOT 
End Of Trial 
F 
Bioavailability 
FDA 
US Food and Drug Administration 
HA 
Haemagglutinin 
HSCT 
Hematopoietic stem cell transplant 
IC50 
50% inhibitory concentration 
IC 
Immuno-Compromised 
IQR 
Inter-Quartile Range 
ITT 
Intent To Treat 
ITTi 
Intent To Treat infected 
IxRS 
Interactive voice/web Recognition System 
LPLV 
Last Patient Last Visit 
LRTC 
Lower Respiratory Tract Complication 
mITTi 
Modified Intend To Treat Infected 
NA 
Neuraminidase 
NP-ELISA 
Nucleoprotein Enzyme-Linked Immunosorbent Assay 
OC 
Oseltamivir Carboxylate 
OwH 
Otherwise healthy 
PAC 
Post Authorization Commitment 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PKEP 
Pharmacokinetic Evaluable Population 
PK 
Pharmacokinetic 
PIP 
Paediatric Investigation Plan 
PMR 
Post Marketing Requirement 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOT 
Solid Organ Transplant 
TAI 
Treatment Assignment Information 
TCID50 
50% tissue culture infectious dose 
TTR 
Time to resolution 
vp/mL 
virus particles per millilitre 


Oseltamivir (Tamiflu)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NV20234 
3 
 
TABLE OF CONTENTS 
ABBREVIATIONS ................................................................................................. 2 
1. 
BACKGROUND ............................................................................................ 6 
2. 
STUDY DESIGN ........................................................................................... 6 
2.1 
PROTOCOL SYNOPSIS ......................................................... 6 
2.2 
OUTCOME MEASURES ......................................................... 6 
2.2.1 
Primary Efficacy Outcome Measures ...................................... 7 
2.2.2 
Secondary Efficacy Outcome Measures .................................. 7 
2.2.2.1 
Symptoms ................................................................................ 7 
2.2.2.2 
Viral load .................................................................................. 8 
2.2.2.3 
Viral shedding .......................................................................... 9 
2.2.2.4 
Secondary illness .................................................................. 10 
2.2.2.5 
Hospitalisation ....................................................................... 10 
2.2.3 
Exploratory Efficacy Outcome Measures ............................... 10 
2.2.4 
Pharmacokinetic Outcome Measures .................................... 10 
2.2.5 
Safety Outcome Measures .................................................... 11 
2.2.6 
Resistance Outcome Measures ............................................. 11 
2.2.6.1 
Genotypic resistance ............................................................. 12 
2.2.6.2 
Phenotypic Resistance .......................................................... 12 
2.3 
DETERMINATION OF SAMPLE SIZE................................... 13 
2.4 
ANALYSIS TIMING ............................................................... 13 
3. 
STUDY CONDUCT ..................................................................................... 14 
3.1 
RANDOMIZATION ................................................................ 14 
3.2 
INDEPENDENT REVIEW FACILITY ..................................... 14 
3.3 
DATA MONITORING ............................................................. 14 
4. 
STATISTICAL METHODS .......................................................................... 14 
4.1 
ANALYSIS POPULATIONS ................................................... 15 
4.1.1 
Intent To Treat (ITT) Population ............................................ 15 
4.1.2 
Intent To Treat infected (ITTi) Population .............................. 15 
4.1.3 
Modified Intent To Treat infected (mITTi) 
Population .............................................................................. 15 


Oseltamivir (Tamiflu)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NV20234 
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4.1.4 
Pharmacokinetic-Evaluable Patient Population ..................... 15 
4.1.5 
Safety Population .................................................................. 16 
4.1.6 
Protocol Deviations ................................................................ 16 
4.2 
ANALYSIS OF STUDY CONDUCT ....................................... 16 
4.3 
ANALYSIS OF TREATMENT GROUP 
COMPARABILITY ................................................................. 17 
4.4 
EFFICACY ANALYSIS .......................................................... 17 
4.4.1 
Primary Efficacy Endpoint ...................................................... 18 
4.4.2 
Secondary Efficacy Endpoints ............................................... 18 
4.4.2.1 
Time to Event Endpoints ........................................................ 18 
4.4.2.2 
Comparison of TTR of All Symptoms to Historical 
Control ................................................................................... 18 
4.4.2.3 
Continuous Endpoints ........................................................... 20 
4.4.2.4 
Binary Endpoints (Incidences) ............................................... 20 
4.4.3 
Exploratory Efficacy Endpoints .............................................. 21 
4.4.4 
Sensitivity Analyses ............................................................... 21 
4.4.4.1 
Efficacy Analyses using ITTi .................................................. 21 
4.4.4.2 
Efficacy Analyses excluding other antiviral 
patient data ............................................................................ 21 
4.4.4.3 
Additional efficacy analyses using alternative 
historical controls ................................................................... 21 
4.4.4.4 
Comparison of TTR of All Symptoms to Historical 
Control ................................................................................... 22 
4.4.4.5 
Additional Secondary Illnesses Analysis................................ 22 
4.4.5 
Subgroup Analyses ............................................................... 22 
4.4.6 
Additional analyses not specified in the protocol ................... 23 
4.4.6.1 
Use of 90% CIs .......................................................................23 
4.4.6.2 
Removal of >48 hour symptom onset to dose 
restriction ............................................................................... 23 
4.5 
PHARMACOKINETIC AND 
PHARMACODYNAMIC ANALYSES ..................................... 23 
4.6 
SAFETY ANALYSES ............................................................. 24 
4.6.1 
Exposure of Study Medication ............................................... 24 
4.6.2 
Adverse Events ..................................................................... 24 
4.6.3 
Laboratory Data ..................................................................... 25 


Oseltamivir (Tamiflu)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NV20234 
5 
4.6.4 
Vital Signs .............................................................................. 25 
4.6.5 
Tissue rejection and/or GVHD in transplant 
patients .................................................................................. 26 
4.7 
RESISTANCE ........................................................................ 26 
4.8 
VIROLOGY ............................................................................ 26 
4.9 
MISSING DATA ..................................................................... 27 
4.10 
INTERIM ANALYSES ............................................................ 27 
5. 
REFERENCES ........................................................................................... 27 
6. 
APPENDIX 1: PROTOCOL SYNOPSIS ...................................................... 28 
7. 
APPENDIX 2: SCHEDULE OF ASSESSMENTS ........................................ 32 
8. 
APPENDIX 3: PATIENT DIARY DATA AND SYMPTOM 
RECORD FOR ADULTS AND CHILDREN ................................................. 34 
9. 
APPENDIX 4: HISTORICAL CONTROL SPECIFICATION 
FOR EFFICACY .......................................................................................... 36 
10. APPENDIX 5: SUMMARY OF MAIN EFFICACY ANALYSES .................... 37 
11. APPENDIX 6: VIRAL MUTATIONS ASSOCIATED WITH 
RESISTANCE ............................................................................................. 44 
12. APPENDIX 7: ALGORITHMS USED FOR DERIVATION AND 
SUMMARIES OF TIME TO ALLEVIATION OF ALL 
SYMPTOMS ............................................................................................... 45 
 
 
LIST OF TABLES 
Table 1 
Expected confidence intervals associated to specific event 
rates ............................................................................................ 13 


Oseltamivir (Tamiflu)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NV20234 
6 
1. 
BACKGROUND 
Study NV20234 is a post-authorization commitment (PAC) of Tamiflu® 
registrations agreed with the European Medicines Agency (EMA) and a post-
marketing requirement (PMR) of Tamiflu registrations agreed with the US Food 
and Drug Administration (FDA).  It also forms part of the EMA Paediatric 
Investigational Plan (PIP). 
This Statistical Analysis Plan (SAP) is based on Protocol Version F (18 June 
2014).   
2. 
STUDY DESIGN 
Study NV20234 is a double-blind, randomized, stratified multi-center trial of 
conventional and double dose oseltamivir in immuno-compromised (IC) patients. 
The conventional dose in adults (≥18 years of age) and adolescents (from ≥13 to 
<18 years of age) is 75 mg twice daily (BID) for 10 days. In children (from 1 to 
<13 years of age) the conventional doses are 30, 45, or 60 mg BID for 10 days 
based on body weight. Immunocompromised (IC) patients who develop an 
influenza-like illness with confirmed influenza from a positive rapid diagnostic 
test, PCR, or viral culture will be enrolled during the influenza season. Patients 
will be stratified by: 
● 
Transplant type: hematopoietic stem cell transplant [HSCT] vs. solid organ 
transplant [SOT] (Protocol Version A and B) or transplant status yes vs. no 
(Protocol Version C onwards). 
● 
The time between onset of influenza symptoms and treatment start (up to 48 
hours) (≤ 24 hours vs. >24 hours) (Protocol Version A and B) or the time 
between onset of influenza symptoms and treatment start (up to 96 hours) 
(≤ 48 hours vs.  > 48 hours) (Protocol Version C onwards). 
● 
 Influenza vaccination status for current influenza season (yes vs. no). 
● 
 Age (≤ 12 years vs. >12 years). 
See section 4.4.5 for further description of subgroup analyses. 
 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule 
of Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
All endpoints (safety, resistance, efficacy and PK) are defined in the SAP 
(descriptions of the endpoints are in Section 2 and the statistical methods used to 
describe the endpoints are described in Section 4). There are two co-primary 
endpoints – safety/tolerability and resistance. It is worth noting that the primary 
endpoint of this study changed during the course of the study.  ‘Time to 
Resolution of All Influenza Symptoms’ was the primary endpoint in versions A 


Oseltamivir (Tamiflu)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan NV20234 
7 
and B of the protocol.  However, this endpoint was relegated to a secondary 
endpoint to reflect the change in objectives introduced in Protocol Version C. 
Baseline is defined for all endpoints as the pre-dose reading on Day 1.   
2.2.1 
Primary Efficacy Outcome Measures 
Not applicable as efficacy is not the primary objective.  
2.2.2 
Secondary Efficacy Outcome Measures 
Secondary efficacy outcome measures are defined below. 
2.2.2.1 
Symptoms 
● 
Time to Resolution (TTR) of All Symptoms in adolescents and adults is 
defined as the time from treatment initiation to the start of the 24 hour period 
in which all seven symptoms have scores ≤ 1 (mild) and remain ≤1 for at least 
21.5 hours. Patients with symptom scores ≤ 1 at baseline, which remain ≤1 for 
at least 21.5 hours thereafter, will have a TTR of all symptoms set to missing. 
Patients with symptom scores > 1 at baseline followed immediately by 
scores ≤1 for at least 21.5 hours will have a TTR of all symptoms set to zero. 
Baseline (time zero) is defined as the time of symptom scores prior to first 
dose. For any subjects who have baseline scores missing, a subsequent set 
of symptom scores that is <12 hours post dose will be used. In order to 
gauge whether the previous action introduces a bias, a sensitivity analysis 
will exclude patients who do not meet the strict definition of baseline 
symptoms. Records in which all baseline symptoms are mild, i.e. ≤1, but any 
rises above 1 after first treatment will be set to missing. Posterior intermittent 
cycles of relapsing and recovery will be ignored. 
● 
TTR of All Symptoms (children) is defined as the time from treatment 
initiation to the start of the 24 hour period in which all 18 symptoms items 
have scores ≤1 (minor or no problem) and remain ≤1 for at least 21.5 hours. If 
a score of 4 (“do not know” or “not applicable”) occurs at any assessment 
during the study for any given symptom, the assessment will not be included 
in the calculation of the resolution of all CARIFS symptoms. Patients with 
symptom scores ≤1 at baseline which remain ≤1 for at least 21.5 hours 
thereafter will have a TTR of all symptoms set to missing. Patients with 
symptom scores ≤1 at baseline followed immediately by scores ≤1 for at least 
21.5 hours will have a TTR of all symptoms set to zero. As above, records in 
which all baseline symptoms are mild, i.e. ≤1, but any rises above 1 after first 
treatment will be set to missing. Posterior intermittent cycles of relapsing and 
recovery will be ignored. 


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● 
Area Under the Effect-Time Curve (AUE) for all symptoms (adults only). This 
will be calculated from baseline (symptom score prior to start of study drug 
or, if missing, before 12 h after starting treatment) to the time at which all 
symptoms are first alleviated, i.e. ≤1. Totals scores will be tracked over time. 
The AUE of these average scores is then calculated for each subject using 
the trapezoidal rule. The median of those AUE will be compared between 
groups using CI. 
● 
TTR of Individual Symptoms (all patients with baseline symptom scores > 1) 
is defined as the time from treatment initiation to the start of the 24 hour 
period at which a specific symptom score is ≤1 and remains ≤1 for at least 
21.5 hours. For children, if a score of 4 (“do not know” or “not applicable”) 
occurs at any assessment during the study for any given symptom(s), the 
assessment will not be included in calculating the TTR. Patients with 
symptom scores ≤1 at baseline which remain ≤1 for at least 21.5 hours 
thereafter will have a TTR set to missing. Patients with symptom scores >1 at 
baseline followed immediately by scores ≤1 for at least 21.5 hours will have a 
TTR set to zero. 
● 
The AUE for Individual symptoms (adults only) will be calculated from 
baseline (symptom score prior to start of study drug) to the time at which the 
individual symptom is first alleviated (≤1). The AUE of the individual symptom 
score is calculated for each subject using the trapezoidal rule. 
● 
Time to resolution of fever is defined as the time from treatment initiation to 
the last time at which temperature was ≥37.8o C (all patients). For patients 
who did not have a temperature ≥37.8oC at baseline and throughout the 
dosing period, the time to resolution of fever will be missing. For patients who 
had a temperature of ≥37.8oC at baseline, followed immediately by a 
temperature of <37.8o C at their first post-baseline assessment, the time to 
resolution of fever will be zero. Patients who still had a temperature ≥37.8o C 
at the end of the follow-up period will be censored at that time point. Patients 
who withdraw prior to resolution of fever will be censored at the time of 
withdrawal. 
Note: As the introduction of the electronic diary removed the requirement for the 
patient to record their own baseline temperature, the baseline for these 
patients will be defined as the temperature recording collected at the first site 
visit. It is recognized that the absence of a true patient recorded temperature, 
using the same thermometer and body site, will limit interpretation of this 
endpoint.  
 
2.2.2.2 
Viral load 
Viral load is the number of viral particles per mL of blood. It is reported in log10 
scale and expressed in 1) virus particles/mL (log10 vp/mL) calculated from the 
quantitative RT-PCR assay (reverse transcriptase polymerase chain reaction) 
and 2) 50% tissue culture infectious dose (log10 TCID50) obtained after viral 
culture. 


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● 
Viral load change from baseline over time expressed in log10 vp/mL, where 
baseline is defined as the pre-dose day 1 result. 
● 
Viral load change from baseline over time expressed in log10 TCID50/mL, 
where baseline is defined as pre-dose day 1 result. Log10 TCID50/mL is 
calculated as: 𝑇𝑇𝑇𝑇50 = −ቀ𝑋0 −𝑑2
ൗ+ 𝑑∑
𝑝𝑥
𝑥𝑚𝑚𝑚
𝑥𝑝=1
ቁ, (Ramakrishnan MA, 2016) 
where: 
X0 = positive logarithm of the highest dilution at which all quadruplicate 
wells are positive in the haemagglutination assay or NP-ELISA,  
𝑝𝑥=
𝑟𝑥
4, where rx is the number of positive wells (out of 4) at dilution x, 
 xp=1 is maximum dilution at which all 4 wells are positive, 
xmin is the dilution at which all four wells are negative for the first time, 
and 
d is the log10 dilution factor, i.e. log1010-1=-1. 
N.B. The data contains two variables: X0 and X1, where 𝑋1 =
−∑
𝑝𝑥
𝑥𝑚𝑚𝑚
𝑥𝑝=1
 and X0=-X0 (see above). Thus, programmatically, 
𝑇𝑇𝑇𝑇50 = 𝑋0 −0.5 + 0.25𝑋1 
● 
Area under the viral titer curve calculated applying the trapezoidal rule to the 
log10 TCID50/mL viral load titer. 
● 
Area under the viral titer curve calculated applying the trapezoidal rule to the 
log10 vp/mL viral load titer. 
● 
Peak viral titer per arm defined as the maximum log10 TCID50/mL. 
● 
Peak viral titer per arm defined as the maximum log10 vp/mL. 
2.2.2.3 
Viral shedding 
Time to cessation of viral shedding is defined as the time from treatment initiation 
to the time of first negative result with no subsequent positive results. Event is 
applicable only to patients infected at baseline. A value of 0.5 or less log10 
TCID50/mL and a value of 0.26 or less log10 vp/mL for Flu A strains and 0.3 or 
less log10 vp/mL for Flu B strains will be interpreted as a negative result. Any 
subsequent missing values for either RT-PCR or culture will be assumed to be 
negative. Patients who did not have the right assay to determine viral shedding 
(Haemagglutination assay or NP-ELISA) will be excluded from this analysis. 
● 
Time to cessation of viral shedding determined by Haemagglutination assay 
for H1N1 and Flu B strains or NP ELISA (NucleoProtein Enzyme-Linked 
Immunosorbent Assay) for H3N2 strains after viral culture and expressed in 
log10 TCID50/mL (50% Tissue Culture Infectious Dose). 
● 
Time to cessation of viral shedding determined by RT-PCR and expressed in 
log10 virus particles/mL (vp/mL).  
● 
Incidence of patients with viral shedding by RT-PCR by visit. 
● 
Incidence of patients with viral shedding by viral culture by visit. 


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● 
Incidence of persistent shedding, defined as <1 log10 vp/mL reduction at end 
of treatment, compared with baseline. 
2.2.2.4 
Secondary illness 
Note that although the secondary illnesses of interest defined in the protocol do not 
include the term LRTC this term will be included to ensure other LRTCs not captured as 
pneumonia or bronchitis will be reported. 
● 
Incidence of any secondary illnesses such as LRTC (otitis media, bronchitis, 
pneumonia or sinusitis) for all patients at any time during the study. 
● 
Incidence of secondary illnesses, i.e. LRTC, for all patients at any time during 
the study that are treated with antibiotics. Antibiotic use for secondary 
illnesses will be selected from the concomitant logs prior to database lock. 
This selection will be based on a medical decision. Cases will be identified as 
any antibiotic treatment received for the above secondary illnesses.  
● 
Time to initiation of treatment with antibiotics from randomisation. 
Note:  Although this endpoint was defined in the protocol using randomization 
date and time as the start of the time period, the time from treatment 
initiation will be used to define the start of the time period.  This decision 
has been made in order to remain consistent with other time to endpoints in 
this study. The time between randomization and treatment initiation will be 
checked to ensure time differences across the two treatment groups are 
balanced.  
2.2.2.5 
Hospitalisation 
● 
Incidence of hospitalisations for all patients. Given that patients will be in the 
study for a short period, i.e. ~40 days, we envisage a maximum of 1 
hospitalisation per patient. Thus, probabilities of hospitalisation will be 
compared across treatment arms. 
● 
Duration of hospitalisation (in days), for those who are hospitalized, as 
recorded directly on the Case Report Form (CRF) for all patients. Given that 
there may be few hospitalisations, this subgroup analysis will only report 
median times and ranges by treatment arm. 
 
2.2.3 
Exploratory Efficacy Outcome Measures 
Not applicable. 
2.2.4 
Pharmacokinetic Outcome Measures 
If estimable, the following model-predicted PK parameters for oseltamivir and 
oseltamivir carboxylate will be calculated on the basis of the oseltamivir 
established population PK model. 
● 
Steady-state area under the concentration-time curve from 0 to 12 hours 
(AUC0-12). 
● 
Maximum plasma concentration Cmax. 


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● 
Trough plasma concentration Ctrough. 
If appropriate, the following model-predicted parameters may also be included. 
● 
Elimination half-life (t1/2). 
● 
Time to maximum concentration (tmax). 
● 
Elimination constant (ke). 
● 
Apparent Clearance (CL/F). 
● 
Apparent volume of distribution (Vc/F). 
● 
Apparent total clearance of metabolite (CLm). 
● 
Last measurable concentration (Clast). 
● 
Time to last measurable concentration (tlast). 
 
2.2.5 
Safety Outcome Measures 
The endpoints used to support the co-primary objective of safety are the 
following: 
● 
Incidence and severity of AEs (including influenza-associated complications 
and abnormal findings from physical examinations), SAEs, and reasons for 
the discontinuation of any study medication. All SAEs and AEs will be 
tabulated including their clinical severity. 
● 
Change from baseline in vital signs (weight, temperature, respiratory rate, 
blood pressure and pulse rate). 
● 
Change from baseline in laboratory parameters (AST, ALT, total bilirubin, 
urea, creatinine, CBC and differential blood cell count, i.e. neutrophils, 
lymphocytes, monocytes, eosinophils, basophils). 
● 
Lab abnormalities by baseline and visit status (see SOP COG 3007 for 
expected normal ranges). 
● 
Incidence of tissue rejection or GVHD (Graft Versus Host Disease) in 
transplant patients. 
Note:  Incidence of transplant rejection or GVHD in transplant patients has been 
defined in the protocol as both a primary and secondary endpoint.  It will be 
reported as a primary safety endpoint. 
 
2.2.6 
Resistance Outcome Measures 
The following endpoint is used to support the co-primary objective of resistance. 
Resistance is defined as the presence of oseltamivir resistance in samples 
identified by sequencing of the neuraminidase (NA) and haemagglutinin (HA) 
genes (genotypic resistance) or by oseltamivir IC50 determination by a NA 
inhibition assay, using statistical outlier rules (phenotypic resistance). 
Resistance (genotypic, phenotypic and pooled) will be summarized per age 
(adults, paediatrics), dose group, viral type and subtype.  


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For patients who are infected with both A and B virus types or two Flu A viruses 
the following algorithm will be applied: 
● "A" if RT-PCR A is positive (i.e. not NEGATIVE) and RT-PCR B is 
NEGATIVE at the 1st timepoint with RT-PCR results. 
● "B" if RT-PCR B is positive (i.e. not NEGATIVE) and RT-PCR A is 
NEGATIVE at the 1st timepoint with RT-PCR results. 
●  “AB” if RT-PCR A and RT-PCR B are positive (i.e. not NEGATIVE) and 
Mixed Flu A if both RT-PCRs for Flu A subtyping are positive (i.e. not 
NEGATIVE) at the 1st time point with RT-PCR results. 
●  "UNK" otherwise. 
For patients with a mixed infection, samples from time points with only one 
detected Flu type will be included in the overall virology analyses. Entire virology 
data will be described separately per patient. 
 
2.2.6.1 
Genotypic resistance 
Baseline and post-baseline genotypic resistance is defined as the presence 
of oseltamivir resistance mutations in the NA or HA genes identified by 
sequencing of influenza viruses isolated from nasopharyngeal samples. 
Genotypic resistance calculation: Presence of genotypic resistance (yes/no), 
together with the specific resistance mutations will be identified (see USPI list in 
Appendix 6) for each nasopharyngeal sample and will be listed.  
Note: a H274Y-specific RT-PCR assay was performed for some H1N1 
samples of season 2008-2009 to determine baseline genotypic resistance 
and results will be also included. 
2.2.6.2 
Phenotypic Resistance 
Baseline and post-baseline phenotypic resistance is defined as the presence 
of phenotypic resistance identified by oseltamivir IC50 determination, using 
statistical outlier rules and in accordance with the algorithm described in 
surveillance studies (Sheu TG et al 2008, Okomo-Adhiambo M et al, 2010). 
Phenotypic resistance calculation: The mean IC50 of the baseline (pre dose 
Day 1 result) samples of all patients will be calculated separately for each virus 
subtype. Extreme outliers will be defined as any baseline or post-baseline IC50 
values > 10-fold the baseline mean IC50. The baseline IC50 distribution statistics 
(i.e. mean, standard deviation [SD], median, 75th percentile [X0.75]) will then be re-
calculated excluding any baseline extreme outliers previously identified. Outliers 
will be defined as any baseline or post-baseline IC50 values less than 10-fold the 
baseline mean, but more than three interquartile ranges (IQRs) greater than the 


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baseline third quartile (X0.75) ( > [X0.75 + {3 × IQR}]). Outliers and extreme outliers 
will be considered to have phenotypic resistance. 
Note: the phenotypic resistance algorithm assumes that the IC50 samples 
are normally distributed. Appropriate transformations will be considered if 
this assumption is not met. Furthermore, alternative algorithms (e.g., 
fold-changes, pooling of NA subtypes) may be used if the number of IC50 
samples per NA subtype is considered small. 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
The sample size has been chosen to provide an adequate number of patients to 
estimate the development of resistance (genotypic and/or phenotypic) with 
reasonable precision.  Assuming that 90% of enrolled patients will have 
laboratory-confirmed influenza, there will be 75 patients in each treatment arm in 
the population evaluable for the development of resistance.  The following table 
shows the 95% Pearson-Clopper confidence intervals that would result with a 
sample size of 75 patients in a treatment arm if certain event rates are observed 
in the study. 
Table 1 
Expected confidence intervals associated to specific event rates  
Observed Rate (%) 
95% Confidence Interval 
0.0 
0.0-4.8 
1.3 
0.0-7.2 
2.7 
0.3-9.3 
5.3 
1.5-13.1 
10.7 
4.7-19.9 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the 
assessment of safety.  This number of patients would provide estimates of 
adverse event rates with similar precision (see Table 1). 
The sample size of 75 patients per group will have 66% power to detect a 
clinically relevant difference (CRD) between active treatment and historical 
placebo of 34 hours in time to resolution of symptoms, assuming a common 
standard deviation (SD) of 98 hours, using a 2-sided 10% alpha. The CRD and 
SD reflect those used to power the original study (original protocol).This has 
been calculated in EAST version 6.0, based on a Wilcoxon sign rank test. As no 
formal hypothesis will be tested in this study, the use of a 2-sided 10% alpha will 
be reflected by the use of 90% CIs.  
2.4 
ANALYSIS TIMING 
The efficacy and safety data will be reported at the end of the study, following 
database lock.  Database lock will occur once the final SAP has been approved 


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and the database is clean. The analysis population datasets will then be created 
and reviewed prior to release of Treatment Allocation Information (TAI).  
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION  
Patients will be randomized 1:1 to conventional oseltamivir or double dose 
oseltamivir, stratified according to 4 binary stratification factors. Patients 
randomized under Protocol versions A and B will be stratified according to 
transplant (SOT vs. HSCT); time between onset of influenza symptoms and 
treatment start (≤24 hours vs. >24 hours); influenza vaccination status for current 
influenza season (yes vs. no), and age (≤12 years vs. >12 years). 
Patients randomized under Protocol C onwards will be stratified according to 
transplant (yes vs. no), time between onset of influenza symptoms and treatment 
start (up to 96 hours, ≤48 hours, >48 hours), influenza vaccination status for 
current influenza season (yes vs. no) and by age (≤12 years vs. >12 years). As 
only transplant patients were enrolled during Protocol A and B, at this time, the 
randomization was not stratified by transplant status. 
The master randomization list is an un-stratified randomization list implemented 
in the Interactive Voice/Web Recognition System (IxRS) using a dynamic block 
allocation algorithm to centrally assign patients to the correct strata. 
Following the release of TAI, the treatment assignments from the IxRS listing will 
be checked against the master randomization list to ensure the correct 
treatments have been assigned.  Furthermore, the date and time of 
randomization will be checked against the date and time of first dose to ensure 
patients were randomized prior to receiving treatment.  Any errors noted will be 
listed as protocol deviations in the clinical study report (CSR). 
Any patients who were assigned to the incorrect strata level at randomization will 
have the strata information corrected for reporting purposes but the original 
randomization will remain unaltered. 
3.2 
INDEPENDENT REVIEW FACILITY 
Not applicable. 
3.3 
DATA MONITORING 
Blinded reviews of the data will be performed on an ongoing basis by the study 
scientist. 
4. 
STATISTICAL METHODS 
All analyses, summaries and listings will be performed using SAS® software 
(version 9.2 or higher) in a UNIX environment. The data will be listed in the CSR.  


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All endpoints previously defined will be listed and summarized using appropriate 
descriptive statistics. 
4.1 
ANALYSIS POPULATIONS 
The main analysis populations are defined below. 
4.1.1 
Intent To Treat (ITT) Population 
All patients randomized will be included in the ITT population. Patients will be 
summarized under the treatment to which they were randomized. This population 
may be used to summarize efficacy endpoints for the purpose of sensitivity 
analyses. This population will generate the most conservative effect estimates 
because there may be allocation errors, non-infected patients and/or non-
adherence to treatment. 
4.1.2 
Intent To Treat infected (ITTi) Population 
All patients randomized and with central laboratory confirmation of influenza 
infection, excluding patients infected with oseltamivir-resistant influenza at 
baseline, will be included in the ITTi population.  
4.1.3 
Modified Intent To Treat infected (mITTi) Population 
All patients randomized to a particular treatment, regardless of whether they 
received that treatment or not, and received at least one dose of study drug and 
with central laboratory confirmation of influenza infection, excluding patients 
infected with oseltamivir-resistant influenza at baseline, will be included in the 
mITTi population. This population will also be used to summarize all efficacy and 
resistance endpoints because it will render least biased effect estimates. This 
population was not defined in the protocol. 
The definition of oseltamivir-resistant influenza at baseline is defined in Section 
2.2.6.  Decisions on patient exclusion from the ITT, ITTi and mITTi population 
sets will be made by the statistician and study scientist after database closure.  
Excluded patients will be documented along with the reason for exclusion.  
4.1.4 
Pharmacokinetic-Evaluable Patient Population 
The Pharmacokinetic Evaluable Patient (PKEP) population comprises all patients 
in the ITT population have at least one post-dose drug concentration 
measurement at a scheduled visit time point.  Patients may be excluded from the 
PKEP population if they significantly violate the inclusion or exclusion criteria, 
deviate significantly from the protocol, or have unavailable or incomplete data 
that may influence the PK analysis. 
Decisions on patient exclusion from the PKEP will be made prior to database 
closure by the clinical pharmacologist based on information supplied by the Data 
acquisition specialist (whether patients in the ITT population have at least one 
post-dose drug concentration measurement at a scheduled visit time point). No 


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PK data will be shared with the team as this would unblind the study.  Excluded 
patients will be documented along with the reason for exclusion. 
4.1.5 
Safety Population 
The safety analysis population will include all patients who receive at least one 
dose of study drug and have had a safety assessment performed post 
randomization.  All safety variables will be summarized and presented in tables 
based on this safety population.  Any patients who receive a dose that differs 
from the dose to which they were randomized will be reported under their actual 
treatment. 
4.1.6 
Protocol Deviations 
Major protocol deviations will be listed in the CSR. Major protocol deviations will 
include those captured during the study conduct (
 file), as well as any 
additional deviations found as a result of programmatic checks of the following 
criteria: 
- Patients who received their first study drug dose more than 96 hours from onset 
of symptoms. 
- Patients with randomization errors – randomized and not dosed, dosed prior to 
randomization. 
- Use of antiviral treatment for influenza in the 2 weeks prior to randomization 
and during the 10 day treatment phase of the study. 
- Less than 16 of the 20 planned doses (80%) of study drug. 
Sensitivity analyses may be carried out excluding any major protocol deviations.  
4.2 
ANALYSIS OF STUDY CONDUCT 
The following tables will be summarized by treatment group according to current 
sponsor data standards. 
● 
Summary of treatment.   
● 
Summary of disposition of patients in the Safety, ITT, ITTi, mITTi and PKEP 
populations. 
● 
Summary of patients excluded and reasons for exclusions from each of the 
analysis populations (Safety, ITT, PKEP, ITTi, mITTi). 
● 
Summary of withdrawals, including the reason for withdrawal (Safety, ITT, 
ITTi, mITTi). 
● 
Summary of concomitant medications split by: immunosuppressive 
treatment; treatment for influenza-like symptoms; treatment for AEs; other 
treatments. 
Protocol deviations, as reported directly by sites or captured through 
programmatic checks of the database of deviations that occur during study 


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conduct, will be listed and summarized by randomized treatment accordingly, as 
per Section 4.1.6.  
 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Baseline patient characteristics will be summarized by treatment group.  The 
main population for these baseline summaries will be the mITTi.  However, 
summaries based on the Safety, ITT and ITTi populations will also be included in 
the CSR.   
All baseline patient characteristics data will be listed.  To assess comparability, 
descriptive statistics will be presented by treatment group as follows: 
● 
Demography including age, gender, race and ethnicity. 
● 
Immunodeficiency conditions at baseline. 
● 
Transplant history. 
● 
Historical CD4 count. 
● 
Influenza vaccination status. 
● 
Previous or current diseases at baseline (Medical History). 
● 
Previous treatments, split by immunosuppressive treatment, treatment for 
influenza-like symptoms, and others.  
● 
Influenza infection status: Flu Type (A or B) and Flu A subtype (H1N1, H3N2) 
(mITTi only). 
No statistical comparisons will be made, as no formal hypothesis is being tested. 
4.4 
EFFICACY ANALYSIS 
All efficacy endpoints are considered secondary or exploratory. As no formal 
efficacy hypothesis is being tested, treatment differences presented in any 
efficacy analyses will be reported with associated confidence intervals (CIs) only. 
Efficacy endpoints will be summarized by age group. All summaries and 
analyses are described below and listed in Appendix 5. All efficacy analyses will 
be based on the mITTi and ITTi populations. ITT will be presented for the main 
efficacy TTR summary tables (all symptoms and temperature only) to investigate 
the effect of treatment in a “real world” scenario, i.e. unknown infection status 
and/or adherence. N.B. Regulatory bodies have asked for these outputs in 
pivotal studies. 
All efficacy summaries and analyses will be carried out separately for adults 
(patients ≥ 18 years) and paediatrics (patients <13 years old). Adolescent data 
(patients aged between ≥13 and <18 years old) will be listed as appropriate. 
As the symptom data are recorded on patient diaries, data errors cannot be 
queried.  Obvious data errors, i.e. temperature 100oC, will be excluded and 
documented. For duplicated data, the worst evaluation will be used to obtain 
conservative estimates. 


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The endpoints as described in the protocol have been expanded to give sufficient 
information of the derivations required, e.g. symptom scores was the endpoint 
defined in the protocol but Time To Resolution of symptom scores is how it is 
described in the SAP. 
4.4.1 
Primary Efficacy Endpoint 
Not applicable. 
4.4.2 
Secondary Efficacy Endpoints 
4.4.2.1 
Time to Event Endpoints 
Time to event endpoints include the following: TTR of all symptoms, TTR of 
individual symptoms, time to cessation of viral shedding and time to resolution of 
fever. These endpoints will be summarized using Kaplan-Meier tables and 
graphs. Viral shedding will be studied also per virus strain. The median TTR and 
associated 95% CIs will be estimated for each of the two treatment groups. The 
exact CIs of the median differences of Hodges-Lehmann (HL) estimators will be 
derived using the PROC NPAR1WAY in SAS. The protocol mentioned 
bootstrapping, however in SAS, bootstrapping calculates differences between 
medians, when the correct estimator in skewed distributions is the median of 
differences (or HL estimator). Asymptotic theory exists to obtain those CI (aka 
Moses CI). 
Patients who have not experienced the event, e.g. resolution of all symptoms, by 
the last day of contact will be censored at this time. Patients who withdraw from 
the study without experiencing the event will be censored at the time of 
withdrawal (see Appendix 7). 
4.4.2.2 
Comparison of TTR of All Symptoms to Historical Control 
It is unethical to treat IC patients with placebo. Nevertheless, it is important to 
ascertain whether treating IC patients for influenza is still better than not treating 
them. Given the ethical constraint, the next best possible comparison available is 
against historical placebo controls. Thus, any difference between these two 
groups will be due to both IC status (yes/no) and oseltamivir effect. It will not be 
possible to differentiate both effects statistically. Historical controls will come first 
and foremost from pivotal historical oseltamivir studies where otherwise healthy 
(OwH) were enrolled. The main comparison of active treatment with historical 
control placebo will be based on a 1:1 matching of all adult NV20234 patients 
with OwH placebo patients from the pivotal studies. All patients in the adult mITTi 
population will be matched to historical patients (from the pivotal studies) that 
received a placebo.  
There are three types of matches in order of priority: 
1. Patients will be matched 1:1 within viral strain and then by age with ± 5 
years caliper (the lowest limit being 18) and gender. Any remaining 
unmatched individual will be matched by age and gender alone. Only 


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pivotal studies will be used. Outputs in appendix 5 refer to this matching 
rule. 
2. Patients will be strictly matched 1:1 by age as above, gender and 
influenza strain. Only pivotal studies will be used. There will probably 
leave more unmatched patients but those matched will be more similar 
than in 1. 
3. Patients will be matched 1:>1 as in 1 above using pivotal and non-pivotal 
but relevant historical studies. Additional matching by time between 
symptoms onset and first treatment (possibly with a caliper) will be used if 
closer matching is required. This is a sensitivity analysis captured in 
section 4.4.4. 
In cases where those matching rules are not sufficient, i.e. more than one patient 
in the 1:1 placebo matching, an additional rule will be the elapsed time from first 
symptoms to first dose. If several matches are still available in the 1:1 ratio, one 
match will be chosen at random (the seed of the random number generator will 
be kept for reproducibility). 
Any patient from study NV20234 who has not been matched will not be included 
in these analyses. Matches will be done independently for historical placebo and 
historical treated. Modifications of the matching rules above may be permitted if 
scientifically required, e.g. matching by time in 3 above requires a window. The 
ITTi population in historical studies is equivalent to the current mITTi population. 
The pivotal studies to be used are: WV15671 (18-65y, OwH, USA, placebo-
conventional-double) and WV15670 (18-65y, OwH, Europe, Canada, Hong-
Kong, placebo-conventional-double). Potential additional studies include: 
WV15730 (18-65y, OwH), M76001 (13-80y, OwH, placebo-conventional) and 
WV15758 (1-12y, OwH, placebo-conventional). 
A similar comparison may be done between current IC patients and historical 
patients defined as at risk. There may be a 1:1 and 1:>1 matching ratios. The 
historical studies with patients at risk include WV15812 (≥13y, placebo-
conventional) and WV15872 (≥12y, placebo-conventional). Additional studies in 
elderly (>65 years of age) are: WV15819, WV15876, WV15978 and WV15707 
(see Appendix 4). 
The following median differences in TTR of all symptoms (90% and 95% CIs) will 
be reported: 
1. Comparison of conventional dose with matched placebo. 
2. Comparison of double dose with matched placebo. 
3. Comparison of combined conventional and double dose with combined 
matched historical placebo (if the results of the NV20234 dose group 
comparisons suggest responses are similar). 


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To aid interpretation of the results, the median TTR of all symptoms and 
associated 90% CIs will be plotted against historical placebo responses for a) 
NV20234 conventional dose b) NV20234 double dose c) NV20234 combined 
dose groups.  
In addition to the comparison of NV20234 active with placebo patients from the 
pivotal studies, a treatment historical control dataset will be created from the 
same adult treatment studies, matching NV20234 patients randomized to the 
conventional dosing arm with the conventional dose from the adult treatment 
studies. This will enable an informal comparison of the treatment response of IC 
patients with the treatment response in otherwise healthy patients. Patients will 
be matched using the same rules as those for historical control. 
The full specifications for historical control groups can be found in Appendix 4. 
The final set of historical placebo patients will be confirmed prior to treatment 
unblinding and database lock. 
 
4.4.2.3 
Continuous Endpoints 
Continuous endpoints will be summarized by treatment group using descriptive 
statistics N, mean (geometric mean where appropriate), SD, median, and range.  
This will apply to: duration of hospitalisation; absolute and change from baseline 
over time in log10 viral load from quantitative RT-PCR (vp/mL), log10 viral load 
titer from culture (log10 TCID50/mL), AUC viral load titer, peak viral load titer, AUE 
total symptom score, and AUE individual symptom scores. 
4.4.2.4 
Binary Endpoints (Incidences) 
The proportion of patients experiencing the event will be presented for each of 
the two treatment groups. This will apply to the patients still shedding virus per 
planned visit, all secondary illnesses endpoints, and hospitalisations (for viral 
shedding it will be presented by treatment group, age cohort and flu type). 
● 
Incidence of any secondary illnesses: each patient can have several LRTCs, 
therefore a table of frequencies of 0 to 4 LRTC will be obtained per treatment 
arm. 
● 
Incidence of secondary illnesses for patients treated with antibiotics: as 
above, the frequency of LRTC will be obtained by treatment arm. 
● 
Incidence of initiation of treatment with antibiotics: The probability of antibiotic 
use will be compared between treatment arms using probability differences 
and confidence intervals of those differences. 
● 
Incidence of hospitalisations: probabilities of hospitalisation per treatment 
arm and their CI’s will be provided. 
● 
Duration of hospitalisation: given that there may be few hospitalisations, this 
subgroup analysis will only report median times and ranges by treatment 
arm. 


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4.4.3 
Exploratory Efficacy Endpoints 
Descriptive statistics may be used to further investigate symptom scoring in 
adults and children considering that symptoms of the patient’s underlying 
immune status and baseline conditions could overlap with influenza-like illness 
symptoms in this patient population. 
4.4.4 
Sensitivity Analyses 
4.4.4.1 
Efficacy Analyses using ITTi  
All analyses relating to TTR of all symptoms and TTR of individual symptoms, 
described in Section 4.4.2.1, will be repeated using the ITTi population.  
 
 
4.4.4.2 
Efficacy Analyses excluding other antiviral patient data 
The TTR (mITTi) of all symptoms analyses described in Section 4.4.2.1 will be 
rerun excluding any follow-up data collected from those patients who began 
treatment with another antiviral for influenza, on or after discontinuation of study 
drug. Note that although Section 8.2.7.1 of the protocol indicates that such 
exclusions should be made for all efficacy analyses, this statement contradicts 
the definition of the ITT, ITTi and mITTi populations, so the exclusions of antiviral 
patient data will be regarded as a sensitivity analysis rather than the main 
analysis. Non-immunocompromised patients will be excluded.  
4.4.4.3 
Additional efficacy analyses using alternative historical 
controls 
Further sensitivity analyses of TTR of all symptoms may be carried out using 
alternative historical control datasets as follows: 
1. 1: >1 mapping with OwH patients.  
2. 1: >1 mapping with At Risk patients. 
The purpose of the alternative historical control datasets is two-fold:  
1) Increase the precision on the historical median response by increasing the 
number of patients contributing to this sample using a 1 :> 1 mapping 
approach.  
2) Provide a range of placebo responses that may be considered plausible 
surrogate responses for an IC untreated population. This is based on the 
evidence of an observed difference in placebo responses for otherwise 
healthy patients compared with at risk and elderly patients in the 
oseltamivir adult treatment database. 
To allow for potential exploratory analyses of other efficacy endpoints, the 
historical control dataset will also include the patient level variables where readily 
available: baseline creatinine clearance, age, gender, virus type and subtype, 


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time to cessation of viral shedding, AUE of symptom scores, AUC of viral titer, 
time to resolution of individual symptoms. 
4.4.4.4 
Comparison of TTR of All Symptoms to Historical Control  
The following Kaplan-Meier analyses will be carried out using the mITTi 
population to support the comparison of Study NV20234 treatment response with 
the historical placebo response with both 1:1 and 1:>1 ratios: 
● 
The TTR of all symptoms for adults using only follow-up symptom data 
recorded up to and including 25 days compared with historical placebo data. 
This is to investigate the impact of differences in the follow-up observation 
periods between study NV20234 and the oseltamivir treatment database. 
Adult patients in Study NV20234 who have not experienced resolution of 
symptoms by day 25 will be censored on day 25. In the historical studies 
(see section 4.4.2.2 above and appendix 4) the final assessment was 
between days 17 and 25 post onset. A sensitivity analysis will be carried out 
comparing results from the previous analyses against an analysis without 
censoring at 25 days, i.e. using the current final assessment ~40 days after 
onset of symptoms.  
● 
The TTR of all symptoms for patients who had symptoms onset ≤48 
hours before first dose, for each active treatment group and combined, 
compared with matched historical control patients. 
4.4.4.5 
Additional Secondary Illnesses Analysis 
The incidence of specified secondary illnesses summaries will be repeated, sub-
setting on any LRTC starting on or after study day 3 or at least 48 hours after first 
study drug intake and treated with antibiotics. This should exclude pre-existing 
secondary illnesses that may not be linked to the treatment. These incidences 
will be repeated for LRTCs regardless of antibiotic use. Antibiotic use for 
secondary illnesses will be selected from the concomitant medications log prior 
to database lock. These will be identified as antibiotic treatment received for the 
above secondary illnesses. 
4.4.5 
Subgroup Analyses 
To check for comparability of treatment groups across the stratification levels 
used to randomize the study, the TTR of All Symptoms in the mITTi population 
will be summarized by treatment group split by:  
● 
Vaccination status (yes vs. no). 
● 
Transplant status (yes vs. no). 
● 
Time from symptom onset to time of first dose (≤ 48 hours vs. > 48 hours). 
● 
Age (≤12 vs. >12 years). 
The stratification by Transplant status was added in Protocol version C. 
A further subgroup analysis of TTR of All Symptoms (mITTi) will be carried out by 
geographical location. The 5 regions will be North America (USA and Mexico), 
South America (Brazil, Colombia and Guatemala), Eastern Europe (Bulgaria, 


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Estonia, Hungary, Latvia, Lithuania, Poland and Ukraine), Western Europe 
(Belgium, Italy, Spain and Israel) and South Africa. A single Kaplan-Meier 
analysis will be done by geographic region. 
4.4.6 
 Additional analyses not specified in the protocol 
Two additional analyses for efficacy (TTR and temperature) that were not in the 
original protocol have been introduced in the SAP. 
 
4.4.6.1 
Use of 90% Cis 
In addition to 95% CI, 90% CI will be also shown when comparing current data 
against historical controls. This was agreed jointly by PDCO, CHMP and Roche 
in a briefing document dated 
 where the possibility of establishing a 
new dose recommendation/regimen was discussed. 
 
4.4.6.2 
Removal of >48 hour symptom onset to dose restriction 
Although the protocol originally specified this comparison would be restricted to 
those patients who received treatment within 48 hours (≤48 hours), such analysis 
will be conducted as a sensitivity analysis only. The rationale for the additional 
analyses is that there is no direct evidence that dosing more than 48 hours after 
the start of symptoms will not be effective. Whilst evidence from a large 
observational study suggests an increased benefit for patients if dosed within 48 
hours, compared with patients dosed after 48 hours, there is still evidence of 
benefit if dosed more than 48 hours after symptom onset. In addition, IC patients 
can have prolonged viral shedding compared to immune-competent patients, 
suggesting that administration of drug after 96 hours after symptom onset may 
still provide benefit to these patients by limiting duration of their influenza.  
 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Individual and mean plasma concentrations from the oseltamivir population PK 
model at each sampling time-point for oseltamivir and oseltamivir carboxylate will 
be presented by listings and descriptive summary statistics, including means, 
geometric means, medians, ranges, standard deviations and coefficients of 
variation. Individual and mean concentration-versus-time profiles will be plotted 
on linear and semi-logarithmic scales. 
Plasma concentration data from sparse sampling will be analysed by the clinical 
pharmacologist using an established population PK model to determine key 
exposure parameters defined in Section 2.2.4.  Note:  For IC children (≤ 12 
years) and adolescents (> 12 - ≤ 17 years), plasma oseltamivir and oseltamivir 
carboxylate concentrations will be modeled in NONMEM using a structure similar 
to a comprehensive population PK model which was previously developed using 
oseltamivir and oseltamivir carboxylate plasma concentration data from non-IC 
children and adults (ages 1 to 80 years). 
The PK parameters will be listed and summarized by treatment group using 
descriptive summary statistics including means, geometric means, medians, 
ranges, standard deviations and coefficients of variation. 


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Exposure-response relationships will be presented in the CSR through the use of 
scatter plots, plotting each of the estimated PK parameters separately against 
the area under the viral titer curve; the peak viral titer, and the time to cessation 
of viral shedding.  Different symbols will be used to differentiate treatment 
groups. 
All listings and summaries of plasma concentrations and estimable PK 
parameters will be based on the PKEP population. 
Further PK and PK/PD analyses may be carried out by the clinical pharmacology 
group. This will be reported in a separate report when appropriate. 
4.6 
SAFETY ANALYSES 
No formal hypothesis is being tested to support the co-primary objective of 
safety. Therefore, there will be no formal statistical comparisons between the two 
treatment groups. Summaries will be based on the Safety Population and will be 
provided by treatment and split by age: adults (≥18 years) vs. pool of adolescents 
and children (<18 years). Only tables for adverse event (AE) and serious adverse 
event (SAE) [summary and incidence by System Organ Class (SOC) and 
Preferred Term (PT)] will be provided separately for adolescents (≥13 to <18 
years) and children (<13 years). 
All continuous safety outcomes will be given as medians or medians and 95% 
confidence intervals per treatment arm. All categorical safety outcomes will be 
shown as frequencies by treatment arm. 
4.6.1 
Exposure of Study Medication 
All treatment data will be listed as collected.  The total treatment duration, 
number of doses, total cumulative doses, missed doses and dose modifications 
will be summarized by treatment group with the use of descriptive statistics (N, 
mean, median, SD, and minimum and maximum values).  
4.6.2 
Adverse Events 
Adverse Events (AEs) will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA) preferred terms using the MedDRA version current at the 
time of reporting, prior to the database lock and will be summarized for the Safety 
Population according to current sponsor safety standards. Summaries to be 
presented: 
● Overall Incidence of AEs.   
● Summary of AEs by relationship to study drug.  
● Summary of AEs by body system and Intensity. 
● Summary of Serious Adverse Events (SAEs). 
● Summary of SAEs by relationship to study drug.  


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● Summary of SAEs by body system and Intensity. 
● Summary of Treatment Emergent AEs resulting in death. 
● Summary of AEs leading to study or study drug withdrawal.  
As well as summarizing all AEs overall, summaries by treatment phase (on 
treatment, off treatment) will be presented, where on treatment is defined as an 
AE starting during treatment or up to 2 days after the last dose, and off treatment 
is defined as any AE starting more than 2 days after the last dose.  
Multiple reports of an event by a subject will only be counted once for tabulations 
of adverse event incidences, with the most severe intensity being used. All AEs 
reported on treatment will be considered to be treatment emergent.  
4.6.3 
Laboratory Data 
Blood samples for planned central laboratory tests for safety evaluation of clinical 
chemistry and haematology are collected at baseline (pre-dose Day 1) and Day 
11/End of Treatment.  Results will be listed and summarized for the Safety 
Population, Adults (≥ 18 years) separately from adolescents and children (≤17 
years). Summaries to be presented: 
● Change in baseline to Day 11 will be summarized using descriptive 
statistics (N, Mean (STD), Median, Min, Max) 
● Incidence of marked laboratory abnormalities will be summarized for 
adults only as per Roche 
 
● Unscheduled laboratory results will not be included in any of the 
summaries. If a test was repeated on the same day, the average result will 
be used in the summary tables. If the scheduled Day 11 laboratory test 
was taken after the end of treatment, these off treatment results will still be 
presented in the summaries.  
Historical and Day 1 (Protocol versions A and B only) creatinine clearance, CD4 
counts and white blood cell (WBC) counts will be listed, where available.  CD4 
counts will be summarized separately using descriptive summaries for patients 
only with the inclusion criteria “HIV with a most recent CD4 count <500/mm3 (or 
<25% in children ≤ 5years old) within the last 6 months and, in the investigator’s 
opinion, considered immunocompromised”. 
4.6.4 
Vital Signs 
Vital sign measurements including weight, temperature, respiratory rate, blood 
pressure (position not specified) and pulse rate are planned on Days 1, 2 or 3, 6, 
8 and Days 11, 15 and 40.  These will be listed and summarized for the Safety 
Population (adults will be summarized separately from adolescent and children) 
according to current sponsor safety standards. 


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4.6.5 
Tissue rejection and/or GVHD in transplant patients 
The proportion of transplant patients in the safety population who experience 
tissue rejection and/or GVHD will be summarized by treatment group and age 
4.7 
RESISTANCE 
To support the co-primary objective of this study, the proportion and Clopper-
Pearson 95% CIs of patients with post-baseline genotypic or phenotypic 
resistance among all patients will be summarized by treatment group. The mITTi 
population will be used whenever possible. 
In addition, the following outputs will be included: 
● 
Incidence of overall post-baseline resistance (i.e. developed after first visit) 
by age (≥18 years vs <18 years old) and treatment group, split by flu type 
and subtype. 
● 
Incidence of overall baseline resistance (i.e. observed at first visit) by age 
and treatment group, split by flu type and subtype in ITT population. N.B. 
Patients with baseline resistance are excluded from both ITTi and mITTi 
populations. 
● 
Profiles (listings) of viral load in log10 vp/mL for patients with phenotypic or 
genotypic resistance at baseline. Also listings of genotypic resistance and 
phenotypic outlier samples. 
● 
Incidence of known OC resistance mutations in phenotypic outlier samples 
compared with phenotypically OC sensitive samples. 
● 
Incidence (in %) of post-baseline resistance in patients with detectable viral 
shedding (in log10 vp/mL) at EOT and during follow-up period, by treatment 
group, age (≥18 years vs <18 years old) and flu type and subtype. 
● 
Summary (median and CI) of the TTR by treatment group, split by post-
baseline resistance status. 
● 
Summary (median and CI) of the TTR by treatment group in patients with 
post-baseline resistance, split by flu type. 
● 
Summary of viral load in log10 vp/mL for patients with phenotypic or 
genotypic resistance at baseline. 
 
4.8 
VIROLOGY 
The main virology outputs are: 
● 
Incidence of persistent shedding (%), defined as < 1 log10 viral load 
(vp/mL) reduction at end of treatment compared with baseline. 
● 
Summary of IC50 at baseline and fold-change over time by treatment 
group split by flu type and subtype using descriptive statistics: mean, SD, 
median, IQR, range. 




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6. 
APPENDIX 1: PROTOCOL SYNOPSIS 
 
TITLE: 
A DOUBLE BLIND, RANDOMIZED, STRATIFIED, MULTI-CENTER 
TRIAL EVALUATING CONVENTIONAL AND DOUBLE DOSE 
OSELTAMIVIR IN THE TREATMENT OF IMMUNOCOMPROMISED 
PATIENTS WITH INFLUENZA 
PROTOCOL NUMBER: 
NV20234 
VERSION NUMBER: 
F 
EUDRACT NUMBER: 
2006-002468-24 
IND NUMBER: 
53,093 
TEST PRODUCT: 
oseltamivir (Tamiflu® RO 64-0796) 
PHASE: 
IIIb 
INDICATION: 
Treatment of influenza in immunocompromised patients 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary 
To evaluate prospectively the safety and tolerability of oseltamivir for the treatment of influenza 
in IC patients under standard and double dose, and characterize the effects of oseltamivir in IC 
patients on the development of resistant influenza virus (see 4.6). 
Secondary 
To evaluate the effects of conventional and double dose oseltamivir in IC patients on: 
● The population pharmacokinetics of both oseltamivir and oseltamivir carboxylate in IC 
patients with confirmed influenza infection, through the application of established population 
pharmacokinetic (PK) models to the sparse plasma concentration data generated. 
● The virologic course of influenza (proportion shedding and viral loads at different 
timepoints) 
● The time to resolution of influenza symptoms 
● The clinical course of influenza (fever, symptoms, secondary illnesses as evidenced by 
otitis media, bronchitis, pneumonia, or sinusitis)  
● To explore the relationship of metrics of exposure (e.g., AUC, Cmin) to relevant 
pharmacodynamic  endpoints 
 
Study Design 
Description of Study 
This is a double-blind, randomized, multi-center trial of twice daily, conventional and double 
dose oseltamivir for the treatment of influenza in IC patients.  Patients will be stratified by age 
(<13 vs. >12 years), transplant status (yes vs. no), time since onset of flu symptoms and 
treatment start (up to 96 hours) (≤ 48 vs. >48 hours) and vaccination status (yes vs. no). 
Number of Patients 
A minimum of 166 (83 per arm) to allow an adequate number of influenza A patients per arm; 
including 50 transplant recipients and at least 15 paediatric patients.   
Number of Centers 
Approximately 125 centers in the Northern and Southern Hemispheres 


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Target Population 
Patients immunocompromised due to a primary or secondary immunodeficiency, 1 year of age 
and older (the paediatric and adolescent patients will be defined as 1 year to less than 18 years of age).  
The patients will be positive for influenza by a rapid diagnostic test, PCR or viral culture at 
baseline. 
Length of Study 
The study comprises 10 days of treatment with follow up visits approximately 5 and 30 days 
later as shown in the schedule of assessments.  Study medication will be administered twice 
daily over 10 days for a total of 20 doses.  A rapid diagnostic test for influenza will be performed 
at the end of the 10 days of treatment.  Patients still having influenza based on the rapid 
diagnostic test will be treated per the local standard of care by the principal investigator, and 
any medication provided during the follow-up period should be captured in the CRF.   
Procedures (summary) 
The key procedures are: 
● Blood draws for serum chemistry, hematology, serology, and PK assessments (for those 
patients who provide additional consent to participate in the PK assessments). 
● Nasal and throat swabs for viral culture and RT-PCR. 
 
Assessments of: 
Safety 
The safety laboratory assessments in this study, including the assessment of serum chemistry 
and hematology will be carried out at a central laboratory.  Serum chemistry assessments 
comprise AST, ALT, total bilirubin, urea and creatinine.  Hematology assessments include CBC 
and differential count.  The total volume of blood loss for laboratory assessments will be 
approximately 20 mL for the entire duration of the study.  
Protection of patient confidentiality (Section16) will extend to any data generated from the 
assaying of these samples.  Biological samples taken from all patients may be infectious and 
will be classified as “diagnostic specimens” for dispatch purposes. 
When clinically indicated, the investigator may draw blood for serum creatinine to be assessed 
at the local laboratory during the study to calculate creatinine clearance 
Resistance 
Development of resistance 
Efficacy 
The efficacy laboratory assessments are used for laboratory confirmation of influenza. These 
are: 
Nasal and throat swabs.  Two nasal and one throat swab will be collected as described in the 
Schedule of Assessments.  All swabs are sent to a central laboratory for RT-PCR and viral 
cultures.  Influenza virus shedding will be assessed.   
At the end of treatment (Day 11), a rapid diagnostic test is permITTed for the diagnosis of 
ongoing influenza. 
Investigational Medicinal Products 
Test Product: 
Oseltamivir/placebo dry powder (to be reconstituted to a concentration of 12 mg/mL or 6 mg/mL 
[the 6 mg/mL will only be used if applicable and not before 2015]) and 75 mg capsules.  The duration 
of dosing in both adults and children is 10 days. 
 


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Conventional dose: 
Children ages 1 −12 years:  Oseltamivir syrup 
≤ 15 kg  
 
30 mg twice daily 
15–23 kg  
 
45 mg twice daily 
 23–40 kg 
 
60 mg twice daily 
 >40 kg  
 
75 mg twice daily  
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules 75 mg twice daily 
 
Patients randomized to the conventional dose will simultaneously receive matching placebo so 
as to blind them and the investigator from the double dose arm.  
 
Double dose: 
Children ages 1 - 12 years: Oseltamivir syrup  
≤ 15 kg   
60 mg twice daily 
15–23 kg  
 
90 mg twice daily 
23–40 kg 
 
120 mg twice daily 
>40 kg  
 
150 mg twice daily 
Adults and adolescents (age ≥ 13 years):  Oseltamivir capsules  
150 mg twice daily  
 
Comparator: 
Placebo (from pivotal registration trials in otherwise healthy adults) 
Statistical Methods 
The sample size has been chosen to provide an adequate number of patients to estimate the 
development of resistance with reasonable precision.  Assuming that 90% of enrolled patients 
will have laboratory-confirmed influenza, there will be 75 patients in each treatment arm in the 
population evaluable for the development of resistance.  The following table shows the 95% 
Pearson-Clopper confidence intervals that would result with a sample size of 75 patients in a 
treatment arm if certain event rates are observed in the study. 
During the study the number of influenza A virus infected patients and the rate of development 
of resistance will be monitored in a blinded fashion, in order to ensure a reasonable precision 
for the estimation is maintained.  Additional patients may be enrolled if necessary. 
Table A1.1. Confidence interval given the rate of events 
 
Observed Rate (%) 
95% Confidence Interval 
0.0 
0.0%−4.8% 
1.3 
0.0%−7.2% 
2.7  
0.3%−9.3% 
5.3 
1.5%−13.1% 
10.7 
4.7%−19.9% 
 
A total of 83 patients will be enrolled per arm and will be evaluable for the assessment of safety.  
This number of patients would provide estimates of adverse event rates with similar precision. 
For the primary objective of evaluating the safety of oseltamivir conventional and double dose 
treatments, AEs, physical examinations, tissue rejection and/or graft versus host disease in 
transplant patients, laboratory tests, and vital signs will be summarized and compared with the 
known safety profile of the drug.  For the summary of the development of resistance for each 
treatment arm, 95% confidence intervals will be provided with the estimated rates.   


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For the secondary objective of evaluating the efficacy of oseltamivir as measured by the time to 
resolution of influenza symptoms, the following two assessments will be made independently of 
each other and without regard to the outcomes in each case. 
● Comparison to placebo control from pivotal registration trials 
From the integrated efficacy database associated with the oseltamivir treatment 
approval, a population of placebo treated patients will be established that is comparable 
to patients in the current study whose first dose of study drug was within 48 hours of 
symptom onset.  For this population, a median time to resolution of all clinical influenza 
symptoms will be determined along with its 95% confidence interval. 
 
● Assessment of relative efficacy 
The two dose groups will be compared to each other by estimating the difference in the 
median times to alleviation of symptoms and deriving an associated 95% confidence 
interval. 
The following are the model-derived PK secondary endpoints for oseltamivir and 
oseltamivir carboxylate: steady-state AUC, Cmax, and Ctrough. 
 
 
 


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7. 
APPENDIX 2: SCHEDULE OF ASSESSMENTS 
 
Table A2.1. Schedule of Assessments and Procedures 
 
Baseline 
Treatment 
Follow-up 
Study Day 
1 (pre-
dose) 
1 
2 or 
3
f,g 
6
 f, g 
8
 f, g 
11
g, h, i 
15
g   
40
 g, j 
Informed Consent/Assent 
l 
x 
 
 
 
 
 
 
 
Medical history  
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Height and weight 
x 
 
 
 
 
x 
 
 
Pregnancy Test 
a 
x 
 
 
 
 
x 
 
x 
Rapid diagnostic test for 
influenza virus shedding
  
 
 
 
 
 
x 
 
 
RIDTPCR/Culture for 
confirmation of influenza virus 
x 
 
 
 
 
 
 
 
Safety Labs
 b 
x 
 
 
 
 
x 
 
 
Physical Examination 
x 
 
 
 
 
x 
 
x 
Vital Signs (including pulse, 
respiratory rate, temperature, 
blood pressure)
 
x 
 
x 
x 
x 
x 
x 
x 
Nasal and throat swabs for 
viral shedding and viral load
 c, d 
k 
x 
 
x 
x 
x 
x 
x 
x 
PK sampling (blood)
 l 
 
 
 
x
m 
 
 
Review of patient diary data 
e    
 
 
x 
x 
x 
x 
x 
x 
Drug Administration 
 
 
 
 
 
 
 
 
Collection of unused study 
drug and empty containers 
 
 
 
 
 
x 
 
 
Previous Diseases  
x 
 
 
 
 
 
 
 
Previous/Concomitant 
medications 
x 
 
 
 
 
 
 
 
Adverse Events/Sec Illnesses 
and Treatments 
 
 
 
 
 
 
 
 
Rejection, Graft versus host 
disease (GVHD) 
 
 
 
 
 
 
 
 
a. Urine pregnancy test for patients of child-bearing potential according to the 
judgment/discretion of the investigator. 
b. Hematology (CBC with differential) and chemistry (AST, ALT, total bilirubin, urea, Cr).  Serum 
creatinine testing may be done at a local laboratory when clinically indicated to calculate 
creatinine clearance. 
c. Baseline swab samples will be assessed for the presence of resistance mutations. 
d. Two nasal and one throat swab for viral culture and RT-PCR. 
e. Influenza symptoms, temperature, and date/time of oseltamivir dose will be recorded by the 
patient in the patient diaries twice daily on Days 1 − 10, and once daily thereafter. 
 
f. A home visit may be made on Day 2 or 3 (for patients who are too ill to come into the clinic) 
and/or, Day 6, and/or Day 8; however, it is recommended that the PK blood draw be 
performed at the clinic. 
g. Day 2/3 visit window  =   + 1 day.  Day 6 visit window  =   ±  1 day; Day 8 visit window  =   + 1 
day.  Day 11 visit window  =  ±  1 day.  Day 15 and Day 40 visit occur approximately 5 and 30 
days after the last dose respectively.  Day 15 window  =   ±  1 day.  Day 40 window  ±  2 days.  


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h. Only weight to be assessed.  Height is not necessary at this visit.  Study drug is taken on 
Day 11, only if the first dose was taken after 4 p.m. on Day 1. 
i. 
 Patients who are rapid diagnostic positive can be treated per standard of care.  They will be 
required to come for their follow-up visits on Day 15 and Day 40. 
j. 
Patients who discontinue treatment prematurely will have an end of treatment (Day 11) 
assessment at the time of treatment discontinuation or the following day.  They will be 
required to attend their follow up visits approximately 5 and 30 days after the last dose 
(Day 15 and Day 40 assessments). 
k. Patients who discontinue during follow-up will have an end of follow-up (Day 40) assessment.  
This visit must occur within 30 days of the last dose. 
l. 
For patients who are unable to attend the clinic, swabs may be taken at home on those days 
where there is a home visit by site personnel. 
m. Plasma PK samples for assessment of oseltamivir and oseltamivir carboxylate will be 
collected from patients who give additional consent to participate in PK sampling using a 
sparse PK sampling approach. 
n. Serial PK samples taken at steady-state no earlier than Day 6 (i.e., not before the 11th dose) 
consisting of as many of the four timepoints as possible:  within 30 minutes prior to the dose 
administration, 1.5 hours ± 30 minutes post dose, 4 hours ± 60 minutes post dose, and 
8 hours ± 1.5 hours post dose (for patients who have given additional consent). 
 
 


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8. 
APPENDIX 3: PATIENT DIARY DATA AND SYMPTOM RECORD 
FOR ADULTS AND CHILDREN 
The purpose of the patient diary is for all adults (13 years and older) to record 
any symptoms of influenza-like illness for the duration of the study.  Temperature 
and date and time of drug administration should also be recorded on the patient 
diary. 
 
 
 
 


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Patient Diary Data and Symptom Record for Children  
Temperature and date and time of drug administration will also be recorded on 
the patient diary. 
 


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9. 
APPENDIX 4: HISTORICAL CONTROL SPECIFICATION FOR 
EFFICACY 
Table A4.1. Studies from which historical controls (both placebo and treated) 
may be selected from. 
*Tables and plots from Statistical Programmer Analysts (SPA)  
# 
Label 
Protocols to 
include 
Specifications 
Comments 
1 
1:1 Otherwise Healthy 
Placebo Adults ITTi  
WV15670, 
WV15671  
Match each NV20234 adult mITTi 
patient with 1 ITTi placebo-treated 
patient who have same age and 
gender 
Potential additional studies: 
M76001, WV15730, WV15758 
2 
1:>1 Otherwise 
Healthy Placebo 
Adults ITTi 
WV15670, 
WV15671 
Match each NV20234 adult mITTi 
patient with ITTi placebo-treated 
patients who have same age and 
gender. 
Potential additional studies: 
M76001, WV15730, WV15758 
3 
1:1 At risk Placebo 
Adults  ITTi 
WV15812, 
WV15872  
Match each NV20234 adult mITTi 
patient with ITTi placebo-treated 
patient who have same age and 
gender. 
Potential additional studies: 
WV15819, WV15876, 
WV15978 and WV15707 
4 
1:>1 At risk Placebo 
Adults  ITTi 
WV15812, 
WV15872  
Match each NV20234 adult mITTi 
patient with ITTi placebo-treated 
patient who have same age and 
gender. 
Potential additional studies: 
WV15819, WV15876, 
WV15978 and WV15707 
5 
ITTi treated adult 
datasets 
 
Repeat datasets 1-2 matching 
NV20234 patients with historical 
treated patients by randomised 
treatment.  
 
N.B. NV20234 will focus on the mITTi population. In historical studies, the definition of 
ITTi population was identical to the current mITTi population. Historical studies contain a 
standard population with a more strict definition i.e. “randomised, infected, no major 
violations and who received at least the first six scheduled doses of treatment within 72 
hours or who received the first five doses within 72 hours but then went on to take nine 
out of ten doses”, however this population is not present in the current study. 
Adolescents will only be listed for efficacy. 
Variables required for each dataset: 
Variables required in each of the datasets, where available: NV20234 patient ID, centre 
ID number, country, age, gender, vaccination status, primary flu type, primary flu A 
subtype, randomised treatment, time from onset of symptoms to start of drug, time to 
alleviation of all symptoms, time to alleviation of individual symptoms, time to cessation 
of viral shedding, AUC viral titer, peak viral titer, AUC total symptom score, AUC 
individual symptom score, time to alleviation of fever.  


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10. 
APPENDIX 5: SUMMARY OF MAIN EFFICACY ANALYSES 
Table A5.1. List of main efficacy analyses 
*Tables and plots from Statistical Programmer Analysts (SPA). Suffixes: AD = adults (age ≥ 18), ADOL = adolescents (13 ≤ 
age < 18), CH = children (1 ≤ age < 18), PED = paediatric (1 ≤ age <13). 
**Benchmarking plots contain median TTR and 90% CI for standard dose, double dose, combined dose, historical control 
and historical treated (separate plots will contain 95% CI) 
N.B. Median differences will be obtained using the Hodges-Lehmann estimator and associated Moses CI. TTR of 
symptoms and temperature will be assessed in adults (≥18), in adults and adolescents (≥13), and paediatrics (<13) 
separately; for all other efficacy, virology and safety data adults will be separated from children (<18). 
 
Endpoint 
Analysis 
Comparisons 
Population 
Purpose 
Age groups 
 
SPA output* 
TTR all 
symptoms 
Kaplan-Meier 
median and 
95%CI 
Conventional- double   
mITTi , 
ITTi, ITT 
Main dose-response comparison 
Adults 
Adults + Adolescents 
Paediatric 
t_ef_ttr_ALLEVA
S_MITI_AD_95 
 
g_km_ttr_LLEVA
S_MITI_AD_95 
 
t_ef_ttr_ALLEVA
S_ITI_AD_95 
 
g_km_ttr_LLEVA
S_ITI_AD_95 
 
t_ef_ttr_ALLEVA
S_IT_AD_95 
 
g_km_ttr_ALLEV
AS_IT_AD_95 
 


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TTR all 
symptoms 
Kaplan-Meier 
median and 
90%CI 
 
a. conventional  
b. double 
c. combined 
d. historical placebo 
e. historical treated  
mITTi  
Main comparison with historical 
control: NV20234 treatment against 
Historical Otherwise Healthy 1:1 
Adults 
t_ttr_hc_5g_1to1
_ALLEVAS_MITI
_AD_90 
 
g_km_ttr_5g_1to
1_ALLEVAS_MI
TI AD 90 
TTR all 
symptoms 
Kaplan-Meier 
a. conventional  
b. double 
c. combined 
d. historical placebo 
e. historical treated  
mITTi  
NV20234 treatment against 
Historical Otherwise Healthy 1:>1 
 
Adults 
t_ttr_hc_5g_1to
m_ALLEVAS_MI
TI_AD_90 
 
g_km_ttr_5g_1to
m_ALLEVAS_MI
TI_AD_90 
TTR all 
symptoms 
Kaplan-Meier 
a. conventional  
b. double 
c. combined 
d. historical placebo 
e. historical treated  
mITTi  
NV20234 treatment against at risk 
1:>1 
 
Adults 
t_ttr_hc_5g_atris
k_ALLEVAS_MI
TI_AD_90 
 
g_km_ttr_5g_atri
sk_ALLEVAS_M
ITI AD 90 
TTR all 
symptoms 
Kaplan-Meier 
a. conventional  
b. double 
c. combined 
d. historical placebo 
e. historical treated  
mITTi  
NV20234 – Historical control 
Otherwise Healthy 1:1 
Sensitivity for follow-up 
observational period : only 
including symptom scores recorded 
≤25 days 
Adults 
t_ttr_hc_5g_25d
_ALLEVAS_MITI
_AD_90 
 
g_km_ttr_5g_25
d_ALLEVAS_MI
TI AD 90 
TTR all 
symptoms 
Kaplan-Meier 
a. conventional  
b. double 
c. combined 
d. historical placebo 
e. historical treated  
mITTi  
NV20234 – Historical Otherwise 
Healthy 1:1 
Sensitivity analysis: patients who 
were dosed no more than 48 hours 
after symptom onset 
Adults 
 
t_ttr_hc_5g_48h
_ALLEVAS_MITI
_AD_90 
 
g_km_ttr_5g_48
h_ALLEVAS_MI
TI_AD_90 
TTR all 
symptoms 
Kaplan-Meier 
a. conventional  
b. double 
 
mITTi  
Subgroup analysis 
● 
By vaccination status (yes/no) 
● 
By transplant status (yes/no) 
● 
By  ≤ 48, >48 h from 
symptoms onset 
● 
By geographical region 
Adults 
 
t ef ttaas vac
MITI_AD 
 
t ef ttaas trans
MITI AD 
 
t ef ttaas onset
MITI AD 
 
t ef ttaas reg
MITI AD 


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Statistical Analysis Plan NV20234 
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TTR 
individual 
symptoms 
Kaplan-Meier 
Treatment Responses by treatment 
arms 
mITTi  
Main Summary for this endpoint 
Adults 
Children 
t_ef_ttais_MITI_
AD 
 
t_ef_ttais_MITI_
CH 
Time to 
cessation 
viral 
shedding 
Kaplan-Meier 
Treatment Responses by treatment 
arms 
mITTi 
Dose-Response main analysis for 
this endpoint 
Adults 
Children 
t_ef_ttr_CESCL
T_MITI_AD 
 
t_ef_ttr_CESPC
R_MITI_AD 
 
g_km_ttr_CESC
LT_MITI_AD 
 
g_km_ttr_CESP
CR_MITI_AD 
 
t_ef_ttr_CESCL
T_MITI_CH 
 
t_ef_ttr_CESPC
R_MITI_CH 
 
g_km_ttr_CESC
LT_MITI_CH 
 
g_km_ttr_CESP
CR_MITI_CH 
 
Time to 
cessation 
viral 
shedding 
Kaplan-Meier 
Treatment median [90% CI] 
Responses for : NV20234 
conventional, NV20234 double, 
NV20234 pooled,  historical 
treatment conventional,  
historical treatment double,  
historical placebo for conventional,  
historical placebo for double,  
historical placebo for pooled. 
mITTi 
Benchmarking plot 
Adults 
All CI’s on one plot 
but also split by  
a) pooled  
b) conventional  
c) double 
g_km_t1_t2_hist
plac_treat_TTCV
S_MITI_AD_95 
 
g_km_t1&2_hist
plac_treat_TTCV
S_MITI_AD_95 
 
Repeated 1:1 
and 1:>1 
matches 
 
TTR fever 
Kaplan-Meier 
Treatment Responses by treatment 
arms 
ITT, 
ITTi ,mITTi 
Dose-Response main analysis for 
this endpoint 
1) 
Adults 
2) 
Adults+Adolesce
nts 
3) 
Paediatric 
g_ef_ttr_RESF_I
TT_AD 
 
g_ef_ttr_RESF_I
TT PE 


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g_ef_ttr_RESF_I
TT_AD_ADOL 
 
t_ef_ttr_RESFBL
_ITT_AD 
 
t_ef_ttr_RESFBL
_ITT_PE 
 
t_ef_ttr_RESFBL
_ITT_AD_ADOL 
 
g_ef_ttr_RESF_I
TI_AD 
 
g_ef_ttr_RESF_I
TI_PE 
 
g_ef_ttr_RESF_I
TI_AD_ADOL 
 
t_ef_ttr_RESFBL
_ITI_AD 
 
t_ef_ttr_RESFBL
_ITI_PE 
 
t_ef_ttr_RESFBL
_ITI_AD_ADOL 
 
g_ef_ttr_RESF_
MITI_AD 
 
g_ef_ttr_RESF_
MITI_PE 
 
g_ef_ttr_RESF_
MITI_AD_ADOL 
 
t_ef_ttr_RESFBL
_MITI_AD 
 
t_ef_ttr_RESFBL
_MITI_PE 
 


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Statistical Analysis Plan NV20234 
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t_ef_ttr_RESFBL
_MITI_AD_ADO
L 
 
TTR fever 
Kaplan-Meier 
Treatment median [90% CI] 
Responses for : NV20234 
conventional, NV20234 double, 
NV20234 pooled,  historical 
treatment conventional,  
historical treatment double,  
historical placebo for conventional,  
historical placebo for double,  
historical placebo for pooled.  
mITTi 
Benchmarking plot** 
1) 
Overall 
2) 
Age cohort ( >= 
18 Y, < 18 Y) 
 
All CI’s on one plot 
but also split by  
a) pooled  
b) conventional  
c) double 
g_km_t1_t2_hist
plac_treat_RES
F_MITI_AD_90 
 
g_km_t1&2_hist
plac_treat_RES
F_MITI_AD_90 
 
Repeated 1:1 
and 1:>1 
matches 
 
AUC total 
symptom 
scores 
Median, IQR 
Treatment Responses by treatment 
arms  
mITTi, ITT, 
ITTi  
Dose-Response main summary for 
this endpoint 
Adults only 
 
g_auc_ALLEVA
S_AD 
 
t_auc_ALLEVAS
AD 
AUC total 
symptom 
scores 
Median, IQR 
Treatment median [IQR] for:  
NV20234 conventional, NV20234 
double, NV20234 pooled, historical 
treatment conventional, 
historical treatment double,  
historical placebo for conventional,  
historical placebo for double,  
historical placebo for pooled.  
mITTi 
Benchmarking plot 
For adults only : 
 
All plots on one plot 
but also split by  
a) pooled  
b) conventional dose 
c) double dose 
g_km_t1_t2_hist
plac_treat_AUC
ALLEVAS_MITI_
AD_90 
 
g_km_t1&2_hist
plac_treat_ALLE
VAS_MITI_AD_
90 
 
Repeated 1:1 
and 1:>1 
matches 
 
AUC 
individual 
symptom 
score 
Median, IQR 
Treatment Responses by treatment 
arm  
mITTi 
Dose-Response main summary for 
this endpoint 
Adults 
 
g_auc_ALLEVIS
_AD 
 
t_auc_ALLEVIS
AD 
AUC viral 
titer 
Median, IQR 
Treatment Responses by treatment 
arm  
mITTi 
Dose-Response main summary for 
this endpoint 
Adults 
Children 
g_ef_auc_AUCC
LT_MITI_AD 
 
t_ef_auc_AUCC
LT_MITI_AD 
 


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t_ef_auc_AUCC
LT_MITI_CH 
 
t_ef_auc_AUCP
CR_MITI_CH 
 
t_ef_auc_AUCP
CR MITI CH 
AUC viral 
titer 
Plot Median, IQR 
Treatment median [IQR] 
Responses for:  
NV20234 conventional, NV20234 
double, NV20234 pooled, historical 
treatment conventional,  
historical treatment double,  
historical placebo for conventional,  
historical placebo for double,  
historical placebo for pooled. 
mITTi 
Benchmarking plot 
All plots on one plot 
but also split by  
a) pooled  
b) conventional  
c) double 
g_km_t1_t2_hist
plac_treat_AUC
CLT_MITI_AD_9
0 
 
g_km_t1&2_hist
plac_treat_ 
AUCCLT 
_MITI_AD_90 
 
Repeated 1:1 
and 1:>1 
matches 
Peak viral 
titer 
Median, IQR 
Treatment Responses by treatment 
arms 
mITTi, ITT, 
ITTi 
Dose-Response main summary for 
this endpoint 
a) 
Adults  
b) 
Children 
t_ef_auc_PEAK
CLT_MITI_AD 
 
t_ef_auc_PEAK
CLT_MITI_PE 
 
t_ef_auc_PEAK
PCR_MITI_AD 
 
t_ef_auc_PEAK
PCR MITI PE 
Virus 
shedding 
Proportions 
Percentage of patients with viral 
shedding by baseline and planned 
visit.  
mITTi 
Main summary table 
a) 
Adults 
b) 
children 
t_ef_shed_CLTR
_MITI_AD 
 
t_ef_shed_CLTR
_MITI_CH 
 
t_ef_shed_PCR
_MITI_AD 
 
t_ef_shed_PCR
MITI CH 


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Viral Load 
RT-PCR 
Change from 
baseline in viral 
load RT-PCR 
Summary Statistics (Mean, SD, 
Median, Range) 
mITTi 
Main summary table 
Adults 
Children 
t_ef_cfb_PCR_
MITI_AD 
 
t_ef_cfb_PCR_
MITI_CH 
Viral Load 
Culture 
Change from 
baseline in viral 
load from culture 
Summary Statistics (Mean, SD, 
Median, Range) 
mITTi 
Main summary table 
Adults 
Children 
t_ef_cfb_CLTR_
MITI_AD 
 
t_ef_cfb_CLTR_
MITI CH 
Secondary 
Illnesses (SI) 
summary only 
N(%) by treatment group 
Safety 
Main summary table 
1) 
Overall 
2) 
Adult 
3) 
Children 
Split by : 
a) any SI starting at 
any time  
b) any SI starting at 
any time that is 
treated with ant biotics  
c) SI started >=48 
hours after start of 
study treatment that is 
treated with ant biotics 
t_ae_secil_MITI 
 
t_ae_secil_ANTI
B_SE 
 


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11. 
APPENDIX 6: VIRAL MUTATIONS ASSOCIATED WITH 
RESISTANCE 
 
 
Table A6.1. USPI table with Neuraminidase (NA) Amino Acid Substitutions 
Associated with Reduced Susceptibility to Oseltamivir* 
Influenza A N1 (N1 numbering in brackets) 
 
I117V (I117V) 
E119V (E119V) 
R152K (R152K) 
Y155H (Y155H) 
F173V (F174V) 
D198G/N (D199G/N) 
I222K/R/T/V (I223K/R/T/V) 
S246N (S247N) 
G248R+I266V (G249R+I267V) 
H274Y (H275Y) 
N294S (N295S) 
Q312R+I427T (Q313R+I427T) 
N325K (N325K) 
R371K (R368K) 
Influenza A N2 
 
E41G 
 
E119I/V 
D151V 
I222L/V 
Q226H 
SASG245-248 
S247P 
R292K 
N294S 
Influenza B (B numbering in brackets) 
 
E119A (E117A) 
 
P141S (P139S) 
G142R (G140R) 
R152K (R150K) 
D198E/N/Y (D197E/N/Y) 
I222L/T/V (I221L/T/V) 
A246D/S/T (A245D/S/T) 
H274Y (H273Y) 
N294S (N294S) 
R371K (R374K) 
G402S (G407S) 
*All numbering is N2, except where indicated 
Haemagglutinin (HA) Amino Acid Substitutions Associated with Reduced 
Susceptibility to Oseltamivir 
According to the current Tamiflu label, HA mutations should include A28T and 
R124M in influenza A H3N2 and H154Q in H1N9.  
Per 2016 FDA feedback: 'the previously-listed substitutions A28T and R124M are 
now referred to as A11T and R453M, respectively, consistent with the convention 
of numbering from the beginning of the processed HA (without the signal 
peptide). We removed previously listed substitutions that were identified in 
strains not currently relevant to humans (H154Q in H1N9)."  In summary, per 
FDA communication the HA residues to be included on the resistance list 
(renamed nomenclature, taking into account only the mature protein, w/o the 
signal peptide) are A11T, K173G, and R453M in H3N2; and H99Q in influenza B 
virus (no HA mutations listed for H1N1) 
 
 
 


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12. 
APPENDIX 7: ALGORITHMS USED FOR DERIVATION AND 
SUMMARIES OF TIME TO ALLEVIATION OF ALL SYMPTOMS 
The purpose of this document is to describe the algorithm used to derive and 
analyse the Time To Resolution of all symptoms in the Tamiflu program (adults + 
adolescents).  
Time to alleviation (TTA) of all symptoms (Efficacy VAD variable TALLSYMP), 
was calculated as the time from start of study drug (Time=0) to the start of 
the first 24 hour period in which all 7 symptoms were less than or equal to 1 
and they remained at one or less for at least 21.5 hours, i.e., up to the end of the 
21.5 hour period. 
 
 
For subjects with missing data or who withdrew or ceased recording data prior to 
alleviation, data was imputed according to the following rules: 
At the individual symptom level, a missing value was estimated by linear 
interpolation between the previously available assessment and the subsequently 
available assessment.  
If the interpolated value was ≤ 1 for the first time (e.g. interpolation between a 
score of 2 and 0 gave 1) then the interpolated time point was not considered as 
the beginning of the 24 hour period that determined whether alleviation of that 
symptom had occurred, instead, the beginning of the 24 hour period started at 
the next observed time point at which the value was ≤1.  The VAD variables 
which denote missing data rules are TESTTYPE AND DATETYPE (refer to the 
efficacy VAD specifications for details).  
If symptoms were missing, 0 or 1 at baseline and were subsequently recorded as 
missing, 0 or 1 for at least 21.5 hours, then the TTA of all symptoms was set to 


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missing. [ Corresponding Efficacy VAD variables TALLSYMP=. And 
CENSORED=0.] 
If all non-missing baselines symptoms were > 1 at baseline and recovered (<=1) 
immediately and remained <=1 for at least 21.5 hours OR if all non-missing 
baselines symptoms were > 1 at baseline and no further recordings of symptom 
scores had been recorded, then the Time to Alleviation of All symptoms was 0. 
[Corresponding Efficacy VAD variables TALLSYMP=0 and CENSORED=0] 
For Paediatric studies, should a subject only have No/mild symptoms from 
baseline onwards, and subsequent visits satisfy the 21.5 hour rule, then set 
TALLSYMP=0 and CENSORED=0. 
Subjects withdrawing prior to alleviation of symptoms were censored at the time 
of withdrawal. [denoted in the efficacy VAD as CENSORED=1] 
The primary endpoint was compared between groups using statistical 
methodology appropriate for survival data since censored data is present. The 
within-treatment group summary measures of median duration, was estimated 
from the Kaplan-Meier curve. A weighted Mantel-Haenszel test was used to 
formally test for a between-treatment group effect since the proportional hazards 
assumption was considered unlikely to hold a priori. 
The weighting scheme used was the generalised Gehan Wilcoxon weights in 
which the weighting is equal to the number in the risk set.  
Kaplan-Meier graphs of duration of symptoms according to treatment group were 
provided. Estimates of the difference between median durations were provided 
by subtracting the observed treatment group medians obtained from the Kaplan-
Meier curve and estimating between group variability through bootstrapping. The 
dataset was sampled 2000 times in order to provide 95% confidence intervals 
using the percentile method (Efron 1993). 
The bootstrap methodology had previously been applied within the influenza 
clinical trial field by the MIST group (MIST 1998) when comparing time to 
alleviation of illness in subjects treated with inhaled Zanamivir or placebo.