A Phase III, Open Label, Randomized, Multicenter Trial of Ofatumumab Maintenance Treatment Versus no Further Treatment in Subjects With Relapsed Chronic Lymphocytic Leukemia (CLL) Who Have Responded to Induction Therapy
Phase: PHASE3
Conditions: Leukaemia, Lymphocytic, Chronic
Sponsor: Novartis Pharmaceuticals

Clinical Development 
GSK1841157
Protocol OMB112517 /  NCT01039376
A phase III, open label, randomized, multicenter trial of 
ofatumumab maintenance treatment versus no further 
treatment in subjects with relapsed chronic lymphocytic 
leukemia (CLL) who have responsed to induction 
therapy
Authors 
 
Document type 
Amended Protocol Version (Clean) 
EUDRACT number 
2009-012518-39 
Version number 
07 (Amendment 06) 
Development phase Phase III 
Document status 
Final 
Release date 
01-Apr-2016
Novartis internal 
reference number 
COMB157C2301 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 

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Amendment 6 
Amendment rationale  
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK1841157, the 
purpose of this protocol Amendment 06 is to: 
- 
Delete or replace references to GlaxoSmithKline or its staff with that of Novartis 
and its authorized agents to align with the change of sponsorship; 
- 
Make administrative changes to align with Novartis processes and procedures; 
As of February 2016: 
480 patients have been randomized into the study in 14 countries;  
 
7 patients in ofatumumab treatment 
 
99 patients in study follow-up (63 for ofatumumab arm and 36 for observation 
arm) 
 
191 patients in survival follow-up. 
The changes described in this amended protocol require Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) approval prior to implementation.  
A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities. 
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of 
study sponsorship described in the protocol amendment. 
Upon approval of this amendment, patients who have already been enrolled in the study 
will sign a new informed consent form indicating Novartis is the new study sponsor and 
continue the appropriate visit schedule. 
 

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Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
UM2008/00446/00 
2009-JUL-14 
Original 
UM2008/00446/01 
2009-NOV-11 
Amendment No.: 01 
UM2008/00446/02 
2009-NOV-20 
Amendment No.: 
01:.(Republished) 
Addition of baseline MRD, 
 post-PD PRO and clarifications 
UM2008/00446/03 
2010-MAY-21 
Amendment No. 2 
Added study name and clarifications, modified I/E 
UM2008/00446/04 
2013-FEB-07 
Amendment No.: 3 
Country specific amendment:  At the request of the French regulatory agency related 
information from the Study Procedures Manual (SPM) was added into Section 6.4.6 
UM2008/00446/05 
2013-DEC-17 
Amendment No. 4 
FDA request for additional HBV information and protocol clarifications 
UM2008/00446/06 
2014-AUG-26 
Amendment No. 5 
As the significance level was met at the interim analysis of efficacy, further enrollment in 
the study will be discontinued. 
Novartis 
2016-APR-01 
Amendment No. 6 
Delete or replace references to GSK or its staff with that of Novartis/Novartis and its 
authorized agents. 
Make administrative changes to align with Novartis processes and procedures. 
 
 

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Protocol No. OMB112517 
 
 
 
SPONSOR SIGNATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Date 
,  
Novartis Pharmaceuticals Corporation 

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SPONSOR INFORMATION PAGE 
Clinical Study Identifier: 
OMB112517 
Sponsor Contact Information: 
Novartis Pharmaceuticals Corporation 
In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents. Where applicable, the details of the Sponsor and contact person will be provided 
to the relevant regulatory authority as part of the clinical trial submission. 
Medical Lead Contact Information:   
, MD  
Novartis Pharma AG 
Postfach, CH -4002 Basel 
Switzerland 
Telephone Number: 
 
Email: 
 
 
Clinical Trial Head Contact Information: 
 
, PhD 
Novartis Pharma AG, Basel 
Telephone Number:
 
Mob: 
 
Email: 
 
 
Sponsor Serious Adverse Events (SAE) Contact Information:   
Please refer to the Study Procedures Manual. 
For study conduct questions not related to patient safety, the first line of contact should 
be with the designated local country company contact.  In the event that the designated 
company contact is not available please contact the medical lead. 
Regulatory Agency Identifying Number(s):  
IND number: 11, 719  
Eudra CT number: 2009-012518-39 
Universal Trial Number (UTN): U1111-1148-0253 

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol OMB112517 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.  
Investigator Name: 
 
Investigator Address: 
 
 
Investigator Phone Number: 
 
 
 
Investigator Signature 
Date 
 

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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS .............................................................................................. 10 
PROTOCOL SUMMARY .................................................................................................. 12 
1. 
INTRODUCTION ....................................................................................................... 15 
1.1. 
Chronic Lymphocytic Leukemia (CLL) .......................................................... 15 
1.2. 
Current Treatment for CLL ............................................................................ 15 
1.3. 
Ofatumumab .................................................................................................. 16 
1.4. 
Rationale ........................................................................................................ 17 
1.5. 
Rationale for Closing Enrollment ................................................................... 17 
2. 
OBJECTIVES ............................................................................................................ 18 
3. 
INVESTIGATIONAL PLAN ........................................................................................ 19 
3.1. 
Study Design.................................................................................................. 19 
3.1.1. 
Screening Phase ............................................................................ 19 
3.1.2. 
Randomization and Stratification ................................................... 19 
3.1.3. 
Treatment Phase ............................................................................ 20 
3.1.4. 
Follow-up Phase ............................................................................ 20 
3.2. 
Discussion of Design and Dose Rationale .................................................... 21 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ........................................ 23 
4.1. 
Number of Subjects ....................................................................................... 23 
4.2. 
Inclusion Criteria ............................................................................................ 23 
4.3. 
Exclusion Criteria ........................................................................................... 23 
4.4. 
Withdrawal Criteria ........................................................................................ 25 
5. 
STUDY TREATMENTS ............................................................................................. 26 
5.1. 
Investigational Product and Reference Therapy ........................................... 26 
5.1.1. 
Ofatumumab................................................................................... 26 
5.1.1.1. 
Ofatumumab Pre-Medication ....................................... 27 
5.1.1.2. 
Ofatumumab Treatment Schedule .............................. 27 
5.1.1.3. 
Management of Infusion Reactions ............................. 28 
5.1.1.3.1. 
Mild and Moderate Intensity 
Adverse Events (Grade 1 and 2) ............ 28 
5.1.1.3.2. 
Severe Intensity Adverse Events 
(Grade ≥3) ............................................... 29 
5.2. 
Treatment Assignment .................................................................................. 29 
5.3. 
Product Accountability ................................................................................... 29 
5.4. 
Prohibited Concomitant Medication or Therapies ......................................... 29 
6. 
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 29 
6.1. 
Clinical Assessments ..................................................................................... 29 
6.1.1. 
Demographics ................................................................................ 29 
6.1.2. 
Disease Characteristics and Medical History ................................ 30 
6.1.3. 
Previous CLL Therapy ................................................................... 30 
6.1.4. 
Height and Weight .......................................................................... 30 
6.1.5. 
Physical Examination ..................................................................... 30 

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6.1.6. 
Electrocardiogram .......................................................................... 30 
6.1.7. 
Vital Signs ...................................................................................... 30 
6.1.8. 
Concomitant Medication ................................................................ 30 
6.1.9. 
ECOG Performance Status ........................................................... 31 
6.1.10. 
Constitutional Symptoms (B-Symptoms) ....................................... 31 
6.1.11. 
Lymph Node and Organ Examination ........................................... 31 
6.1.12. 
Pre-treatment Computed Tomography (CT) Scans ...................... 31 
6.1.13. 
Pre-treatment Bone Marrow Examination ..................................... 31 
6.2. 
Efficacy .......................................................................................................... 32 
6.2.1. 
Definition of Response ................................................................... 32 
6.2.1.1. 
Complete Remission (CR) ........................................... 32 
6.2.1.2. 
Partial Remission (PR) ................................................. 33 
6.2.1.3. 
Progressive Disease (PD) ............................................ 33 
6.2.2. 
Bone Marrow Examination ............................................................. 34 
6.2.3. 
Minimal Residual Disease (MRD) .................................................. 34 
6.2.4. 
CT-Scans ....................................................................................... 35 
6.3. 
Laboratory Assessments ............................................................................... 35 
6.3.1. 
Flow Cytometry for B-CLL Diagnosis/Confirmation of 
Phenotype and B-cell Monitoring ................................................... 36 
6.3.1.1. 
B-CLL Diagnosis/Phenotype Confirmation .................. 36 
6.3.1.2. 
B-Cell Monitoring .......................................................... 36 
6.3.2. 
Peripheral Blood Sampling for Hematology and 
Biochemistry ................................................................................... 36 
6.3.3. 
Prognostic Factors ......................................................................... 36 
6.3.4. 
Peripheral Blood Sampling for Safety and Disease Status ........... 37 
6.4. 
Safety Assessments ...................................................................................... 37 
6.4.1. 
Liver chemistry stopping and follow-up criteria ............................. 37 
6.4.1.1. 
Liver Chemistry Stopping Criteria ................................ 37 
6.4.1.2. 
Liver Chemistry Follow-up Assessments..................... 39 
6.4.2. 
Adverse Events .............................................................................. 40 
6.4.3. 
Definition of an AE ......................................................................... 40 
6.4.4. 
Definition of a SAE ......................................................................... 41 
6.4.5. 
Toxicity Assessment of AEs and SAEs ......................................... 42 
6.4.6. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs ........................................................... 43 
6.4.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs ................................................ 45 
6.4.8. 
Time Period and Frequency of Detecting AEs and SAEs ............. 45 
6.4.9. 
Pregnancy ...................................................................................... 46 
6.4.10. 
Prompt Reporting of Serious Adverse Events and Other 
Events to Novartis .......................................................................... 46 
6.5. 
Patient Reported Outcome (PRO) Measures ............................................... 47 
6.5.1. 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 (EORTC 
QLQ-C30) ....................................................................................... 47 
6.5.2. 
European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire Chronic Lymphocytic 
Leukaemia 16 item module (EORTC QLQ-CLL 16) ...................... 48 
6.5.3. 
EuroQoL Five-Dimension (EQ-5D) ................................................ 48 
6.5.4. 
Patient Reported Constitutional Symptoms (‘B-
Symptoms’) score .......................................................................... 49 
6.5.5. 
Health Change Questionnaire ....................................................... 49 

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6.5.6. 
Administration of PRO Measures .................................................. 49 
6.6. 
Pharmacokinetics .......................................................................................... 49 
6.7. 
Biomarkers ..................................................................................................... 50 
7. 
DATA MANAGEMENT .............................................................................................. 50 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................... 51 
8.1. 
Hypotheses .................................................................................................... 51 
8.2. 
Study Design Considerations ........................................................................ 51 
8.2.1. 
Sample Size Assumptions ............................................................. 51 
8.2.2. 
Sample Size Sensitivity .................................................................. 52 
8.2.3. 
Sample Size Re-estimation ........................................................... 52 
8.3. 
Data Analysis Considerations ....................................................................... 52 
8.3.1. 
Analysis Populations ...................................................................... 52 
8.3.1.1. 
Populations defined for the analyses ........................... 52 
8.3.2. 
Analysis Data Sets ......................................................................... 53 
8.3.3. 
Treatment Comparisons ................................................................ 53 
8.3.3.1. 
Primary Comparisons of Interest ................................. 53 
8.3.3.2. 
Secondary and Other Comparisons of Interest ........... 53 
8.3.4. 
Interim Analysis .............................................................................. 54 
8.3.5. 
Key Elements of Analysis Plan ...................................................... 54 
8.3.5.1. 
Efficacy Analyses ......................................................... 55 
8.3.5.2. 
Safety Analyses ........................................................... 58 
8.3.5.3. 
PRO Analyses .............................................................. 59 
8.3.5.4. 
Pharmacokinetic Analyses ........................................... 59 
 
 
60 
9. 
STUDY CONDUCT CONSIDERATIONS .................................................................. 60 
9.1. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................... 60 
9.2. 
Quality Control (Study Monitoring) ................................................................ 61 
9.3. 
Quality Assurance .......................................................................................... 61 
9.4. 
Study and Site Closure .................................................................................. 61 
9.5. 
Records Retention ......................................................................................... 62 
9.6. 
Provision of Study Results and Information to Investigators ........................ 62 
9.7. 
Independent Data Monitoring Committee (IDMC) ........................................ 63 
10.  REFERENCES .......................................................................................................... 64 
11.  APPENDICES ............................................................................................................ 69 
11.1. 
Appendix 1: Time and Events ....................................................................... 69 
11.2. 
Appendix 2: Response Definition Summary ................................................. 71 
11.3. 
Appendix 3: Patient Reported Outcome Measures ...................................... 72 
11.4. 
Appendix 4: Country Specific Requirements ................................................ 78 
11.5. 
Appendix 5: Liver Chemistry Stopping and Follow-up Criteria† .................... 79 
11.6. 
Appendix 6: Protocol Changes ...................................................................... 80 
 

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LIST OF ABBREVIATIONS 
ADCC 
Antibody-dependent cell mediated cytotoxicity 
AE 
Adverse Event 
AIHA 
Autoimmune hemolytic anemia 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
B-CLL 
B-cell chronic lymphocytic leukemia 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CDC 
Complement-dependent cytotoxicity 
CL 
Clearance 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration or predose (trough) 
concentration 
CNS 
Central nervous system 
CR 
Complete remission/response 
eCRF 
Electronic case report form 
CRu 
Complete remission/response unconfirmed 
CT-Scan 
Computed tomography scan 
EC 
Ethics committee 
ECOG 
Easter Cooperative Oncology Group 
EOI 
End of infusion 
EORTC QLQ-C30 
European organization for research and treatment of cancer, 
core 30 item questionnaire 
EORT QLQ-CLL16 
European organization for research and treatment of cancer, 
quality of life questionnaire chronic lymphocytic leukemia 
16 item module 
EQ-5D 
Euro-QoL five dimension 
FISH 
Fluorescent in-situ hybridization 
FL 
Follicular lymphoma 
GSK 
GlaxoSmithKline 
HAHA 
Human anti-human antibodies 
HB(V) 
Hepatitis B(Virus) 
HCG 
Human chorionic gonadatropin 
HIV 
Human immunodeficiency virus 
h 
Hour(s) 
IB 
Investigator Brochure 
IDMC 
Independent data monitoring committee 
Ig 
Immunoglobulin 
IRC 
Independent review committee 
ITT 
Intent to treat 
IWCLL 
International workshop for chronic lymphocytic leukemia 
LDH 
Lactic acid dehydrogenase 
MedDRA 
Medical dictionary for regulatory activities 

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mAb 
Monoclonal antibody 
mL 
Milliliter 
MRD 
Minimal residual disease 
MTD 
Maximum tolerated dose 
NCI-WG 
National Cancer Institute-sponsored working group 
NONMEM 
Nonlinear mixed-effects modeling approach 
OR 
Overall response 
ORR 
Overall response rate 
nPR 
Nodular partial remission/response 
PD 
Progressive disease 
PFS 
Progression free survival 
PGx 
Pharmacogenetics 
PLL 
Prolymphocytic leukemia 
PP 
Per protocol 
PR 
Partial remission/response 
PRO 
Patient reported outcome 
RAP 
Reporting and analysis plan 
SAE 
Serious adverse event 
SD 
Stable disease 
SPM 
Study procedures manual 
t½ 
Terminal half-life 
tmax 
Time at which maximum concentration is observed 
TTP 
Time to progression 
VAS 
Visual analog scale 
vs. 
Versus 
Vss 
Volume of distribution at steady state 
WHO 
World Health Organization 
ZAP-70 
Zeta-chain-associated protein kinase 70 
 

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PROTOCOL SUMMARY 
Rationale 
Despite progress in therapy, chronic lymphocytic leukemia (CLL) remains incurable.  
Response rates are promising but remain transient and all subjects eventually relapse.  
There is currently no approved maintenance therapy.  The objective of this study is to 
evaluate if maintenance therapy with ofatumumab will prolong remission duration.   
Objective(s) 
The primary objective is to evaluate progression free survival (PFS) of ofatumumab 
maintenance treatment versus no further treatment after remission induction in subjects 
with relapsed CLL. 
Secondary objectives are to evaluate clinical benefit, safety, tolerability and health-
related quality of life of subjects treated with ofatumumab versus no further treatment.  
An additional secondary objective is to evaluate the pharmacokinetics in CLL subjects on 
maintenance ofatumumab. 
Study Design 
This is an open-label, two-arm, randomized, Phase III study of ofatumumab or no further 
treatment in subjects in CR or PR after remission induction treatment for relapsed CLL. 
A total of 280 events are needed for the study to have 80% power to detect a 40% 
difference in PFS between study arms.  Subjects in CR or PR after remission induction 
treatment for relapsed CLL will be randomized in a 1:1 ratio to receive either 
ofatumumab maintenance or no further treatment in order to obtain 478 evaluable 
subjects (assuming a 10% drop out).   
An independent data monitoring committee (IDMC) will be used for 2 interim analyses. 
The first interim analysis will assess safety endpoints after 100 subjects in the 
maintenance arm have been treated for at least 6 months.  The second interim analysis of 
will assess efficacy of the primary endpoint, progression free survival, as well as evaluate 
safety and will be performed when 2/3 of the total number of events have occurred (187 
events) utilizing a conservative significance level (0.001).  As the significance level was 
met at the interim efficacy analysis, further enrollment in the study will be discontinued.  
There will be no changes to the study design, treatment, assessments, or follow-up. The 
final analysis will be conducted at the significance level of 0.0498.  Further details are 
specified in the IDMC charter. 
At screening, upon informed consent, peripheral blood samples, physical assessment, CT 
scan (to confirm CR or PR) will be obtained to determine disease status and study 
eligibility.  Bone marrow examination may be done ONLY to confirm CR.  Refer to 
Appendix 1: Time and Events for complete list of screening procedures. 
 

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Eligible subjects will be stratified at randomization based on: 
1) CR or PR at study entry 
2) Number of previous induction treatments (2 vs 3) 
3) Type of prior treatment :  chemoimmunotherapy, only alkylating monotherapy, or 
other treatment  
During the treatment phase, subjects will be randomized 1:1 to receive either: 
Arm A:  ofatumumab as infusions every 8 weeks (The first dose will be 300mg followed 
1 week later by 1000 mg and 1000 mg every 8 weeks thereafter for up to 2 years) or  
Arm B:  No treatment (i.e. observation only) 
Blood samples, lymph node examination, spleen and liver measurement, and 
constitutional symptoms evaluation are performed every 8 weeks throughout the 
treatment phase.  Follow-up assessments are performed every 3 months for 5 years to 
evaluate survival and disease status. 
A bone marrow examination is required to confirm Complete Remission (CR) at least 
2 months after completion of therapy and when a subject fulfills the International 
Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer 
Institute-Sponsored Working Group (NCI-WG) requirements for Complete Remission 
(CR) [Hallek, 2008].  Previous results may be used or if not available, a bone marrow 
exam may be done at screening. If a subject’s response improves to a CR while on study, 
then a bone marrow examination is required to confirm CR at least 2 months after 
response as per the updated IWCLL NCI-WG requirements for CR [Hallek, 2008].  
Additionally, CT Scans are required at screening, for confirmation of a new CR, yearly 
while on study, and at disease progression. 
 
Study Endpoints/Assessments 
Primary Endpoint: 
 
Progression free survival (PFS), defined as the interval from randomization until 
disease progression or death  
Secondary Endpoints: 
Clinical 
 
Improvement in response 
 
Time to next treatment 
 
Overall survival 
 
Progression-free survival after next-line therapy 

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 
Time to progression after next-line therapy 
 
Changes in patient reported outcome (PRO) measures 
 
Changes in patient reported outcome (PRO) scores 
 
Improvement of ECOG performance status 
 
B-symptoms/Constitutional symptoms/fatigue 
 
Incidences of and number of subjects with grade 3 and 4 infections 
 
Incidence, severity of adverse events, serious adverse events and other safety 
parameters 
 
Evaluation of myelosuppression (anemia, neutropenia, thrombocytopenia) 
 
Frequency of transfusions 
 
Incidence of Autoimmune Hemolytic Anemia  (AIHA)   
 
Human Anti Human Antibodies (HAHA) 
 
IgG, IgA, IgM serum levels 
Disease markers 
 
Minimal Residual Disease (MRD) 
 
B-cell monitoring 
 
Prognostic markers correlating with clinical response:  
 
Cytogenetics by fluorescent in situ hybridization (FISH) 
 
IgVH mutational status 
 
2 microglobulin 
 
Changes in complement levels 
 
Pharmacokinetics 
 
Plasma ofatumumab concentrations 

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1. 
INTRODUCTION 
1.1. 
Chronic Lymphocytic Leukemia (CLL) 
Chronic Lymphocytic Leukemia (CLL or B-CLL) is a chronic leukemia in which 
peripheral, clonal B-cells progressively accumulate. The disease is a hematological 
neoplasm of unknown etiology, characterized by monomorphic small, round 
B-lymphocytes in the peripheral blood, bone marrow, and lymph nodes that aberrantly 
co-express T-cell (CD5+) and B-cell (CD19+, CD23+) cell surface markers, with a low 
expression of CD20.  Over the past decade, new information suggests B-CLL originates 
from antigen-stimulated mature B-lymphocytes, which either avoid cell death through the 
effect of external signals, or die by apoptosis, but are replenished by proliferating 
precursor cells [Chiorazz, 2005]. 
Chronic Lymphocytic Leukemia is the most common type of leukemia in the western 
world, accounting for 40% of all leukemia types in individuals over the age of 65  
[Oscier, 2004].  It is estimated that in the US alone 15,110 adults (8,750 men and 6,360 
women) will be diagnosed and 4,390 adults will die of CLL in 2008 [Jemal, 2008]. CLL 
follows a variable clinical course with overall survival times ranging from months to 
decades.  Median survival from diagnosis is approximately 10 years in the overall CLL 
population, but is only 18 months for patients with advanced disease [Nabhan, 2004]; and 
to 9-13 months for CLL cases refractory to fludarabine [Byrd, 2004].  
Traditional clinical staging systems devised by Rai and Binet are the simplest and still 
best validated means of assessing prognosis for CLL patients [Rai, 1975; Binet, 1981], 
however, there is substantial heterogeneity in the course of the disease within defined 
stages. In recent years molecular and cellular markers have been correlated with disease 
aggressiveness.  These allow further stratification of subjects into risk groups such as: 
abnormal cytogenetics, CD38, ZAP-70, beta-2-microglobulin, IgVH mutational status 
[Oscier, 2004; Abbott, 2006; Shanafelt, 2007; Zenz, 2007].  So far, unfortunately these 
parameters have only limited use in determining when and what type of therapy to use 
[Binet, 2006].  One exception is that p53 deletion was shown to predict for non-response 
to purine analogues like fludarabine and for poor clinical outcome, but is not predictive 
for response to a particular therapy [Dohner, 1995]. 
The prevalence of CLL increases with age and the median age at the time of diagnosis is 
65 to 70 years [Redaelli, 2004].  Approximately 50% of patients are initially 
asymptomatic and are observed for several years before treatment is needed, therefore 
more than half of patients who finally require therapy are older than 70 years. 
1.2. 
Current Treatment for CLL 
Over the last two decades, the treatment goal of CLL has undergone a paradigm shift 
changing from simple symptom palliation to attainment of maximal disease control and 
consequently prolonged survival [Tam, 2007].  A first generation of clinical trials 
assessing single agent chemotherapy was followed by a second generation of trials 
investigating combination chemotherapies which showed no significant difference in 
overall survival [Shanafelt, 2007]. Subjects receiving monotherapy or combination 

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chemotherapy experience a range of different levels of toxicity, with the more aggressive 
therapies being also more toxic and choice of therapy has to be performed as a risk based 
approach [Abbott, 2006].  Currently, FCR seems to be the most potent regimen, both in 
previously untreated and relapsed patients [Hallek, 2008; Tam 2008].  In general, as with 
most clinical studies, all these trials endorse strict eligibility criteria often excluding 
subjects older than 65 plus those with inferior organ function. This causes a limitation in 
assessing the suitability of these studied therapy regimen regarding their efficacy and 
tolerability for the treatment of unselected patients in practice of which the majority is 
older and in poor health. 
Despite numerous studies with various therapies demonstrating overall and complete 
response rates in both previously untreated and relapsed or refractory CLL patients 
[Hallek, 2001; Huhn, 2001; O'Brien, 2001a; O'Brien, 2001b; Keating, 2002; 
Wierda, 2005], there is no curative treatment and the disease is marked by relentless 
relapse.  There is no current maintenance therapy to prolong the time between relapses 
improving the overall quality of life or to improve overall survival.    
The biological behavior of CLL is similar to follicular lymphoma (FL), wherein the 
disease is incurable and the clinical course is characterized by a high relapse rate.  After 
relapse, both the response rate and progression-free survival after subsequent salvage 
regimens steadily decrease [Montoto, 2002].  Recently, in relapsed FL patients, 
maintenance treatment with the chimeric CD20 mAb, rituximab, resulted in a median 
PFS of 51.5 months versus 14.9 months with observation only (p<.001).  Significantly 
improved PFS was noted regardless of induction treatment (CHOP vs R-CHOP).  
Additionally, rituximab maintenance also improved overall survival at 3 years (85% vs 
77%, p=.011) [van Oers, 2006].  Similar results of improved PFS and overall survival 
with rituximab maintenance in FL patients have been noted [Forstpointner, 2006; 
Hochster, 2009]. 
While rituximab monotherapy is not very effective in previously untreated or relapsed 
CLL patients, possibly due to the relatively low CD20 expression on CLL cells 
[Byrd, 2001], a recent small phase II study with rituximab consolidation and maintenance 
treatment showed a significantly longer response duration in patients with minimal 
residual disease (MRD)-positive CLL in first remission after fludarabine induction  
[Del Poeta, 2008]. 
1.3. 
Ofatumumab 
Ofatumumab is a fully human monoclonal antibody (mAb), IgG1κ, targeting a unique 
epitope on the CD20 molecule expressed on human B-cells, resulting in increased 
binding affinity to CD20, prolonged dissociation rate, and increased cell kill due to 
greater CDC activity and similar ADCC activity, especially in low CD20 expressing cells 
[Teeling, 2006].  Thus, depletion of B-cells by ofatumumab treatment may provide 
clinical benefits to subjects with CD20-expressing cell tumors. In B-CLL, the goal of 
treatment is to achieve complete abnormal B-cell depletion in the blood and to induce an 
objective tumor response in the lymph nodes.   

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In a Phase I dose-ranging trial of ofatumumab 500mg (n=3), 1000mg (n=3), or 2000mg 
(n=27) given weekly x 4, 50% PR was observed in the 2000mg dose amongst relapsed 
CLL patients [Coiffier, 2008].  Objective response significantly correlated with 
maximum observed concentration (Cmax), minimum observed concentration (Cmin), 
area under the concentration-time curve (AUC), and half-life (t½) and survival endpoints 
correlated with exposure.  The maximum tolerated dose (MTD) was not reached and 
treatment was well tolerated.  Adverse events were limited to grade 1-2 infusion reactions 
and easily managed with premedication. Grade 3-4 neutropenia occurred in only 6% of 
patients.  Non-opportunistic grade 1-2 infections were observed in 51% of patients. 
Interim analysis for the pivotal trial evaluated 154 patients with refractory CLL (Study 
Hx-CD20-406).  In the 138 evaluable patients, approximately half (59) were refractory to 
both fludarabine and alemtuzumab and the other patients were refractory to fludarabine 
and considered inappropriate for alemtuzumab due to bulky disease of the lymph nodes.  
An objective response rate of approximately 50% consisting of 30 partial responses was 
achieved in the fludarabine and alemtuzumab refractory group and an objective response 
rate of approximately 44% was achieved in the fludarabine refractory group including 1 
complete response and 34 partial responses.  In this study, ofatumumab was generally 
well tolerated by the patients.  The most frequently reported adverse events (>15% 
frequency) were pyrexia, diarrhea, fatigue, cough, neutropenia, anemia and pneumonia.  
There were no unexpected safety findings. 
Studies clearly indicate monoclonal antibodies (mAbs) play an important role in the 
treatment of CLL.  Anti-CD20 mAbs with a low toxicity can be applied advantageously 
in subjects who cannot tolerate highly toxic treatments (i.e. advanced age), in 
combination with chemotherapy and as maintenance treatment.  Ofatumumab preclinical 
data demonstrates superior CDC activity in CLL compared to rituximab.  Based on this, it 
is suggested that ofatumumab’s stronger B-cell depletion potential may translate into 
longer duration of treatment response.   
1.4. 
Rationale 
The purpose of this study is to assess the benefit of ofatumumab maintenance treatment 
in subjects in remission from relapsed CLL based upon: 
1) the similarities in biological behavior between CLL and FL;  
2) in relapsed FL, maintenance treatment with anti-CD20 MAb, rituximab is the standard 
of care;  
3) results in a phase II study with rituximab induction and maintenance resulted in 
prolongation of PFS in MRD positive CLL in first remission after fludarabine; 
4) ofatumumab has higher in vitro activity against CLL cells; and  
5) ofatumumab has also demonstrated efficacy in refractory CLL as monotherapy (Study 
Hx-CD20-406).  
1.5. 
Rationale for Closing Enrollment 
At the start of the study, it was expected that the study would fully enroll prior to the 
IDMC review at 2/3 of the events.  When the required number of events occurred prior to 
fully enrolling the study, but with the full number of evaluable subjects available, and 

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before the results were known, it was decided that if the primary endpoint met the 
predefined significance level of p<0.001, demonstrating clinical benefit for the 
ofatumumab arm, further enrollment would be discontinued.  The independent data 
monitoring committee (IDMC) communicated that the significance level of p<0.001 for 
the primary endpoint at the interim analysis had been met.  Additionally, the study had 
obtained the number of evaluable subjects required (the number of evaluable subjects at 
the time of the interim analysis was 479, with 478 evaluable required). 
 
The conduct of the study will continue without modification, with continuation of the 
assessments of the efficacy and safety endpoints and no change in study design, in 
accordance with the IDMC recommendation.  Currently, the standard of care is still 
observation, so that those subjects on the observation arm are receiving the standard of 
care and are not being jeopardized by continuation of observation.  The recommendation 
of the IDMC was that subjects should continue in their assigned study arms without 
change in treatment. Additionally, the IDMC did not identify any safety concerns 
associated with long-term treatment with ofatumumab. 
2. 
OBJECTIVES 
Primary objective: 
 
To evaluate PFS of subjects treated with ofatumumab maintenance treatment 
compared to no further treatment after remission induction in subjects with relapsed 
chronic CLL 
Secondary objectives: 
 
To evaluate the improvement in response, improvement in response time to next 
CLL treatment and overall survival in subjects receiving ofatumumab maintenance 
compared to no further treatment 
 
To evaluate the PFS after next-line therapy and the time to progression after next-
line therapy 
 
To evaluate the safety and tolerability in subjects with CLL receiving ofatumumab 
maintenance compared to no further treatment 
 To evaluate the health-related quality of life in subjects with CLL receiving 
ofatumumab maintenance compared to no further treatment as assessed by changes in 
patient reported outcome (PRO) measures relative to baseline 
 To evaluate prognostic marker correlation with clinical response in subjects with CLL 
receiving ofatumumab maintenance compared to no further treatment 
 
To evaluate ofatumumab pharmacokinetic parameters in subjects with CLL receiving  
maintenance ofatumumab every 2 months 
 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
 
This is an open-label, two-arm, randomized, Phase III study of ofatumumab or no further 
treatment in subjects who are in CR or PR after 1 to 2 treatments for relapsed CLL. 
3.1.1. 
Screening Phase 
Subjects will give informed consent.  Blood samples, physical examination, CT scan and 
bone marrow examination will be performed to determine the study baseline.  All 
examinations must be performed ≤ 14 days prior to dosing, with the exception of the CT 
scan and bone marrow examination, which can be performed ≤ 6 weeks prior to dosing.  
At the discretion of the physician, rescreening is acceptable.  Refer to Appendix 1 Time 
and Events for complete list of screening procedures. 
3.1.2. 
Randomization and Stratification 
Subjects will be randomized 1:1 to treatment arm A or B.   
Eligible subjects will be stratified at randomization based on: 
1) CR or PR at study entry 
2) Number of previous induction treatments 
3) Type of prior treatment :  chemoimmunotherapy, only alkylating monotherapy, or 
other treatment  

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3.1.3. 
Treatment Phase 
Subjects randomized to treatment arm A will receive ofatumumab whereas subjects 
randomized to treatment arm B will receive no further treatment (i.e. observation only).  
Arm A: 
Ofatumumab: 
 
300mg IV Week 1 followed by 1000mg IV on Week 2 
 
1000mg IV (1 dose every 8 weeks for up to 2 years following the first 1000 mg 
dose)  
OR 
Arm B: 
 
No further treatment (observation and assessments as per arm A) 
Disease status assessments to determine subject response or progression will be 
performed approximately every 8 weeks for up to 2 years for both arms according to NCI 
Criteria [Hallek, 2008] and will include: 
 
Physical examination including lymph node examination, spleen and liver 
measurement, and detection of constitutional symptoms  
 
Peripheral blood sample evaluation of complete blood count (CBC) and differential 
(expressed in % and absolutes) 
Monitoring and treatment of potential Tumor Lysis Syndrome (TLS) during the first 
cycle will be performed as per oncology standard of care.   
Patient Reported Outcome (PRO) measures (EORTC QLQ-C30, EORTC QLQ-CLL16, 
EQ-5D will be administered for completion by subjects at baseline, at each treatment visit 
beginning with Visit 3, at last visit, and at follow-up visits.  A Health Change 
Questionnaire will be administered for completion by the subjects at all post baseline 
visits, as per Section 6.5.6. 
3.1.4. 
Follow-up Phase 
Survival and disease status assessments (physical examination and evaluation of 
peripheral blood samples) will be performed post treatment every 3 months for 5 years 
after last treatment. 
A bone marrow examination is required to confirm Complete Remission (CR) at least 
2 months after completion of therapy and when a subject fulfills the International 
Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer 
Institute-Sponsored Working Group (NCI-WG) requirements for Complete Remission 
(CR) [Hallek, 2008].  Previous results may be used or if not available, a bone marrow 
exam may be done at screening. If a subject’s response improves to a CR while on study, 
then a bone marrow examination is required to confirm CR at least 2 months after 
response as per the updated IWCLL NCI-WG requirements for CR [Hallek, 2008].  

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Additionally, CT Scans are required yearly while on study, including during follow-up, 
and at disease progression, whenever that may occur. 
Subjects demonstrating disease progression will be followed for survival status until 
study completion.  Follow-up assessment after disease progression on treatment will 
assess survival status, date of next CLL therapy, type of therapy and response to therapy. 
It is acceptable for the information for survival follow-up visits to be collected remotely 
(via telephone, email), as necessary.  The frequency of the survival follow-up visits 
should be per local standard of care, suggested every 3 months for CLL. Minimally, this 
should be collected at least annually. 
PRO measures (EORTC QLQ-C30, EORTC QLQ-CLL16, EQ-5D and a Health Change 
Questionnaire) will be administered for completion by the subject at follow-up visits, as 
per Section 6.5.6. 
Please refer to Section 6:  Study Assessments and Procedures for detailed assessment 
instructions. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with additional administrative and detailed technical information. 
3.2. 
Discussion of Design and Dose Rationale 
As discussed in the rationale, CLL is characterized by relapse and there is currently no 
approved maintenance therapy.  This study will evaluate the use of ofatumumab as 
maintenance treatment in second/third line CLL.  Subjects will be randomized to receive 
either ofatumumab or no treatment in a 1:1 ratio to provide a direct comparison of 
treatment versus observation, the current standard of care.  
The study does not utilize a placebo and is not blinded as the infusion reactions to 
ofatumumab would not maintain the blind.  As the endpoints of the study are objective, 
this will not affect the interpretation of the study. 
The design of the study is considered sufficient at 80% power to detect a clinically 
meaningful difference in maintenance treatment vs no treatment. 
With the current treatment options, patients receiving chemoimmunotherapy (i.e. FCR) 
have the longest PFS.  For patients not naïve to rituximab, this PFS represents a median 
of 28 months [Wierda, 2005] and a 40% increase of this PFS would be 39.2 months. 
The proposed ofatumumab dose and schedule in this study was selected based on several 
considerations:  preclinical data with ofatumumab and clinical population 
pharmacokinetic modeling and simulation, prior clinical experience with rituximab, and 
prior clinical experience with ofatumumab. 
An initial dose of 300 mg of ofatumumab is given in Week 1 to minimize infusion-
related events before introducing the higher dose at Week 2 to provide higher 
ofatumumab concentrations.   

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Preclinical data suggest that ofatumumab plasma concentrations >10 g/mL are sufficient 
to suppress peripheral B-cell recovery in cynomolgus monkeys as well as suppress tumor 
cell growth in Daudi tumor-bearing SCID mice [Bleeker, 2008].  Ofatumumab 
concentrations above 50 g/mL were sufficient for complete B-cell depletion.  Recovery 
of CD20+ cells in peripheral blood and lymph nodes was detected when plasma 
ofatumumab concentrations had dropped below 5-10 g/mL.  Thus, a potential clinical 
target in developing ofatumumab dosing regimens is prolonged maintenance of plasma 
concentrations >10 g/mL. 
Pharmacokinetic data from the Phase I study in 33 patients with relapsed or refractory 
CLL (Study Hx-CD20-402) were analyzed using a two-compartment model with a 
decrease in clearance after the first dose and assuming a constant rate infusion using a 
nonlinear mixed-effects modeling approach (NONMEM).  Assuming that ofatumumab 
pharmacokinetics with maintenance administration in subjects with CLL who have 
responded to their most recent therapy is similar to that observed with repeated weekly 
ofatumumab administration, the resulting model was used to simulate concentration-time 
data for 500 subjects receiving ofatumumab at 300 mg at Week 1 and 1000 mg at 
Week 2, followed seven weeks later by 1000 mg every eight weeks for two years.  Based 
on these simulations, the probability of maintaining plasma ofatumumab concentrations 
>10 g/mL was approximately 75% after the third 1000-mg dose at Week 17, increasing 
over time to approximately 90% during continued maintenance dosing and for 8 weeks 
after the last dose.  Thus, a dosing schedule, with the first infusion of 300 mg at Week 1 
and subsequent infusions of 1000 mg at Week 2 and at eight-week intervals starting with 
Week 9, is expected to achieve prolonged maintenance of plasma concentrations 
>10 g/mL in a high proportion of patients with CLL. 
Prior clinical experience with rituximab suggests that prolonged administration schedules 
enhance response duration in patients with non-Hodgkin’s lymphoma 
[Collins-Burow, 2007; van Oers, 2007].  Various dosing regimens have been examined as 
maintenance therapy, including administration of single infusions every two months, and 
safety has been demonstrated for up to two years of maintenance therapy.  Two Phase II 
studies have examined maintenance therapy with rituximab in patients with CLL, one 
examining four weekly infusions of 375 mg/m2 every six months for up to two years in 
patients with objective response or stable disease after initial rituximab treatment 
[Hainsworth, 2003] and one examining four monthly infusions of 375 mg/m2 followed by 
twelve monthly infusions of 150 mg/m2 in patients with CR or PR positive for minimal 
residual disease after fludarabine/rituximab treatment [Del Poeta, 2008].  These studies 
suggest that prolonged administration schedules enhance response duration in patients 
with CLL.  The existing clinical experience with maintenance rituximab suggests that 
administration of an anti-CD20 monoclonal antibody should be tolerated for up to two 
years.   
Prior clinical experience in a Phase I/II trial of ofatumumab in patients with relapsed or 
refractory CLL (Study Hx-CD20-402) suggested that a total dose of 6500 mg (weekly 
doses of 500, 2000, 2000, and 2000 mg) was effective and tolerated [Coiffier, 2008].  In 
the pivotal trial in patients with refractory CLL (Study Hx-CD20-406), ofatumumab was 
given as an initial infusion of 300 mg, followed by seven 2000 mg infusions at weekly 
intervals, followed five weeks later by 2000 mg infusions every four weeks for four 

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doses.  This initial high-dose/intense regimen followed by monthly high-dose infusions 
was tolerated, suggesting that 1000 mg ofatumumab every two months for two years 
should be tolerated.  Adverse events in previous trials had been primarily infusion-related 
events on the day of the first infusion; therefore, the prolonged treatment schedule in 
Study OMB112517 is not expected to affect the overall safety profile. 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects 
Subjects who meet all the following inclusion/exclusion criteria will be eligible for 
randomization into the study.  The original plan was for approximately 583 subjects to be 
screened (with 532 randomized) to obtain 478 evaluable subjects (assuming 10% screen 
failure and 10% drop out rates).  All evaluable subjects were obtained, and as the 
significance level was met at the interim efficacy of analysis, further enrollment will be 
stopped.  
4.2. 
Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Adults with documented diagnosis of CLL based on the modified IWCLL 
updated NCI-WG guidelines [Hallek, 2008]  
2. At least PR according to the revised 2008 NCI-WG CLL criteria within 3 months 
of the response assessment after the last dose of 2nd/3rd line treatment  
3. The anti-leukemic treatment before study entry should have been for at least 
3 months or 3 cycles  
4. ECOG Performance Status of 0-2  
5. Signed written informed consent prior to performing any study-specific 
procedures 
French subjects:  In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category. 
4.3. 
Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Known primary or secondary fludarabine-refractory subjects, defined as treatment 
failure (failure to achieve a CR or PR) or disease progression within 6 months 
[Hallek, 2008]   
2. Prior maintenance therapy 
3. Known transformation of CLL (e.g. Richter’s transformation), prolymphocytic 
leukemia (PLL), or CNS involvement of CLL 

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4. Active Autoimmune Hemolytic Anemia (AIHA) requiring treatment except if in 
the opinion of the investigator it is thought not to affect the subject’s safety, the 
conduct of the study or the interpretation of the data 
5. Previous autologous or allogeneic stem cell transplantation 
6. Chronic or current active infectious disease requiring systemic antibiotics, 
antifungal, or antiviral treatment such as, but not limited to, chronic renal 
infection, chronic chest infection with bronchiectasis, tuberculosis and active 
Hepatitis B or C 
(Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb 
status), a HBV DNA test will be performed and if positive the subject will be 
excluded*.) 
7. Other past or current malignancy (with the exception of basal cell carcinoma of 
the skin or  in situ carcinoma of the cervix or breast) unless the tumor was 
successfully treated with curative intent at least 2 years prior to trial entry except 
if in the opinion of the investigator it is thought not to affect the subject’s safety, 
the conduct of the study or the interpretation of the data 
8. Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within 6 months prior to screening, congestive heart failure, and 
arrhythmia requiring therapy, with the exception of extra systoles or minor 
conduction abnormalities except if in the opinion of the investigator it is thought 
not to affect the subject’s safety, the conduct of the study or the interpretation of 
the data 
9. History of significant cerebrovascular disease or event with symptoms or sequelae 
10. Significant concurrent, uncontrolled medical condition that in the opinion of the 
investigator contraindicates participation in this study 
11. Other anti-leukemic use of medications including glucocorticoids 
12. Known HIV positive 
13. Screening laboratory values: 
 Platelets<50 x 109/L  
 Neutrophils<1.0 x 109/L  
 Creatinine > 1.5 times upper normal limit (unless normal creatinine clearance) 
 Total bilirubin > 1.5 times upper normal limit (unless due to liver involvement 
of CLL or Gilbert’s syndrome) 
 Alanine Aminotransferase (ALT) > 2.5 times upper normal limit (unless due 
to liver involvement of CLL) 
 Alkaline phosphatase >2.5 times upper normal limit 
14. Known or suspected hypersensitivity to ofatumumab that in the opinion of the 
investigator or medical lead contraindicates study participation 

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15. Subjects who have received treatment with any non-marketed drug substance or 
experimental therapy within 5-terminal half-lives or 4 weeks whichever is longer 
prior to first dose of study medication or currently participating in any other 
interventional clinical study 
Note:  Participation in any other interventional clinical study after disease 
progression during post PD follow-up is permitted 
16. Lactating women, women with a positive pregnancy test at Visit 1 or women (of 
childbearing potential) as well as men with partners of childbearing potential, who 
are not willing to use adequate contraception from study start through one year 
following last ofatumumab dose.  Adequate contraception is defined as 
abstinence, oral hormonal birth control, implants of levonorgestrel, estrogenic 
vaginal ring, percutaneous contraceptive patches, intrauterine device, and male 
partner sterilization if male partner is sole partner for that subject.  For females in 
the USA, the use of a double barrier method is also considered adequate (condom 
or occlusive cap plus spermicidal agent). 
* If HBV DNA is negative, subject may be included but must undergo HBV DNA 
monitoring (see Section 6.3.4). Prophylactic antiviral therapy may be initiated at the 
discretion of the investigator.  Consult with a physician experienced in the care and 
management of subjects with hepatitis B to manage/treat subjects who are anti-HBc 
positive. 
4.4. 
Withdrawal Criteria 
Subjects may be withdrawn from investigational product at any time if it is the wish of 
the subject (or their legally acceptable representative) for any reason, the investigator 
judges it necessary due to medical reasons including disease progression or the subject 
becomes pregnant. (See also Section 8.3.5.) The subject will be evaluated for disease 
status and survival per the follow-up visit schedule outlined in Section 3.1.4.   
Furthermore, a subject may withdraw from study participation (i.e., withdraw consent) at 
any time for any reason.  The reason for withdrawal from study participation must be 
documented in the eCRF.   
The investigator must make every effort to perform and document the following in the 
eCRF: 
 Disease assessment  
 Hematology and Chemistry 
 Physical examination, vital signs and body weight assessment 
 Response Assessment 
 AE/SAE Assessment 
 Concomitant Medication assessment 
 Subject completion of PRO measures (EORTC QLQ-C30, EORTC QLQ-
CLL16, EQ-5D and the Health Change Questionnaire)  

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For data collection purposes, subjects are considered as completing the study if they have 
died during the treatment or follow-up phases, are lost to follow-up, or withdraw consent. 
5. 
STUDY TREATMENTS 
5.1. 
Investigational Product and Reference Therapy 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from 
Novartis upon request. Adequate precautions must be taken to avoid direct contact with 
the investigational product.   
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator and authorized site staff.  Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol. 
Please refer to the SPM for detailed instructions related to: 
 storage conditions 
 infusion preparation 
 premedication 
 dosing schedule  
 handling of infusion reactions 
 observations required during infusions 
5.1.1. 
Ofatumumab 
The investigational medical product, ofatumumab, is a clear liquid concentrate for 
solution for infusion presented in glass vials.  Ofatumumab will be infused intravenously 
on day 1 (300mg) and day 8 (1000mg) in the first cycle, followed by infusions of 
1000mg every 2 months. 
The ofatumumab infusions will be prepared in 1000 mL sterile, pyrogen free 0.9% NaCl  
to yield a 0.3 mg/mL and 1 mg/mL ofatumumab concentration for the first and 
subsequent infusions, respectively.  Please refer to the SPM for instruction correct 
preparation of the investigational medical product. 

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5.1.1.1. 
Ofatumumab Pre-Medication 
Pre-medication before each ofatumumab infusion must be given within 30 minutes to 
2 hours prior to the treatment as detailed in Table 1: 
Table 1 
Pre-medication Requirements prior to Ofatumumab Infusions 
Infusion # 
Acetaminophen (po) 
or equivalent 
Antihistamine  
(iv or po) 
diphenhydramine  
or equivalent 
Glucocorticoid (iv) 
prednisolone  
or equivalent1 
1st  
1000 mg 
50 mg 
50 mg 
2nd  
1000 mg  
50 mg 
50 mg 
3rd -Nth  
1000 mg 
50 mg 
0 
– 50 mg2  
1. 
Please refer to the SPM for glucocorticoid equivalent doses. 
2. 
If the 2nd infusion has been completed without the subject experiencing any grade = 3 AEs, pre-medication with 
glucocorticoid may be reduced or omitted before the 3rd to Nth infusion at the discretion of the investigator.  
5.1.1.2. 
Ofatumumab Treatment Schedule 
Please refer to the study procedures manual for the preparation of the ofatumumab 
infusion. 
First Infusion of 300mg Ofatumumab 
The initial rate of the first infusion of 300mg ofatumumab (0.3mg/mL) should be 
12mL/hour (hr). If no infusion reactions occur the infusion rate should be increased every 
30 minutes, to a maximum of 400 mL/hr, according to Table 2. If this schedule is 
followed, the infusion duration will be approximately 4.5 hours. 
Table 2 
Infusion rate at 1st Ofatumumab (300 mg) infusion 
Time 
mL/hour 
0 – 30 minutes 
12 
31 – 60 minutes 
25 
61 – 90 minutes 
50 
91 – 120 minutes 
100 
121 - 150 minutes 
200 
151 - 180 minutes 
300 
181+ minutes 
400 
 
If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. 
Upon restart, the infusion rate should be half of the infusion rate at the time the infusion 
was paused. If, however, the infusion rate was 12 mL/hr before the pause, the infusion 
should be restarted at 12 mL/hour.  Hereafter, the infusion rate may be increased 
according to the judgment of the investigator, in the manner described in this section. 
 

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Subsequent infusions of 1000mg Ofatumumab 
If the previous infusion has been completed without grade ≥ 3 infusion-associated AEs, 
the subsequent infusion of 1000 mg (1mg/mL) can start at a rate of 25 mL/hr and should 
be doubled every 30 minutes up to a maximum of 400 mL/h, according to Table 3. 
Duration of the infusion will be approximately 4 hours if this schedule is followed. If the 
previous infusion has been completed with grade ≥ 3 infusion associated AEs, the 
subsequent infusion should start at a rate of 12 mL/hour according to Table 2. 
Table 3 
Infusion rate at subsequent Ofatumumab (1000 mg) infusion 
Time 
mL/hour  
0 – 30 minutes 
25 
31 – 60 minutes 
50 
61 – 90 minutes 
100 
91 – 120 minutes 
200 
121+ minutes 
400 
Subsequent infusions=2nd and 3-14th infusions 
 
During infusion the patient should be monitored closely and appropriate measurements 
should be performed whenever judged necessary. For details please refer to the SPM. 
 
Dose reductions or modifications of ofatumumab are not permitted with the exception of 
those initiated for patient safety (i.e.  due to infusion reactions).  If a dose delay is 
required for ofatumumab, due to but not limited to adverse events, dosing may resume at 
physician discretion, and if the patient is still considered to be in remission. 
5.1.1.3. 
Management of Infusion Reactions 
5.1.1.3.1. Mild and Moderate Intensity Adverse Events (Grade 1 and 2) 
If the investigator judges the AE to be related to the infusion, the infusion may be 
temporarily slowed or interrupted.  
When the subject’s condition is stable, the infusion can be restarted according to the 
judgment of the investigator.  
Upon restart, the infusion rate should be half of the infusion rate at the time the infusion 
was paused. If, however, the infusion rate was 12mL/hr before the pause, the infusion 
should be restarted at 12mL/hr. 
Hereafter, the infusion rate may be increased according to the judgment of the 
investigator, in the manner described in Table 2 and Table 3 (i.e. not more than doubled 
and no earlier than every 30 minutes). 

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5.1.1.3.2. Severe Intensity Adverse Events (Grade ≥3) 
If the investigator judges a grade ≥3 AE to be related to the infusion, the infusion must be 
interrupted and the appropriate clinical intervention begun.  When the AE decreases to 
grade <3, the investigator may restart the infusion.  
Upon restarting the infusion, the infusion rate must be 12mL/hr for the first infusion or 
25mL/hr for subsequent infusions, and may subsequently be increased according to the 
judgment of the investigator, as described in Table 2 and Table 3 (i.e. not more than 
doubled and no earlier than every 30 minutes).  
If the severity of the AE does not resolve to grade <3 despite adequate clinical 
intervention, or the same AE increases to grade =3 on three occasions during one 
infusion, the subject should be withdrawn from treatment. 
5.2. 
Treatment Assignment 
Subjects will be assigned to study treatment in accordance with the randomization 
schedule (see Section 3.1.2).  Please refer to the SPM for detailed instruction. 
5.3. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to Novartis, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study. 
5.4. 
Prohibited Concomitant Medication or Therapies 
 Anti-cancer medication not part of the protocol treatment (e.g. alkylating agents, 
anti-metabolites, purine analogues, other monoclonal antibodies, and other 
medications including glucocorticoids) 
 Any non-marketed drug substance or experimental therapy 
Note:  Glucocorticoids given for other indications such as exacerbations of 
asthma or as premedication for ofatumumab infusions are allowed. 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to Appendix 1 Time and Events  
6.1. 
Clinical Assessments 
6.1.1. 
Demographics 
At screening, date of birth, sex, and race/ethnicity is collected. 

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6.1.2. 
Disease Characteristics and Medical History 
At screening, relevant medical history is collected including: 
 
Date of initial CLL diagnosis  
 
Rai and Binet staging at diagnosis and screening 
 
Listing of relevant past and current diseases 
6.1.3. 
Previous CLL Therapy 
Prior treatment of CLL will be recorded including name of therapy, start and end date, 
dosing information, response and duration of response. 
6.1.4. 
Height and Weight 
Height (without shoes) will be measured at screening and recorded in the eCRF.  Body 
weight (without shoes) will be measured at screening and throughout treatment and 
follow-up phases and recorded on the eCRF. 
6.1.5. 
Physical Examination 
A general physical examination is required at the screening visit and at visits during the 
study.  This physical will include general appearance including examination of the 
following:  skin, palpation of the lymph nodes, extremities, abdomen including 
determination of hepatomegaly, respiratory, cardiovascular, musculoskeletal, and 
neurological systems. 
6.1.6. 
Electrocardiogram 
A standard 12-lead electrocardiogram (ECG) is required at screening.  The investigator 
will perform an overall interpretation of the ECG or may delegate this task to a 
cardiologist, if applicable.  Additional ECGs may be obtained as clinically warranted at 
the discretion of the PI or delegate. 
6.1.7. 
Vital Signs 
Vital signs including temperature, blood pressure (BP), and pulse are documented per 
Appendix 1 Time and Events and during ofatumumab intravenous infusions. 
Temperatures for individual subjects must be measured using the same method at all 
visits. 
6.1.8. 
Concomitant Medication 
Any medication other than the trial drug is considered concomitant medication (apart 
from protocol defined premedication given prior to the infusions of ofatumumab) and 
will be documented, including the following information: 
 Indication 

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 Dose information 
 Start date  
 Stop date of administration or ongoing at study termination 
Of note:  Intravenous gamma globulin, prophylactic antibiotics, and G-CSF may be given 
per local standard of care, at the physician’s discretion.  
6.1.9. 
ECOG Performance Status 
An Eastern Cooperative Oncology Group (ECOG) Performance Status value is required 
at screening and throughout treatment and follow-up phases, to evaluate daily living 
abilities.  Please refer to SPM for definitions of the ECOG performance status. 
6.1.10. 
Constitutional Symptoms (B-Symptoms) 
Assessment for the presence of the following symptoms will be performed at screening 
and at each visit:  
 night sweats without signs of infection 
 unintentional weight loss  10% within the previous 6 months 
 recurrent, unexplained fever of greater than 100.5F for 2 weeks without signs of 
infection 
 extreme fatigue  
6.1.11. 
Lymph Node and Organ Examination 
A physical lymph node and organ (spleen and liver) examination will be performed at 
screening and throughout the trial as part of disease status assessment. 
Lymph nodes evaluation requires physical exam recording the diameter in two planes of 
the largest palpable node in each of the following sites: cervical, axillary, supraclavicular, 
inguinal and femoral.  Lymphadenopathy is defined as lymph nodes with the largest 
diameter greater than 1.5 cm. 
Liver and spleen size is assessed by physical exam and documented as ‘cm’ under the 
costal margin.  
6.1.12. 
Pre-treatment Computed Tomography (CT) Scans 
All subjects must have a CT scan with contrast of the thorax, abdomen, and pelvis 
performed at screening to confirm remission status.  CT scans performed within 6 weeks 
prior to entering the study and collected according to defined standards can be used as 
screening CT scans. Clinical staging is independent of CT scan results. 
6.1.13. 
Pre-treatment Bone Marrow Examination 
Unilateral bone marrow aspirate smear and a suitable bone marrow biopsy will be 
performed at baseline (or within 6 weeks prior to entering the study) ONLY to confirm 

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CR. A pathologist at a central laboratory will evaluate the biopsy and smear.  Details 
regarding collection of bone marrow samples are provided in a separate procedure 
manual. 
6.2. 
Efficacy 
6.2.1. 
Definition of Response 
While subjects will be entering the study in remission, changes in status to disease 
progression or even from PR to CR will be determined according to the definitions of 
response in the IWCLL updated NCI-WG guidelines [Hallek, 2008] and documented at 
visits outlined in the time and events table.  For a tabular summary of all criteria of 
response definition in CLL patients see Appendix 2.  The IWCLL updated NCI-WG 
guidelines should be applied in the context of clinical judgment and determination of 
disease progression is at the physician’s discretion. 
6.2.1.1. 
Complete Remission (CR) 
CR requires all of the following criteria as assessed at least 2 months after therapy or at 
the earliest 2 months after beginning this maintenance protocol (i.e. ofatumumab 
treatment/observation): 
Peripheral blood lymphocytes (evaluated by blood and differential count) below 4x109 
(4000/µL) 
Absence of significant lymphadenopathy (e.g. lymph nodes > 1.5 cm diameter). 
No hepatomegaly or splenomegaly. 
Absence of constitutional symptoms 
Blood counts above the following values: 
a. 
Neutrophils > 1.5 x 109/L* 
b. Platelets > 100 x 109/L* 
c. 
Hemoglobin > 11.0 g/dL (6.8mmol/L)** 
*without need for exogenous growth factors 
**without red blood cell transfusion or need for exogenous erythropoietin 
 
Bone marrow aspirate and biopsy should be performed at least 2 months after the 
final treatment and if clinical and laboratory results listed above in Section 6.2.1.1 
(items 1 to 5) demonstrated that a CR has been achieved. The marrow sample should 
be analyzed by flow cytometry to demonstrate that the marrow is free of clonal CLL 
cells.  Cases with residual CLL cells by conventional flow cytometry are defined as 
PR.  
To define a CR, the marrow sample must be at least normocellular for age, with less 
than 30% of nucleated cells being lymphocytes.  Lymphoid nodules should be 
absent.  If lymphoid nodules can be found, immunohistochemistry analysis should be 
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other than CLL cells or of CLL cells.  If marrow is hypocellular, repeat after 4-6 
weeks, provided the blood counts have recovered (as defined in Section 6.2.1.1 item 
5).  Marrow biopsies should be compared with any pretreatment marrow.  In some 
cases, it is necessary to postpone the marrow biopsy until after all other criteria to 
define a CR have been satisfied, however, this time interval should not exceed 6 
months after treatment. 
Subjects who fulfill all the preceding criteria for CR (Section 6.2.1.1 items 1 to 6) but 
have persistent anemia, thrombocytopenia or neutropenia, apparently unrelated to CLL 
but related to drug toxicity, should be considered as CR with incomplete bone marrow 
recovery.  
6.2.1.2. 
Partial Remission (PR) 
PR is defined by the criteria described in Section 6.2.1.2 items 1, 2, and /or 3 (if abnormal 
prior to therapy), as well as one or more of the features listed in item 4. To define a PR at 
least one of these parameters needs to be documented for a minimal duration of 2 months.  
Constitutional symptoms persisting for more than 1 month should also be documented. 
1. A decrease in the number of peripheral blood lymphocytes by 50% or more from 
the value prior to therapy  
2. Reduction in lymphadenopathy as defined by: 
 
A decreased lymph node size by below 50% or more either in the sum product 
of up to 6 lymph nodes or in the largest diameter one of the enlarged lymph 
node(s) detected prior to therapy 
 
No increase in any lymph node and no new lymph nodes. In small lymph nodes 
(<2cm), an increase of <25% is not considered to be significant 
3. A decrease in the noted pre treatment enlargement of liver or spleen by 50% or more 
4. The blood count should show at least one of the following results: 
 
Neutrophils more than 1.5 x 109/L (1500/µL) *  
 
Platelet counts greater than 100 x 109/L (100,000/µL) or 50% improvement over 
baseline* 
 
Hemoglobin greater than 110g/L (11.0g/dL, 6.8mmol/L) or 50% improvement 
over baseline ** 
*without need for exogenous growth factors 
** without red blood cell transfusion or need for exogenous erythropoietin. 
6.2.1.3. 
Progressive Disease (PD) 
PD during or after therapy is characterized by at least one of the following: 
1. Lymphadenopathy. Progression of lymphadenopathy, if one of the following is 
observed: 

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 
Appearance of new lesion such as enlarged lymph nodes (>1.5cm), 
splenomegaly, hepatomegaly or other organ infiltrates 
 
An increase by 50% or more in greatest determined diameter of any previous 
site.  
An increase by 50% or more in the previously noted enlargement of the liver or spleen or 
de novo appearance of hepatomegaly or splenomegaly 
An increase by 50% or more in the numbers of blood lymphocytes with at least 
5000 B-lymphocytes per microliter (5.0 x 109/L). 
Transformation to a more aggressive histology (e.g. Richter’s transformation). 
Occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL 
 
During therapy: Cytopenias cannot be used to define disease progression 
 
After treatment: The progression of any cytopenia (unrelated to autoimmune 
cytopenia), as documented by a decrease of Hb levels by more than 20g/L 
(2 g/dL) or to less than 100g/L (10g/dL), or by a decrease of platelet counts by 
more than 50% or to less than 100 x 109/L (100.000/μL), which occurs at least 
3 months after treatment, defines disease progression, if the marrow biopsy 
demonstrates an infiltrate of clonal CLL cells. 
 
Note:  Physician’s discretion should be used to distinguish between potential 
infection versus progressive disease base on lymphocyte count.  It is acceptable 
to defer definitive judgment of progressive disease until further evidence is 
available. 
6.2.2. 
Bone Marrow Examination 
Unilateral bone marrow aspirate smear and a suitable bone marrow biopsy will be 
performed at baseline (or within 6 weeks prior to entering the study) ONLY as part of the 
CR evaluation for patients entering or during the study in CR. A pathologist at a central 
laboratory will evaluate the biopsy and smear.  Details regarding collection of bone 
marrow samples are provided in a separate procedure manual.  
Bone marrow examination (aspirate smear and biopsy) to confirm CR, as determined by 
the clinical and laboratory results listed in Section 6.2.1.1 is required at least 2 months 
after completion of therapy or at least 2 months of therapy or response while on study. 
The marrow should be analyzed by flow cytometry to confirm absence of clonal CLL 
cells.  Samples are to be reviewed in conjunction with any prior pathology, as available. 
Minimal residual disease assessment will also be performed on bone marrow aspirate 
obtained after CR (see Section 6.2.3). When possible, the first drop from bone marrow 
aspirate will be used for MRD measurement. 
6.2.3. 
Minimal Residual Disease (MRD) 
For subjects enrolling in the study who are in CR, baseline MRD will be assessed at 
screening, prior to any treatment visit. 

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For subjects who improve to a CR while on study, a bone marrow examination will be 
performed after at least 2 months of therapy or response while on study. 
The bone marrow sample if available, and/or peripheral blood sample will be examined 
by flow cytometry with the following B-CLL MRD panel [Rawston, 2007]: 
 
CD5/CD19 with CD20/CD38 
 
CD5/CD19 with CD81/CD22 
 
CD5/CD19 with CD79b/CD43 
In addition CD3/CD19 with CD14/CD45 analysis is performed to allow enumeration of 
CD19+ cells and contamination assessment and CD5/CD19 with Igλ/Igκ analysis is 
performed to confirm clonality.  
Subjects with negative MRD will receive follow-up MRD assessments of the peripheral 
blood until MRD analysis becomes positive.  
The absence of MRD is defined as less than one B-CLL cell per 10,000 leukocytes. 
6.2.4. 
CT-Scans 
According to the IWCLL updated NCI-WG response criteria for CLL [Hallek, 2008], 
CT-scans are recommended in clinical trials to assess response.  This study will 
prospectively explore the validity of CT scans for a more sensitive detection of disease 
progression.  CT-Scans are required prior to start of therapy.  CT scans will be done 
approximately yearly while on study including at the end of treatment/observation, and/or 
upon relapse.  If a scheduled CT scan indicates disease progression, and the subject will 
be withdrawn, it is not necessary to repeat a CT scan for a withdrawal visit.  The actual 
CT scan (not just the radiologist report) should be available and performed to the criteria 
specified in the SPM. 
6.3. 
Laboratory Assessments 
All the analyses will be performed by a central laboratory, except for the direct 
antiglobulin test (Coomb’s test) that will be performed locally.  A detailed description of 
the procedures for sampling, handling, storage, and shipment of the laboratory samples 
and all material such as test tubes and labels is provided in the SPM or by the central 
laboratory. 
The protocol should be followed as closely as possible, but if as per local practice, a 
blood draw for hematology analysis prior to the visit date is required, it would be 
acceptable for hematology analysis, but the blood draw can be taken no more than 3 days 
ahead of the visit date.  Blood draws performed by local laboratories (e.g. for quicker 
pre-dose response assessment) of protocol required lab assessments are acceptable, 
however, it is important that the sample for the central laboratory analysis is taken at the 
same time.  The local laboratory results of absolute neutrophil count (ANC), platelet 
count, peripheral blood lymphocytes, and hemoglobin must also be entered into the 
eCRF, if these results are used to manage a treatment decision.  Central laboratory 

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information will also be entered into the eCRF.  Safety assessments, such as hematology 
not specified in the protocol, are allowed between visits, per investigator discretion and 
local practice. 
6.3.1. 
Flow Cytometry for B-CLL Diagnosis/Confirmation of Phenotype 
and B-cell Monitoring 
6.3.1.1. 
B-CLL Diagnosis/Phenotype Confirmation 
The B-CLL immunophenotype will be assessed by analysis of surface expression of: 
CD5, CD19, CD20, CD23, CD76b, and surface Ig at screening, if possible and at relapse.  
If the subject is in CR, results prior to latest response may be used, if available. 
6.3.1.2. 
B-Cell Monitoring 
B-cell monitoring (CD5+CD19+ and CD5-CD19+) will be performed every two months 
and at every follow-up visit until values return to normal levels on two consecutive 
determinations. 
6.3.2. 
Peripheral Blood Sampling for Hematology and Biochemistry 
Blood samples will be drawn for analysis of the following parameters at visits according 
to the time and events schedule: 
 
Hematology: hemoglobin,  hematocrit, reticulocytes, platelets, leukocytes, and  
white blood cell differential (neutrophils, eosinophils, basophils, lymphocytes 
and monocytes, prolymphocytes - all expressed in % and in absolute numbers)  
 
Biochemistry:  sodium, potassium, chloride, bicarbonate, calcium, blood urea 
nitrogen (BUN), creatinine, uric acid, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
lactic acid dehydrogenase (LDH),  albumin, glucose (random). Haptoglobin will 
be analyzed at screening and 3 months after last treatment.   
6.3.3. 
Prognostic Factors 
Whole blood will be collected at the baseline visit, if possible, and/or upon relapse for 
later analysis of the following prognostic factors: 
 IgVH mutational status  
 VH3-21 usage 
 Cytogenetics (by FISH) including but not limited to; 6q-, 11q-, +12q, 17p-, 13q-  
 β2 microglobulin   
Analysis of these factors are performed in batches by a central laboratory.  Details for 
procedures and shipments are provided separately. 

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6.3.4. 
Peripheral Blood Sampling for Safety and Disease Status 
The following laboratory tests will be performed: 
 Direct antiglobulin test (Coombs test) at screening and 3 months after last 
treatment. 
 Hepatitis B (HBV) and Hepatitis C (HCV) at screening. 
For subjects that are HBsAg negative, HBcAb positive and HBV DNA negative 
(see Section 4.3) blood samples will be collected for HBV DNA testing every 
2 months during the treatment/observation and during follow-up at the 3 months 
and 6 months visit. 
 Screening pregnancy test (HCG) for women of childbearing potential, unless 
they have had a hysterectomy, have undergone tubal ligation within one year 
before the screening visit, or have been postmenopausal for at least one year. 
 Human Anti-Human Antibody (HAHA) prior to first dose of ofatumumab, every 
6 months during ofatumumab treatment, and at 3 and 6 months post treatment 
(i.e. predose Visit 1, at Months 7, 13, 19, and 25 during treatment and at 3 and 
6 months after last ofatumumab dose, regardless of when it occurs).  A HAHA 
sample (and a pharmacokinetic sample) should also be obtained at the last 
treatment visit if it does not occur at a scheduled sampling time (e.g., if 
treatment is discontinued early).  HAHA samples will only be collected for 
subjects randomized to ofatumumab. 
 Complement: CH50 at baseline and after last treatment visit.  
 IgA, IgG and IgM at screening, every 6 months during treatment, and after last 
treatment visit and/or upon relapse.  In case of infection, these immunoglobulins 
may be tested at the physician’s discretion.  Additional samples may be collected 
post last treatment (such as 3 and 6 months f/u), if warranted. 
6.4. 
Safety Assessments 
6.4.1. 
Liver chemistry stopping and follow-up criteria 
According to Novartis policy across all compounds, liver chemistry stopping and 
follow-up criteria have been designed to assure subject safety and evaluate liver event 
etiology.  (Refer to Appendix 5) 
6.4.1.1. 
Liver Chemistry Stopping Criteria 
1. ALT > 3xULN and bilirubin  2xULN (>35% direct bilirubin; bilirubin 
fractionation required*) 
2. ALT > 8xULN 
3. ALT  5xULN for more than 2 weeks 
*NOTE: serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable and a subject meets the criterion of total bilirubin >2.0 xULN, then 
the following actions must still be performed. 

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When any of the liver chemistry stopping criteria is met, do the following: 
 
Immediately withdraw investigational product  
 
Report the event to Novartis within 24 hours of learning its occurrence 
 
Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT  3xULN and bilirubin  2xULN (>35% 
direct bilirubin), termed ‘Hy’s Law’, must be reported as an SAE.  
NOTE: serum bilirubin fractionation should be performed if testing is available. If testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating 
direct bilirubin elevations and suggesting liver injury. 
 
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed 
 
Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.  
 
Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below. 
 
Do not re-challenge with investigational product. 
In addition, for criterion 1:  
 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring 
 
A specialist or hepatology consultation is recommended 
 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values 
For criteria 2 and 3: 
 
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below) 
 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 3 subjects 
should be monitored as frequently as possible. 
Subjects with ALT 5xULN which exhibit a decrease to ALT x3xULN, but <5xULN 
and bilirubin <2xULN without hepatitis symptoms or rash, and who can be monitored 
weekly for 4 weeks: 
 
Can continue ofatumumab 
 
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline  
 
If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above 

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 
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.  
6.4.1.2. 
Liver Chemistry Follow-up Assessments 
Make every attempt to carry out the liver event follow up assessments described below: 
 
Viral hepatitis serology including: 
 
Hepatitis A IgM antibody; 
 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
 
Hepatitis C RNA;  
 
Cytomegalovirus IgM antibody;   
 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);   
 
Hepatitis E IgM antibody (if subject resides outside the US or Canada, or has 
travelled outside US or Canada in past 3 months); 
 
Blood sample for PK analysis of ofatumumab, obtained within as soon as possible 
but no later than 5 months of last dose (approximately 5 half-lives of the drug).  
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of investigational product prior to blood sample draw on the CRF. If the date or time 
of the last dose is unclear, provide the subject’s best approximation. If the date/time 
of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM.  
 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
 
Fractionate bilirubin, if total bilirubin 2xULN 
 
Obtain complete blood count with differential to assess eosinophilia 
 
Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form 
 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. 
 
Record alcohol use on the liver event alcohol intake case report form 
The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries: 
 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies. 

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 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
6.4.2. 
Adverse Events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
6.4.3. 
Definition of an AE 
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
Events meeting the definition of an AE include: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
 
New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication (overdose per se will not be 
reported as an AE/SAE) 
All infections must be reported as an AE regardless of causality. 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE.   

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Events that do not meet the definition of an AE include: 
 
Any clinically significant abnormal laboratory finding or other abnormal safety 
assessment that is associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.  
 
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
 
B cell depletion and hypogammaglobulinemia due to ofatumumab treatment 
6.4.4. 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
An overnight hospital stay due to slow infusion rates will not be considered a Serious 
Adverse Event.  
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 

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interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Medical or scientific judgment should be exercised in deciding whether reporting 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, 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. 
6.4.5. 
Toxicity Assessment of AEs and SAEs 
The investigator is required to make an assessment of the toxicity grade of each AE or 
SAE reported.  In this protocol, the maximum toxicity grade of each non-hematologic 
AE/SAEs will be evaluated according to the National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE) version 4.0 (please refer to the SPM for 
details).   
It is important to consider low blood counts at the initiation of therapy when evaluating 
hematologic toxicity of CLL subjects.  Due to this, standard solid tumor toxicity criteria 
cannot be used or subjects would exhibit grade II to IV toxicity at study onset.  For this 
reason, hematologic toxicity (platelets, hemoglobin and neutrophils) of each AE/SAE 
will be evaluated according to an adaptation of the IWCLL Grading Scale for 
Hematological Toxicity in CLL Studies [Hallek, 2008]. 
Table 4 
Grading scale for Hematological Toxicity 
Grade1 
Decrease in Platelets2 or Hb3 (nadir) from 
pretreatment value (%) 
Absolute Neutrophil Count/L4 (nadir) 
1 
11%-24% 
1500 and <2000 
2 
25%-49% 
1000 and <1500 
3 
50%-74% 
  500 and <1000 
4 
75% 
  <500 
1. Grades: 1-mild; 2-moderate; 3-severe; 4-life-threatening; 5-fatal. Death occurring as a result of toxicity at any level 
of decrease from pretreatment will be recorded as grade 5. 
2. Platelet counts must be below normal levels for grades 1-4.  If, at any level of decrease the platelet count is 
<20,000/μL, this will be considered grade 4 toxicity, unless a severe or life threatening decrease in the initial 
platelet count (e.g., 20,000/μL) was present pretreatment, in which case the subject is not evaluable for toxicity 
referable to platelet counts. 
3. Hb levels must be below normal levels for grades 1-4. Baseline and subsequent Hb determinations must be 
performed before any given transfusions. The use of erythropoietin is irrelevant for the grading of toxicity, but 
should be documented. 
4. If the absolute neutrophil count (ANC) reaches less than 1,000/μL, it should be judged to be grade 3 toxicity. 
Other decreases in the white blood cell count, or in circulating granulocytes, are not to be considered, since a 
decrease in the white blood cell count is a desired therapeutic endpoint. A gradual decrease in granulocytes is not 
a reliable index in CLL for stepwise grading of toxicity. If the ANC was less than 1,000/μL prior to therapy, the 
subject is not evaluable for toxicity referable to the ANC. The use of G-CSF is irrelevant for the grading of toxicity, 
but should be documented. 
 

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6.4.6. 
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, vital signs measurements), including those that 
worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs. 
B cell depletion, IgG below LLN, low CD19+ count, and hypogammaglobulinemia due 
to treatment with ofatumumab are not to be reported as AEs or SAEs. 
Infusion related AEs may lead to a prolonged infusion time. Overnight stay at the 
hospital due to slow infusion rate is not to be reported as a SAE. 
Specific attention will be paid to monitor events of special interest such as infusion 
reactions, tumor lysis syndrome, infections and progressive multifocal 
leukoencephalopathy (PML).  Please refer to the SPM and/or the following text*. 
Handling Infusion Reactions: 
Infusion reactions are commonly associated with anti-CD20 antibody therapy. 
Ofatumumab can cause serious infusion reactions manifesting as bronchospasm, dyspnea, 
laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, 
cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and 
angioedema. Infusion reactions occur more frequently with the first 2 infusions. 
The site staff must be prepared to intervene if an infusion reaction occurs. Special caution 
should be taken during the first infusion for each subject and during the infusion for any 
subject who did not tolerate a previous infusion well.  It is recommended that a crash cart 
is readily accessible in the event of an emergency. Infusion reactions should be treated 
according to the investigators judgment and best clinical practice.   
Interruption, restart and increasing the rate of the infusion depending on the severity of 
the AE must be according to the description below and at the investigator’s discretion. 
An increase of the infusion rate after an interruption must not exceed the scheduled 
amount as described in Table 2 and Table 3 (i.e. not more than doubled rate and no 
earlier than every 30 minutes).  See Section 5.1.1.3 for details on management related to 
intensity of adverse events. 
Handling Tumor Lysis Syndrome: 
 
Monitoring and treatment of potential Tumor Lysis Syndrome (TLS) should be 
performed as per oncology standard of care.  
 
Symptoms of TLS include: 

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 
Hyperkalemia, potentially leading to cardiac conduction abnormalities, muscle 
weakness or paralysis 
 
Hyperphosphatemia, potentially leading to renal failure 
 
Hypocalcemia. Symptoms include (but are not limited to):  tetany, seizures, mental 
retardation / dementia, parkinsonian (extrapyramidal) movement disorders, 
papilledema, emotional instability / agitation / anxiety, myopathy 
 
Hyperuricemia, potentially leading to renal failure 
 
Risk factors for TLS include a high tumor burden, high concentrations of circulating cells 
(≥ 25,000/mm3), hypovolemia, renal insufficiency, elevated pre-treatment uric acid 
levels and elevated lactate dehydrogenase levels. Thus TLS should be suspected in 
subjects with large tumor burden who develop acute renal failure along with 
hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). Acute uric acid 
nephropathy is associated with little or no urine output. The urinalysis may show uric 
acid crystals or amorphous urates. The hypersecretion of uric acid can be detected with a 
high urine uric acid:creatinine ratio > 1.0, compared to a value of 0.6-0.7 for most other 
causes of acute renal failure. 
 
In those patients considered to be at risk for TLS, management includes correction of 
electrolyte abnormalities, monitoring of renal function, maintenance of fluid balance 
(consider aggressive hydration i.e. ~3,000 ml/m2/day fluid administered parenterally)  
and supportive care. If signs of TLS occur, the investigator can administer rasburicase or 
allopurinol (e.g. Zyloprim, Allohexal, Allosig, Progout, Zyloric) or other drugs used to 
treat hyperuricemia, per prescribing information, if deemed appropriate.  
 
Handling Progressive multifocal leukoencephalopathy (PML): 
 
PML is a viral-induced demyelinating disease of the central nervous system usually 
occurring in the immunocompromised individual and has been reported with 
ofatumumab. JC virus (JCV) infection resulting in PML and death has been reported in 
rituximab-treated subjects with hematologic malignancies or with systemic lupus 
erythematosus, an indication for which rituximab has not been approved. Investigators 
and nurses should pay careful attention for signs and symptoms consistent with a 
diagnosis of PML. Signs and symptoms of PML include visual disturbances, ocular 
movements, ataxia, and changes in mental status such as disorientation or confusion. 
These symptoms are not an exhaustive list, and the investigator should exercise judgment 
in deciding to report signs and symptoms to sponsor promptly. 
 
If a subject develops neurological signs or symptoms consistent with PML, treatment 
should be halted and the subject referred to a neurologist for evaluation. At a minimum, 
blood JCV PCR and/or MRI should be performed; if either test is positive, Cerebrospinal 
Fluid (CSF) JCV PCR should be performed. If blood JCV PCR and MRI are negative, 
the investigator should contact the Sponsor for appropriate action to be taken. If blood 
JCV PCR and/or MRI are positive, the subject should be withdrawn from treatment, 
proceed to the Follow-Up Period, and be followed until resolution. There are no known 
tests that can reliably determine who is at increased risk for developing PML. There are 
no known interventions that can reliably prevent PML or adequately treat PML if it 
occurs. 

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The investigator will do the following when reporting a serious infection (including 
PML) or sign/symptom consistent with PML. 
 
 Refer to Section 6.4.10 of this document for further information and detailed 
guidance for completing and transmitting these and other SAE reports for subjects 
who experience a serious infection, malignancy, death, or sign or symptom of 
PML. 
 Provide key source documentation for the Sponsor to assist with the safety 
evaluation process. 
Examples of key source documents include but are not limited to: hospitalization records, 
discharge summaries, laboratory evaluations, biopsy results, culture/sensitivity results, 
death certificates, and autopsy reports. 
If the subject has not otherwise been withdrawn from the study, then the investigator 
should contact the Sponsor to discuss the appropriate course of action regarding study 
continuation. 
Monitoring of Hepatitis in patients: 
For subjects who are HBsAg negative, HBcAb positive and HBV DNA negative, blood 
samples will be collected for HBV DNA testing every 2 months during the 
treatment/observation period and during follow-up at the 3 months and 6 months post last 
dose visits.  
For subjects who require hepatitis monitoring, extra visits outside those defined in the 
protocol may be required. 
6.4.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease 
progression) does not need to be reported as an SAE.  However, if the progression of the 
underlying disease is greater than that which would normally be expected for the subject, 
or if the investigator considers that there was a causal relationship between treatment 
with investigational product or protocol design/procedures and the disease progression, 
then this must be reported as an SAE.   
6.4.8. 
Time Period and Frequency of Detecting AEs and SAEs 
All SAEs and AEs regardless of relationship to investigational product will be collected 
from the first dose of investigational product to 60 days after the last dose of 
investigational product and will be documented on the eCRF.  All SAEs and AEs for 
subjects not receiving treatment (observation) will be collected for the same duration of 
time (i.e. Visit 1 until 60 days after last visit, up Visit 14).  Only SAEs will be reported 
from 60 days after the last dose of investigational product or last treatment/observation 

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visit to the end of the follow-up period. All SAEs regardless of causality will be collected 
until the end of the follow-up period.   
Subject who are HBsAg negative, anti-HBc positive and HBV DNA negative may be 
included in the study but must undergo HBV DNA monitoring.  Consult with a physician 
experienced in care and management of subjects with hepatitis B to manage/treat subjects 
who are anti-HBC positive.  Anti-viral therapy should be initiated, if required.  If a 
subject’s HBV DNA becomes positive during the study, the Novartis medical lead should 
be notified.  The risks and benefits of continuing ofatumumab or discontinuing 
ofatumumab should be discussed with the medical lead before appropriate treatment 
decisions are made for that individual subject. 
From the time a subject consents to participate in and completes the study (See 
Section 4.4), all SAEs assessed as related to study participation (e.g., 
protocol-mandated procedures, invasive tests, or change in existing therapy) will be 
reported promptly to Novartis. 
Any pre-existing condition or signs and symptoms present prior to investigational 
product will be recorded as medical history.   
Any SAE brought to the investigator’s attention after the subject has completed the study 
and considered by the investigator as possibly related to investigational product must be 
reported to Novartis. 
6.4.9. 
Pregnancy 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to 
Novartis within 24 hours of learning of its occurrence.  The pregnancy must be followed 
up to determine outcome (including premature termination) and status of mother and 
child.  Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the investigational product, must be promptly reported to Novartis. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study. Pregnancy information must be reported to Novartis as described above. 
6.4.10. 
Prompt Reporting of Serious Adverse Events and Other Events 
to Novartis 
SAEs and pregnancies meeting the pre-defined criteria will be reported promptly to 
Novartis as described in the following table once the investigator determines that the 
event meets the protocol definition for that event. 

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Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data 
collection tool 
24 hours 
Updated “SAE” 
data collection tool 
Pregnancy 
24 hours 
Pregnancy Form 
2 Weeks 
Updated 
Pregnancy Form
 
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to Novartis are provided in the 
SPM. Procedures for post-study AEs/SAEs are provided in the SPM. 
6.5. 
Patient Reported Outcome (PRO) Measures 
Subjects will be asked to complete the following PRO measures at baseline, selected 
treatment and follow-up visits throughout the trial to document changes in symptoms and 
functioning that are important for patients with B-CLL.  All PRO questionnaires are 
included in Appendix 3: Patient Reported Outcome Measures. 
6.5.1. 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) 
The EORTC QLQ-C30 was developed for use in a wide range of oncology clinical trial 
populations and is intended to be supplemented by tumor specific modules 
[Aaronson, 1993; Osoba, 1994]. The 30 items of the EORTC QLQ-C30 are scored in the 
following domains: Physical Functioning (5 items), Role Functioning (2 items), 
Emotional Functioning (4 items), Cognitive Functioning (2 items), Social Functioning (2 
items), Pain (2 items), Fatigue (3 items), Nausea and Vomiting (2 items).  There are also 
five single item symptom scores (Insomnia, Loss of Appetite, Constipation, Diarrhoea, 
and Dyspnoea), a single item asking about Financial Difficulties and a global health 
status/quality of life domain consisting of two items.  Thus the EORTC-QLQ-C30 
provides a measure of symptom and Health Related Quality of Life (HRQL) domains 
from the perspective of the subject.   
Subjects respond to the items on a four point Likert scale ranging from 1 ‘Not at all’ to 4 
‘Very much’ and it takes approximately 11 minutes to complete.    Subjects are asked to 
think back over the past week when responding to the items. The EORTC QLQ-C30 is 
self-administered and has been widely used in various oncology populations.  It is 
available in over 50 languages and higher scores indicate better HRQL.  The EORTC 
QLQ-C30 is widely used and has been well validated in a number of different cancer 
indications.  The QLQ-C30 has been used in several recent studies with B-CLL patients 
[Catovsky, 2007; Doorduijn, 2005; Holzner, 2004].   

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6.5.2. 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire Chronic Lymphocytic Leukaemia 16 
item module (EORTC QLQ-CLL 16) 
The EORTC QLQ-CLL16 EORTC QLQ-CLL 16] has been developed to the high 
standards of rigour required by the EORTC group, but its psychometric properties are as 
yet untested.  The first three phases of the EORTC development process have been 
completed for the CLL16 module including generation of items based on literature 
review and semi-structured interviews with specialists and patients; review of the draft 
items by professionals and 3-5 patients; and pre-testing of the module for acceptability 
and relevance through cognitive debriefing in a sample of patients.  Subjects respond to 
the items on a four point Likert scale ranging from 1 ‘Not at all’ to 4 ‘Very much’ and it 
is estimated to take less than ten minutes to complete.  Subjects are asked to think back 
over the past week when responding to 12 of the items and the past four weeks for the 
remaining four items which are all included in the hypothesized Infection domain.  
Hypothesized scoring for the QLQ-CLL16 module has been recommended but thus far 
has not been validated.   QLQ-CLL16 domain scores will also be developed based upon 
the recommendations of the authors and, again, psychometric validation of these domains 
will be described in the detailed psychometric validation statistical analysis plan.  
6.5.3. 
EuroQoL Five-Dimension (EQ-5D) 
The EQ-5D is a self-administered, generic, indirect utility measure 
[EuroQoL Group, 1990]. The EQ-5D consists of a 0-100 Visual Analogue Scale (VAS) 
on which subjects are asked to rate their current overall health status and five single-item 
dimensions which ask subjects to rate their health in terms of mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression.  The five single items can be summed 
and expressed as a single global index of health-related quality of life. For each of the 
five items patients must choose between three levels of difficulty in accomplishing tasks 
in that dimension.  The VAS is then used in combination with the dimension scores to 
generate a patient profile. 
One response exists per dimension, such that: 
 
Level 1 (no problem) is coded as “1” 
 
Level 2 (some or moderate problems) is coded as “2” 
 
Level 3 (unable, or extreme problems) is coded as “3” 
The health states are described in terms of five-digit numbers based on the answers to 
each of the five questions.  The states can then be converted to a single score using a 
table that contains health utility values for the 243 different possible health states.  Thus a 
health utility score is created that can be incorporated into analyses of cost effectiveness.  
Additionally, a three-digit number between 0 and 100 is read off the VAS, from the exact 
point where the subject has marked the scale.   The EQ-5D takes less than five minutes to 
complete.  The EQ-5D was recently used in a study of B-CLL patients [Doorduijn, 2005]. 

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6.5.4. 
Patient Reported Constitutional Symptoms (‘B-Symptoms’) score 
The EORTC QLQ-C30 and QLQ-CLL16 module include items asking about symptoms 
due to B-CLL and other problems commonly associated with B-CLL or its treatment, 
such as increased risk of infections.  To provide a clear indication of the change in 
constitutional or ‘B’-symptoms, an additional scoring approach will be evaluated based 
on items that reflect ‘B-symptoms’ from the QLQ-C30 and the QLQ-CLL16 module, 
namely, need to rest (C30 item 10), felt weak (C30 item 12), tired (C30 item 18), weight 
loss (CLL item 31), temperature changes (CLL item 35), night sweats (CLL item 36) and 
skin problems such as itching (CLL item 37) lethargic (CLL item 39), slowed down 
(CLL item 40). This score is proposed to provide patient reported data that might be 
supportive of the ‘B-symptoms’ clinician rating.  The validity and reliability of this ‘B-
symptoms’ score will be assessed through psychometric validation using blinded data 
from this trial, as summarised in the psychometric validation RAP.   
6.5.5. 
Health Change Questionnaire 
The Health Change Questionnaire consists of a single question in which the subject is 
asked if he/she has experienced any change in his/her health overall since beginning the 
study.  The Health Change Questionnaire should be administered at all post-baseline 
visits at which PRO measures are administered.  It is included for the purpose of 
validating the PRO measures (in particular the QLQ-CLL16 measure which has not been 
previously validated). 
6.5.6. 
Administration of PRO Measures 
The EORTC QLQ-C30, EORTC QLQ-CLL16, and EQ-5D should be administered at 
baseline and at each treatment clinic visits; beginning with Visit 3, and at each follow-up 
visit post treatment; every 3 months through Month 60.  The Health Change 
Questionnaire should be administered at all the aforementioned post-baseline visits.  If a 
subject demonstrates disease progression, the measures should be completed at the 
progression visit and again one time after determination of progression.  If a subject in 
PD will be available and willing, post-PD questionnaires may be administered through 
the date that would correspond to the subject’s Month 60 visit.  If a subject withdraws 
from the study then the PRO questionnaires should be administered at the point of 
withdrawal.   
6.6. 
Pharmacokinetics 
Blood samples will be collected from subjects receiving ofatumumab predose and 0.5 h 
after the end of the infusion (EOI) at treatment on Month 1 Week1 (Day 1), Month 1 
Week 2 (Day 8), Months 3, 7, 13, 19 and 25.  In addition, predose samples will be 
collected prior to ofatumumab administration on Months 5 and 9.  A pharmacokinetic 
sample (and a HAHA sample) should also be obtained at the last treatment visit if it does 
not occur at a scheduled sampling time (e.g., if treatment is discontinued early). Samples 
will also be collected at any time of day during clinic visits at 3 and 6 months post-last 
ofatumumab dose.  Table 5 provides the pharmacokinetic sample collection schedule.   

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Predose samples may be collected at any time prior to dosing, and 0.5 h post-EOI 
samples may be collected within a   15 minute window around the scheduled time.  The 
actual date and time of each sample collection will be recorded in the eCRF. 
Table 5 
Ofatumumab pharmacokinetic sample collection schedule 
Month 
Week 
Visit 
Sampling time 
1  
1 
1 
Predose, 0.5 h post-EOI 
1 
2 
2 
Predose, 0.5 h post-EOI 
3 
9 
3 
Predose, 0.5 h post-EOI 
5 
 
4 
Predose 
7 
 
5 
Predose, 0.5 h post-EOI  
9 
 
6 
Predose 
13 
 
8
Predose, 0.5 h post-EOI 
19 
 
11 
Predose, 0.5 h post-EOI 
25 
 
14 
Predose, 0.5 h post-EOI  
28 
 
15 
3 months after last dose1,2 
31 
 
16 
6 months after last dose1,2 
1. Collect sample at any convenient time on study day. 
2. Collect sample relative to last dose of ofatumumab regardless of when it occurs 
 
Sample collection, processing, and shipping instructions are provided in the study 
procedures manual. 
6.7. 
Biomarkers 
Biomarker analysis is integral part of disease status confirmation and monitoring, as well 
as identification of prognostic markers. See Section 6.3 for more detail. 
7. 
DATA MANAGEMENT 
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets that support the 
protocol objectives. 
For this study subject data will be entered into the electronic case report forms (eCRFs), 
transmitted electronically to Novartis and its authorized agents and be combined with 
data provided from other sources in a validated data system.  
Management of clinical data will be performed in accordance with applicable standards 
and data cleaning procedures to ensure the integrity of the data, e.g., resolving errors and 
inconsistencies in the data.  Adverse events and concomitant medications terms will be 
coded using the MedDRA and a custom drug dictionary.  eCRFs (including queries and 
audit trails) will be retained by Novartis, and copies will be sent to the investigator to 
maintain as the investigator copy. 

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8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Hypotheses 
The primary endpoint for this study is progression-free-survival (PFS).  The null and 
alternative hypotheses are designed with the goal of demonstrating the superiority of 
ofatumumab maintenance treatment over no further treatment after remission induction in 
subjects with relapsed chronic CLL.  The following hypotheses will be evaluated: 
H0:  Distribution of the progression-free survival events for the ofatumumab maintenance 
treatment and for the no further treatment groups are the same (Hazard ratio is equal to 1) 
H1:  Distribution of the progression-free survival events for the ofatumumab maintenance 
treatment and for the no further treatment groups are not the same (Hazard ratio is not 
equal to 1) 
8.2. 
Study Design Considerations 
8.2.1. 
Sample Size Assumptions 
The primary objective of this study is to evaluate progression-free survival (PFS) of 
ofatumumab maintenance treatment vs. no further treatment after remission induction in 
patients with relapsed CLL as determined by investigator assessment based on NCI-WG 
CLL criteria [Hallek, 2008].  The sample size calculation is based on the primary 
endpoint, PFS, using the following assumptions: 
 Exponential survival curves where the ratio of the hazard rates is constant over 
time 
 Median PFS for the no further treatment group is 28 months 
 Median PFS for the ofatumumab maintenance treatment group is 39.2 months 
 A 1:1  stratified randomization scheme 
 A 5% two-sided risk of erroneously claiming a difference in the presence of no 
true underlying difference (alpha level) 
 An 80% chance of successfully declaring a difference in the presence of a true 
underlying difference (power) 
 Accrual rate of 12 subjects per month 
 Stratified Log-rank test for hypothesis testing  
Using the above assumptions, approximately 280 total events from both treatment arms 
are needed for the study to attain 80% power.  With a total sample size of 478 evaluable 
subjects, the total duration of the study will be approximately 63.5 months in order to 
obtain the 280 total events.  Assuming a drop out rate of 10%, the total sample size for 

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both arms combined will be about 532 and the total duration of the study will be 
approximately 68 months 
8.2.2. 
Sample Size Sensitivity 
The robustness and sensitivity of the above sample size calculation is considered in order 
to assess the impact on power should the assumed median PFS vary in the ofatumumab 
maintenance group.  The following Table 6 shows the estimated power for different 
median values of PFS for the ofatumumab maintenance group.  The total number of 
events is 280, and the total number of evaluable subjects is 478. 
Table 6 
Estimated Power for Differing Median Values of PFS 
Median PFS (months) for 
Ofatumumab Maintenance 
Median PFS (months) for No 
Further Treatment 
Estimated Power 
35 
28 
0.47 
36.4 
28 
0.60 
39.2 
28 
0.80 
42 
28 
0.92 
 
8.2.3. 
Sample Size Re-estimation 
Sample size re-estimation will not be performed for this study. 
8.3. 
Data Analysis Considerations 
8.3.1. 
Analysis Populations 
8.3.1.1. 
Populations defined for the analyses 
1)  Intent-to-Treat (ITT) Population:  This population will include subjects who are 
randomized in this study.  This will be the primary population used for evaluation of the 
efficacy data for all efficacy assessments.  In the analyses, subjects will be grouped based 
on how they are randomized regardless of which treatment they receive.  The ITT 
population will also be used for all PRO analyses. 
2)  Safety Population:  This population will include all randomized subjects.  This 
population will be used for evaluation of all safety measurements.  In the analyses, 
subjects will be grouped based on the treatment they received regardless of how they are 
randomized.   
3)  Per Protocol (PP) Population:  This population will exclude subjects with major 
protocol deviations that will impact the efficacy outcome.  The Per Protocol Population 
will be used in the primary endpoint analysis to check the robustness of the result when 
using the ITT population.  However, if the number of subjects in the PP population is 
10% or smaller than the ITT population, then the analysis will not be performed.  

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4)  Pharmacokinetic Population:   This population will consist of all subjects in the ITT 
population for whom a pharmacokinetic sample is obtained and analyzed. 
8.3.2. 
Analysis Data Sets 
The primary data set for efficacy will be based on the response assessments.  The primary 
data sets for safety will based on the adverse events and the laboratory data. 
The responses will be assessed by the investigators and changes in response will be 
determined according to the IWCLL updated NCI-WG CLL criteria [Hallek, 2008].   
8.3.3. 
Treatment Comparisons 
8.3.3.1. 
Primary Comparisons of Interest 
The primary treatment comparison of interest will be ofatumumab maintenance treatment 
vs. no further treatment.  The primary comparison will be based on progression-free 
survival (PFS) when the total number of events reaches 280 in the ITT population. 
8.3.3.2. 
Secondary and Other Comparisons of Interest 
The primary efficacy endpoint will serve as a gatekeeper for the interpretation of 
treatment comparisons for the ‘inferential’ secondary endpoints.  If H0 is rejected at the 
0.001 significance level at the planned interim analysis (see Section 8.3.4) or at the 
0.0498 significance level at the final analysis, the conclusion will be that there is a 
treatment difference between ofatumumab maintenance treatment and no further 
treatment, and the p-values for the ‘inferential’ secondary endpoints may be interpreted 
and tested at the 0.05 significance level for the final analysis. If H0 is not rejected at the 
interim or final analysis, the conclusion will be that there is no difference between 
ofatumumab maintenance treatment and the no further treatment arm, and all other 
p-values will be used for descriptive 
 purposes only. 
The following endpoints are considered as ‘inferential secondary endpoints’ and will be 
tested and compared between the ofatumumab maintenance treatment and the no further 
treatment group only if the primary endpoint, PFS, is significant. 
1. Time to next CLL therapy 
2. Overall survival 
The control for multiplicity across the ‘inferential secondary endpoints’, test of H0 will be 
performed in a sequential manner to control the type I error at 0.05 as follows: 
1- Time to next CLL Therapy 
2- Overall survival 

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For the primary efficacy endpoint and the inferential secondary endpoints, any p-values 
for the comparison of ofatumumab maintenance treatment vs no further treatment that 
achieve statistical significance under multiplicity adjustment will be identified in the 
study report as inferentially significant for confirmatory purposes. 
Any other comparisons of interest will between the ofatumumab maintenance treatment 
and no further treatment arms for other secondary endpoints will be done at an alpha 
equals to 0.05.  No multiplicity will be considered in the other secondary endpoints and 
any p-value that is ≤0.05 will be identified as nominally significant 
8.3.4. 
Interim Analysis 
Two interim analyses will be performed.  The first interim will assess safety endpoints.  
The second interim will be done to assess efficacy based on the primary endpoint, and it 
will also evaluate safety. 
An independent data monitoring committee (IDMC) will be convened to perform an 
interim analysis of the safety data after 100 subjects in the maintenance arm have been on 
treatment for at least 6 months.  Details of the interim analysis for safety will be given in 
the IDMC Charter. 
An interim analysis of the primary endpoint, PFS, will be performed when 2/3 of the total 
number of events have occurred (187 events).  The interim analysis for PFS will be 
performed by an IDMC utilizing a conservative significance level of 0.001.  Performing 
this interim analysis with an IDMC applying conservative statistical criteria would allow 
for an earlier detection of clinical benefit to patients with ofatumumab maintenance and if 
this analysis is positive, may support a submission that enables earlier access to patients. 
Enrollment was expected to be completed at the time of this analysis.  
 
However, when the required number of events occurred prior to fully enrolling the study, 
but with the full number of evaluable subjects available, and before the results were 
known, it was decided that if the primary endpoint met the predefined significance level 
of p<0.001, demonstrating clinical benefit for the ofatumumab arm, further enrollment 
would be discontinued.  
The study conduct will continue regardless of the outcome of the interim analysis of the 
primary endpoint.  This interim analysis will also evaluate safety.  The interim analysis of 
the primary endpoint, PFS, will be conducted as described in Section 8.3.5.1, and further 
details of the interim analysis will be provided in the IDMC Charter.  The final analysis 
will be conducted at a significance level of 0.0498. 
8.3.5. 
Key Elements of Analysis Plan 
The final analysis will take place when the total number of events is reached in the study.  
An event is defined as when a subject has disease progression (PD) or death due to any 
cause during the study.  All available data will be analyzed and the results will be 
presented in a report.  Released data that are available from later visits will also be 
included. 

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Withdrawal 
Subjects will be treated until disease progression or withdrawal from study treatment due 
to unacceptable adverse event(s), consent withdrawal or other reasons.  All data up to 
time of withdrawal will be included in the analysis.   
Subjects who are withdrawn prematurely from study treatment, but who are not 
withdrawn from the study at the time of analysis, will be included in the analysis, 
regardless of treatment duration.   
Missing Data 
Since the period of follow-up for any subject will be dependent on efficacy and toxicity, 
the duration of follow-up will vary among subjects.  Consequently, there will be no 
imputation for missing data, with the exception of objective response.  Treated subjects 
who do not have any response data will be assumed to be non-responders.  Further details 
will be given in the Reporting and Analysis Plan (RAP). 
Derived and Transformed Data 
The evaluation of progression-free-survival will be determined by investigator 
assessment of response according to the IWCLL updated NCI-WG CLL criteria 
[Hallek, 2008].  
Other Issues 
Data from all participating centers will be pooled for the analyses.  It is anticipated that 
subject accrual will be spread thinly across centers.  Therefore, summaries of data by 
center would probably not be informative and will not be provided. 
8.3.5.1. 
Efficacy Analyses 
Primary Analysis 
The primary endpoint is progression-free-survival which is defined as the time from 
randomization to the date of disease progression or death due to any cause.  The 
investigator assessment of response will be assessed according to the IWCLL updated 
NCI-WG CLL criteria [Hallek, 2008].  
An interim analysis of the primary endpoint, PFS, will be performed when 2/3 of the total 
number of events have occurred (187 events).  The interim analysis for PFS will be 
performed by an IDMC utilizing a significance level of 0.001.   The interim analysis of 
PFS will be conducted in the same manner as described for the final analysis, and further 
details of the interim analysis will be provided in the IDMC Charter.   
The final analysis of PFS will be tested based on a two-sided test with a significance level 
of 0.0498.  The survival distributions will be estimated using Kaplan-Meier survival 
curves and will be compared using a stratified log-rank test. 

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In addition to the stratified log-rank test based on the Kaplan-Meier procedure, a Cox 
regression model will be used and will include covariates for treatment, stratification 
factors, and other baseline data deemed appropriate.  Analytical results will include the 
estimated hazard ratios along with 95% confidence intervals, and associated probabilities 
for the effect of treatment, stratification factors and the covariates.  The hazard ratio for 
treatment will express the risk of experiencing disease progression or death for 
‘ofatumumab’ vs ‘no further treatment’.  
Table 7 
PFS Assignment 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline tumour 
Randomization 
Censored 
Progression documented 
between scheduled visits 
- Date of assessment of new 
lymph node (if progression is 
based on new lymph node) 
- Date of last assessment (if 
progression is based on 
increase in sum of measured 
lymph nodes) 
Progressed 
No progression (at end of trial) 
Date of last assessment of 
measured lymph nodes 
Censored 
Treatment discontinuation for 
undocumented progression 
Date of last assessment of 
measured lymph nodes
Censored 
New anticancer treatment 
started 
Date of last assessment of 
measured lymph nodes 
Censored 
Death before first assessment  
Date of death 
Progressed 
Death between adequate 
assessment visits  
Date of death 
Progressed 
Death or progression after 
more than one missed visit 
Date of last assessment of 
measured lymph nodes 
Censored 
 
Subgroup analyses will be conducted for PFS for the stratification factors. 
Secondary Analyses 
Clinical Benefit: 
 Improvement in response 
Improvement in response will be assessed by calculating the percentage of subjects who 
change from PR at baseline to CR during the study.  Improvement in response will also 
be assessed by providing the frequency and percentage of subjects with positive minimal 
residual disease (MRD).  These rates will be compared between treatment groups with 
the Cochran-Mantel-Haenszel test adjusting for stratification factors (response, number of 
prior treatments and type of prior treatment). 

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 Overall survival 
Overall survival is defined as time from randomization to date of death.  The same 
analysis will be conducted as described for the primary endpoint, PFS. 
 Time to next therapy 
Time to next therapy is defined as the time from randomization to date of receiving the 
next CLL treatment. The same analysis will be conducted as described for the primary 
endpoint. 
 Progression-free survival after next-line therapy 
This endpoint will be defined as time from randomization until progression or death 
following next-line therapy and counting as events deaths prior to next-line therapy. 
 
 
 
 Time to progression after next-line therapy 
This endpoint will be defined as time from progression following randomization until 
progression or death following next-line therapy and counting as events deaths prior to 
next-line therapy. 
 
 
 Frequency of transfusions 
The number and percentage of subjects who receive blood transfusions during the study 
will be provided. 
 Evaluation of myelosuppression (anemia, neutropenia, thrombocytopenia) 
The number and percentage of patients with myelosuppression will be provided. 
 IgG, IgA, IgM 
Summaries of IgG, IgA, and IgM will be provided at scheduled visits. 
Disease Markers: 
 Minimal Residual Disease (MRD) 
The number and percentage of subjects with positive MRD will be provided.  The 
proportion of subjects wills positive MRD will be compared between treatment groups 
with the Cochran-Mantel-Haenszel test adjusting for stratification factors (response, 
number of prior treatments and type of prior treatment). 
 B-cell monitoring 

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CD5/CD19 change from baseline will be summarized to assess the treatment effect. The 
number and percentage of subjects with complete B-cell depletion will be summarized. 
 Prognostic markers correlating with clinical response 
Cox-regression will be used to explore the relationship between PFS and the following 
explanatory variables:  treatment group, cytogenetics (analyzed by FISH) at baseline, 
IgVH mutational status at baseline, β2 microglobulin at baseline, baseline CD20 and 
baseline complement level. 
8.3.5.2. 
Safety Analyses 
An independent data monitoring committee (IDMC) will be convened to perform an 
interim analysis of the safety data after 100 subjects in the maintenance arm have been on 
treatment for at least 6 months. Details of the interim analysis for safety will be given in 
the IDMC Charter. 
The safety population will be used for the safety analyses.  For continuous variables, the 
mean, median, standard deviation (std), minimum, and maximum will be provided in the 
summary tables.  For categorical variables, the frequency and percentage will be provided 
in the summary tables. 
Extent of Exposure 
Extent of exposure will be provided by summarizing the number of doses received by 
each subject and the duration of each infusion. 
Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary, and grouped by system organ class.   
Events will be summarized by frequency and proportion of subjects by system organ 
class and preferred terms. 
If the AE is listed in the IWCLL Grading Scale for Hematological Toxicity in CLL 
Studies [Hallek, 2008] or NCI CTCAE (version 4.0) tables, the maximum grade will be 
summarized. 
The incidence of AEs, severity of AE, deaths and the primary cause of death will also be 
provided.  
The incidence of subjects with grade 3, 4, and 5 infections will also be provided at each 
visit. 
The number and percentage of subjects with Autoimmune Hemolytic Anemia (AIHA) 
will be calculated. 
Clinical Laboratory Evaluations 
Hematology and clinical chemistry data will be summarized at each scheduled visit 
according to IWCLL Grading Scale for Hematological Toxicity in CLL Studies 

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[Hallek, 2008] and NCI CTCAE version 4.0.  The proportion of subjects with values 
outside the reference range will also be presented.   
The change in HAHA titers from predose to post-baseline visits and the number and the 
proportion of positive and negative results at each visit will be provided in the 
ofatumumab arm only.  A listing of HAHA results and associated ofatumumab plasma 
concentration at each timepoint will be generated.   
8.3.5.3. 
PRO Analyses 
The EORTC QLQ-C30 and the EQ-5D will be scored as per the developers instructions, 
with scores created for each pre-specified domain.  For the EORTC QLQ-CLL16, the 
developers have proposed a scoring, but it has not been validated yet. Therefore this 
scoring will be validated using the blinded data from the present trial.   
In addition to the developer’s hypothesized domains for both EORTC instruments it is 
also proposed that a ‘B-symptoms’ score will be created including the following items 
from the two instruments: need to rest (C30 item 10), felt weak (C30 item 12), tired (C30 
item 18), weight loss (CLL item 31), temperature changes (CLL item 35), night sweats 
(CLL item 36), and skin problems such as itching (CLL item 37), lethargic (CLL item 
39), slowed down (CLL item 40). This score is proposed to provide patient reported data 
that might be supportive of the constitutional symptoms assessment by the clinician.   
Details of the scoring methods of all PRO measures will be provided in the RAP.  Each 
PRO domain will be summarized for each treatment group and the total PRO sample at 
each time point will be presented in tabular format as mean, standard deviation, median, 
minimum, and maximum.  Methods for imputation of missing data will be detailed in the 
RAP.   
At each post-baseline timepoint, changes in PRO scores will be calculated by subtracting 
the baseline score from the score at the subsequent timepoint. Appropriate statistical tests 
will be proposed in the RAP to evaluate the significance of the change in scores over 
time, and to compare the scores between treatment arms.  
Standard psychometric validation analyses will be performed for all PRO measures 
(EORTC QLQ C30, EORTC QLQ CLL16, ‘B-Symptoms score’, and EQ-5D).  For the 
EORTC QLQ-CLL16 and B-Symptoms score, estimation of minimal clinically important 
differences will also be explored.  Details of the methods for all of these psychometric 
validation analyses will be provided in the psychometric validation RAP. 
8.3.5.4. 
Pharmacokinetic Analyses 
The plasma concentrations for individual subjects will be determined using validated 
analytical methods for ofatumumab.  Plasma ofatumumab concentration-time data will be 
summarized and displayed in tabular and graphical form.  Individual plasma 
concentrations of ofatumumab will be listed.   
Population pharmacokinetic modeling, using non-linear mixed effects modeling will be 
performed using validated software such as the computer program NONMEM, if data 

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permit.  Data from this study may be combined with data from other studies for analysis.  
The aims of this modeling approach are to:   
a.) Define the structural pharmacokinetic model that characterizes the population 
time course of plasma levels of ofatumumab in this patient population 
b.) Describe between-subject variability for pharmacokinetic parameter estimates 
c.) Estimate intra-subject variability on predicted concentrations.  
If possible, the effects of patient characteristics (such as gender, weight, height, disease 
status, etc.) will be investigated in order to account for potential sources of inter-
individual variability in systemic exposure.  If there are sufficient data for analysis, the 
details of the population pharmacokinetic analyses will be provided in a reporting and 
analysis plan.  
 
 
 
 
 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, Novartis will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with applicable country-specific 
regulatory requirements, including those required under a US IND. 
The study will be conducted in accordance with all applicable regulatory requirements, 
including IND Number 11,719. 
The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2000, as amended in 2002 and 2004 including, but not limited to: 
 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval of study protocol and any subsequent amendments. 
 
Subject informed consent. 
 
Investigator reporting requirements. 
Novartis will provide full details of the above procedures, either verbally, in writing, or 
both. 

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Written informed consent must be obtained from each subject prior to participation in the 
study. 
9.2. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Novartis procedures, Novartis 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
Novartis requirements.  When reviewing data collection procedures, the discussion will 
include identification, agreement and documentation of data items for which the CRF 
will serve as the source document. 
Novartis will monitor the study to ensure that the: 
 
Data are authentic, accurate, and complete. 
 
Safety and rights of subjects are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
9.3. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Novartis 
may conduct a quality assurance audit of the site records, and the regulatory agencies 
may conduct a regulatory inspection at any time during or after completion of the study. 
In the event of an audit or inspection, the investigator (and institution) must agree to grant 
the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their 
time and the time of their staff to discuss any findings/relevant issues. 
9.4. 
Study and Site Closure 
Upon completion or termination of the study, the Novartis monitor will conduct site 
closure activities with the investigator or site staff (as appropriate), in accordance with 
applicable regulations, GCP, and Novartis Standard Operating Procedures. 
Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
non-compliance.  If Novartis determine that such action is required, Novartis will discuss 
the reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, Novartis will provide advance notice to the 
investigator or head of the medical institution of the impending action. 
If a study is suspended or terminated for safety reasons, Novartis will promptly inform 
all investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action.  Where 

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required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 
9.5. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a Novartis audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless the Sponsor 
provides written permission to dispose of them or, requires their retention for an 
additional period of time because of applicable laws, regulations and/or guidelines. 
The investigator must notify Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site. 
9.6. 
Provision of Study Results and Information to Investigators 
The database results will be provided to 
 for the purposes of independent 
analysis for publication purposes in a peer reviewed journal.  Where required by 
applicable regulatory requirements, an investigator signatory will be identified for the 
approval of the clinical study report.  The investigator will be provided reasonable access 
to statistical tables, figures, and relevant reports and will have the opportunity to review 
the complete study results at a Novartis site or other mutually-agreeable location. 
Upon completion of the clinical study report, Novartis will ensure public disclosure of the 
clinical trial research results via the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) according to the Novartis SOP and will provide the 
investigator with the full summary of the study results.  The investigator is encouraged to 
share the summary results with the study subjects, as appropriate. 

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9.7. 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter, which is available upon request. 

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O'Brien SO, Kantarjian HK, Cortes JC, Beran MB, Koller CK, Giles FG, Lerner SL, 
Keating MK. Results of the Fludarabine and Cyclophosphamide Combination Regimen 
in Chronic Lymphocytic Leukemia. J  Clin Oncol. 2001(a);19:1414-1420.  
O'Brien SO, Kantarjian HK, Thomas DT, Giles FG, Freireich EF, et al. Rituximab Dose 
Escalation Trial in Chronic Lymphocytic Leukemia. J Clin Oncol.  2001(b);19:2165-
2170.  
Ofatumumab Investigator’s Brochure, GSK Version 1.  February 2009. 
Oscier DO, et al. Guidelines on the diagnosis and management of chronic lymphocytic 
leukaemia. Br J Haematol. 2004;125:294-317.  
Osoba D, Zee B, Pater J, Warr D, Kaizer L, Latreille J. Psychometric properties and 
responsiveness of the EORTC quality of Life Questionnaire (QLQ-C30) in patients with 
breast, ovarian and lung cancer. Qual Life Res. 1994;3:353-364 
Rai, KR, et al. Clinical Staging of Chronic Lymphocytic Leukemia. Blood 1975;46:219-
234. 

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Rawston AC, Villamor N, Ritgen M, Bottcher S, Ghia P, et al. (2007). International 
standardized approach for flow cytometric residual disease monitoring in chronic 
lymphocytic leukaemia. Leukemia 21(5): 956-964 
Redaelli, A., et al. The Clinical and Epidemiological Burden of Chronic Lymphocytic 
Leukaemia. Eur J Cancer Care. 2004;13:279-287. 
Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlander N, Horner MJ, Mariotto 
A, Miller BA, Feuer EJ, Altekruse SF, Lewis DR, Clegg L, Eisner MP, Reichman M, 
Edwards BK.  SEER Cancer Statistics Review, 1975-2005. National Cancer Institute.  
Bethesda, MD  USA; 2008. 
Robak T et al.  Rituximab, Fludarabine, and Cyclophosphamide (R-FC) prolongs 
progression free survival in relapsed or refractory chronic lymphocytic leukemia (CLL) 
compared with FC alone :  Final results from the international randomized phase III 
REACH trial.  Blood 2008;112  ASH Abstract 1ba-1. 
Robak TR. Recent progress in the management of chronic lymphocytic leukemia. Cancer 
Treatment Reviews 2007;33:710-728.  
Shanafelt TS, Kay NK, Morrison VM, Goldin LG. Comprehensive Management of the 
CLL Patient:  A Holistic Approach. Hematology 2007;1:324-331.  
Schlulz HS, Klein S, Rehwald U, Reiser M, et al. Phase 2 Study of a Combined 
Immunochemotherapy using Rituximab and Fludarabine in Patients with Chronic 
Lymphocytic Leukemia. Blood 2002;100:3115-3120.  
Tam CT, Keating MK. Chemoimmunotherapy of Chronic Lymphocytic Leukemia. Best 
Pract & Res Clin Haematol. 2007;20:479-498.  
Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, 
Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and 
rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 
15;112(4):975-80 
Teeling, J. L., et al. The Biological Activity of Human CD20 Monoclonal Antibodies Is 
Linked to Unique Epitopes on CD20. J Immunol. 2006;177:362-371. 
van Oers MH.  Rituximab maintenance in indolent lymphoma:  indications and 
controversies.  Curr Oncol Re 2007; 9: 378-83. 
van Oers MHJ, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, et al.  
Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-
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on a prospective randomized phase 3 intergroup trial.  Blood 2006; 108:  3295-3301. 

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Wierda WW, O'Brien SO, Wen SW, Faderl SF, Garcia-Manero GG, Thomas DT, et al. 
Chemoimmunotherapy with Fludarabine, Cyclophoshamide, and Rituximab for Relapsed 
and Refractory Chronic Lymphocytic Leukemia. J Clin Oncol.  2005;23:4070-4078.  
Zenz TZ, Dohner HD, Stilgenbauer SS. Genetics and Risk-Stratified Approach to 
Therapy in Chronic Lymphocytic Leukemia. Best Pract Res Clin Haematol. 
2007;20:439-453.  
 

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11. 
APPENDICES 
11.1. 
Appendix 1: Time and Events 
Phase 
SCREEN 
Treatment  
or Observation 
(~ every 8 wks after 1st visit) 
Follow-up  
(every 3 
months for 5 
years) 
WD 
Visit 
Screening 
1 
2 
3-14 
15-34 
 
Week 
(-6 to -1) 
1 
2 
9-97 
109-337 
 
Month 
0 
1 
1 
3-25 
28-85 
 
Visit Window 
  
± 7d 
± 3d 
± 7d 
± 14d 
 
Administration of Ofatumumab (if 
assigned to treatment group) 
 
X 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History1  
X 
 
 
 
 
 
Height  
X 
 
 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
X 
X 
Lymph node evaluation 
X 
 
X 
X 
X 
X 
Organ Evaluation 
X 
 
X 
X 
X 
X 
ECOG  
X 
 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
Adverse Event Assessments 
 
X 
X 
X 
X12 
X 
Concomitant Medications 
 
X 
X 
X 
X12 
X 
CT Scan 
X 
 
 
X2 
X2 
X 
Bone marrow biopsy 
X3 
 
 
X3 
 
 
Flow cytometry (MRD) 
X3 
 
 
X3 
X3 
X3 
Flow cytometry(CD5/CD19) 
X 
 
 
X 
X4 
X 
Prognostic Factors5 
X 
 
 
 
 
X 
Response Evaluation 
 
X 
X 
X 
X 
X 
PRO 
X 
 
 
X 
X 
X 
Hematology6 
X 
X 
X 
X 
X 
X 
Biochemistry6 
X 
X 
X 
X 
X 
X 
Hepatitis7 and Pregnancy Test 
X 
 
 
 
 
 
Igs  
X 
 
 
X8,9 
 
 
HAHA 10 
 
X 
 
X8,9 
X9 
X 
Coombs and CH50 
X 
 
 
 
X 
 
PK Sampling11 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
 
 
 
 

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1. Medical history to include disease characteristics as defined in Section 6.1. 
2. Sreening, yearly while on study, at the subject’s last treatment visit and upon relapse 
3. For subjects in CR ONLY- may be confirmed with bone marrow biopsy/flow cytometry 
4. Until B-cell value is within normal levels (See Section 6.3.1.2.) 
5. Prognostic Factors as defined in Section 6.3.3  
6. See Section 6.3.2 
7. Subjects that are HBsAg negative, HBcAb positive and HBV DNA negative  may be included but must undergo 
HBV DNA monitoring as listed in  Section 6.3.4 
8. At the subject’s last treatment visit  
9. Every six months.  Igs may be assessed during infection per PI.  (See Section 6.3.4) 
10. HAHA for ofatumumab treatment only-predose, every six months, at last treatment, and 3& 6 months post last 
ofatumumab dose, regardless of when it occurs.  
(See Section 6.3.4) 
11. For pharmacokinetic sampling, see Table 5, Section 6.6; + 15 min window for 0.5h post EOI samples is allowed 
12.  Only SAEs and associated concomitant medications are to be reported from 60 days after the last 
dose/observation time. (See Section 6.4.8.) 
 
 

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11.2. 
Appendix 2: Response Definition Summary 
This table is based on the parameters described in Section 6.2.1.  
 
 
Parameter 
 
CR 
PR 
PD 
Response 
definition: 
All criteria to be 
met 
At least 2 of criteria 1, 
2, 3  plus one criteria 
of 5a-c to be met 
(minimum duration of 2 
months) 
At least one criteria 
to be met 
1 
Blood lymphocytes 
<4000/µL 
≥50% decrease from 
BL 
≥50% increase over 
BL (and ≥5000/µL B-
cells) 
2 
Lymphadenopathy1  absent (none 
>1.5cm) 
≥50% decrease from 
BL, no increase or new 
≥50% increase or 
new (>1.5cm) 
3 
Hepato/spleno 
megaly 
absent 
≥50% decrease from 
BL 
Increase ≥50%, or 
new 
4 
Constitutional 
symptoms 
absent 
n/a 
n/a 
5a Neutrophils 
>1500/μL 
>1500/μL or ≥50% 
increase over BL 
n/a 
5b 
Platelet count 
>100,000/uL 
>100,000/uL or ≥50% 
increase over BL 
≥50% decrease from 
B, or to >100,000/uL 
second. to CLL2  
5c 
Hemoglobin 
>11 g/dL 
>11 g/dL or increase 
≥50% over BL 
Decrease of >2 g/dL 
from BL or to <10 
g/dL second. to CLL2 
6 
Marrow 
Normocellular, no 
B-lymphoid nodules, 
<30% lymphocytes 
n/a 
n/a 
7 
other 
n/a 
n/a 
CLL- transformation, 
cytopenia after 
treatment  
1. Sum of the products of multiple lymph nodes 
2. Occurrence of cytopenia attributable to CLL at least 3 months after treatment defines disease progression, if the 
marrow biopsy demonstrates an infiltrate of clonal CLL cells 
BL=baseline,  
Note: SD is defined as absence of progressive disease (PD) and failure to achieve at least a PR. 
 
Modified from Table 4 IWCLL guidelines [Hallek, 2008].  For complete description and 
guidance, please refer to Hallek, 2008. 

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11.3. 
Appendix 3: Patient Reported Outcome Measures 
 EORTC QLQ-C30 
 

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EORTC QLQ-CLL 16 
 

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EuroQoL Five-Dimension (EQ-5D) 
 
 
 

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Health change Questionnaire 
Since you began the study, has there been any change in your health overall (please mark 
only one box)?  
 
 
 
 
My Health is:  
 
A great deal better 
 
Moderately better 
 
A little better 
 
Almost the same, hardly any better at all 
 
Unchanged 
 
Almost the same, hardly any worse at all 
 
A little worse 
 
Moderately worse 
 
A great deal worse 
 
 
 

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11.4. 
Appendix 4: Country Specific Requirements 
The French regulatory agency required that information from the Study Procedures 
Manual be included in Section 6.4.8 of the protocol.  Therefore, Amendment 3 was 
required for France. 

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11.5. 
Appendix 5: Liver Chemistry Stopping and Follow-up 
Criteria† 
 
† In order to align with the change of sponsorship from GSK to Novartis, all references to ‘GSK’ 
in this Appendix 5 should refer to ‘Novartis.’ 

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11.6. 
Appendix 6: Protocol Changes 
Note: deleted language is printed as strikethrough and added language is printed in bold. 
Protocol Changes for Amendment 1 
The main purpose for this amendment is to specify baseline MRD assessment, to add 
post-PD PRO questionnaires,
 
  Other 
clarifications have also been included in amendment 1. 
Note: deleted language is printed as strikethrough and added language is printed in bold. 
Sponsor Information Page: 
GlaxoSmithKline 
 
 
Telephone:  
  
 MD, PhD 
 
 
 
 
Tel: 
 
Mob: 
 
Fax: 
 
Email: 
 
, MD 
 
 
Telephone Number: 
 
Mob: 
 
Fax: 
 
Email:
 
 
List of Abbreviations: 
CIRS  Cumulative Illness Rating Scale 
Ig 
Immunoglobulins 

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PROTOCOL SUMMARY 
Study Design 
CT Scans are required for confirmation of CR and partial remission (PR) and yearly 
while on study. 
Study Endpoints/Assessments 
Secondary Endpoints: 
 Progression-free survival after next-line therapy 
 Time to progression after next-line therapy 
Section 2 
Objectives 
Secondary Objectives 
 
To evaluate the improvement in response, improvement in response time to next 
CLL treatment and overall survival in subjects receiving ofatumumab maintenance 
compared to no further treatment 
 
To evaluate the PFS after next-line therapy and the time to progression after 
next-line therapy 
 
Section 3.1.3 Treatment Phase 
 
300mg IV Day 1 Week 1 followed by 1000mg IV on Day 8 Week 2 
Section 3.14 Follow-up Phase: 
Follow-up assessment after disease progression on treatment will include a 1 month post-
treatment safety assessment and subsequent follow-up visits to assess survival status, date 
of next CLL therapy, type of therapy and response to therapy. 
Section 3.2 
Discussion of Design and Dose Rationale 
With the current treatment options, patients receiving chemoimmunotherapy (i.e. 
FCR) have the longest PFS.  For patients not naïve to rituximab, this PFS represents 
a median of 28 months [Wierda, 2005] and a 40% increase of this PFS would be 39.2 
months. 
Section 4.3 
Exclusion Criteria 
Criteria 3, 4, 5 combined into one criteria (#3).  Criteria following #3 re-numbered.  
Criteria #6 regarding heptatic DNA monitoring modified.  Criteria #10 added. 
Criteria #17 deleted.   
3. Known transformation of CLL (e.g. Richter’s transformation) 
4. Known prolymphocytic leukemia (PLL) 
5. Known CNS involvement of CLL 

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3. Known transformation of CLL (e.g. Richter’s transformation), prolymphocytic 
leukemia (PLL), or CNS involvement of CLL 
4. Active Autoimmune Hemolytic Anemia (AIHA) requiring treatment except if in the 
opinion of the investigator and medical monitor it is thought not to affect the subject’s 
safety, the conduct of the study or the interpretation of the data 
5. Previous autologous or allogeneic stem cell transplantation 
6. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, 
or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest 
infection with bronchiectasis, tuberculosis and active Hepatitis B or C (Hepatitis B: 
Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if 
negative for HBsAg but HBcAb positive and HBsAb negative, a HB DNA test will be 
performed and if positive the subject will be excluded. Note: If HBcAb positive and 
HBsAb positive, which is indicative of a past infection, the subject can be included.) 
(Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a 
HB DNA test will be performed and if positive the subject will be excluded*.) 
7. Other past or current malignancy (with the exception of basal cell carcinoma of the 
skin or  in situ carcinoma of the cervix or breast) unless the tumor was successfully 
treated with curative intent at least 2 years prior to trial entry except if in the opinion 
of the investigator and medical monitor it is thought not to affect the subject’s safety, 
the conduct of the study or the interpretation of the data 
8. Clinically significant cardiac disease including unstable angina, acute myocardial 
infarction within 6 months prior to screening  (Visit 1), congestive heart failure, and 
arrhythmia requiring therapy, with the exception of extra systoles or minor 
conduction abnormalities except if in the opinion of the investigator and medical 
monitor it is thought not to affect the subject’s safety, the conduct of the study or the 
interpretation of the data 
9. History of significant cerebrovasculaor disease or event with symptoms or sequelae 
10.  Significant concurrent, uncontrolled medical condition that in the opinion of 
the investigator or GSK medical monitor contraindicates participation in this 
study 
11. Glucocorticoid unless given in doses ≤ 100 mg/day hydrocortisone (or equivalent 
dose of other glucocorticoid) if for exacerbations other than CLL (e.g. asthma) 
12. Known HIV positive 
13. Screening laboratory values: 
 Platelets<50 x 109/L  
 Neutrophils<1.0 x 109/L  
 Creatinine > 1.5 times upper normal limit (unless normal creatinine clearance) 
 Total bilirubin > 1.5 times upper normal limit (unless due to liver involvement 
of CLL) 

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 Alanine Aminotransferase (ALT) > 2.5 times upper normal limit (unless due 
to liver involvement of CLL) 
 Alkaline phosphatase > 2.5 times upper normal limit 
14. Known or suspected hypersensitivity to ofatumumab that in the opinion of the 
investigator or medical monitor contraindicates study participation 
15. Subjects who have received treatment with any non-marketed drug substance or 
experimental therapy within 5-terminal half-lives or 4 weeks whichever is longer 
prior to first dose of study medication or currently participating in any other 
interventional clinical study 
Note:  Participation in any other interventional clinical study after disease 
progression during post PD follow-up is permitted OR participation in any other 
interventional clinical study where the subject received ONLY standard approved 
CLL therapy is permitted. 
16. Lactating women, women with a positive pregnancy test at Visit 1 or women (of 
childbearing potential) as well as men with partners of childbearing potential, who 
are not willing to use adequate contraception from study start through one year 
following last ofatumumab dose.  Adequate contraception is defined as abstinence, 
oral hormonal birth control, implants of levonorgestrel, estrogenic vaginal ring, 
percutaneous contraceptive patches, intrauterine device, and male partner 
sterilization if male partner is sole partner for that subject.  For females in the USA, 
the use of a double barrier method is also considered adequate (condom or occlusive 
cap plus spermicidal agent). 
17. Subjects known or suspected of not being able to comply with a study protocol (e.g. 
due to alcoholism, drug dependency or psychological disorder) 
* If HBV DNA is negative, subject may be included but must undergo HBV DNA 
monitoring (see Section 6.3.4). Prophylactic antiviral therapy may be initiated at the 
discretion of the investigator. 
Section 6.1.3 Cumulative Illness Rating Scale (CIRS): 
This section was deleted as the CIRS is not applicable to this relapsed patient population 
entering the study in remission. 
Section 6.1.6 Electrocardiogram 
Additional ECGs may be obtained as clinically warranted at the discretion of the PI 
or delegate. 
Cumulative Illness Rating Scale (CIRS) 
The CIRS will be assessed at screening.  The CIRS is a tool to measure multi-morbidity.  
This index measures the chronic medical illness burden and severity of co-existing 
chronic diseases [Miller, 1992].  See Appendix 4. 
 
 

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Section 6.2.3 Minimal Residual Disease (MRD): 
For subjects enrolling in the study who are in CR, baseline MRD will be assessed at 
screening, prior to any treatment visit. 
Section 6.3.4 Peripheral Blood Sampling for Safety and Disease Status: 
 Direct antiglobulin test (Coombs test) at screening and 1month post last dose  3 
months after last treatment. 
 Human Anti-Human Antibody (HAHA) at screening, every 6 months during 
treatment, 3 and 6 months post treatment visit, or at last treatment visit.   
A HAHA sample (and a pharmacokinetic sample) should also be obtained at the 
last treatment visit if it does not occur at a scheduled sampling time (e.g., if 
treatment is discontinued early).  
 
Section 6.3.4. Peripheral Blood Sampling for Safety and Disease Status 
For subjects that are HBsAg negative, HBcAb positive and HBV DNA negative (see 
Section 4.3) blood samples will be collected for HBV DNA testing every 2 months 
during the treatment/observation and during follow-up at the 3 months and 6 
months visit. 
Section 6.4.8 Time Period and Frequency of Detecting AEs and SAEs: 
All SAEs and AEs for subjects not receiving treatment (observation) will be 
collected for the same duration of time (i.e. Visit 1 until 60 days after last visit, to 
Visit 14).  Only SAEs will be reported from 60 days after the last dose of investigational 
product or last treatment/observation visit to the end of the follow-up period. 
Section 6.5.6 Administration of PRO Measures: 
If a subject in PD will be available and willing, post-PD questionnaires may be 
administered through the date that would correspond to the subject’s Month 60 
visit. 
Section 6.6 
Pharmacokinetics: 
A pharmacokinetic sample (and a HAHA sample) should also be obtained at the last 
treatment visit if it does not occur at a scheduled sampling time (e.g., if treatment is 
discontinued early). 
Table 5:  Added “Week” column to clarify that Visit 1 Month 1 will be at Week 1; Visit 
2 Month 1 will be at Week 2 and Visit 3 Month 3 will be at Week 9. 
To footnote 2 “regardless of when it occurs” added. 

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Section 8.1 
Hypotheses 
H0:  Distribution of the progression-free survival curves events for the ofatumumab 
maintenance treatment and for the no further treatment groups are the same (Hazard ratio 
is equal to 1) 
H1:  Distribution of the progression-free survival curves events for the ofatumumab 
maintenance treatment and for the no further treatment groups are not the same (Hazard 
ratio is not equal to 1) 
 
Section 8.3.3.2 
Secondary and Other Comparisons of Interest: 
The following secondary endpoints will also be assessed and compared between the 
ofatumumab maintenance treatment and the no further treatment groups: 
 Overall survival 
 Time to next CLL therapy 
 Improvement in response  
 
The primary efficacy endpoint will serve as a gatekeeper for the interpretation of 
treatment comparisons for the ‘inferential’ secondary endpoints.  If H0 is rejected at 
the 0.001 significance level at the planned interim analysis (see Section 8.3.4) or at 
the 0.0498 significance level at the final analysis, the conclusion will be that there is 
a treatment difference between ofatumumab maintenance treatment and no further  
treatment, and the p-values for the ‘inferential’ secondary endpoints may be 
interpreted and tested at the 0.05 significance level for the final analysis. If H0 is not 
rejected at the interim or final analysis, the conclusion will be that there is no 
difference between ofatumumab maintenance treatment and the no further 
treatment arm, and all other p-values will be used for descriptive 
 
purposes only. 
The following endpoints are considered as ‘inferential secondary endpoints’ and will 
be tested and compared between the ofatumumab maintenance treatment and the 
no further treatment group only if the primary endpoint, PFS, is significant. 
1. Time to next CLL therapy 
2. Overall survival 
 
The control for multiplicity across the ‘inferential secondary endpoints’, test of H0 
will be performed in a sequential manner to control the type I error at 0.05 as 
follows: 
1- Time to next CLL Therapy 
2- Overall survival 

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For the primary efficacy endpoint and the inferential secondary endpoints, any p-
values for the comparison of ofatumumab maintenance treatment vs no further 
treatment that achieve statistical significance under multiplicity adjustment will be 
identified in the study report as inferentially significant for confirmatory purposes. 
Any other comparisons of interest will between the ofatumumab maintenance 
treatment and no further treatment arms for other secondary endpoints will be 
done at an alpha equals to 0.05.  No multiplicity will be considered in the other 
secondary endpoints and any p-value that is ≤0.05 will be identified as nominally 
significant 
Section 8.3.5.1 
Efficacy Analyses: 
 Progression-free survival after next-line therapy 
This endpoint will be defined as time from randomization until progression or death 
following next-line therapy and counting as events deaths prior to next-line therapy.  
 
 
 Time to progression after next-line therapy 
This endpoint will be defined as time from progression following randomization 
until progression or death following next-line therapy and counting as events deaths 
prior to next-line therapy.  
 
Section 11.1 Appendix 1: 
Time and Events Table updated to reflect changes as above.  Visit numbers and weeks 
corrected.  HAHA and Igs assessment rows combined. Hepatitis, Coombs and 
complement (CH50) testing added. 
Phase 
SCREEN 
Treatment  
or Observation 
(~ every 8 wks after 1st visit) 
Follow-up  
(every 3 
months for 5 
years) 
WD 
Visit 
Screening 
1 
2 
3-14 
15-34 
 
Week 
(-6 to -1) 
1 
2 
9-97 
109-329 
 
Month 
0 
1 
1 
3-25 
28-85 
 
Visit Window 
  
± 7d 
± 3d 
± 7d 
± 14d 
 
Administration of Ofatumumab (if 
assigned to treatment group) 
 
X 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History1  
X 
 
 
 
 
 

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Phase 
SCREEN 
Treatment  
or Observation 
(~ every 8 wks after 1st visit) 
Follow-up  
(every 3 
months for 5 
years) 
WD 
Height and Body weight 
X 
 
 
 
 
 
Body weight Physical Exam 
X 
 
X 
X 
X 
X 
Physical Exam Review of Systems 
X 
 
X 
X 
X 
X 
Lymph node evaluation 
X 
 
X 
X 
X 
X 
Organ Evaluation 
X 
 
X 
X 
X 
X 
ECOG  
X 
 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
Adverse Event Assessments 
 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
CT Scan 
X 
 
 
X2 
X2 
X 
Bone marrow biopsy 
X 
 
 
X3 
 
 
Flow cytometry (MRD) 
X3 
 
 
X3 
X3 
X3 
Flow cytometry(CD5/CD19) 
X 
 
 
X 
 
X 
Prognostic Factors4 
X 
 
 
 
 
X 
Response Evaluation 
 
X 
X 
X 
X 
X 
PRO 
X 
 
 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
Hepatitis7 and Pregnancy Test 
X 
 
 
 
 
 
Igs and HAHA 
X 
 
 
X5,6 
X6 
 
Coombs and CH50 
X 
 
 
 
X 
 
PK Sampling8 
 
X 
X 
X 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
1. Medical history to include disease characteristics and CIRS as defined in Section 6.1. 
2. Sreening, yearly while on study, at the subject’s last treatment visit and upon relapse 
3. For subjects in CR ONLY- may be confirmed with bone marrow biopsy/flow cytometry  
4. Prognostic Factors as defined in Section 6.3.3  
5. At the subject’s last treatment visit  
6. Every six months.  IgGs may be assessed during infection per PI. HAHA also at last treatment and 3& 6 
months post last ofatumumab dose, regardless of when it occurs. 
7. Subjects that are HBsAg negative, HBcAb positive and HBV DNA negative  may be included but must 
undergo HBV DNA monitoring as listed in  Section 6.3.4. 
8. For pharmacokinetic sampling, see Table 5, Section 6.6 
 
Appendix 4:  Cumulative Illness Rating Scale- deleted as noted in Section 6.1.3  

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[Miller, 1992] 

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Protocol Changes for Amendment 2 
The main purpose for this amendment is to clarify specifics in the protocol and changes 
to the inclusion/exclusion criteria as requested by regulatory agencies and investigators.  
Other additions such as study name, update to CTCAE version to be used and other 
clarifications and changes have been included in Amendment 2 as noted below. 
The CTCAE throughout the entire document including Section 6.4.5 and Section 8.3.5.2 
has been updated to the new version, version 4.0. 
 
This amendment applies to all study sites. 
Amendment Summary of Main Changes 
Section(s) 
Change 
Rationale 
Title 
Name of study  
Added 
Sponsor information 
page 
Eudra CT number added 
Updated 
Protocol Summary, 
Study Design and  
3.1.4 Follow-up Phase 
If a subject improves to CR 
during the study, then a bone 
marrow exam is required to 
confirm CR at least 2 months 
after response. CT scan 
requirements at screening, to 
confirm new CR, yearly while 
on study and at disease 
progression. 
Modified bone marrow exam and CT 
scans  for a maintenance study. 
4.2 Inclusion criteria 
CT scan confirmation removed Subjects entering the study may not 
have participated in clinical trial leading 
to remission- in alignment with IWCLL 
NCI-WG guidelines (2008) 
4.2 Inclusion criteria 
Remission within 3 months of 
response assessment 
Added for consistency with study design 
(Section 3.1) 
4.2 Inclusion criteria 
Anti-leukemic therapy 
changed to 3 months/cycles 
In alignment with current practices 
4.3 Exclusion criteria 
Deleted ref to last tx.  
Rituximab information 
removed. 
Simplied statement for clarity. 
4.3 Exclusion criteria 
Exemption of Gilbert’s 
syndrome from bilirubin 
eligibility restriction 
No clinical significance of safety 
concern  
4.3 Exclusion criteria 
Participation in other 
interventional studies removed 
To avoid confounding study endpoints  

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Section(s) 
Change 
Rationale 
4.3 Exclusion criteria 
& Section 5.4 
Prohibited 
Concomitant 
Medication or 
Therapies 
Other anti-leukemic 
medication including 
glucorticoids  
Clarified intent of glucocorticoid 
restriction and made consistent with 
Section 5.4 
6.2.1.1 CR 
Added timing for bone marrow 
assessment if CR achieved 
during maintenance treatment 
Modified for a maintenance study 
6.2.1.4 SD 
Removed 
Modified for a maintenance study 
6.3 Lab Assessments 
Exception of Coomb’s test as 
local lab  
Test too sensitive for shipping 
6.3.1.2 B-cell 
monitoring 
Change in f/u B-Cell 
monitoring 
Additional labs once values are within 
normal levels are not needed clinically 
6.3.2 Peripheral Blood 
Sampling 
Change in haptoglobin 
analysis frequency 
Bi-monthly monitoring not considered 
standard of care 
6.3.4 and 8.3.5.2 
HAHA sample assessments 
and analysis 
Clarified for subjects receiving 
ofatumumab (including pre-dose 
sample following randomization) and 
analyses 
6.4.5 and 8.3.5.2 
CTCAE version from 3.0 to 4.0 Updated 
6.6 PK 
Sample window added for 0.5 
EOI samples 
Site logistics taken into consideration 
T&E Table 
Changes per protocol 
amendment 
Urinalysis removed 
Updated 
Urinalysis – no value added and no 
clinical significance of safety concern 
 
Amendment Details 
Cover page (p. 1) 
Name of study added: 
PROLONG: 
Phase III Trial in Relapsed CLL Of a MonocLonal Antibody Ofatumumab 
mainteNance therapy to delay proGression vs observation 
 
Ofatumumab Maintenance Treatment versus No Further Treatment in 
Relapsed CLL Responding to Induction Therapy 
OMB112517 
 
p.2 
(PFS)  
p. 4 
Eudra CT number: 2009-012518-39 
 

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List of Abbreviations 
HB(V)  
Hepatitis B (Virus) 
Protocol Summary, Disease Markers and Section 6.3.3. Prognostic Factors 
soluble CD20 
Rationale:  The soluble CD20 assay has been deleted from the protocol as this assay is 
currently not available and the development of the assay has been problematic due to 
limitations in the availability of an assay standard. 
Protocol Summary, Study Design and Section 3.1.4 Follow-up Phase 
A bone marrow examination is required to confirm Complete Remission (CR) at least 2 
months after completion of therapy and when a subject fulfills the International 
Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer 
Institute-Sponsored Working Group (NCI-WG) requirements for Complete Remission 
(CR) [Hallek, 2008].  Previous results may be used or if not available, a bone marrow 
exam may be done at screening. If a subject’s response improves to a CR while on 
study, then a bone marrow examination is required to confirm CR at least 2 months 
after response as per the updated IWCLL NCI-WG requirements for CR  
[Hallek, 2008].  Additionally, CT Scans are required at screening, for confirmation of a 
new CR, and partial remission (PR) and yearly while on study, and at disease 
progression. 
 
Rationale:  Clarified for a maintenance study. 
Section 1.4  
Rationale 
5) 
relapased refractory 
 
Rationale:  correction 
Section 3.1 
Study Design 
Reworded entry box from “CR or PR within 3 months of max 2 re-induction treatments 
for relapsed CLL” to “CR or PR within 3 months after relapsed CLL treatment (max 
2 prior tx)” 
 
Rationale:  To clarify remission after last treatment for relapsed CLL 
Section 3.1.3 Treatment Phase 
and then every 3 months  
 
Rationale:  Redundant information provided in Section 3.1.4 Follow-up Phase  
Section 4.2 
Inclusion Criteria 
2.  CR or At least PR according to the revised 2008 NCI-WG CLL criteria, confirmed by 
CT scan, within 3 months of the response assessment after the last dose of 2nd/3rd line 
treatment  

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Rationale:  Confirmation of remission by CT scan is not per current guidelines, and as it 
is unlikely that a baseline CT scan at induction treatment would have been done, it would 
not be interpretable.  Clarified duration of 3 months to be consistent with Section 3.1. 
3. The anti-leukemic treatment before study entry should have been for at least 4 3 
months of monotherapy with alkylating agents and/or at least 4 consecutive 3 cycles of 
polychemotherapy (e.g. CVP), fludarabine-containing chemotherapy or 
immunochemotherapy 
Rationale:  To simplify the wording to take into account all of the variations of 
treatments and regimens.  As most therapy is assessed after 3 months or 3 cycles, this has 
been modified to reflect practice. 
Section 4.3 
Exclusion Criteria 
1.  Known Pprimary or secondary fludarabine-refractory subjects, defined as treatment 
failure (failure to achieve a CR or PR) or disease progression within 6 months of prior 
anti-leukemic therapy [Hallek, 2008]  NOTE:  Subjects refractory to rituximab therapy as 
last therapy are permitted 
 
Rationale:  Simplifed statement for clarity.  Removed rituximab as not relevant to 
fludarabine-refractory information. 
4, 7, 8, 10 medical monitor 
Rationale:  Reference to GSK medical monitor’s input for clinical assessments removed 
as per Chief Medical Officer. 
6.  a HBV DNA test will be performed 
Rationale:  To add missing letter “V” in abbreviation. 
11.  Other anti-leukemic use of medications including glucocorticoids Glucocorticoid 
unless given in doses ≤ 100 mg/day hydrocortisone (or equivalent dose of other 
glucocorticoid) if for exacerbations other than CLL (e.g. asthma) 
Rationale:  Clarification of the intent of glucocorticoid restrictions and consistency with 
Section 5.4. 
13.  Total bilirubin > 1.5 times upper normal limit (unless due to liver involvement of 
CLL or Gilbert’s syndrome) 
Rationale:  To clarify that increased bilirubin values would not apply to subjects with 
Gilbert’s syndrome  
  
15. OR participation in any other interventional clinical study where the subject received 
ONLY standard approved CLL therapy is permitted 
Rationale:  This was removed to avoid potential confounding of other study endpoints. 

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Section 4.4 
Withdrawal Criteria 
Subjects may be withdrawn from investigational product at any time if it is the wish of 
the subject (or their legally acceptable representative) for any reason, the investigator 
judges it necessary due to medical reasons including disease progression or the subject 
becomes pregnant. (See also Section 8.3.5.) 
 
Rationale:  To clarify withdrawal criteria at the request of Korean FDA. 
Section 5.1.1.2 
Ofatumumab Treatment Schedule 
Reference in text to appropriate table corrected. 
 
Table 2 
Title: Infusion rate at 1st Ofaumumab(300 mg) Infusion 
Table 3 
Title: Infusion rate at subsequent Ofatumumab (1000 mg) Infusion 
 
 
Footnote: subsequent infusions= 2nd and 3-14th infusions 
Rationale:  To clarify the dose of the infusions and which infusions are considered 
subsequent. 
Section 5.4 
Prohibited Concomitant Medication or Therapies 
 Anti-cancer medication not part of the protocol treatment (e.g. alkylating agents, 
anti-metabolites, purine analogues, other monoclonal antibodies, and other 
medications including glucocorticoids) 
 Glucocorticoid unless given in doses equivalent to  100 mg/day of 
hydrocortisone, for less than 7 days if for exacerbations other than CLL (e.g. 
asthma), or unless given as premedication for ofatumumab infusions 
 Any non-marketed drug substance or experimental therapy 
Note:  Glucocorticoids given for other indications such as exacerbations of 
asthma or as premedication for ofatumumab infusions are allowed. 
Section 6.2.1.1 
Complete Remission (CR) 
or at the earliest 2 months after beginning this maintenance protocol (i.e. 
ofatumumab treatment/observation) 
Rationale:  To clarify when during the study an improvement to CR may be noted and 
additional assessments such as bone marrow aspirate and biopsy be performed. 
Section 6.2.1.4 Stable Disease (SD) 
Subjects who have changed from a CR or a PR, but who have not exhibited PD, may be 
considered to have SD. 
Rationale:  This section was deleted as SD in a maintenance study is not as applicable. 

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Section 6.2.2. Bone Marrow Examination 
or at least 2 months of therapy or response while on study 
 
Rationale:  Provide clarity and consistency with updated sections of protocol. 
Section 6.2.3. Minimal Residual Disease (MRD) 
For subjects who improve to a CR while on study, a bone marrow examination will be 
performed after at least 2 3 months of therapy or response while on study. 
Rationale:  Provide consistency with other updated sections of the protocol. 
Section 6.3 
Laboratory Assessments 
 
All the analyses will be performed by a central laboratory, except for the direct 
antiglobulin test (Coomb’s test) that will be performed locally. 
 
Rationale:  This test is very sensitive to disruption, therefore, to ensure accurate results, 
the assay will be done locally. 
Section 6.3.1.2  
B-Cell Monitoring 
until values return to normal levels on two consecutive determinations 
 
Rationale:  To clarify that if values are within normal levels for two consecutive 
assessments, no further testing is required. 
Section 6.3.2 Peripheral Blood Sampling for Hematology and Biochemistry 
, and haptoglobulin Haptoglobin will be analyzed at screening and 3 months after last 
treatment. 
 
Rationale:  Bi-monthly haptoglobin monitoring is not considered standard of care.  One 
pretreatment and one post-treatment assessment will be performed in alignment with the 
Coombs test analysis schedule for determination of autoimmune hemolytic anemia.  
Section 6.3.4 Peripheral Blood Sampling for Safety and Disease Status 
 
Human Anti-Human Antibody (HAHA) at screening, prior to first dose of ofatumumab, 
every 6 months during ofatumumab treatment, and at 3 and 6 months post treatment 
(i.e., screening predose Visit 1, at Months 7, 13, 19, and 25 during treatment and at 3 and 
6 months after last ofatumumab dose, regardless of when it occurs).  A HAHA sample 
(and a pharmacokinetic sample) should also be obtained at the last treatment visit if it 
does not occur at a scheduled sampling time (e.g., if treatment is discontinued early).  
HAHA samples will only be collected for subjects randomized to ofatumumab. 
 
Rationale:  To clarify HAHA sample collection for those subjects receiving ofatumumab. 
 
Immunoglobulins-Additional samples may be collected post last treatment (such as 3 
and 6 months follow-up), as warranted. 
 

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Rationale:  To allow additional Ig samples to be collected if needed (i.e. clinical concern 
regarding previous low values.) 
Section 6.4.1.1. 
Liver Chemistry Stopping Criteria 
 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 3subjects 
should be monitored as frequently as possible. 
Rationale:  Correction of typo (only 3 criteria). 
Section 6.6 
Pharmacokinetics 
Predose samples may be collected at any time prior to dosing and EOI samples may 
be collected within a 15 minute window around the scheduled time. 
 
Rationale:  To provide clarification on logistics of pharmacokinetic sample collection. 
Section 8.3.2 Analysis Data Sets 
The primary data set for efficacy will be based on the tumor response assessments.  The 
primary data sets for safety will based on the adverse events and the laboratory data. 
The tumor responses will be assessed by the investigators and changes in response will be 
determined according to the IWCLL updated NCI-WG CLL criteria [Hallek, 2008].   
The primary data set for efficacy will be based on the response assessments.  The primary 
data set for safety will be the adverse events and the laboratory data sets. 
Response will be assessed by the investigators.  Data will be summarized for investigator 
assessed response, and statistical inference for efficacy claims will be based on the data 
assessed by the investigators. 
 
Rationale:  Redundant information removed. 
 
Section 8.3.5.2  
Safety Analyses/Clinical Laboratory Evaluations 
The change in Human Anti-Human Antibodies (HAHA) titers from screening to post-
baseline visits will also be provided. 
The change in HAHA titers from predose to post-baseline visists and the number 
and the proportion of positive and negative results at each visit will be provided in 
the ofatumumab arm only.  A listing of HAHA results and associated ofatumumab 
plasma concentration at each timepoint will be generated.   
Rationale:  Clarification of context of HAHA information to be provided. 

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Section 11.1 
Appendix 1: Time and Events 
Phase 
SCREEN 
Treatment  
or Observation 
(~ every 8 wks after 1st visit) 
Follow-up  
(every 3 
months for 5 
years) 
WD 
Visit 
Screening 
1 
2 
3-14 
15-34 
 
Week 
(-6 to -1) 
1 
2 
9-97 
109-337 
 
Month 
0 
1 
1 
3-25 
28-85 
 
Visit Window 
  
± 7d 
± 3d 
± 7d 
± 14d 
 
Administration of Ofatumumab (if 
assigned to treatment group) 
 
X 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History1  
X 
 
 
 
 
 
Height  
X 
 
 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
X 
X 
Lymph node evaluation 
X 
 
X 
X 
X 
X 
Organ Evaluation 
X 
 
X 
X 
X 
X 
ECOG  
X 
 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
 
Adverse Event Assessments 
 
X 
X 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
CT Scan 
X 
 
 
X2 
X2 
X 
Bone marrow biopsy 
X3 
 
 
X3 
 
 
Flow cytometry (MRD) 
X3 
 
 
X3 
X3 
X3 
Flow cytometry(CD5/CD19) 
X 
 
 
X 
X4 
X 
Prognostic Factors45 
X 
 
 
 
 
X 
Response Evaluation 
 
X 
X 
X 
X 
X 
PRO 
X 
 
 
X 
X 
X 
Hematology6 
X 
X 
X 
X 
X 
X 
Biochemistry6 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
Hepatitis7 and Pregnancy Test 
X 
 
 
 
 
 
Igs and HAHA 
X 
 
 
X5,6 8,9 
X6 9 
 
HAHA10 
 
X 
 
X 8,9 
X 9 
X 
Coombs and CH50 
X 
 
 
 
X 
 
PK Sampling811 
 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
 
 
 
 

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1. Medical history to include disease characteristics as defined in Section 6.1. 
2. Sreening, yearly while on study, at the subject’s last treatment visit and upon relapse 
3. For subjects in CR ONLY- may be confirmed with bone marrow biopsy/flow cytometry  
4. Prognostic Factors as defined in Section 6.3.3 Until B-cell value is within normal levels (See Section 6.3.1.2.) 
5. Prognostic Factors as defined in Section 6.3.3At the subject’s last treatment visit  
6. Every six months.  Igs may be assessed during infection per PI.  HAHA also at last treatment and 3& 6 months 
post last ofatumumab dose, regardless of when it occurs. See Section 6.3.4 
7. Subjects that are HBsAg negative, HBcAb positive and HBV DNA negative  may be included but must undergo 
HBV DNA monitoring as listed in  Section 6.3.4  
8. For pharmacokinetic sampling, see Table 5, Section 6.6.  At the subject’s last treatment visit. 
9. Every six months.  Igs may be assessed during infection per PI.  HAHA also at last treatment and 3& 6 
months post last ofatumumab dose, regardless of when it occurs. (See Section 6.3.4) 
10. HAHA for ofatumumab treatment only-predose, every six months, at last treatment, and 3& 6 months post 
last ofatumumab dose, regardless of when it occurs. (See Section  6.3.4) 
11. For pharmacokinetic sampling, see Table 5, Section 6.6;  15 min window for 0.5h post EOI samples is 
allowed 
 
 
Rationale: Urinalysis has been removed at screening as it does not add value to the safety 
data.  Addition of footnote for B-cell values and subsequent footnotes nos. updated.  A 
PK window was added as detailed in Section 6.6. for footnote 9. 
 

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Protocol Changes for Amendment 3 
Where the Amendment Applies 
Amendment 3 is applicable to all study sites that are required to include information from 
the Study Procedures Manual into Section 6.4.8 of the protocol. 
General Protocol Changes for Amendment 3 (07-Feb.-2013) from 
Amendment 2 (dated 21-MAY-2010) 
 Specific details on how to handle the time period and frequency of detecting AEs 
and SAEs such as infusion reactions, Tumor Lysis Syndrome, Progressive 
multifocal leukoencephalopathyand Hepatitis described in Section 6.4.8 of the 
protocol. 
Amendment Details 
Section 6.4.6 Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs Specific attention will be paid to monitor events of special interest 
such as infusion reactions, tumor lysis syndrome, infections and progressive 
multifocal leukoencephalopathy (PML).  Please refer to the SPM and/or the 
following text*. 
Handling Infusion Reactions: 
 
Infusion reactions are commonly associated with anti-CD20 antibody therapy. 
Ofatumumab can cause serious infusion reactions manifesting as bronchospasm, 
dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, 
syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, 
urticaria, and angioedema. Infusion reactions occur more frequently with the first 
2 infusions. 
 
The site staff must be prepared to intervene if an infusion reaction occurs. Special 
caution should be taken during the first infusion for each subject and during the 
infusion for any subject who did not tolerate a previous infusion well.  It is 
recommended that a crash cart is readily accessible in the event of an emergency. 
Infusion reactions should be treated according to the investigators judgment and 
best clinical practice.   
 
Interruption, restart and increasing the rate of the infusion depending on the 
severity of the AE must be according to the description below and at the 
investigator’s discretion. An increase of the infusion rate after an interruption must 
not exceed the scheduled amount as described in Table 2 and Table 3 (i.e. not more 
than doubled rate and no earlier than every 30 minutes).  See Section 5.1.1.3 for 
details on management related to intensity of adverse events. 

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Handling Tumor Lysis Syndrome: 
 
Monitoring and treatment of potential Tumor Lysis Syndrome (TLS) should be 
performed as per oncology standard of care.  
 
Symptoms of TLS include: 
 
Hyperkalemia, potentially leading to cardiac conduction abnormalities, muscle 
weakness or paralysis 
 
Hyperphosphatemia, potentially leading to renal failure 
 
Hypocalcemia. Symptoms include (but are not limited to):  tetany, seizures, 
mental retardation / dementia, parkinsonian (extrapyramidal) movement 
disorders, papilledema, emotional instability / agitation / anxiety, myopathy 
 
Hyperuricemia, potentially leading to renal failure 
 
Risk factors for TLS include a high tumor burden, high concentrations of 
circulating cells (≥ 25,000/mm3), hypovolemia, renal insufficiency, elevated pre-
treatment uric acid levels and elevated lactate dehydrogenase levels. Thus TLS 
should be suspected in subjects with large tumor burden who develop acute renal 
failure along with hyperuricemia (> 15 mg/dL) or hyperphosphatemia (> 8 mg/dL). 
Acute uric acid nephropathy is associated with little or no urine output. The 
urinalysis may show uric acid crystals or amorphous urates. The hypersecretion of 
uric acid can be detected with a high urine uric acid:creatinine ratio > 1.0, 
compared to a value of 0.6-0.7 for most other causes of acute renal failure. 
 
In those patients considered to be at risk for TLS, management of TLS includes 
correction of electrolyte abnormalities, monitoring of renal function, maintenance of 
fluid balance (consider aggressive hydration i.e. ~3,000 ml/m2/day fluid 
administered parenterally) and supportive care. If signs of TLS occur the 
investigator can administer rasburicase allopurinol (e.g. Zyloprim, Allohexal, 
Allosig, Progout, Zyloric) or other drugs used to treat hyperuricemia, per 
prescribing information, if deemed appropriate.  
 
Handling Progressive multifocal leukoencephalopathy (PML): 
 
PML is a viral-induced demyelinating disease of the central nervous system usually 
occurring in the immunocompromised individual and has been reported with 
ofatumumab. JC virus (JCV) infection resulting in PML and death has been 
reported in rituximab-treated subjects with hematologic malignancies or with 
systemic lupus erythematosus, an indication for which rituximab has not been 
approved. Investigators and nurses should pay careful attention for signs and 
symptoms consistent with a diagnosis of PML. Signs and symptoms of PML include 
visual disturbances, ocular movements, ataxia, and changes in mental status such as 
disorientation or confusion. These symptoms are not an exhaustive list, and the 
investigator should exercise judgment in deciding to report signs and symptoms to 
sponsor promptly. 
 
If a subject develops neurological signs or symptoms consistent with PML, 
treatment should be halted and the subject referred to a neurologist for evaluation. 

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At a minimum, blood JCV PCR and/or MRI should be performed; if either test is 
positive, Cerebrospinal Fluid (CSF) JCV PCR should be performed. If blood JCV 
PCR and MRI are negative, the investigator should contact the Sponsor for 
appropriate action to be taken. If blood JCV PCR and/or MRI are positive, the 
subject should be withdrawn from treatment, proceed to the Follow-Up Period, and 
be followed until resolution. There are no known tests that can reliably determine 
who is at increased risk for developing PML. There are no known interventions that 
can reliably prevent PML or adequately treat PML if it occurs. 
 
The investigator will do the following when reporting a serious infection (including 
PML) or sign/symptom consistent with PML. 
 
 Refer to Section 6.4.10 of this document for further information and detailed 
guidance for completing and transmitting these and other SAE reports for 
subjects who experience a serious infection, malignancy, death, or sign or 
symptom of PML. 
 Provide key source documentation for the Sponsor to assist with the safety 
evaluation process. 
Examples of key source documents include but are not limited to: hospitalization 
records, discharge summaries, laboratory evaluations, biopsy results, 
culture/sensitivity results, death certificates, and autopsy reports. 
If the subject has not otherwise been withdrawn from the study, then the 
investigator should contact the Sponsor to discuss the appropriate course of action 
regarding study continuation. 
Monitoring of Hepatitis in patients: 
 
For subjects who are HBsAg negative, HBcAb positive and HBV DNA negative, 
blood samples will be collected for HBV DNA testing every 2 months during the 
treatment/observation period and during follow-up at the 3 months and 6 months 
post last dose visits.  
For subjects who require hepatitis monitoring, extra visits outside those defined in 
the protocol may be required. 
 
Rationale: French regulatory requirement. 
 
 

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Protocol Changes for Amendment 4 
The main purpose for this amendment is to incorporate the recommendations related to 
HBV reactivation which are based on the update to internal global safety information for 
ofatumumab. Recommendations are given on HBV screening, monitoring and 
management for all subjects who are receiving or may receive ofatumumab in the future 
and all subjects who have completed treatment with ofatumumab in the past 12 months 
and are in the follow-up phase of the protocol. This additional guidance for subjects with 
hepatitis was requested by the FDA for all anti-CD20 monoclonal antibodies.  Other 
additions, clarifications and changes that have been included in Amendment 4 are noted 
below, and also include the additions for Amendment 3. 
This amendment applies to all study sites. 
Amendment Summary of Main Changes 
Section(s) 
Change 
Rationale 
Sponsor information 
page 
Medical monitor contact 
Universal Trial Number added 
Updated 
3.1.1.  
Clarification that re-screening 
is acceptable 
Clarification 
3.1.4. 
Survival f-u remotely 
Clarification 
4.3 
Further guidance re. HBV 
reactivation 
Addition on HBV per regulatory request 
5.1.1.2 
Clarification on dose 
interruption 
Additional guidance 
6.2.1 
Clarification on application of 
CLL guidelines
Additional guidance 
6.2.1.3 
Clarification on PD 
Additional guidance 
6.2.4 
Clarification on CT scans 
Clarification 
6.3 
Clarification on the use of local 
labs 
Clarification 
6.4.8 
Further guidance re. HBV 
reactivation 
Addition on HBV per regulatory request 
8.3.5.1 
Deletion of one censoring rule 
Correction 
Appendix 2 
Clarification for response 
definition summary, to be 
consistent with Section 6.2.1. 
Clarification 
 
Amendment Details 
Section 3.1.1  Screening Phase 
At the discretion of the physician, rescreening is acceptable. 
Rationale:  clarification 
Section 3.1.4 Follow-up Phase 
It is acceptable for the information for survival follow-up visits to be collected 

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remotely (via telephone, email), as necessary.  The frequency of the survival follow-
up visits should be per local standard of care, suggested every 3 months for CLL. 
Minimally, this should be collected at least annually. 
Rationale:  clarification 
Section 4.3 
Exclusion Criteria 
Consult with a physician experienced in the care and management of subjects with 
hepatitis B to manage/treat subjects who are anti-HBc positive. 
Rationale:  Addition per regulatory request 
Section 5.1.1.2  Ofatumumab Treatment Schedule 
Dose reductions or modifications of ofatumumab are not permitted with the 
exception of those initiated for patient safety (i.e. due to infusion reactions).  
If a dose delay is required for ofatumumab, due to but not limited to adverse events, 
dosing may resume at physician discretion, and if the patient is still considered to be 
in remission. 
Rationale:  Additional guidance  
Section 6.2.1 Definition of Response 
The IWCLL updated NCI-WG guidelines should be applied in the context of 
clinical judgment and determination of disease progression is at the physician’s 
discretion. 
Rationale:  Additional guidance 
Section 6.2.1.3  Progressive Disease (PD) 
*Note:  Physician’s discretion should be used to distinguish between potential 
infection versus progressive disease based on lymphocyte count.  It is acceptable to 
defer definitive judgment of progressive disease until further evidence is available.  
Rationale:  Additional guidance 
Section 6.2.4 CT-Scans 
approximately yearly  
If a scheduled CT scan indicates disease progression, and the subject will be 
withdrawn, it is not necessary to repeat a CT scan for a withdrawal visit. 
The actual CT scan (not just the radiologist report) should be available and 
performed to the criteria specified in the SPM. 
Rationale:  Clarification 
Section 6.3 
Laboratory Assessments 
The protocol should be followed as closely as possible, but if as per local practice, a 
blood draw for hematology analysis prior to the visit date is required, it would be 
acceptable for hematology analysis , but the blood draw can be taken no more than 
3 days ahead of the visit date.  Blood draws performed by local laboratories (e.g. for 
quicker pre-dose response assessment ) of protocol required lab assessments are 
acceptable, however, it is important that the sample for the central laboratory 
analysis is taken at the same time.  The local laboratory results of absolute 
neutrophil count (ANC), platelet count, peripheral blood lymphocytes, and 
hemoglobin must also be entered into the eCRF, if these results are used to manage 
a treatment decision.  Central laboratory information will also be entered into the 

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eCRF.   
 
Safety assessments, such as hematology not specified in the protocol, are allowed 
between visits, per investigator discretion and local practice. 
Rationale:  Clarification 
Section 6.4.8 Time Period and Frequency of Detecting AEs and SAEs 
Subject who are HBsAg negative, anti-HBc positive and HBV DNA negative may be 
included in the study but must undergo HBV DNA monitoring.  Consult with a 
physician experienced in care and management of subjects with hepatitis B to 
manage/treat subjects who are anti-HBC positive.  Anti-viral therapy should be 
initiated, if required.  If a subject’s HBV DNA becomes positive during the study, 
the GSK medical monitor should be notified.  The risks and benefits of continuing 
ofatumumab or discontinuing ofatumumab should be discussed with the medical 
monitor before appropriate treatment decisions are made for that individual 
subject. 
Rationale:  Addition per regulatory request 
Section 8.3.5.1  Efficacy Analyses 
Table 7 PFS Assignment 
Treatment discontinuation for 
toxicity or other reason 
Date of last assessment of  
measured lymph nodes 
Censored 
 
Rationale:  Correction, does not apply to subjects already in remission. 
Appendix 2:  Response Definition Summary 
 
PD Blood Lymphocytes:  (and ≥5000/µL B-cells) 
PR Neutrophils:  >1500/μL or ≥50% increase over BL 
 
Modified fromTable 4 IWCLL guidelines [Hallek, 2008].  For complete description 
and guidance, please refer to Hallek, 2008. 
Rationale: Clarification 

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Protocol Changes for Amendment 5 
The purpose of this amendment is to stop further enrollment of new subjects in the study 
because the interim analysis of efficacy met the predefined significance level of p<0.001, 
indicating clinical benefit of the ofatumumab arm.  The number of evaluable subjects as 
defined in the protocol (478) has been met.  Minor clarifications have also been included 
in this amendment. 
This amendment applies to all sites. 
Amendment Summary of Main Changes 
Section(s) 
Change 
Rationale 
Protocol Summary-
study design 
Deletion 
 
 
Addition 
Number of subjects to be randomized 
deleted, as study will close to 
enrollment 
Addition on closing enrollment 
1.5 
New section 
Added to explain rationale for closing 
enrollment 
3.1.1. 
Addition 
Clarification
3.1.3. 
Change 
Correction 
3.1.4 
Change 
Clarification of CT scans during F/U 
4.1 
Update 
Clarify study numbers 
6.5.6 
Change 
Clarification of PRO administration 
8.3.4 
Change 
New information and update to close 
enrollment 
T& E 
Addition 
Footnote added to clarify SAE and 
concomitant collection in F/U. 
 
Amendment Details 
Protocol Summary, study design 
Approximately 532  
Rationale:  deletion, as enrolment will stop and evaluable number of subjects reached. 
As the significance level was met at the interim efficacy analysis, further enrollment 
in the study will be discontinued.  There will be no changes to the study design, 
treatment, assessments, or follow-up. 
 
Rationale: Addition to explain stopping enrolment and emphasis that study design will 
remain the same. 
Section 1.5 Rationale for Closing Enrollment 
At the start of the study, it was expected that the study would fully enroll prior to 
the IDMC review at 2/3 of the events.  When the required number of events 
occurred prior to fully enrolling the study, but with the full number of evaluable 

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subjects available, and before the results were known, it was decided that if the 
primary endpoint met the predefined significance level of p<0.001, demonstrating 
clinical benefit for the ofatumumab arm, further enrollment would be discontinued.  
The independent data monitoring committee (IDMC) communicated that the 
significance level of p<0.001 for the primary endpoint at the interim analysis had 
been met.  Additionally, the study had obtained the number of evaluable subjects 
required (the number of evaluable subjects at the time of the interim analysis was 
479, with 478 evaluable required). 
 
The conduct of the study will continue without modification, with continuation of 
the assessments of the efficacy and safety endpoints and no change in study design, 
in accordance with the IDMC recommendation.  Currently, the standard of care is 
still observation, so that those subjects on the observation arm are receiving the 
standard of care and are not being jeopardized by continuation of observation.  The 
recommendation of the IDMC was that subjects should continue in their assigned 
study arms without change in treatment. Additionally, the IDMC did not identify 
any safety concerns associated with long-term ofatumumab treatment. 
Rationale: Addition- due to new information. 
Section 3.1.1. Screening Phase 
Blood samples, physical examination, CT scan and bone marrow examination will be 
performed to determine the study baseline disease status and study eligibility. 
 
Rationale:  Clarification, not all procedures required for study eligibility per se.  
Section 3.1.3 Treatment Phase 
Patient Reported Outcome (PRO) measures (EORTC QLQ-C30, EORTC QLQ-CLL16, 
EQ-5D will be administered for completion by subjects at baseline, and Cycle 4 Day 85, 
at each treatment visit beginning with Visit 3, and end of treatment at last visit, and at 
follow-up visits. 
Rationale: Correction and clarification of study times for PRO administration. 
Section 3.1.4 Follow-up Phase 
Additionally, CT Scans are required at screening, for confirmation of a new CR, yearly 
while on study, including during follow-up, and at disease progression, whenever that 
may occur. 
Rationale:  Clarification of  CT scan requirements for follow-up phase only. 
Section 4.1 Number of Subjects 
The original plan was for approximately 583 subjects will to be screened (with 532 
randomized) to obtain 478 evaluable subjects (assuming 10% screen failure and 10% 
drop out rates).  All evaluable subjects were obtained, and as the significance level 
was met at the interim efficacy of analysis, further enrollment will be stopped.  

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Rationale: Update due to new information. 
Section 6.5.6 Administration of PRO Measures 
The EORTC QLQ-C30, EORTC QLQ-CLL16, and EQ-5D should be administered at 
baseline and at each treatment clinic visits; Days 1 and 85 beginning with Visit 3, and at 
each follow-up visits post treatment; every 3 months through Month 60.   
Section 8.3.4 Interim Analysis 
Enrollment was is expected to be completed at the time of this analysis.  
 
However, when the required number of events occurred prior to fully enrolling the 
study, but with the full number of evaluable subjects available, and before the 
results were known, it was decided that if the primary endpoint met the predefined 
significance level of p<0.001, demonstrating clinical benefit for the ofatumumab 
arm, further enrollment would be discontinued.  
The study conduct will continue regardless of the outcome of the interim analysis of the 
primary endpoint. 
Rationale: Change- due to new information. 
Section:  Time and Events Table 
12Only SAEs and associated concomitant medications are to be reported from 60 
days after the last dose/observation time. (See Section 6.4.8.) 
Rationale: Addition to clarify collection of AEs and concomitant medication during 
follow-up.

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Protocol Changes for Amendment 6 
The purpose of this amendment is to delete or replace references to GSK or its staff with 
that of Novartis/Novartis and its authorized agents and to make administrative changes to 
align with Novartis processes and procedures. 
This amendment applies to all sites. 
Amendment Summary of Main Changes 
Section(s) 
Change 
Rationale 
Sponsor signatory 
Change of sponsor signatory Change in study sponsor from GSK to Novartis
Multiple 
Delete or replace references 
to GlaxoSmithKline or its 
staff with that of Novartis and 
its authorized agents 
To align with the change of sponsorship from 
GSK to Novartis.  
Multiple 
Make administrative changes To align with the change of sponsorship from 
GSK to Novartis. 
 
Amendment Details 
Section: Title Page:  
The title page replaced as per Novartis requirements.  
Rationale: Change in study sponsorship. 
Section: Sponsor Information Page 
The GSK contact information has been replaced with Novartis details. 
The term medical monitor has been replaced by medical lead and the email for medical 
lead provided. 
Rationale: Change in study sponsorship. 
Section 4.3 Exclusion Criteria 
14. Known or suspected hypersensitivity to ofatumumab that in the opinion of the 
investigator or medical monitor medical lead contraindicates study participation 
Rationale: To align with Novartis processes and procedures. 
Section 5.1 Investigational Product and Reference Therapy 
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 

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describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from 
GSKNovartis upon request. Adequate precautions must be taken to avoid direct contact 
with the investigational product.   
Section 5.3 Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of GSK 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSKNovartis, 
when applicable.  Product accountability records must be maintained throughout the 
course of the study. 
Rationale: Change in study sponsorship. 
Section 6.4.1 
Liver chemistry stopping and follow-up criteria 
According to GSKNovartis policy across all compounds, liver chemistry stopping and 
follow- up criteria have been designed to assure subject safety and evaluate liver event 
etiology.  (Refer to Appendix 5) 
Section 6.4.1.1 
Liver Chemistry Stopping Criteria 
 
Report the event to GSKNovartis within 24 hours of learning its occurrence 
6.4.8 Time Period and Frequency of Detecting AEs and SAEs 
Subject who are HBsAg negative, anti-HBc positive and HBV DNA negative may be 
included in the study but must undergo HBV DNA monitoring.  Consult with a physician 
experienced in care and management of subjects with hepatitis B to manage/treat subjects 
who are anti-HBC positive.  Anti-viral therapy should be initiated, if required.  If a 
subject’s HBV DNA becomes positive during the study, the GSK medical 
monitorNovartis medical lead should be notified.  The risks and benefits of continuing 
ofatumumab or discontinuing ofatumumab should be discussed with the medical 
monitormedical lead before appropriate treatment decisions are made for that individual 
subject. 
From the time a subject consents to participate in and completes the study (See 
Section 4.4), all SAEs assessed as related to study participation (e.g., protocol- mandated 
procedures, invasive tests, or change in existing therapy) or related to GSK concomitant 
medication, will be reported promptly to GSKNovartis. 
Any pre-existing condition or signs and symptoms present prior to investigational 
product will be recorded as medical history.   
Any SAE brought to the investigator’s attention after the subject has completed the study 
and considered by the investigator as possibly related to investigational product must be 
reported to GSKNovartis. 

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Section 6.4.9 
Pregnancy 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to 
GSKNovartis within 2 weeks24 hours of learning of its occurrence.  The pregnancy 
must be followed up to determine outcome (including premature termination) and status 
of mother and child.  Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE.  Spontaneous abortions must be reported as 
an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the investigational product, must be promptly reported to 
GSKNovartis. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study. Pregnancy information must be reported to GSKNovartis as described above. 
Section 6.4.10 
Prompt Reporting of Serious Adverse Events and Other 
Events to GSKNovartis 
SAEs and pregnancies meeting the pre-defined criteria will be reported promptly to 
GSKNovartis as described in the following table once the investigator determines that 
the event meets the protocol definition for that event. 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
“SAE” data 
collection tool 
24 hours 
Updated “SAE” 
data collection tool 
Pregnancy 
2 weeks24 
hours 
Pregnancy Form 
2 Weeks 
Updated 
Pregnancy Form
 
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSKNovartis are provided in 
the SPM. Procedures for post-study AEs/SAEs are provided in the SPM. 
Rationale: Change in study sponsorship and to align with Novartis processes and 
procedures. 
Section 7 
Data Management 
For this study subject data will be entered into GSK definedthe electronic case report 
forms (eCRFs), transmitted electronically to GSKNovartis and its authorized agents 
and be combined with data provided from other sources in a validated data system.  

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Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removingresolving errors and inconsistencies in the data.  Adverse events and 
concomitant medications terms will be coded using the MedDRA and an internal 
validated medicationa custom drug dictionary, GSKDrug.  eCRFs (including queries and 
audit trails) will be retained by GSKNovartis, and copies will be sent to the investigator 
to maintain as the investigator copy.  In all cases, subject initials will not be collected or 
transmitted to GSK according to GSK policy. 
Rationale: Change in study sponsorship and to align with Novartis processes and 
procedures. 
Section 8.3.5.2 
Safety Analyses 
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) dictionary, and grouped by system organ 
class.   
Rationale: To align with Novartis processes and procedures. 
Section 9.1 Regulatory and Ethical Considerations, Including the Informed 
Consent Process 
Prior to initiation of a study site, GSKNovartis will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with applicable country-specific 
regulatory requirements, including those required under a US IND. 
The study will be conducted in accordance with all applicable regulatory requirements, 
including IND Number 11,719. 
The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2000, as amended in 2002 and 2004 including, but not limited to: 
 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval of study protocol and any subsequent amendments. 
 
Subject informed consent. 
 
Investigator reporting requirements. 
GSKNovartis will provide full details of the above procedures, either verbally, in 
writing, or both. 
Section 9.2 Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and GSKNovartis procedures, 
GSKNovartis monitors will contact the site prior to the start of the study to review with 
the site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSKNovartis requirements.  When reviewing data collection 

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procedures, the discussion will include identification, agreement and documentation of 
data items for which the CRF will serve as the source document. 
GSKNovartis will monitor the study to ensure that the: 
 
Data are authentic, accurate, and complete. 
 
Safety and rights of subjects are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents. 
Section 9.3 Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, 
GSKNovartis may conduct a quality assurance audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. In the event of an audit or inspection, the investigator (and 
institution) must agree to grant the auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss any 
findings/relevant issues. 
Section 9.4. Study and Site Closure 
Upon completion or termination of the study, the GSKNovartis monitor will conduct site 
closure activities with the investigator or site staff (as appropriate), in accordance with 
applicable regulations, GCP, and GSKNovartis Standard Operating Procedures. 
GSKNovartis reserves the right to temporarily suspend or terminate the study at any time 
for reasons including (but not limited to) safety issues, ethical issues, or severe non- 
compliance.  If GSK determinesNovartis determine that such action is required, 
GSKNovartis will discuss the reasons for taking such action with the investigator or head 
of the medical institution (where applicable).  When feasible, GSKNovartis will provide 
advance notice to the investigator or head of the medical institution of the impending 
action. 
If a study is suspended or terminated for safety reasons, GSKNovartis will promptly 
inform all investigators, heads of the medical institutions (where applicable),and/or 
institutions conducting the study.  GSKNovartis will also promptly inform the relevant 
regulatory authorities of the suspension/termination along with the reasons for such 
action.  Where required by applicable regulations, the investigator or head of the medical 
institution must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 
Section 9.5  Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 

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regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSKNovartis audit or regulatory 
inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements. 
Essential documents (written and electronic) should be retained for a period of not 
less than fifteen (15) years from the completion of the Clinical Trial unless the 
Sponsor provides written permission to dispose of them or, requires their retention 
for an additional period of time because of applicable laws, regulations and/or 
guidelines. 
The investigator must notify GSKNovartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site. 
Section 9.6 Provision of Study Results and Information to Investigators 
The database results will be provided to 
 for the purposes of independent 
analysis for publication purposes in a peer reviewed journal.  Where required by 
applicable regulatory requirements, an investigator signatory will be identified for the 
approval of the clinical study report.  The investigator will be provided reasonable access 
to statistical tables, figures, and relevant reports and will have the opportunity to review 
the complete study results at a GSKNovartis site or other mutually-agreeable location. 
Upon completion of the clinical study report, GSKNovartis will ensure public disclosure 
of the clinical trial research results via the GSKNovartis Clinical Trials RegisterTrial 
Results website (www.novartisclinicaltrials.com) according to the GSKNovartis SOP 
and will provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
Rationale: Change in study sponsorship and to align with Novartis processes and 
procedures. 

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Appendix 5: Liver Chemistry Stopping and Follow-up Criteria† 
 
† In order to align with the change of sponsorship from GSK to Novartis, all references to 
‘GSK’ in this Appendix 5 should refer to ‘Novartis.’ 
Rationale: Change in study sponsorship.