Switching From Regimens Consisting of a RTV-Boosted Protease Inhibitor Plus TDF/FTC to a Combination of Raltegravir Plus Nevirapine and Lamivudine in HIV Patients With Suppressed Viremia and Impaired Renal Function (RANIA Study) (Pilot Study) Protocol MK-0518-284-03
Phase: PHASE2
Conditions: HIV Infections
Sponsor: Merck Sharp & Dohme LLC

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: Switching from regimens consisting of a RTV-boosted protease 
inhibitor plus TDF/FTC to a combination of RAltegravir plus 
NevIrapine and lAmivudine in HIV patients with suppressed 
viremia and impaired renal function (RANIA Study) (Pilot study) 
Protocol MK-0518-284-03 
NCT number: 
NCT02116660 
Document Date: 
16-April-2015 

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Abbreviated Title 
RANIA Study 
Title 
Switching from regimens consisting of a RTV-boosted protease 
inhibitor plus TDF/FTC to a combination of RAltegravir plus 
NevIrapine and lAmivudine in HIV patients with suppressed 
viremia and impaired renal function (RANIA Study) (Pilot study)  
Protocol MK-0518-284-03 
Sponsor 
MSD Italia s.r.l. 
Trial Physician 
 
  
 
Date of Finalization of This 
Current Version of the Protocol 
APRIL 16th 2015  
 
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR 
PRODUCT IS PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF THIS 
DRUG OR PRODUCT AND IS SUBJECT TO RECALL AT ANY TIME.  THE 
INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH 
DISCLOSURE IS REQUIRED BY APPLICABLE LAWS OR REGULATIONS.  SUBJECT 
TO THE FOREGOING, THIS INFORMATION MAY BE DISCLOSED ONLY TO THOSE 
PERSONS INVOLVED IN THE TRIAL WHO HAVE A NEED TO KNOW, WITH THE 
OBLIGATION NOT TO FURTHER DISSEMINATE THIS INFORMATION.  THESE 
RESTRICTIONS ON DISCLOSURE WILL APPLY EQUALLY TO ALL FUTURE ORAL 
OR WRITTEN INFORMATION, SUPPLIED TO YOU BY THE SPONSOR OR ITS 
AFFILIATES OR REPRESENTATIVES THAT IS DESIGNATED AS "PRIVILEGED" OR 
"CONFIDENTIAL". 
 
 
  
 
 
 
 
Name and Degree of Sponsor Representative 
dd MMM yyyy 
Department of Sponsor Representative 
 
I have read Protocol No. MK-0518-284-03 dated 16-APRIL-2015, including all appendices, and agree to 
conduct the trial in accordance with the protocol.  The protocol and trial documents must also be approved 
by the IRBs/IECs and regulatory authorities as appropriate, before implementation at the site.  I agree to 
implement the protocol and trial documents only after all necessary approvals have been obtained and the 
sponsor has confirmed that it is acceptable to do so. 
 
 
 
 
 
 
 
 
Name, Degree, full mailing address of Investigator 
Site Number 
dd MMM yyyy 
 
 
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1.0 TITLE PAGE 
 
Abbreviated Title 
RANIA Study 
Title 
Switching from regimens consisting of a RTV-boosted 
protease inhibitor plus TDF/FTC to a combination of 
RAltegravir plus NevIrapine and lAmivudine in HIV patients 
with suppressed viremia and impaired renal function (RANIA 
Study). (Pilot study) Protocol MK-0518-284-03 
Sponsor 
MSD Italia s.r.l. 
Sponsor’s Address 
Via Vitorchiano, 151 
00189 Roma 
 
 
EudraCT No. 
2013-001637-40  
Trial Physician 
 
  
 
Phase 
2b 
Date of Finalization of This Current 
Version of the Protocol 
 APRIL 16th 2015 
Protocol Template Approval Date 
30-Jan-2013 
                                                 
                                                     C O N F I D E N T I A L 
TRIAL PROTOCOL 
THIS CONFIDENTIAL INFORMATION ABOUT AN INVESTIGATIONAL DRUG OR 
PRODUCT IS PROVIDED FOR THE EXCLUSIVE USE OF INVESTIGATORS OF 
THIS DRUG OR PRODUCT AND IS SUBJECT TO RECALL AT ANY TIME.  THE 
INFORMATION IN THIS DOCUMENT MAY NOT BE DISCLOSED UNLESS SUCH 
DISCLOSURE IS REQUIRED BY APPLICABLE LAW OR REGULATIONS.  
SUBJECT TO THE FOREGOING, THIS INFORMATION MAY BE DISCLOSED 
ONLY TO THOSE PERSONS INVOLVED IN THE TRIAL WHO HAVE A NEED TO 
KNOW, WITH THE OBLIGATION NOT TO FURTHER DISSEMINATE THIS 
INFORMATION.  THESE RESTRICTIONS ON DISCLOSURE WILL APPLY 
EQUALLY TO ALL FUTURE ORAL OR WRITTEN INFORMATION SUPPLIED TO 
YOU BY THE SPONSOR OR ITS AFFILIATES OR REPRESENTATIVES THAT IS 
DESIGNATED AS “PRIVILEGED” OR “CONFIDENTIAL” 
 
 
 
 
 
 
 
 
 
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SUMMARY OF CHANGES 
This amendment is to provide the most updated information on drug-drug interactions from 
the latest SmPCs. The remaining revisions are to provide more clarity on the procedures 
(administrative in nature).  The following provides an overview of the changes made to the 
protocol: 
• 
update to the list of drug-drug interactions according to the most updated SmPC for 
raltegravir and nevirapine. The most significant modification of which is for aluminum 
and magnesium antacids listed as an excluded/prohibited medication; 
• 
update to text for consistent wording relating to the study subject participation/study 
duration; 
• 
addition of the protocol overdose language from the SmPC for raltegravir, lamivudine, 
nevirapine which was previously inadvertently omitted; 
• 
update to the pharmacokinetics text to further clarify sampling requirements (regarding 
drug/food intake) the clarify the subset of patients eligible for intensive PK. 
Below is a summary table of the sections affected, with the description of the changes and 
rationale. 
 
Section 
Numbers 
Section Titles 
Description of Changes 
Rationale 
Sections 
2.0, 7.2 
Study subject 
participation 
Clarified 
the 
study 
duration 
participation 
of 
each 
subject 
including the 2 weeks of follow-up 
post therapy (104 weeks). 
For consistency. 
Section 2.0 
Study duration 
Clarified 
the 
study 
duration  
including the 2 weeks  of follow-up 
post therapy (128 weeks). 
For consistency. 
Sections 
2.0, 7.3.1 
Inclusion Criteria 
Inclusion Criteria #10 was updated 
to 
add 
a 
specification 
about  
genotype testing  timelines.   
For completeness. 
Sections 
2.0, 7.7.3 
Pharmacokinetics Added 
clarity 
regarding 
the 
pharmacokinetics 
sampling 
requirements (regarding drug/food 
intake) and the subset of patients 
eligible for intensive PK. 
Update made for clarity. 
Section 2.1 
Trial Design 
Diagram 
Added in the Trial Design Diagram 
footnotes, a box specifying the study 
duration including the 2 weeks of 
follow-up post therapy. 
For completeness. 
 
 
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Section 2.2 
Trial Flow Chart 
Footnote on PK updated to remain 
consistent with the Synopsis and 
Section 7.7.3. 
Footnotes 
updated 
for 
procedural clarity. 
Section 2.2 
Trial Flow Chart 
For “Visit 11” cell added the 
abbreviation 
“EOT” 
(End-of-
Treatment) and for “Visit 99” 
“EOS” (End-of-study). 
For completeness. 
Section 2.2 
 
Trial Flow 
Chart/Footnote 6 
and Appendix 1 
The footnote was updated to clarify 
that 
blood 
samples 
for 
viral 
resistance will be collected only  at 
virologic failure confirmation visit.  
Only genotype testing will be 
performed. 
For consistency. 
Section 2.2 
Trial Flow Chart 
“Footnote 11” formatting issue 
Formatting issue 
Sections 
7.2, 
7.7.2.3.1 
Monitoring 
Adverse Events 
Text which describes the period of 
AE monitoring was clarified. 
Based on recent guidance added 
additional protocol language to 
describe the AEs to be reported in 
the pre-randomization phase. 
Update made for clarity 
and 
based 
on 
recent 
guidance. 
Section 
7.3.3 
Subject 
Discontinuation 
Criteria 
Updated list to include criteria # 7, 8 
and re-worded criteria #4. 
For completeness. 
Section 
7.4.1.1 
Treatments 
Formatting issue “daily” deletion. 
Formatting issue 
Section 
7.4.2.1.1 
Medications, 
Supplements, 
and Other 
Substances 
prohibited Prior 
to baseline and 
During the Trial 
Updated the lists of drug-drug 
interactions according to the most 
updated SmPC for raltegravir and 
nevirapine. The most significant 
modification 
of 
which 
is 
for 
aluminum and magnesium antacids  
listed as an excluded/prohibited 
medication. 
To update according to the 
most updated SmPC for 
raltegravir, nevirapine and 
lamivudine. 
Section 
7.4.3 
Procedures for 
Monitoring 
Subject 
Compliance With 
Administration 
of Trial 
Treatments 
Added a specification about the 
patient questionnaire provided to 
monitor the treatment compliance.  
For completeness. 
Section 7.6 
Trial Procedures 
For “Laboratory Tests” added a 
specification according to the Trial 
Flow Chart  
To further clarify. 
Section 
Overdose 
Removed reference to the product’s 
Previously 
inadvertently 
 
 
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7.7.2.2.4 
 
 
 
 
 
Investigator’s brochure and added  
overdose information from the 
SmPC for raltegravir, lamivudine, 
nevirapine. 
Specified that an overdose of the 
control arm does not need to be 
reported as an ECI or SAE. 
omitted. 
Section 
7.7.2.5.1 
Clinical 
complaint 
reporting 
Updated to align with the standard 
process for commercial drugs 
To 
align 
with 
Merck 
standard process. 
Section 11 
References 
Reference n. 17 updated to support 
IC #10  
For completeness. 
 
 
 
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2.0. SYNOPSIS 
 
 
TITLE OF TRIAL:  Switching from regimens consisting of a RTV-boosted protease inhibitor plus TDF/FTC to 
a combination of RAltegravir plus NevIrapine and lAmivudine in HIV patients with suppressed viremia and 
impaired renal function (RANIA Study) (Pilot, Phase 2b study - Protocol No. MK-0518-284-03) 
ABBREVIATED TITLE: RANIA Study 
OBJECTIVES: To assess the change in renal function, efficacy and the safety of a switch from a regimen 
consisting of PI/r (LPV/r, ATV/r, DAR/r) plus TDF/FTC to a combination of Raltegravir plus Nevirapine plus 
Lamivudine in patients with a stable HIV-1 RNA < 50 copies/mL in the previous 12 months with no 
documentation of HIV RNA ≥ 50 copies/mL during this time, without a change in antiretroviral therapy from at 
least 6 months and with an eGFR (MDRD-6 variables) between 60 and 90 mL/min/1.73 m2 at screening. 
Primary Trial Objective:  
 To assess the changes in renal function (e.g. estimated GFR measured by MDRD formula with 6 variables 
that is MDRD 4 variables plus blood urea nitrogen and albumin) from baseline to 48 weeks.  
Secondary Trial Objectives:  
 
a) To assess the efficacy (stable suppressed HIV-RNA <50 copies/ml) after switch from PI/r (LPV/r, 
ATV/r, DAR/r) + TDF/FTC to RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 50 copies/mL 
in the previous 12 months during 48 and 96 weeks of treatment. 
b) To evaluate the changes in T-lymphocyte CD4 cell count during 48 and 96 weeks of treatment 
c) To assess laboratory alterations (liver enzymes, lipid profile) after switch from PI/r (LPV/r, ATV/r, 
DAR/r) + TDF/FTC to RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 50 copies/mL in the 
previous 12 months during 48 and 96 weeks of treatment. 
d) To assess the safety (e.g. skin rash, GI disturbances) after switch from PI/r+ TDF/FTC to RAL + NVP 
+ 3TC in patients with a stable HIV-1 RNA < 50 copies/mL in the previous 12 months during 48 and 
96 weeks of treatment. 
e) To assess the alterations of the tubular kidney injury markers: b2-microglobulin (b2M) and retinol-
binding protein (RBP) and N-acetyl-b-D-glucosaminidase (NAG) during 48 and 96 weeks of 
treatment. 
f) To assess metabolic bone markers changes: Serum Bone Specific Alkaline Phosphatase (s-BSAP), 
C-telopepdides of type I Collagen (s-CTx) during 48 and 96 weeks of treatment. 
g) To assess bone mineral density modifications during 48 and 96 weeks of treatment. 
h) To evaluate pharmacokinetics of RAL and NVP. 
i) To assess the development of genotypic resistance at virologic failure  
j) To evaluate the adherence during 48 and 96 weeks of treatment. 
k) To assess the Fracture Risk (FRAX® score in persons > 40 years) during 48 and 96 weeks of 
treatment 
l) To assess the VACS Risk Index during 48 and 96 weeks of treatment 
m) The frequency of experiencing a decline of renal function in HIV-infected patients with an eGFR 
(MDRD-6 variables) < 60 mL/ min/1.73 m2 at 48 weeks of treatment 
n) To evaluate the changes in eGFR-MDRD at 96 weeks of treatment 
 
 
Trial Design 
Overview:  
This is a pilot multicenter randomized, open-label, active-controlled, parallel-group, in patients with 
persistently (previous 12 months) suppressed plasma HIV viremia (< 50 copies/mL) after switch from PI/r plus 
TDF/FTC to a combination of Raltegravir 400 mg BID, plus 3TC 150 mg BID plus Nevirapine 200 mg BID.  
This study is a pilot switch study with a comparator used as internal control. No comparisons will be made 
 
 
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between the groups. This study is designed as an estimation study only and no formal comparison between 
the two regimens is planned. The control arm will be not directly compared with the experimental arm and will 
act as a check to assess the internal validity of the study. 
Number of Trial Centers: Approximately 15 Italian centers. 
Duration of Participation:  Each subject will participate in the trial for 104 weeks from the time the subject 
signs the Informed Consent Form (ICF) through the final contact. After a screening phase of 6 weeks, each 
subject will be receiving assigned treatment for 96 weeks with 2 additional weeks of follow-up post therapy.  
Duration of Trial:  The trial will require approximately 128  weeks from the beginning to the end of the overall 
trial (first subject signing informed consent to last contact with last subject, considering a screening phase of 
6 weeks, 24 weeks for enrollment, 96 weeks for treatment and 2 weeks of follow-up post therapy). 
Key Inclusion Criteria: 
1. Each subject must be willing and able to provide written informed consent for the trial 
2. Each subject must be  18 years of age 
3. Each subject must be male or non-pregnant, non-breastfeeding female 
4. Each subject must have diagnosis of HIV infection  
5. Each subject must have no history of previous virological failure (defined as 2 consecutive plasma HIV-
1 RNA >200 copies/mL at least two weeks apart  while on previous or current ARV therapy)   
6. Each subject must have no history of previous exposure to NNRTIs or INIs prior to entering the study 
7. Each subject must have no history of previous intolerance to Lamivudine 
8. Each subject must have at least 2 documented plasma HIV-1 RNA <50 copies/mL and no HIV-1 RNA 
>50 copies/mL in the 12 months prior to the screening visit 
9. Each subject must be taking the same PI/r (LPV/r, ATV/r, DAR/r) + TDF/FTC based ARV combination 
for at least 6 months before screening 
10. Each subject mustn't have major IAS-USA mutations on genotypic testing performed before starting 
ARV treatment (genotype testing done before starting the first line therapy) 
11. Each subject must have results of clinical laboratory tests (CBC, blood chemistries, and urinalysis) 
within normal limits or clinically acceptable to the investigator 
12. Each subject must have results of a physical examination, including blood pressure, within normal limits 
or clinically acceptable limits to the investigator 
13. Each subject must be able to adhere to dose and visit schedules 
14. Each subject should have Creatinine Clearence between 60 and 90 mL/min/1.73 m2 calculated 
according to MDRD 6 variables 
15. Each sexually active subject and subject's partner(s) of child-bearing potential must agree to use a 
medically acceptable method of contraception 2 weeks prior to Day 1 and at least 6 months after last 
dose of study drug 
 
Key Exclusion Criteria:   
1. The subject has HBsAg+ or anticipated need for HCV-treatment  
2. The subject has grade 2-4 laboratory abnormality of liver transaminases (ALT and AST) 
3. The subject has experiencing liver cirrhosis 
4. The subject has history of diabetes mellitus (defined as initiation of antidiabetic treatment or verification 
of diabetes in a case report form) 
5. The subject has any cancer (excluding stable Kaposi Sarcoma) 
6. The subject has an allergy/sensitivity to investigational product or its/their excipients. 
7. The female subject is nursing. 
8. The female subject is pregnant or intending to become pregnant. 
9. The subject has any clinically significant condition or situation, other than the condition being studied 
 
 
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that, in the opinion of the investigator, would interfere with the trial evaluations or optimal participation in 
the trial. The subject in the opinion of the investigator has an excessive intake of alcohol and 
substances. 
10. The subject has active AIDS-defining event (CDC-C), exception for stable Kaposi Sarcoma, HIV 
Wasting Syndrome. 
11. The subject has used any investigational drugs within 30 days of screening. 
12. A subject who has participated in any other clinical trial within 30 days, inclusive, of signing the informed 
consent form of the current trial. 
13. The subject or a family member is among the personnel of the investigational or sponsor staff directly 
involved with this trial 
 
 
INVESTIGATIONAL PRODUCT, DOSE, MODE OF ADMINISTRATION 
Investigational Product:   
Raltegravir, 400 mg BID taken PO without regard to food + Lamivudine 150 mg BID PO without regard to 
food + Nevirapine  200 mg QD for 14 days followed by Nevirapine 200 mg BID PO without regard to food, for 
96 weeks. 
Non investigational Product:   
Continuing the previous regimen PI/r (LPV/r, ATV/r, DAR/r) + TDF/FTC, for 96 weeks 
STATISTICAL METHODS:  
This is a pilot phase 2b, multicenter, randomized, open-label, active controlled, parallel group design.  
Patients meeting all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio to 
one of the following two treatment groups: 
 
Regimen A: switching to a regimen containing Raltegravir 400 mg BID PO+ Lamivudine 150 BID PO + 
Nevirapine 200 mg QD for 14 days followed by Nevirapine 200 mg BID PO 
 
Regimen B (control arm): continue with the current regimen containing PI/r (LPV/r, ATV/r, DAR/r) 
+TDF/FTC 
The primary endpoint of this study is the eGFR (MDRD) change from baseline to Week 48.  
This randomized phase 2 study is mainly designed as an estimation study without a planned formal 
comparison between the two regimens. The control arm, not directly compared with the experimental arm, will 
be considered for assessing the internal validity of the study. A safety monitoring with more frequently visits 
will be ensured for the control arm only. 
 
Data Set(s) to be Analyzed:  
The primary analysis on primary and secondary endpoints will be performed on the Full Analysis Set (FAS) 
which includes all randomized subjects who received at least one dose of study medications, and have both a 
baseline assessment and at least one post-baseline assessment of any primary or secondary endpoints, 
irrespective of compliance with the study protocol and procedures.  
In addition, a Per Protocol Set is defined as all FAS subjects who meet key eligibility criteria. Sensitivity 
analyses will be based on this Per Protocol Set. A supportive analysis using the Per-Protocol population will 
be performed for the primary endpoint only in case more than 10% of patients are identified as protocol 
violators.  
Other safety analyses will be performed on the All Treated Set. The All Treated Set consists of all randomized 
patients who received at least one dose of study treatment. 
 
Sample Size:   
Patients to screen: 148; Patients evaluable: 100 (50 in each group). 
It is expected that Regimen A is generally safe and well tolerated and can cause an improvement of the renal 
 
 
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function. A pre vs post design will be used to examine changes in eGFR (MDRD) in the Regimen A arm.  
For sample size calculation our data and results from a pilot tenofovir switching study recently published (1) 
were used.  
Sample size calculation was based on the primary endpoint of the study, defined as the change from baseline 
to week 48 in eGFR (MDRD),  with the following assumptions:  
Test: One group Student’s t-test (two-sided). 
Null hypothesis (H0): Expected mean change from baseline to week 48 is 0.0 ml/min. 
Alternative hypothesis (H1): Expected mean change from baseline to week 48 is 15 ml/min. 
Expected SD = 31.5 ml/min 
Alpha = 0.05; Power = 90%;   
When the sample size is 50, a single group Student’s t-test with a 0.05 two-sided significance level will have 
90% power to detect a difference between a null hypothesis mean of 0.0 ml/min and an alternative hypothesis 
mean of 15.0 ml/min, assuming that the standard deviation is 31.5 ml/min. 
Overall 100 subjects (50 per arm) need to be evaluated. In order to obtain 50 subjects and assuming a 20% 
rate of non evaluable subjects the required set of patients will be approximately 63 per arm and considering a 
screen failure rate of 15%, such number should be increased to 74. Overall, approximately 148 subjects (74 
per arm) will need to be screened to obtain 100 subjects valuables (50 per arm).  
Calculations were made by using nQuery Advisor® 7.0. 
 
Analysis of primary end-point: 
The primary endpoint of this study is the eGFR (MDRD) change from baseline to Week 48.  
The primary analysis will be conducted on the Full Analysis Set. An additional sensitivity analysis will be 
based on the Per Protocol Set.  
The Primary Endpoint will be analyzed using a one-group (two-sided) Student’s t test on the Regimen A 
group.  
For the Regimen B group, the difference from baseline to week 48 will be estimated together with its pertinent 
95% Confidence Interval. No formal comparison between the two arms will be carried out.  
If missing data on primary end-point will be ≤ 5%, a LOCF approach (Last Observation Carried Forward 
procedure) will be used. In that case, if a patient permanently discontinues the treatment during the 48-week 
treatment period or does not have an eGFR (MDRD) value at week 48, the last post-baseline eGFR (MDRD) 
measurement during the on-treatment period will be used as the eGFR (MDRD) value at week 48. Otherwise, 
missing data will be imputed by using a multiple imputation method considering the previous trend and/or the 
baseline covariates. 
Analysis of main secondary end-point:  
The main secondary efficacy end-point will be the proportion of subjects with HIV-RNA < 50 copies/ml at 48 
week. Based on the above criteria, patients will be classified as responders or not responders (failures). If a 
patient permanently discontinues the treatment during the 48-week treatment period or does not have an 
HIV-RNA assessment at week 48, a conservative approach will be used: all missing values due to premature 
discontinuations will be considered failures, regardless of the reason for discontinuation. Counts and 
percentages of “Responders” and “Not Responders” and their 95% two-sided exact confidence intervals will 
be presented for both arms.  
Analysis of the main secondary end-points will be based on the Full Analysis Set. 
Analysis of other secondary end-points:  
Other secondary endpoints will be:  
a) Proportion of subjects with HIV-RNA < 50 copies/mL at 96 weeks of treatment.  
b) Time to virologic failure (HIV-1 RNA > 50 copies/mL). 
c) Changes of HIV-RNA absolute values at different time points.  
d) Changes of absolute CD4+ T-lymphocyte count at 48 and 96 weeks of treatment. 
 
 
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e) Proportion of subjects with laboratory alterations (liver enzymes, lipid profile). 
f) 
Proportion of subjects with alterations of the tubular kidney injury markers. 
g) Proportion of subjects with metabolic bone markers changes  
h) Proportion of patients with bone mineral density modifications  
i) 
Pharmacokinetics determination (only for RAL and NVP) (see PK paragraph). 
j) 
Proportion of subjects with genotypic resistance at virologic failure.  
k) Incidence of mutations associated to resistance to NRTIs, NNRTIs, PI and INI, at virological failure. 
l) 
Proportion of subjects with adherence to therapy during 48 and 96 weeks of treatment. 
m) Changes in the Bone disease Risk assessment (FRAX® score in persons > 40 years) during 48 and 96 
weeks of treatment. 
n) Changes in the VACS Index during 48 and 96 weeks of treatment. 
o) Proportion of subjects experiencing a decline of renal function defined as eGFR (MDRD-6 variables) < 60 
mL/min/1.73 m2 at 48 weeks of treatment. 
p) Changes in eGFR-MDRD at 96 weeks of treatment 
 
Analysis of the secondary end-points will be based on the Full Analysis Set.  
Continuous data will be summarized by treatment group using the number of observations available n, mean, 
SD, minimum, median, and maximum at each time point. 
Categorical data will be summarized by treatment group using counts and percentages at each time point. 
Missing data will not be categorized in the summaries. In general, descriptive statistics of quantitative efficacy 
and safety endpoints (result and change from baseline) by scheduled visit will be provided on observed 
cases, i.e., the inclusion of only patients having non-missing assessments at a specific visit. 
 
Safety Analysis:   
Safety analyses will be descriptive, based on the safety population.  
Interim Analysis No formal interim analysis are planned. 
Pharmacokinetics:  
Determination of raltegravir and nevirapine AUCs (areas under the curve) will be carried out at steady state 
according to the dosing interval with blood sampling taking place at the end of dosing interval at time 0 
(fasted state), and  1, 2, 3, 6 and 12 h after drug intake (regardless food) in a subset of enrolled patients with 
available data in the experimental arm at week 12 (~ the first 10 patients). The remaining 40 patients in the 
experimental arm will undergo Ctrough sampling (at the end of dosing interval at 12 h) at week 12 and 48. 
Adequate documentation of drug and food intake will be required. 
Blood will be collected into 7 ml lithium heparin and plasma obtained by centrifugation (3000 rpm for 10 
minutes at 4 °C) will be stored in two criovials at -20 °C. Plasma concentrations will be analyzed by a 
validated HPLC-PDA method at the Clinical Pharmacology and Pharmacogenetics Laboratory of the 
University of Torino, Torino, Italy. 
In Torino centre, CYP2B6 single nucleotide polymorphisms (SNPs) will be screened in both patients 
undergoing AUC determination and those being sampled for Ctrough. 
 
 
 
 
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2.2 Trial Flow Chart 
 
 
Timing of Evaluation and Procedures (Relative to Initiation of Product) 
Visit Title 
Screening 
Baselin
e 
Monito
ring 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monitori
ng 
Disconti
nuation 
Visit 
Viral Failure 
Confirmation 
Fasting 14 days 
post-therapy 
Follow-up 
Visit Number 
Visit 1 
Visit 2 Visit 3 Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
EOT 
Visit U 
Visit 99 
EOS 
Scheduled Week  Days -42 
to day 1 
 
Day 1 
Week  
25 
Week  
4 
Week 
 65 
Week  
85 
Week 
12 
Week 
 24 
Week 
48 
Week 
72 
Week 
96 
 
 
Scheduling 
Window 
 
 
±2days 
±2 days 
±2days 
±2days 
±6days 
±6days 
± 12 days 
±12days 
±12 days 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Identification 
Card- Dispensed 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Identification 
Card-Returned   
 
 
 
 
 
 
 
 
 
 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test1 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Inclusion/esclusio
n Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Review 
prior/Concomitan
t Medications 
X 
X 
 
 
 
 
X2 
X 
X 
X 
X 
 
 
CYP 2B6 SNP3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PK intensive 
blood  
sampling (AUC 
subgroup)4 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
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Timing of Evaluation and Procedures (Relative to Initiation of Product) 
Visit Title 
Screening 
Baselin
e 
Monito
ring 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monitori
ng 
Disconti
nuation 
Visit 
Viral Failure 
Confirmation 
Fasting 14 days 
post-therapy 
Follow-up 
Visit Number 
Visit 1 
Visit 2 Visit 3 Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
EOT 
Visit U 
Visit 99 
EOS 
Scheduled Week  Days -42 
to day 1 
 
Day 1 
Week  
25 
Week  
4 
Week 
 65 
Week  
85 
Week 
12 
Week 
 24 
Week 
48 
Week 
72 
Week 
96 
 
 
Scheduling 
Window 
 
 
±2days 
±2 days 
±2days 
±2days 
±6days 
±6days 
± 12 days 
±12days 
±12 days 
 
 
PK Ctrough 
sampling 
(experimental 
arm)4 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
Review Adverse 
Events 
X 
X 
X5 
X 
X5 
X5 
X 
X 
X 
X 
X 
 
X 
Blood for HIV-
RNA 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Blood for CD4 
cell count, for 
CD8 cell count 
and for CD4/CD8 
ratio 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
Plasma for viral 
resistance6 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Adherence 
Questionnaire 
evaluation 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Physical 
Examination7 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Blood for hepatic  
Safety8 
X 
X 
X5 
X 
X5 
X5 
X 
X 
X 
X 
X 
 
 
Blood for safety8-
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
 
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Timing of Evaluation and Procedures (Relative to Initiation of Product) 
Visit Title 
Screening 
Baselin
e 
Monito
ring 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monitori
ng 
Disconti
nuation 
Visit 
Viral Failure 
Confirmation 
Fasting 14 days 
post-therapy 
Follow-up 
Visit Number 
Visit 1 
Visit 2 Visit 3 Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
EOT 
Visit U 
Visit 99 
EOS 
Scheduled Week  Days -42 
to day 1 
 
Day 1 
Week  
25 
Week  
4 
Week 
 65 
Week  
85 
Week 
12 
Week 
 24 
Week 
48 
Week 
72 
Week 
96 
 
 
Scheduling 
Window 
 
 
±2days 
±2 days 
±2days 
±2days 
±6days 
±6days 
± 12 days 
±12days 
±12 days 
 
 
9 
MDRD-6 
assessment 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Urine Kidney 
Tubular Markers 
( )8 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Test for renal 
safety (control 
arm) 11 
 
X 
 
 
 
 
X 
X 
and 36 
weeks 
X 
and 60 
weeks 
X  
and 84 
weeks 
X 
 
 
Metabolic bone 
markers 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
Perform BMD 
measurement 
(DXA scan-Total 
Hip and Lumbar 
spine)10 
 
X 
 
 
 
 
 
 
 
X 
 
      X 
 
 
Dispense Trial 
Medication 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
Fracture Risk 
Assessment 
(FRAX® score in 
persons > 40 
years) 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
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Timing of Evaluation and Procedures (Relative to Initiation of Product) 
Visit Title 
Screening 
Baselin
e 
Monito
ring 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monito
ring 
Monitori
ng 
Monitori
ng 
Monitori
ng 
Disconti
nuation 
Visit 
Viral Failure 
Confirmation 
Fasting 14 days 
post-therapy 
Follow-up 
Visit Number 
Visit 1 
Visit 2 Visit 3 Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 
EOT 
Visit U 
Visit 99 
EOS 
Scheduled Week  Days -42 
to day 1 
 
Day 1 
Week  
25 
Week  
4 
Week 
 65 
Week  
85 
Week 
12 
Week 
 24 
Week 
48 
Week 
72 
Week 
96 
 
 
Scheduling 
Window 
 
 
±2days 
±2 days 
±2days 
±2days 
±6days 
±6days 
± 12 days 
±12days 
±12 days 
 
 
VACS Risk index 
assessment 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
Investigational 
Product 
Accountability 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
1Serum pregnancy test 
 2 Concomitant Medications from day 0 to Week 12  
3CYP2B6 single nucleotide polymorphisms (SNPs) will be screened in both patients undergoing AUC determination and those being sampled for Ctrough 4Procedures for collection 
of samples are described in the protocol. Determination of raltegravir and nevirapine AUCs (areas under the curve) will be carried out at steady state according to the dosing interval 
with blood sampling taking place at the end of dosing interval at time 0 (fasted state), and  1, 2, 3, 6 and 12 h after drug intake (regardless food) in a subset of enrolled patients with 
available data in the experimental arm at week 12 (~ the first 10 patients). The remaining 40 patients in the experimental arm will undergo Ctrough sampling (at the end of dosing 
interval at 12 h ± 2h) at week 12 and 48. Adequate documentation of drug and food intake will be required.  
5only for the patients enrolled in the experimental arm 
6If viral failure or relapse is confirmed (with a confirmatory HIV RNA at least two week apart) defined as 2 consecutive plasma HIV-1 RNA >200 copies/mL plasma for genotype 
resistance testing will be collected and sent to a local qualified hospital laboratory for testing. 
7 Full physical exam including vital signs (blood pressure, heart rate, temperature, breathing rate). At investigator discretion a chest x-ray and/or an ECG could be obtained if felt 
necessary 
8see Appendix 1 
9Fasting for at least 12 hours 
10 Perform BMD only in patients already qualifies by medical history, kidney function evaluation and medication review 
11A safety monitoring with more frequently visits will be ensured for the control arm. Visits each 3 months according to the international and national guidelines for monitoring TDF 
safety profile have been planned. Test for renal safety planned each months are creatinine clearance evaluation and serum phosphate. If serum phosphate is < 1.5 mg/dl (0.48 
mmol/l) renal function should be re-evaluated within one week including measurement of blood glucose, blood potassium, urine glucose concentrations and proteinuria. 
 
 
 
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3.0  TABLE OF CONTENTS 
1.0 TITLE PAGE ....................................................................................................... 2 
2.1 Trial Design Diagram .................................................................................. 11 
2.2 Trial Flow Chart .......................................................................................... 12 
3.0  TABLE OF CONTENTS ................................................................................... 16 
3.2 List of Appendices ..................................................................................... 18 
4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 19 
5.0  INTRODUCTION .............................................................................................. 23 
5.1 Background and Therapeutic Rationale ................................................... 23 
5.2  Subject Population Rationale ................................................................... 24 
5.3  Dose and Administration Rationale ......................................................... 25 
6.0  TRIAL OBJECTIVES ........................................................................................ 25 
6.1 Primary Trial Objectives............................................................................. 25 
7.0 INVESTIGATIONAL AND ANALYSIS PLAN ................................................... 26 
7.1 
Overall Trial Design ............................................................................... 26 
7.2 
Beginning and End of the Trial ............................................................. 26 
7.3 
Trial Population ...................................................................................... 27 
7.3.1 
Subject Inclusion Criteria ................................................................ 27 
7.3.2 
Subject Exclusion Criteria ............................................................... 28 
7.3.3 
Subject Discontinuation Criteria ...................................................... 29 
7.3.4 
Replacement of Subjects ................................................................ 30 
7.4 
Treatments ............................................................................................. 30 
7.4.1 
Trial Treatments .............................................................................. 30 
7.5 
Trial Schedules ...................................................................................... 48 
7.6 
Trial Procedures .................................................................................... 48 
7.7 
Assessments .......................................................................................... 50 
7.7.1 
Efficacy Assessments ..................................................................... 50 
7.7.2 
Safety Monitoring And Assessments .............................................. 51 
7.7.3 Other Endpoints ................................................................................... 57 
7.7.4  Criteria For Early Termination Of The Trial .......................................... 58 
8.0 STATISTICAL AND ANALYTICAL PLAN ....................................................... 58 
9.0 ADHERENCE TO ETHICAL, REGULATORY AND ADMINISTRATIVE 
CONSIDERATIONS ......................................................................................... 64 
9.1 
Ethical Conduct of the Trial .................................................................. 64 
9.1.1 
Independent Ethics Committee or Institutional Review Board ........ 64 
 
 
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9.1.2 
Subject Information and Consent .................................................... 64 
9.1.3 
Registration of the Trial ................................................................... 65 
9.2 Reporting Trial Data to the Sponsor ......................................................... 65 
9.2.1 Data Collection Forms .......................................................................... 65 
9.2.2 Preparing Case Report Forms for All Subjects ..................................... 65 
9.2.3 Preparing Case Report Forms for Subjects Who Fail Screening ......... 66 
9.3 Publications and Other Rights .................................................................. 66 
9.3.1 Rights to Publish by the Investigator .................................................... 66 
9.3.2 Use of Proprietary or Confidential Information in a Publication ............ 66 
9.3.3 Use of Trial Information in a Publication ............................................... 67 
9.3.4 Authorship of Publications .................................................................... 67 
9.4 Trial Documents and Records Retention ................................................. 67 
10.0 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE ................. 68 
10.1 Sponsor ..................................................................................................... 68 
10.2 Investigators ............................................................................................. 68 
10.2.1 Selecting Investigators ....................................................................... 68 
10.2.2 Financial Disclosure Requirement ...................................................... 68 
10.2.3 Clinical Study Report Coordinator Investigator ................................... 68 
11. REFERENCES .................................................................................................. 70 
APPENDICES .................................................................................................... 72 
 
 
 
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3.1 List of Appendices 
Appendix 1:  
 Laboratory Analyses For Admission To Study And For Safety 
Assessment  
 
Appendix 2:  
 Guidelines For Grading Severity Of Laboratory Adverse 
Experiences For Toxicity Management 
 
Appendix 3:  
Adherence Questionnaire 
Appendix 4:            Merck Code Of Conduct For Clinical Trials 
 
 
 
 
 
 
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4.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Term 
Definition 
3TC 
Lamivudine 
AE 
Adverse Event 
AIDS 
Acquired  Immune Deficiency Sindrome 
AKI 
Acute Kidney Injury 
ALT 
Alanine aminotransferase (SGPT) 
APTT 
Activated Partial Thromboplatin Time 
AST 
Aspartate aminotransferase (SGOT) 
ATV/r 
Atazanavir/ritonavir 
AUC 
Area Under the Curve 
AV (block) 
Atrio Ventricular 
b2M 
Beta-2 microglobuline 
BID, b.i.d. 
Bis in Die 
BL 
Baseline 
BMD 
Bone Mineral Density 
cART, ART 
Current Antiretroviral Therapy, Antiretroviral Therapy 
CBC 
Complete Blood Count 
CCR5 
Cysteine-Cysteine Chemokine Receptor 5 
CD4 cell 
Cluster of Differentiation 4 cell 
CD8 cell 
Cluster of Differentiation 8 cell 
CDC, CDC-C 
United States Centers for Disease Control and Prevention, CDC-Classification 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTC 
Clinical Trial Coordinator 
CTD 
Clinical Trial Directive 
CVD 
Cardiovascular Disease 
CYP 
Cytochrome P 
DAIDS 
Division of AIDS (National Institutes of Health, USA) 
DAR/r 
Darunavir/ritonavir 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data and Safety Monitoring Board 
 
 
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Term 
Definition 
DXA 
Dual-Energy X-Ray Absorptiometry 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
EDC  
Electronic Data Capture 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration, USA 
FRAX 
Fracture Risk Assessment Tool 
FTC 
Emtricitabine 
Global Safety Intake 
Form  
The sponsor’s collection form used to report serious adverse events (SAE) or other 
events to Global Safety  
GCP 
Good Clinical Practice 
GFR, eGFR 
Glomerular Filtration Rate, estimated GFR 
GGT 
Gamma-glutamyl-transpeptidase 
GI 
Gastrointestinal 
HAART 
Highly  Active Antiretroviral Therapy 
HBsAg 
Hepatitis B surface Antigen  
HBV 
Hepatitis B Virus 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HDL-C 
High Density Lipoprotein - Cholesterol 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HIVAN 
HIV - Associated Nephropathy 
HPLC 
High Performance Liquid Chromatography 
IAS-USA (mutation) 
International AIDS Society 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application; legal instrument in the USA that allows trial of 
unapproved, investigational new drugs in human subjects 
INI 
Integrase Inhibitor 
 
 
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Term 
Definition 
INR 
International Normalized Ratio  
Investigational Product The drug, biologic, and/or device being investigated in the current trial 
IRB 
Institutional Review Board 
IRR 
Incidence Rate Ratio  
IUD 
Intrauterine Device 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
K-M 
Kaplan-Meier 
LDH 
Lactate Dehydrogenase 
LDL-C 
Low-Density Lipoprotein Cholesterol 
LPV/r 
Lopinavir/ritonavir 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities   
mITT, ITT 
Modified ITT, Intention To Treat 
NA, N/A 
Not applicable 
NAG 
N-acetyl-b-D-glucosaminidase 
ND 
Not determined 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitor 
NVP 
Nevirapine 
NRTI 
Nucleoside/ Nucleotide Reverse Transcriptase Inhibitor 
OT 
Observed Treatement  
PCP 
Pneumocystis carinii Pneumonia 
PCR 
Polymerase Chain Reaction 
PDA 
Photo Diode Array 
PDF 
Portable Document Format 
PGt 
Pharmacogenetics 
PGx 
Pharmacogenomics 
pH 
pH (/piː eɪtʃ/ or /piː heɪtʃ/) is a measure of the acidity or basicity of an aqueous solution  
PI, PI/r 
Protease Inhibitor, PI/ritonavir 
PK 
Pharmacokinetics 
PO 
Per Os 
PQC 
Product Quality Complaint 
PT 
Prothrombin test  
PTH 
Parathyroid Hormone 
PTT 
Partial Thromboplastin Time 
QD, q.d. 
quaque die (every day/once daily) 
RAL 
Raltegravir 
 
 
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Term 
Definition 
RBC 
Red Blood Cell 
RBP 
Retinol-Binding Protein 
RNA 
Ribonucleic Acid 
rpm 
revolutions per minute 
RSI 
Reference Safety Information 
RTV 
Ritonavir 
SAE 
Serious Adverse Event 
(S)AE 
All Adverse Events, including Serious Adverse Events 
s-BSAP 
Serum Bone Specific Alkaline Phosphatase  
s-CTx 
C-telopepdides of type I Collagen  
SGOT 
Serum Glutamic Oxaloacetic Transaminase (AST) 
SGPT 
Serum Glutamic Pyruvic Transaminase (ALT) 
SmPC 
Summary of Product Characteristics 
SNP 
Single Nucleotide Polymorphisms  
SOP 
Standard Operating Procedure 
TDF 
Tenofovir Disoproxyl Fumarate 
TID 
Ter in Die (three times a day) 
UDP 
Uridine diphosphatase 
UGT, UGT1A1 
UDP-glucuronosyltransferases; UDP-glucuronosyltransferases 1 (family) polypetdide 
A1 
ULN 
Upper Limit of Normal 
USA 
United States of America 
User ID 
User Identification 
VACS 
Veterans Aging Cohort Study 
WBC 
White Blood Cell 
 
 
 
 
 
 
 
 
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5.0  INTRODUCTION 
5.1 Background and Therapeutic Rationale 
Persistency in treatment and stable virological suppression are main driven factors associated to 
long-term cART efficacy. However a saving toxicity profile of regimen may improve tolerability and 
minimize drug discontinuation. The use of antiretroviral drugs has been associated with a number of 
toxicities, including those affecting the kidney. The kidney plays a major role in the metabolism and 
excretion of antiretroviral drugs and this makes it vulnerable to various types of injuries from some of 
these agents, including acute kidney injury (AKI), tubulopathies, chronic kidney disease (CKD), and 
end-stage renal disease requiring renal replacement therapy. As the population of HIV-infected 
patients ages and remains on HAART for longer periods of time, age-, HIV- and HAART-related 
metabolic disorders are increasingly being encountered by clinicians looking after these patients. HIV 
can cause direct injury to the kidneys as manifested by HIV-associated nephropathy (HIVAN). This 
entity was described before the era of HAART but continues to be a significant problem despite the 
advent of HAART. HAART has also been associated with CKD. The major drugs implicated in this 
include indinavir, atazanavir and tenofovir (1). NRTI-sparing strategies may protect from long-term 
renal and bone toxicity, and boosted PI-sparing regimens may have favorable impact on GI tolerance 
and potential reduction of CVD risk as well as reduce the challenges of drug to drug interactions. 
Preclinical studies with tenofovir identified renal and bone toxicities as potential issues with this agent, 
however, the incidence of nephrotoxicity in the pivotal clinical studies, which excluded subjects with 
low estimated glomerular filtration rate (eGFR), was relatively low. Subsequently, case reports have 
described serious renal toxicity, including acute renal failure requiring dialysis, progressive decline in 
renal function, proximal renal tubular dysfunction, and Fanconi syndrome. Further studies have 
suggested in older age, more advanced HIV-1 infection, lower body mass, impaired renal function, 
and coadministration of protease inhibitors or additional nephrotoxic drugs as possible risk factors for 
tenofovir-associated nephrotoxicity (2). Data from Eurosida cohort implicated concomitant use of ATV 
and TDF with a 41% increased incidence of CKD per year of exposure and a significantly increased 
risk of CKD was implicated also with lopinavir. In a recent study a significantly increased risk of 
developing renal impairment associated with atazanavir and lopinavir independent of exposure to 
tenofovir has also been demonstrated (3). In the PROGRESS study, a pilot study on NRTI-sparing 
regimen, the renal function as estimated by changes from baseline in eGFR showed a greater mean 
decrease for the LPV/r + TDF/FTC group versus the LPV/r + RAL group (4). These findings may 
provide a rationale for the use of a TDF-sparing ART approach given the recent findings from the 
EuroSIDA Study Group. This cohort study of 6,843 HIV-infected persons with a median follow-up 
duration of 3.7 years demonstrated that 3.3% of the cohort progressed to chronic kidney disease 
(CKD) during 21,482 person-years follow-up resulting in an incidence of 1.05 per 100 person-years 
follow-up. After adjusting for traditional factors associated with CKD and confounding factors, 
increasing cumulative exposure to tenofovir with an incidence rate ratio (IRR) per year of 1.16 (95% 
CI: 1.06–1.25, P<0.0001) was associated with a significantly increased rate of CKD (5). The 
improvement of renal function in subjects on the LPV/r + RAL regimen in PROGRESS could be 
related to the absence of tenofovir in that arm, even when LPV/r itself may be associated with a 
worsening of renal function itself (4). The switch to raltegravir-based regimens has been investigated 
in several trials,  with different results. SWITCHMRK 1 and 2 compared substitution of RAL for LPV/r 
with continuation of LPV/r in those with viral suppression on LPV/r-based therapy. A total of 707 
patients were randomized in this multicenter, double-blind, double-dummy trial. Switching to RAL 
resulted in significant improvement in lipid profile (the primary endpoint) but inferior virological efficacy 
compared to continuation of LPV/r therapy (84.4% with VL < 50 copies/ml vs 90.6%, respectively) and 
the studies were terminated. Of note, 84% (27 of 32) of patients with confirmed virological failure in 
the RAL group were on at least their second ART regimen and 66% (18 of 27) reported a history of 
prior virological failure. The SPIRAL study was a similarly designed randomized, multicenter, open-
label trial of 273 patients with HIV RNA < 50 copies/ml (for at least 6 months) on a PI/r-based 
regimen. Switching to RAL was non inferior to continuing PI/r-based treatment at 48 weeks (89.2 vs 
86.6% free of treatment failure, respectively), with an improvement in plasma lipids. Early evidence 
suggests that RAL may have anti-inflammatory properties, and data have shown improvement in 
inflammatory biomarkers and T-cell activation when PI/r are switched to RAL. (6). 
 
 
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A pilot study, Rasta Study (The Raltegravir Switch for Toxicity or Adverse Events) explored the safety 
and efficacy at 48 weeks of a treatment switch to raltegravir associated with tenofovir/emtricitabine or 
abacavir/lamivudine in patients with regimens with optimal virological control. The investigated switch 
strategy was associated with rare virological failure. Improvements in lipid levels, quality of life 
measures, neuropsychological performance, and bone composition suggest good tolerability of 
raltegravir-based regimens. (7) Also a retrospective study in a cohort of 263 HIV-1 infected patients 
attended in routine daily practice with sustained virological suppression confirms that switching to 
raltegravir due to toxicity, convenience or interactions was well-tolerated and secured virological 
suppression in the large majority of patients. (8). Switch to NRTI and PI-sparing regimen with RAL 
plus NVP, considering their renal tolerability, it could be a good therapeutic option for patients with 
risk factors for development of renal alterations. The combination of RAL based regimen to 
Nevirapine may have an additional favorable impact on lipid changes and allow marked viral 
suppression under threshold and control of HIV reservoirs, especially CNS compartment. Indeed, 
NVP has shown during the last years that patients switching from other regimen with undetectable 
viral load did not have a significantly higher risk of hepatotoxicity or rash when stratified by gender 
and CD4 cell count (9-10). More recently these results where strengthened showing a safe lipid 
profile with reduced hepatoxicity in a cohort of 508 patients through 9 years follow-up (11). NRTI and 
PI-sparing regimens may be useful to some HIV-infected patients and raltegravir and nevirapine are 
both potent antiretrovirals with good long-term safety profiles and may allow a durable suppression 
and a sustained improvement in renal function. Raltegravir, the first available INSTI, has 
demonstrated good tolerability over 5 years. Neither of these two antiretrovirals are associated with 
drug-limiting adverse events in the long-term, such as increased cardiovascular risk, lipid elevations, 
renal, bone or central nervous system toxicity. Furthermore, Raltegravir is metabolized primarily via 
uridine diphosfate glucuronosyltransferase (UGT) 1A1, instead of cytochrome P-450; therefore, no 
clinically meaningful drug-to-drug interaction is expected between raltegravir and nevirapine. The low 
genetic barrier of resistance of representatives of these classes could present a limitation to this 
combination, although their use in the setting of long-term virological suppression and good 
adherence might be less of an issue.  Reliquet has published an experience of the use of this 
combination in 39 patients with long-term virological suppression on antiretroviral therapy throughout 
36 months of follow-up, shown that this dual therapy was effective and had acceptable tolerance 
(median values of serum creatinine and lipids significantly improved after switch) and may provide an 
alternative strategy for those unable to tolerate NRTI or PI/r agents. (12).  
Dual therapy based on raltegravir and nevirapine has been also recently proposed as a possible 
switching strategy in selected patients, by different italian groups. 75 patients on RAL and NVP since 
at least 3 months were retrospectively evaluated at 6 Italian HIV clinics. Switch to RAL/NVP regimen 
in patients with long-lasting virological suppression showed to be highly effective over a 2-years 
follow up (failure only in 2.7% of patients and limited to subgroup administered with RAL once-daily 
schedule). No patients discontinued the regimen due to tolerability issues and a significant decrease 
in abnormal triglycerides was reported. (13).  
Lamivudine is an NRTI administered once daily or twice daily with optimal tolerability. Despite a low 
genetic barrier to resistance, the rapid development of the M184V mutation, conferring a high level of 
lamivudine resistance in vitro, has been associated with slower development or prevention of 
thymidine analogue mutations and increased susceptibility to tenofovir, zidovudine and other NRTIs. 
(14).  
On these bases, a combination of raltegravir, nevirapine and lamivudine could be a suitable option for 
treatment simplification in stable suppressed patients. 
5.2   Subject Population Rationale 
The risk of experiencing CKD/ESRD/renal death is high only in patients with baseline eGFR ≤ 60 
mL/min. The EuroSIDA study on 18295 HIV-positive patients reported that during a median follow-up 
period of 5.0 years, 58 persons  experienced advanced CKD/ESRD/renal death. The median baseline 
eGFR in those with and without advanced CKD/ESRD/renal death was 59 and 98 mL/min, 
 
 
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respectively (p < 0.0001). Of those experiencing the endpoint, 51.7% had a baseline eGFR ≤ 60 
mL/min compared with 3.2% of those not experiencing the endpoint. At 6 years after baseline, 0.83% 
were estimated to have experienced advanced CKD/ESRD/ renal death; in those with baseline eGFR 
≤ 60 mL/min this was 11.26%, with much lower proportions in the eGFR 61–90 and > 90 mL/min 
groups (15).  
The italian guidelines recommend that in patients treated with regimens including tenofovir, especially 
if associated with PI/r, physicians should reevaluate ongoing therapy only if the glomerular filtration 
rate is <60 mL/min or in the case of rapid decline of the same, taking into account the incomplete 
reversibility of the damage once instituted. No other recommendations are made for patients treated 
with TDF + PI/r with eGFR 61–90 mL/min, therefore these patients can continue on the current 
regimen (16)  
In case of progressive impairment of renal function (measured by eGFR-MDRD 6 variables), the 
recommendations indicated in the TDF/FTC's IMP should be followed. 
So according to these considerations HIV-infected patients without a history of virological failure, with 
stable suppressed HIV-1 RNA at < 50 copies/mL from at least 12 months and with a current stable 
ARV regimen based on TDF/FTC + PI/r (LPV/r, ATV/r, DAR/r)  from at least 6 months will be enrolled 
No previous exposure to NNRTI or INI drug-classes and no previous intolerance to Lamivudine will be 
allowed, with a GFR estimated with MDRD formula with 6 variables between 60 and 90 mL/min/1.73 
m2 at baseline. This study is considered a pilot switch study with a comparator used as internal 
control without the aim to compare the two treatment groups. 
The rationale of this study is to evaluate the feasibility of the experimental combination based on 
Raltegravir + Nevirapine + Lamivudine in virological suppressed patients, since the data in the clinical 
setting under this therapeutic approach are limited.  
The hypothesis is that patients, stable suppressed, without any virological failure, switching to a 
regimen containing Raltegravir 400 mg BID + Lamivudine 150 mg BID + Nevirapine 200 mg QD for 
14 days followed by 200 mg BID, will have an improvement in renal safety from the baseline (> or 
equal to 15 ml/min is expected)., 
5.3  Dose and Administration Rationale 
Patients in Regimen A switch to a regimen containing Raltegravir 400 mg BID (PO without regard to 
food) + Lamivudine 150 mg BID (PO without regard to food) + Nevirapine 200 mg QD for 14 days 
followed by 200 mg BID (PO without regard to food). All the drugs of the investigational arm are 
marketed in Italy and doses used correspond to the current approved dosing for regulatory purpose. 
According to the label indication of nevirapine into the IMP the lead-in period for nevirapine is 
mandatory (200 mg tablet daily for 14 days, followed by one 200 mg tablet twice daily). 
Patients in Regimen B continue with the current regimen containing PI/r (LPV/r, ATV/r, DAR/r) + 
TDF/FTC. All the drugs of the non investigational arm are marketed in Italy and doses used 
correspond to the current approved dosing for regulatory purpose. 
 
6.0  TRIAL OBJECTIVES 
6.1 Primary Trial Objectives 
To assess the changes in renal function (e.g. estimated GFR measured by MDRD formula with 6 
variables that is MDRD 4 variables plus blood urea nitrogen and albumin) from baseline to 48 weeks.   
 
 
 
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6.2 Secondary Trial Objectives 
 
a) To assess the efficacy (stable suppressed HIV-RNA <50 copies/ml) after switch from PI/r 
(LPV/r, ATV/r, DR/r) + TDF/FTC to RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 
50 copies/mL in the previous 12 months during 48 and 96 weeks of treatment. 
b) To evaluate the changes in T-lymphocyte CD4 cell count during 48 and 96 weeks of 
treatment 
c) To assess laboratory alterations (liver enzymes, lipid profile) after switch from PI/r (LPV/r, 
ATV/r, DAR/r) + TDF/FTC to RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 50 
copies/mL in the previous 12 months during 48 and 96 weeks of treatment. 
d) To assess the safety (e.g. skin rash, GI disturbances) after switch from PI/r+ TDF/FTC to 
RAL + NVP + 3TC in patients with a stable HIV-1 RNA < 50 copies/mL in the previous 12 
months during 48 and 96 weeks of treatment. 
e) To assess the alterations of the tubular kidney injury markers: b2-microglobulin (b2M) and 
retinol-binding protein (RBP) and N-acetyl-b-D-glucosaminidase (NAG) during 48 and 96 
weeks of treatment. 
f) To assess metabolic bone markers changes: Serum Bone Specific Alkaline Phosphatase (s-
BSAP), C-telopepdides of type I Collagen (s-CTx) during 48 and 96 weeks of treatment. 
g) To assess bone mineral density modifications during 48 and 96 weeks of treatment. 
h) To evaluate pharmacokinetics of RAL and NVP. 
i) To assess the development of genotypic resistance at virologic failure  
j) To evaluate the adherence during 48 and 96 weeks of treatment. 
k) To assess the Fracture Risk (FRAX® score in persons > 40 years) during 48 and 96 weeks of 
treatment 
l) To assess the VACS Risk Index during 48 and 96 weeks of treatment 
m) The frequency of experiencing a decline of renal function in HIV-infected patients with an 
eGFR (MDRD-6 variables) < 60 mL/ min/1.73 m2 at 48 weeks of treatment 
n) To evaluate the changes in eGFR-MDRD at 96 weeks of treatment 
 
 
7.0 INVESTIGATIONAL AND ANALYSIS PLAN 
7.1 
Overall Trial Design 
This is a pilot multicenter randomized, open-label, active-controlled, parallel-group, in patients with 
persistently (previous 12 months) suppressed plasma HIV viremia (< 50 copies/mL) after switch from 
PI/r plus TDF/FTC to a combination of Raltegravir 400 mg BID, plus 3TC 150 mg BID plus Nevirapine 
200 mg BID. This study is a pilot switch study with a comparator used as internal control. No 
comparisons will be made between the groups. This study is designed as an estimation study only 
and no formal comparison between the two regimens is planned. The control arm will be not directly 
compared with the experimental arms and will act as a check to assess the internal validity of the 
study. 
7.2 
Beginning and End of the Trial 
Each subject is considered to be enrolled in the trial when the subject (or the subject’s legal 
representative) has provided written informed consent. 
Each subject is considered to have ended participation in the trial when he/she has completed the 
last protocol-specified contact (e.g.,, visits or telephone contacts) or prematurely discontinues from 
the trial. 
 
 
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A subject is considered to have been a completer of the trial after he/she has completed all of the 
protocol-specified visits and activities. 
A subject is considered to have discontinued after he/she has withdrawn consent or has been 
discontinued under the conditions specified in Section 7.3.3. 
A subject is considered to have been lost to follow-up if he/she is unable to be contacted by the 
investigator.  The end of participation for a subject lost to follow-up is the last known contact (e.g., 
visit or telephone contact). 
The overall trial begins when the first subject is enrolled (i.e., signs the informed consent form).  The 
overall trial ends when the last remaining subject has ended participation in the trial, by completing 
the trial, being discontinued from the trial, or being lost to follow-up. 
Each subject will be monitored for the occurrence of any AEs immediately after the subject has 
signed informed consent and until the last protocol specified visit (14 days post therapy follow-up) or 
discontinued the study.  
Adverse events that are to be reported in the pre-randomization phase are limited to: 
– 
Events that cause the subject to be excluded from the trial 
– 
Events that are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Follow-up procedures related to pregnancy or SAEs may continue beyond the end of the clinical trial. 
Once a subject has ended participation in the trial, the investigational product from the trial will no 
longer be available to the subject and any future care will be provided according to the subject's 
clinical site. 
Each subject will participate in the trial for approximately 104 weeks, from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified contact.  After a screening 
phase of 6 weeks, each subject will receive assigned treatment (Section 7.4.1.1) for approximately 
96 weeks and will be followed for 2 additional weeks post therapy.  
7.3 
Trial Population 
HIV-infected adult subjects with stable suppressed HIV-1 RNA (< 50 copies/mL) from at least 12 
months prior to the screening visit and with a current stable ARV regimen from at least 6 months (PI/r 
+ TDF/FTC) and GFR measured by MDRD formula between 60 and 90 mL/min/1.73 m2 will be 
selected to participate in the trial. 
7.3.1 
Subject Inclusion Criteria 
A subject must meet all the criteria listed below to participate in the trial. 
1. Each subject must be willing and able to provide written informed consent for the trial 
2. Each subject must be  18 years of age 
3. Each subject must be male or non-pregnant, non-breastfeeding female 
4. Each subject must have diagnosis of HIV infection   
5. Each subject must have no history of previous virological failure (defined as 2 consecutive 
plasma HIV-1 RNA >200 copies/mL at least two week apart while on previous or current ARV 
therapy)   
 
 
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6. Each subject must have no history of previous exposure to NNRTIs or INIs prior to entering the 
study 
7. Each subject must have no history of previous intolerance to Lamivudine 
8. Each subject must have at least 2 documented plasma HIV-1 RNA <50 copies/mL and no HIV-1 
RNA > 50 copies/mL in the 12 months prior to the screening visit 
9. Each subject must be taking the same PI/r (LPV/r, ATV/r, DAR/r) + TDF/FTC based ARV 
combination for at least 6 months before screening 
10. Each subject mustn't have major IAS-USA mutations on genotypic testing performed before 
starting ARV treatment (genotype testing done before starting the first line therapy)  
11. Each subject must have results of clinical laboratory tests (CBC, blood chemistries, and 
urinalysis) within normal limits or clinically acceptable to the investigator 
12. Each subject must have results of a physical examination, including blood pressure, within 
normal limits or clinically acceptable limits to the investigator 
13. Each subject must be able to adhere to dose and visit schedules 
14. Each subject should have Creatinine Clearance between 60 and 90 mL/min/1.73 m2 calculated 
according to MDRD 6 variables  
15.  Each sexually active subject and subject's partner(s) of child-bearing potential must agree to 
use each a medically acceptable method of contraception 2 weeks prior to Day 1 and at least 6 
months after last dose of study drug 
Medically accepted methods of contraception include condoms (male or female) with or without a 
spermicidal agent, diaphragm or cervical cap with spermicide, medically prescribed IUD, inert or 
copper-containing IUD, hormone-releasing IUD, systemic hormonal contraceptive, and surgical 
sterilization (e.g., hysterectomy or tubal ligation). 
Postmenopausal women are not required to use contraception.  Postmenopausal is defined as at 
least 12 consecutive months without a spontaneous menstrual period. 
Each sexually active male subject with a female partner(s) of child-bearing potential must also 
provide written informed consent to provide information regarding any pregnancy. 
 
7.3.2 
Subject Exclusion Criteria 
A subject meeting any of the exclusion criteria listed below must be excluded from participating in the 
trial: 
1 
The subject has HBsAg+ or anticipated need for HCV-treatment  
2 
The subject has grade 2-4 laboratory abnormality of liver transaminases (ALT and AST) 
3 
The subject has experiencing liver cirrhosis 
4 
The subject has history of diabetes mellitus (defined as initiation of antidiabetic treatment or 
verification of diabetes in a case report form) 
5 
The subject has any cancer (excluding stable Kaposi Sarcoma) 
6 
The subject has an allergy/sensitivity to investigational product or its/their excipients 
7 
The female subject is nursing 
8 
The female subject is pregnant or intending to become pregnant 
9 
The subject has any clinically significant condition or situation, other than the condition being 
studied that, in the opinion of the investigator, would interfere with the trial evaluations or 
optimal participation in the trial. The subject in the opinion of the investigator has an 
excessive intake of alcohol and substances 
10 The subject has active AIDS-defining event (CDC-C), exception for stable Kaposi Sarcoma, 
HIV Wasting Syndrome 
11 The subject has used any investigational drugs within 30 days of screening 
 
 
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12 A subject who has participated in any other clinical trial within 30 days, inclusive, of signing 
the informed consent form of the current trial 
13 The subject or a family member is among the personnel of the investigational or sponsor staff 
directly involved with this trial 
 
 
7.3.3 
Subject Discontinuation Criteria 
A subject may discontinue from the clinical trial at any time for any reason. 
It is the right and the duty of the investigator or subinvestigator to stop treatment in any case in which 
emerging effects are of unacceptable risk to the individual subject. In addition, the investigator or 
subinvestigator is to stop treatment of any subject with unmanageable factors that may interfere 
significantly with the trial procedures and/or the interpretation of results. If a subject discontinues prior 
to completion of the study, the reason for the discontinuation will be obtained. The date of the last 
dose of study medication and the date of the last assessment and/or contact will be obtained. This 
information will be documented in the appropriate section of the case report form (CRF). A follow-up 
contact (telephone or visit) will be arranged as appropriate. At the time of discontinuation, every effort 
should be made to ensure that all procedures and evaluations scheduled for the final treatment visit 
are performed. For all discontinued subjects, AEs should be recorded and medication compliance 
should be assessed.  
 
Discontinuation from treatment is “permanent”: once a subject is discontinued, he/she shall not be 
allowed to enroll again. 
At a minimum collect the following information when a subject discontinues: 
1. The reason the subject discontinued 
2. The date of the last dose of test products from the trial 
3. The date of the last assessment and/or contact.  A follow-up contact (telephone or visit) will be 
arranged as appropriate; 
4. Serious and non serious adverse events; 
5. Compliance with the test product administration as specified in this protocol; 
6. Final Assessments: 
Every effort should be made to ensure that all procedures and evaluations scheduled for the 
final trial visit are performed (Section 2.2, Trial Flow Chart) 
7. Retrieve all IMPs from the subject. 
 
A subject must be discontinued from the trial for any of the following reasons: 
1. The subject or legal representative (such as a parent or legal guardian) withdraws consent; 
2. Any patient who becomes pregnant during the course of the study must immediately be 
discontinued from all study medication. All pregnancies must be reported immediately to the 
SPONSOR and must be followed to the completion/termination of the pregnancy. The outcome 
of all pregnancies must be reported to the SPONSOR. Patients who become pregnant will be 
asked to join a pregnancy registry which collects information about the outcome of the 
pregnancy.  
 
 
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3. Patients who are compliant to therapy and who have virologic relapse, defined as: HIV RNA > 
50 copies/mL (on 2 consecutive measurements at least 1 week apart.) 
4. The subject requires any study drug dose and administration modifications. 
5. Any other severe organ dysfunction/impairment treatment related and that require switching 
6. In case of continuous deterioration of renal function (measured by eGFR-MDRD 6 variables), 
especially in patients assigned to continue baseline therapy (PI and TDF containing regimen) if 
creatinine clearance < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l). 
7. Subject requires use of a prohibited medication (see Section 7.4.2.1.1). 
8. Subject experiences a severe toxicity due to nevirapine (see Section 7.7.2.3.2). 
 
 
7.3.4 
Replacement of Subjects 
A subject who discontinues from the trial will not be replaced. 
 
7.4 
Treatments 
7.4.1 Trial Treatments 
7.4.1.1 Treatments Administered in the Experimental arm (Investigational Product, Dose, 
mode of Administration) - Regimen A 
 
Raltegravir 400 mg tab., 400 mg b.i.d. PO plus Nevirapine 200 mg tab.,  200 mg QD for 14 
days followed by 200 mg b.i.d. PO plus Lamivudine 150 mg tab., 150 mg b.i.d. PO 
(The choice to use nevirapine and lamivudine BID is to propose a symmetric therapy since 
Raltegravir should be administered twice) 
 
7.4.1.2 Treatments Administered in the Non Experimental arm/control arm (Product, Dose, 
mode of Administration) - Regimen B 
 
Tenofovir Disoproxil Fumarate/Emtricitabine 300/200 mg tab., 300/200 mg q.d. PO plus 
Lopinavir/ritonavir  200/50 mg tab., 400/100 mg b.i.d., PO or 800 mg/200 mg q.d. PO 
or 
 
Tenofovir Disoproxil Fumarate/Emtricitabine 300/200 mg tab., 300/200 mg q.d. PO plus 
Atazanavir + Ritonavir  300 mg + 100 mg tab., 300 mg + 100 mg q.d., PO 
or 
 
Tenofovir Disoproxil Fumarate/Emtricitabine 300/200 mg tab., 300/200 mg q.d. PO plus 
Darunavir + Ritonavir 400 mg + 100 mg tab., 800 mg + 100 mg q.d., PO or 600 mg + 100 
mg tab., 600 mg + 100 mg b.i.d. PO  
 
 
 
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7.4.1.3 Method of Treatment Assignment, Randomization, and/or Stratification 
For identification purposes during the screening period (Visit 1 – Screening) , each eligible patient will 
be sequentially assigned by eCRF to a unique identification screening number with the format XXX-S-
YYY, where “XXX” is the site number, “S” stands for  “Screening” and “YYY” is the progressive patient 
number within each site.  If a subject discontinues from the study, the subject number will not be re-
used, and the subject will not be allowed to re-enter the study. The screening failure patients will be 
registered in the eCRF collecting only the demographic data and the reason for screening failure.  
The subjects must meet all the inclusion criteria and none of the exclusion criteria to receive 
treatment assignment. All drugs will be dispensed to all subjects in an open-label manner. At Visit 2 
(Baseline), patients meeting all the inclusion criteria and none of the exclusion criteria will be 
randomized in a 1:1 ratio, via e-CRF, to one of the following two treatment groups:   
• 
Regimen A: switching to a regimen containing Raltegravir 400 mg BID PO+ Lamivudine 150 
BID PO, + Nevirapine 200 mg QD for 14 days followed by 200 mg BID PO  
• 
Regimen B: continue with the current regimen containing PI/r (LPV/r, ATV/r, DAR/r) + 
TDF/FTC 
The principal investigator will receive a notification via the e-CRF assigning the treatment group 
(“REGIMEN A” or  “REGIMEN B”) and the randomization number to the patients.   Each randomized 
patient, will be sequentially assigned to a unique 3-digits randomization number (starting from 001 up 
to 100). It is the responsibility of the Investigator (or designee) to explain, and make sure patient fully 
understands any appropriate treatment related information. Before dispensing the treatment kit to the 
patient, the investigator must report on the label the site number, the Investigator name, the 
randomization number and the treatment group assigned.  
The randomization list will be generated using PROC PLAN procedure (SAS® System version 9.2). 
No stratification factors based on age, sex, or other patient characteristics will be performed.  
Recruitment will be competitive among the study sites, until the planned number of patients is 
enrolled.  Competitive recruitment has been chosen to increase the speed of recruitment. 
 
Treatment should be started as close as possible to the date in which randomized treatment is 
assigned, preferably on the same day. 
7.4.1.4 Selection and Timing of Dose for Each Subject 
7.4.1.3.1. 
Selecting the Dose for Each Subject 
The rationale for the selection of doses to be used in this trial is presented in Section 5.3. 
7.4.1.3.2. 
Determining the Timing of Dose Administration for Each Subject 
• Regimen A: Switching to a regimen containing Raltegravir 400 mg BID PO+ Lamivudine 150 BID 
PO + Nevirapine 200 mg QD for 14 days followed by 200 mg BID  PO  
• Regimen B (control arm): continue with the current regimen containing PI/r (LPV/r, ATV/r, 
DAR/r) PO + TDF/FTC 300 mg/200 mg QD PO. 
 
 
 
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7.4.1.5 Blinding Trial Treatments 
All drugs will be dispensed to all subjects in an open-label manner. 
7.4.1.6 Investigational Medicinal Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, handling, storage, distribution, and usage of these materials in 
accordance with the protocol and any applicable laws and regulations. 
7.4.1.6.1 
Identity of Investigational Medicinal Product(s) 
• 
Raltegravir 400 mg 
• 
Nevirapine 200 mg 
• 
Lamivudine 150 mg 
7.4.1.6.2 
Source 
MSD will provide all supplies as follows:  
• 
Raltegravir 400 mg film-coated tablets 
• 
Nevirapine  200 mg tablets 
• 
Lamivudine 150 mg film-coated tablets 
All the above listed supplies will be locally sourced. 
For this study MSD will provide the branded drugs of Nevirapine - Viramune® - and Lamivudine - 
Epivir® - . No generic forms of 3TC and NVP will be provided. 
7.4.1.6.3 
Labeling 
Raltegravir, Lamivudine and Nevirapine, will be provided open label with commercial labels. A 
secondary label specifying study number, Labeling Request number, investigational use statement, 
appropriate caution statement, instructions to take as directed and Sponsor details will be applied. 
Secondary label will also contain a space for the subject number, site number and investigator name 
that will be written in at the study center.   
7.4.1.6.4 
Packaging 
Raltegravir 400 mg tablets will be supplied as single bottles with child-resistant closure containing 60 
tablets or multi-pack containing 3 bottles of 60 tablets, depending on country availability. 
Nevirapine 200 mg tablets will be supplied as cartons containing 6 or 12 blister cards (60 or 120 
tablets), depending on country availability. 
Lamivudine 150 mg tablets will be supplied as bottles with child resistant closure or blister packs each 
containing 60 tablets, depending on country availability. 
 
 
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7.4.1.6.5 
Storage 
Trial treatment supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the supply label.  Site storage conditions should be monitored by the site 
personnel for adherence to label specifications and reviewed during site visits. 
7.4.1.6.6 
Dispensing 
The investigator or qualified designee(s) will dispense trial treatments at the designated site(s) to 
subjects who have provided written informed consent and have met the entry criteria.  Clinical 
supplies may not be used for any purpose other than that which is stated in this protocol. 
See the Trial Flow Chart in Section 2.2 for a schedule of when clinical supplies are to be dispensed 
to the subjects. 
Subjects should be dispensed a quantity of drugs that will allow them to have an adequate supply 
until their next visit plus one week extra supply in case their visit is delayed. 
The principal investigator agrees neither to dispense study drugs from nor store them at any site(s) 
other than the study site(s). The principal investigator agrees that study drugs will be dispensed by 
the site’s designee. The principal investigator and site personnel also agree that study drugs will be 
dispensed only to study subjects who have provided written informed consent and have met all entry 
criteria. Study drugs may not be used for any purpose other than that stated in the protocol. Study 
drugs should be dispensed as appropriate based on the subject’s treatment visit schedule.  
7.4.1.6.7 
Replacement of Investigational Product 
Lost or damaged supplies of Raltegravir, Nevirapine and Lamivudine will be replaced by the study center 
as needed.  
7.4.1.6.8 
Investigational Medicinal Product Accountability 
Accurate and current accounting of the dispensing and return of investigational product(s) will be 
maintained on an ongoing basis by a member of the trial site staff: 
• Investigational medicinal product(s) dispensed to each site will be recorded in the trial-specific 
Site Investigational Medicinal Product (IMP) Accountability Log (or equivalent document approved 
by the sponsor); 
• Investigational medicinal product(s) dispensed to each subject will be recorded in the trial-specific 
Subject IMP Accountability Log (or equivalent document approved by the sponsor). 
 
The Site IMP Accountability Log and Subject IMP Accountability Log will be verified by the sponsor's 
trial monitor or sponsor’s designee. The original Site IMP Accountability Log and Subject IMP 
Accountability Log will be approved by the investigator and retained at the trial site and a copy 
supplied to the sponsor or designee when the trial is complete. 
Each subject will be instructed by the investigator or designee to return all unused and partially used 
IMPs to the site at all protocol-specified visits. In the event the investigational product destruction is 
arranged by the site (only under instructions from the sponsor), copies of the destruction records 
should be returned to the sponsor. The sponsor’s trial monitor or its designee will instruct the site on 
the return of all investigational product(s) supplies.  A final inventory of the total amount of 
investigational product(s) received at each trial site against the amount used and returned must be 
 
 
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recorded in the Site IMP Accountability Log.  Inventory records must be readily available for 
inspection by the trial monitor and/or auditor, and open to government inspection at any time. 
 
 7.4.2 Non-Trial Treatments 
  7.4.2.1 Prior and Concomitant Medications 
    7.4.2.1.1 Medications, Supplements, and Other Substances Prohibited Prior to Baseline and 
During the Trial 
The prohibited Substances are listed in the drug-drug interactions section into the drugs SmPC.. It is 
responsibility of the investigator to check on potential drug-drug interactions, before placing a patient 
on a specific therapy. 
The list of drug-drug interactions for each drug reported below is referring to the SmPC in force at the 
time of finalization of Amendment 03. For any future updates to the SmPC it is the responsibility of 
the investigator to check on potential drug-drug interactions, before placing a patient on a specific 
therapy. 
The drug-drug interaction profiles of the experimental IMP are: 
 
Raltegravir 
In vitro studies indicate that raltegravir is not a substrate of cytochrome P450 (CYP) enzymes, does 
not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A, does not induce 
CYP3A4 and does not inhibit P glycoprotein mediated transport. Based on these data, raltegravir is 
not expected to affect the pharmacokinetics of medicinal products that are substrates of these 
enzymes or P-glycoprotein. Based on in vitro and in vivo studies, raltegravir is eliminated mainly by 
metabolism via a UGT1A1-mediated glucuronidation pathway. Although in vitro studies indicated that 
raltegravir is not an inhibitor of the UDP glucuronosyltransferases (UGTs) 1A1 and 2B7, one clinical 
study has suggested that some inhibition of UGT1A1 may occur in vivo based on effects observed on 
bilirubin glucuronidation. However, the magnitude of the effect seems unlikely to result in clinically 
important drug drug interactions. Considerable inter- and intra-individual variability was observed in 
the pharmacokinetics of raltegravir. The following drug interaction information is based on Geometric 
Mean values; the effect for an individual patient cannot be predicted precisely.  
In interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of 
etravirine, maraviroc, tenofovir, hormonal contraceptives, methadone, or midazolam.  
Given that raltegravir is metabolised primarily via UGT1A1, caution should be used when co 
administering raltegravir with strong inducers of UGT1A1 (e.g., rifampicin). Rifampicin reduces 
plasma levels of raltegravir; the impact on the efficacy of raltegravir is unknown. However, if co 
administration with rifampicin is unavoidable, a doubling of the dose ofraltegravir can be considered. 
The impact of other strong inducers of drug metabolizing enzymes, such as phenytoin and 
phenobarbital, on UGT1A1 is unknown. Less potent inducers (e.g., efavirenz, nevirapine, etravirine, 
rifabutin, glucocorticoids, St. John's wort, pioglitazone) may be used with the recommended dose of 
raltegravir. 
Co administration of raltegravir with medicinal products that are known to be potent UGT1A1 
inhibitors (e.g., atazanavir) may increase plasma levels of raltegravir. Less potent UGT1A1 inhibitors 
(e.g., indinavir, saquinavir) may also increase plasma levels of raltegravir, but to a lesser extent 
compared with atazanavir. In addition, tenofovir may increase plasma levels of raltegravir, however, 
the mechanism for this effect is unknown (see Table 1). From the clinical trials, a large proportion of 
patients used atazanavir and / or tenofovir, both agents that result in increases in raltegravir plasma 
levels, in the optimised background regimens. The safety profile observed in patients who used 
 
 
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atazanavir and / or tenofovir was generally similar to the safety profile of patients who did not use 
these agents. Therefore no dose adjustment is required. In healthy subjects, co administration of 
raltegravir with omeprazole increases raltegravir plasma levels. As the effects of increasing gastric pH 
on the absorption of raltegravir in HIV-infected patients are uncertain, use raltegravir with medicinal 
products that increase gastric pH (e.g., proton pump inhibitors and H2 antagonists) only if 
unavoidable. 
In the pharmacokinetic Interaction Data table are listed the recommendations concerning the co-
administration of raltegravir with the others drugs and the drugs contraindicated with raltegravir and 
not allowed during the study. 
 
Pharmacokinetic Interaction Data 
 
Medicinal products by therapeutic 
area 
Interaction 
(mechanism, if known) 
Recommendations 
concerning 
co-administration 
ANTI-RETROVIRAL 
Protease inhibitors (PI) 
atazanavir /ritonavir 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  41 % 
raltegravir C12hr  77 % 
raltegravir Cmax  24 % 
(UGT1A1 inhibition) 
No dose adjustment required 
for ISENTRESS. 
tipranavir /ritonavir 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  24 % 
raltegravir C12hr  55 % 
raltegravir Cmax  18 % 
(UGT1A1 induction) 
No dose adjustment required 
for ISENTRESS. 
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 
efavirenz 
(raltegravir 400 mg Single Dose) 
raltegravir AUC  36 % 
raltegravir C12hr  21 % 
raltegravir Cmax  36 % 
(UGT1A1 induction) 
No dose adjustment required 
for ISENTRESS. 
etravirine 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  10 % 
raltegravir C12hr  34 % 
raltegravir Cmax  11 % 
(UGT1A1 induction) 
etravirine AUC  10 % 
etravirine C12hr  17 % 
etravirine Cmax  4 % 
No dose adjustment required 
for ISENTRESS or etravirine. 
Nucleoside/tide reverse transcriptase inhibitors 
 
 
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tenofovir 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  49 % 
raltegravir C12hr  3 % 
raltegravir Cmax ↑ 64 % 
(mechanism of interaction 
unknown) 
tenofovir AUC  10 % 
tenofovir C24hr  13 % 
tenofovir Cmax ↓ 23 % 
No dose adjustment required 
for ISENTRESS or tenofovir 
disoproxil fumarate. 
CCR5 inhibitors 
maraviroc 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  37 % 
raltegravir C12hr  28 % 
raltegravir Cmax  33 % 
(mechanism of interaction 
unknown) 
maraviroc AUC  14 % 
maraviroc C12hr  10 % 
maraviroc Cmax ↓ 21 % 
No dose adjustment required 
for ISENTRESS or maraviroc. 
HCV ANTIVIRALS 
NS3/4A protease inhibitors (PI) 
boceprevir 
(raltegravir 400 mg Single Dose) 
raltegravir AUC  4 % 
raltegravir C12hr  25 % 
raltegravir Cmax  11 % 
(mechanism of interaction 
unknown) 
No dose adjustment required 
for ISENTRESS or boceprevir. 
ANTIMICROBIALS 
Antimycobacterial 
rifampicin 
(raltegravir 400 mg Single Dose) 
raltegravir AUC  40 % 
raltegravir C12hr  61 % 
raltegravir Cmax  38 % 
(UGT1A1 induction) 
Rifampicin reduces plasma 
levels of ISENTRESS. If 
co-administration with 
rifampicin is unavoidable, a 
doubling of the dose of 
ISENTRESS can be considered 
(see section 4.4). 
 
NOTE: Doubling of the 
raltegravir dose is not permitted 
in P284.  Patients who require 
use of rifampicin will need to be 
discontinued from the study. 
SEDATIVE 
 
 
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midazolam 
(raltegravir 400 mg Twice Daily) 
midazolam AUC  8 % 
midazolam Cmax ↑ 3 % 
No dosage adjustment required 
for ISENTRESS or midazolam. 
These results indicate that 
raltegravir is not an inducer or 
inhibitor of CYP3A4, and 
raltegravir is thus not 
anticipated to affect the 
pharmacokinetics of medicinal 
products which are CYP3A4 
substrates. 
METAL CATION ANTACIDS 
aluminium and magnesium 
hydroxide antacid 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  49 % 
raltegravir C12 hr  63 % 
raltegravir Cmax  44 % 
2 hours before raltegravir 
raltegravir AUC  51 % 
raltegravir C12 hr  56 % 
raltegravir Cmax  51 % 
2 hours after raltegravir 
raltegravir AUC  30 % 
raltegravir C12 hr  57 % 
raltegravir Cmax  24 % 
6 hours before raltegravir 
raltegravir AUC  13 % 
raltegravir C12 hr  50 % 
raltegravir Cmax  10 % 
6 hours after raltegravir 
raltegravir AUC  11 % 
raltegravir C12 hr  49 % 
raltegravir Cmax  10 % 
(chelation of metal cations) 
Aluminium and magnesium 
containing antacids reduce 
raltegravir plasma levels. Co- 
administration of ISENTRESS 
with aluminium and/or 
magnesium containing antacids 
is not recommended. 
calcium carbonate antacid 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC  55 % 
raltegravir C12 hr  32 % 
raltegravir Cmax  52 % 
(chelation of metal cations) 
No dose adjustment required 
for ISENTRESS. 
H2 BLOCKERS AND PROTON PUMP INHIBITORS 
omeprazole 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC ↑ 37 % 
raltegravir C12 hr ↑ 24 % 
raltegravir Cmax ↑ 51 % 
(increased solubility) 
No dose adjustment required 
for ISENTRESS. 
 
 
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famotidine 
(raltegravir 400 mg Twice Daily) 
raltegravir AUC ↑ 44 % 
raltegravir C12 hr ↑ 6 % 
raltegravir Cmax ↑ 60 % 
(increased solubility) 
No dose adjustment required 
for ISENTRESS. 
HORMONAL CONTRACEPTIVES 
Ethinyl Estradiol 
Norelgestromin 
(raltegravir 400 mg Twice Daily) 
Ethinyl Estradiol AUC  2 % 
Ethinyl Estradiol Cmax ↑ 6 % 
Norelgestromin AUC ↑ 14 % 
Norelgestromin Cmax ↑ 29 % 
No dosage adjustment required 
for ISENTRESS or hormonal 
contraceptives (estrogen- 
and/or progesterone-based). 
OPIOID ANALGESICS 
methadone 
(raltegravir 400 mg Twice Daily) 
methadone AUC ↔ 
methadone Cmax ↔ 
No dose adjustment required 
for ISENTRESS or methadone. 
 
(18)  
 
 
Nevirapine 
Nevirapine is an inducer of CYP3A and potentially CYP2B6, with maximal induction occurring within 2-
4 weeks of initiating multiple-dose therapy. Compounds using this metabolic pathway may have 
decreased plasma concentrations when coadministered with nevirapine. Careful monitoring of the 
therapeutic effectiveness of P450 metabolised medicinal products is recommended when taken in 
combination with nevirapine. The absorption of nevirapine is not affected by food, antacids or medicinal 
products which are formulated with an alkaline buffering agent. 
The interaction data is presented as geometric mean value with 90% confidence interval (90% CI) 
whenever these data were available in the below table 2. ND = Not Determined, ↑ = Increased, ↓ = 
Decreased, ↔ = No Effect 
 
Pharmacokinetic Interaction Data 
 
Medicinal products 
by therapeutic areas 
Interaction 
Recommendations concerning co- 
administration 
ANTI-INFECTIVES 
ANTIRETROVIRALS 
NRTIs 
Didanosine 
100-150 mg BID 
Didanosine AUC  1.08 (0.92-1.27) 
Didanosine Cmin ND 
Didanosine Cmax  0.98 (0.79-1.21) 
Didanosine and Viramune can be co- 
administered without dose 
adjustments. 
Emtricitabine 
Emtricitabine is not an inhibitor of 
human CYP 450 enzymes. 
Viramune and emtricitabine may be 
coadministered without dose 
adjustments. 
Abacavir 
In human liver microsomes, abacavir 
did not inhibit cytochrome P450 
isoforms. 
Viramune and abacavir may be 
coadministered without dose 
adjustments. 
 
 
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Lamivudine 
150 mg BID 
No changes to lamivudine apparent 
clearance and volume of distribution, 
suggesting no induction effect of 
nevirapine on lamivudine clearance. 
Lamivudine and Viramune can be co- 
administered without dose 
adjustments. 
Stavudine: 
30/40 mg BID 
Stavudine AUC  0.96 (0.89-1.03) 
Stavudine Cmin ND 
Stavudine and Viramune can be co- 
administered without dose 
 
Stavudine Cmax  0.94 (0.86-1.03) 
Nevirapine: compared to historical 
controls, levels appeared to be 
unchanged. 
adjustments. 
Tenofovir 
300 mg QD 
Tenofovir plasma levels remain 
unchanged when co-administered 
with nevirapine. 
Nevirapine plasma levels were not 
altered by co-administration of 
tenofovir. 
Tenofovir and Viramune can be co- 
administered without dose 
adjustments. 
Zidovudine 
100-200 mg TID 
Zidovudine AUC  0.72 (0.60-0.96) 
Zidovudine Cmin ND 
Zidovudine Cmax  0.70 (0.49-1.04) 
Nevirapine: Zidovudine had no 
effect on its pharmacokinetics. 
Zidovudine and Viramune can be co- 
administered without dose 
adjustments 
Granulocytopenia is commonly 
associated with zidovudine. 
Therefore, patients who receive 
nevirapine and zidovudine 
concomitantly and especially 
paediatric patients and patients who 
receive higher zidovudine doses or 
patients with poor bone marrow 
reserve, in particular those with 
advanced HIV disease, have an 
increased risk of granulocytopenia. In 
such patients haematological 
parameters should be carefully 
monitored. 
NNRTIs 
Efavirenz 
600 mg QD 
Efavirenz AUC  0.72 (0.66-0.86) 
Efavirenz Cmin  0.68 (0.65-0.81) 
Efavirenz Cmax  0.88 (0.77-1.01) 
It is not recommended to co- 
administer efavirenz and Viramune 
(see section 4.4), because of additive 
toxicity and no benefit in terms of 
efficacy over either NNRTI alone (for 
results of 2NN study, see section 5.1). 
 
 
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Delavirdine 
Interaction has not been studied. 
The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4). 
Etravirine 
Concomitant use of etravirine with 
nevirapine may cause a significant 
decrease in the plasma 
concentrations of etravirine and loss 
of therapeutic effect of etravirine. 
The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4). 
Rilpivirine 
Interaction has not been studied. 
The concomitant administration of 
Viramune with NNRTIs is not 
recommended (see section 4.4). 
PIs 
 
Atazanavir/ritonavir 
300/100 mg QD 
400/100 mg QD 
Atazanavir/r 300/100mg: 
Atazanavir/r AUC  0.58 (0.48-0.71) 
Atazanavir/r Cmin  0.28 (0.20-0.40) 
Atazanavir/r Cmax  0.72 (0.60-0.86) 
Atazanavir/r 400/100mg: 
Atazanavir/r AUC  0.81 (0.65-1.02) 
Atazanavir/r Cmin  0.41 (0.27-0.60) 
Atazanavir/r Cmax  1.02 (0.85– 
1.24) 
(compared to 300/100mg without 
nevirapine) 
Nevirapine AUC  1.25 (1.17-1.34) 
Nevirapine Cmin  1.32 (1.22–1.43) 
Nevirapine Cmax  1.17 (1.09-1.25) 
It is not recommended to co- 
administer atazanavir/ritonavir and 
Viramune (see section 4.4). 
Darunavir/ritonavir 
400/100 mg BID 
Darunavir AUC  1.24 (0.97-1.57) 
Darunavir Cmin  1.02 (0.79-1.32) 
Darunavir Cmax  1.40 (1.14-1.73) 
Nevirapine AUC  1.27 (1.12-1.44) 
Nevirapine Cmin  1.47 (1.20-1.82) 
Nevirapine Cmax  1.18 (1.02-1.37) 
Darunavir and Viramune can be co- 
administered without dose 
adjustments. 
 
 
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Fosamprenavir 
1,400 mg BID 
Amprenavir AUC  0.67 (0.55-0.80) 
Amprenavir Cmin  0.65 (0.49-0.85) 
Amprenavir Cmax  0.75 (0.63-0.89) 
Nevirapine AUC  1.29 (1.19-1.40) 
Nevirapine Cmin  1.34 (1.21-1.49) 
Nevirapine Cmax  1.25 (1.14-1.37) 
It is not recommended to co- 
administer fosamprenavir and 
Viramune if fosamprenavir is not co- 
administered with ritonavir (see 
section 4.4). 
Fosamprenavir/ritona 
vir 700/100 mg BID 
Amprenavir AUC  0.89 (0.77- 
1.03) 
Amprenavir Cmin  0.81 (0.69-0.96) 
Amprenavir Cmax  0.97 (0.85-1.10) 
Nevirapine AUC  1.14 (1.05-1.24) 
Nevirapine Cmin  1.22 (1.10-1.35) 
Nevirapine Cmax  1.13 (1.03-1.24) 
Fosamprenavir/ritonavir and 
Viramune can be co-administered 
without dose adjustments 
Lopinavir/ritonavir 
(capsules) 
400/100 mg BID 
Adult patients: 
Lopinavir AUC  0.73 (0.53-0.98) 
Lopinavir Cmin  0.54 (0.28-0.74) 
Lopinavir Cmax  0.81 (0.62-0.95) 
An increase in the dose of 
lopinavir/ritonavir to 533/133 mg (4 
capsules) or 500/125 mg (5 tablets 
with 100/25 mg each) twice daily 
with food is recommended in 
combination with Viramune. Dose 
adjustment of Viramune is not 
required when co-administered with 
lopinavir. 
Lopinavir/ritonavir 
(oral solution) 
300/75 mg/m2 BID 
Paediatric patients: 
-1.09) 
-0.82) 
-1.16) 
For children, increase of the dose of 
lopinavir/ritonavir to 300/75 mg/m2 
twice daily with food should be 
considered when used in 
combination with Viramune, 
particularly for patients in whom 
reduced susceptibility to 
lopinavir/ritonavir is suspected. 
Ritonavir 
600 mg BID 
Ritonavir AUC
-1.07) 
-1.14) 
-1.07) 
 
Nevirapine: Co-administration of 
ritonavir does not lead to any 
clinically relevant change in 
nevirapine plasma levels. 
Ritonavir and Viramune can be co- 
administered without dose 
adjustments. 
 
 
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Saquinavir/ritonavir 
The limited data available with 
saquinavir soft gel capsule boosted 
with ritonavir do not suggest any 
clinically relevant interaction between 
saquinavir boosted with ritonavir and 
nevirapine 
Saquinavir/ritonavir and Viramune 
can be co-administered without dose 
adjustments. 
Tipranavir/ritonavir 
500/200 mg BID 
No specific drug-drug interaction 
study has been performed. 
The limited data available from a 
phase IIa study in HIV-infected 
patients have shown a clinically non 
significant 20% decrease of TPV 
Cmin. 
Tipranavir and Viramune can be co- 
administered without dose 
adjustments. 
ENTRY INHIBITORS 
Enfuvirtide 
Due to the metabolic pathway no 
clinically significant 
pharmacokinetic interactions are 
expected between enfuvirtide and 
nevirapine. 
Enfuvirtide and Viramune can be co- 
administered without dose 
adjustments. 
Maraviroc 
300 mg QD 
Maraviroc AUC  1.01 (0.6 -1.55) 
Maraviroc Cmin ND 
Maraviroc Cmax  1.54 (0.94-2.52) 
compared to historical controls 
Nevirapine concentrations not 
measured, no effect is expected. 
Maraviroc and Viramune can be co- 
administered without dose 
adjustments. 
INTEGRASE INHIBITORS 
Elvitegravir/ 
cobicistat 
Interaction has not been studied. 
Cobicistat, a cytochrome P450 3A 
inhibitor significantly inhibits 
hepatic enzymes, as well as other 
metabolic pathways. Therefore 
coadministration would likely result 
Coadministration of Viramune with 
elvitegravir in combination with 
cobicistat is not recommended (see 
section 4.4). 
 
in altered plasma levels of cobicistat 
and Viramune. 
Raltegravir 
400 mg BID 
No clinical data available. Due to the 
metabolic pathway of raltegravir no 
interaction is expected. 
Raltegravir and Viramune can be co- 
administered without dose 
adjustments. 
 
 
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ANTIBIOTICS 
Clarithromycin 
500 mg BID 
Clarithromycin AUC  0.69 (0.62- 
0.76) 
Clarithromycin Cmin  0.44 (0.30- 
0.64) 
Clarithromycin Cmax  0.77 (0.69- 
0.86) 
Metabolite 14-OH clarithromycin 
AUC  1.42 (1.16-1.73) 
Metabolite 14-OH clarithromycin 
Cmin  0 (0.68-1.49) 
Metabolite 14-OH clarithromycin 
Cmax  1.47 (1.21-1.80) 
Nevirapine AUC  1.26 
Nevirapine Cmin  1.28 
Nevirapine Cmax  1.24 
compared to historical controls. 
Clarithromycin exposure was 
significantly decreased, 14-OH 
metabolite exposure increased. 
Because the clarithromycin active 
metabolite has reduced activity 
against Mycobacterium avium- 
intracellulare complex overall 
activity against the pathogen may be 
altered. Alternatives to 
clarithromycin, such as azithromycin 
should be considered. Close 
monitoring for hepatic abnormalities 
is recommended 
Rifabutin 
150 or 300 mg QD 
Rifabutin AUC  1.17 (0.98-1.40) 
Rifabutin Cmin  1.07 (0.84-1.37) 
Rifabutin Cmax  1.28 (1.09-1.51) 
Metabolite 25-O-desacetylrifabutin 
AUC  1.24 (0.84-1.84) 
Metabolite 25-O-desacetylrifabutin 
Cmin  1.22 (0.86-1.74) 
Metabolite 25-O-desacetylrifabutin 
Cmax  1.29 (0.98-1.68) 
A clinically not relevant increase in 
the apparent clearance of nevirapine 
(by 9%) compared to historical data 
was reported. 
No significant effect on rifabutin and 
Viramune mean PK parameters is 
seen. Rifabutin and Viramune can be 
co-administered without dose 
adjustments. However, due to the 
high interpatient variability some 
patients may experience large 
increases in rifabutin exposure and 
may be at higher risk for rifabutin 
toxicity. Therefore, caution should be 
used in concomitant administration. 
Rifampicin 
600 mg QD 
Rifampicin AUC  1.11 (0.96-1.28) 
Rifampicin Cmin ND 
Rifampicin Cmax  1.06 (0.91-1.22) 
Nevirapine AUC  0.42 
Nevirapine Cmin  0.32 
Nevirapine Cmax  0.50 
compared to historical controls. 
It is not recommended to co- 
administer rifampicin and Viramune 
(see section 4.4). Physicians needing 
to treat patients co-infected with 
tuberculosis and using a Viramune 
containing regimen may consider co- 
administration of rifabutin instead. 
ANTIFUNGALS 
Fluconazole 
Fluconazole AUC  0.94 (0.88- 
Because of the risk of increased 
 
 
 
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200 mg QD 
1.01) 
Fluconazole Cmin  0.93 (0.86-1.01) 
Fluconazole Cmax  0.92 (0.85-0.99) 
Nevirapine: exposure: 100% 
compared with historical data where 
nevirapine was administered alone. 
exposure to Viramune, caution should 
be exercised if the medicinal products 
are given concomitantly and patients 
should be monitored closely. 
Itraconazole 
200 mg QD 
Itraconazole AUC  0.39 
Itraconazole Cmin  0.13 
Itraconazole Cmax  0.62 
Nevirapine: there was no significant 
difference in nevirapine 
pharmacokinetic parameters. 
A dose increase for itraconazole 
should be considered when these two 
agents are administered 
concomitantly. 
Ketoconazole 
400 mg QD 
Ketoconazole AUC  0.28 (0.20- 
0.40) 
Ketoconazole Cmin ND 
Ketoconazole Cmax  0.56 (0.42- 
0.73) 
Nevirapine: plasma levels:  1.15- 
1.28 compared to historical controls. 
It is not recommended to co- 
administer ketoconazole and 
Viramune (see section 4.4). 
ANTIVIRALS FOR CHRONIC HEPATITIS B AND C 
Adefovir 
Results of in vitro studies showed  a 
weak antagonism of nevirapine by 
adefovir (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Adefovir did not influence any of the 
common CYP isoforms known to be 
involved in human drug metabolism 
and is excreted renally. No clinically 
relevant drug-drug interaction is 
expected. 
Adefovir and Viramune may be 
coadministered without dose 
adjustments. 
 
 
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Boceprevir 
Boceprevir is partly metabolized by 
CYP3A4/5. Co-administration of 
boceprevir with medicines that 
induce or inhibit CYP3A4/5 could 
increase or decrease exposure. 
Plasma trough concentrations of 
boceprevir were decreased when 
administered with an NNRTI with a 
similar metabolic pathway as 
nevirapine. The clinical outcome of 
this observed reduction of boceprevir 
trough concentrations has not been 
directly assessed. 
It is not recommended to 
coadminister boceprevir and 
Viramune (see section 4.4). 
Entecavir 
Entecavir is not a substrate, inducer 
or an inhibitor of cytochrome P450 
(CYP450) enzymes. Due to the 
metabolic pathway of entecavir, no 
Entecavir and Viramune may be 
coadministered without dose 
adjustments. 
 
clinically relevant drug-drug 
interaction is expected. 
Interferons (pegylated 
interferons alfa 2a and 
alfa 2b) 
Interferons have no known effect on 
CYP 3A4 or 2B6. No clinically 
relevant drug-drug interaction is 
expected. 
Interferons and Viramune may be 
coadministered without dose 
adjustments. 
Ribavirin 
Results of in vitro studies showed a 
weak antagonism of nevirapine by 
ribavirin (see section 5.1), this has 
not been confirmed in clinical trials 
and reduced efficacy is not expected. 
Ribavirin does not inhibit 
cytochrome P450 enzymes, and there 
is no evidence from toxicity studies 
that ribavirin induces liver enzymes. 
No clinically relevant drug-drug 
interaction is expected. 
Ribavirin and Viramune may be 
coadministered without dose 
adjustments. 
 
 
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Telaprevir 
Telaprevir is metabolised in the liver 
by CYP3A and is a P-glycoprotein 
substrate.  Other  enzymes  may  be 
involved   in   the   metabolism.   Co- 
administration    of    telaprevir    and 
medicinal    products    that    induce 
CYP3A  and/or  P-gp  may  decrease 
telaprevir plasma concentrations. No 
drug-drug    interaction    study    of 
telaprevir with nevirapine has been 
conducted,     however,     interaction 
studies of telaprevir with an NNRTI 
with a similar metabolic pathway as 
nevirapine    demonstrated    reduced 
levels   of   both.   Results   of   DDI 
studies  of  telaprevir  with  efavirenz 
indicate   that   caution   should   be 
exercised     when    co-administering 
telaprevir with P450 inducers. 
Caution  should  be  exercised  when 
co-administering     telaprevir     with 
nevirapine. 
If co-administered with Viramune, an 
adjustment   in   the   telaprevir   dose 
should be considered. 
Telbivudine 
Telbivudine is not a substrate, 
inducer or inhibitor of the 
cytochrome P450 (CYP450) enzyme 
system. Due to the metabolic 
pathway of telbivudine, no clinically 
relevant drug-drug interaction is 
expected. 
Telbivudine and Viramune may be 
coadministered without dose 
adjustments. 
ANTACIDS 
Cimetidine 
Cimetidine: no significant effect on 
cimetidine PK parameters is seen. 
Nevirapine Cmin  1.07 
Cimetidine and Viramune can be co- 
administered without dose 
adjustments. 
ANTITHROMBOTICS 
Warfarin 
The interaction between nevirapine 
and the antithrombotic agent 
Close monitoring of anticoagulation 
levels is warranted. 
 
warfarin is complex, with the 
potential for both increases and 
decreases in coagulation time when 
used concomitantly. 
CONTRACEPTIVES 
Depo- 
medroxyprogesterone 
acetate (DMPA) 
150 mg every 3 
months 
DMPA AUC 
DMPA Cmin 
DMPA Cmax 
Nevirapine AUC  1.20 
Nevirapine Cmax  1.20 
Viramune co-administration did not 
alter the ovulation suppression effects 
of DMPA. DMPA and Viramune can 
be co-administered without dose 
adjustments. 
 
 
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Ethinyl estradiol (EE) 
0.035 mg 
EE AUC  0.80 (0.67 - 0.97) 
EE Cmin ND 
EE Cmax  0.94 (0.79 - 1.12) 
Oral hormonal contraceptives should 
not be used as the sole method of 
contraception in women taking 
Viramune (see section 4.4). 
Appropriate doses for hormonal 
contraceptives (oral or other forms of 
application) other than DMPA in 
combination with Viramune have not 
been established with respect to 
safety and efficacy. 
Norethindrone (NET) 
1.0 mg QD 
NET AUC  0.81 (0.70 - 0.93) 
NET Cmin ND 
NET Cmax  0.84 (0.73 - 0.97) 
ANALGESICS/OPIOIDS 
Methadone Individual 
Patient Dosing 
Methadone AUC  0.40 (0.31 - 0.51) 
Methadone Cmin ND 
Methadone Cmax  0.58 (0.50 - 0.67) 
Methadone-maintained patients 
beginning Viramune therapy should 
be monitored for evidence of 
withdrawal and methadone dose 
should be adjusted accordingly. 
HERBAL PRODUCTS 
St. John's Wort 
Serum levels of nevirapine can be 
reduced by concomitant use of the 
herbal preparation St. John's Wort 
(Hypericum perforatum). This is due 
to induction of medicinal product 
metabolism enzymes and/or 
transport proteins by St. John’s 
Wort. 
Herbal preparations containing St. 
John‘s Wort and Viramune must not 
be co-administered (see section 4.3). 
If a patient is already taking St. 
John‘s Wort check nevirapine and if 
possible viral levels and stop St. 
John‘s Wort. Nevirapine levels may 
increase on stopping St. John‘s Wort. 
The dose of Viramune may need 
adjusting. The inducing effect may 
persist for at least 2 weeks after 
cessation of treatment with St. John‘s 
Wort. 
(19) 
 
 
Lamivudine 
 
The likelihood of metabolic interactions is low due to limited metabolism and plasma protein binding 
and almost complete renal clearance. 
Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg results in a 40 % increase in 
lamivudine exposure, because of the trimethoprim component; the sulfamethoxazole component did 
not interact. However, unless the patient has renal impairment, no dosage adjustment of lamivudine 
is necessary. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole. 
When concomitant administration is warranted, patients should be monitored clinically. Co-
administration of lamivudine with high doses of co-trimoxazole for the treatment of Pneumocystis 
carinii pneumonia (PCP) and toxoplasmosis should be avoided. 
The possibility of interactions with other medicinal products administered concurrently should be 
considered, particularly when the main route of elimination is active renal secretion via the organic 
cationic transport system e.g. trimethoprim. Other medicinal products (e.g. ranitidine, cimetidine) are 
 
 
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eliminated only in part by this mechanism and were shown not to interact with lamivudine. The 
nucleoside analogues (e.g. didanosine) like zidovudine, are not eliminated by this mechanism and are 
unlikely to interact with lamivudine. 
A modest increase in Cmax (28 %) was observed for zidovudine when administered with lamivudine, 
however overall exposure (AUC) is not significantly altered. Zidovudine has no effect on the 
pharmacokinetics of lamivudine. 
Lamivudine metabolism does not involve CYP3A, making interactions with medicinal products 
metabolised by this system (e.g. PIs) unlikely (20). 
 
7.4.2.1.2 Concomitant Medications, Supplements, and Other Substances Allowed During the 
Trial 
The concomitant use of other medications/therapies is allowed unless specifically prohibited in the 
Medications, Supplements, and Other Substances Prohibited Prior to Baseline and During the Trial 
section. It is responsibility of the investigator to check on potential drug-drug interactions, before 
placing a patient on a specific therapy. Note that the use of any concomitant medication must relate 
to the documented medical history, prophylaxis, or an adverse event of the subject. 
7.4.2 
Other Treatments 
None. 
 
 7.4.3 Procedures for Monitoring Subject Compliance With Administration of Trial 
Treatments 
At all protocol-specified visits, the investigator or qualified designee is to record whether treatment 
had been taken per protocol in the preceding interval.  If not, the date(s) and reason for each dosing 
non compliance must be recorded. A specific adherence questionnaire in Italian language will be 
completed (appendix 3). 
 
7.5 Trial Schedules 
An overview of the study is provided in the Study Design Diagram (see section 2.1), and the study 
schedule is shown in the Study Flow Chart (see section 2.2). All treatment visits must be scheduled 
based on the Day 1 visit date, which is defined as the day of switch. 
All visits should be performed within the windows specified in Section 2.2, the Trial Flow Chart.  Every 
attempt should be made to have each subject attend each visit as scheduled.  However, if a subject is 
unable to attend a visit within the specified windows, the visit should be scheduled as closely as 
possible to these windows.  A subject should not miss a protocol-specified visit due to scheduling 
difficulties. 
 
7.6 
Trial Procedures 
The Trial Flow Chart in Section 2.2 summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described below. In order to minimize variability of evaluations, it is 
preferred that the same individuals perform  the same types of evaluations for all subjects at each trial 
site. 
 
 
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METHODS USED 
 
DEMOGRAPHIC INFORMATION 
Date of birth, sex, race, ethnicity.  
 
MEDICAL HISTORY 
Any relevant medical history and/or current medical conditions 
 
MAIN PROTOCOL ASSESSMENTS 
 
Clinical and physical assessment 
Clinical and biological safety and tolerability (specific untoward effects in the setting of renal and bone 
metabolism and functions) 
Metabolic changes, renal function (by MDRD 6 variables), tubular cell damage markers and bone 
mineral density modifications 
Change in CD4 cell count and in viral load 
Pharmacokinetics 
Genotypic resistance at virologic failure 
Adherence questionnaire 
Bone mineral density assessed by DXA 
Fracture Risk assessment with the FRAX® score  in persons > 40 years 
VACS index assessment 
 
1. Explain Trial and Obtain Written Informed Consent 
The investigator or qualified designee will explain the trial to the subject, answer all of his/her 
questions, and obtain written informed consent before performing any trial-related procedure.  A 
copy of the informed consent will be given to the subject (see Section 9.1.2 for further description 
of the Informed Consent). 
2. Obtain Medical History 
A medical history will be obtained by the investigator or qualified designee.  Subject history 
should include information on personal history. 
3. Review Inclusion/Exclusion Criteria 
The inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
4. Review Prior Medications 
Review of appropriate prior medications, including the necessary washout times, with the subject.  
A record of prior medication taken by the subject within 30 days before starting the trial is to be 
obtained. 
5. Record Concomitant Medications 
A record of medication taken by the subject during the trial is to be obtained. 
6. Record Adverse Events and Serious Adverse Events 
See Section 7.7.2.3, for instructions on the assessment and reporting of Adverse Events and 
Serious Adverse Events and Section 7.7.2.4 for instructions on the reporting of Adverse Events 
and Serious Adverse Events to the sponsor. 
7. Physical Examination 
A complete physical examination will be performed, including vital signs (blood pressure, heart 
rate, temperature, breathing rate).  If the subject is discontinued for any reason during the 
treatment phase, every attempt should be made to perform a final physical examination. 
 
 
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8. List Other Assessments/Procedures 
      see section 7.7.3   
9. Pregnancy Assessment  
Assess whether a subject is pregnant with a medically acceptable test, serum hCG 
test. 
10. Laboratory Tests 
Laboratory tests for hematology, blood chemistry, and urinalysis are specified in Appendix 1. Blood 
samples for laboratory tests are to be taken prior to investigational product(s) administration at day 
1 and at visits specified into Trial Flow Chart (section 2.2). 
11. Alcohol/Substance Abuse 
Patients should be questioned about their estimated daily intake of alcohol and about substance 
abuse during the screening evaluation of eligibility. Any patient who in the opinion of the investigator 
has an excessive intake of any of these substances must be excluded from the study.  
 
 
7.7 
 Assessments 
7.7.1 
Efficacy and Safety Assessments 
7.7.1.1 
 Primary endpoint 
 
The primary endpoint of this study is the eGFR (MDRD) change from baseline to Week 48.  
No formal comparison between the two arms will be carried out.  
 
7.7.1.2 
Secondary Endpoint(s) 
 
The main secondary efficacy end-point will be the proportion of subjects with HIV-RNA < 50 copies/ml 
at 48 week.  
Other secondary endpoints will be: 
a) 
Proportion of subjects with HIV-RNA < 50 copies/mL at 96 weeks of treatment.  
b) 
Time to virologic failure (HIV-1 RNA > 50 copies/mL). 
c) 
Changes of HIV-RNA absolute values at different time points.  
d) 
Changes of absolute CD4+ T-lymphocyte count at 48 and 96 weeks of treatment. 
e) 
Proportion of subjects with laboratory alterations (liver enzymes, lipid profile). 
f) 
Proportion of subjects with alterations of the tubular kidney injury markers. 
g) 
Proportion of subjects with metabolic bone markers changes  
h) 
Proportion of patients with bone mineral density modifications  
i) 
Pharmacokinetics determination (only for RAL and NVP) (see PK paragraph). 
j) 
Proportion of subjects with genotypic resistance at virologic failure.  
k) 
Incidence of mutations associated to resistance to NRTIs, NNRTIs, PI and INI, at virological 
failure. 
l) 
Proportion of subjects with adherence to therapy during 48 and 96 weeks of treatment. 
m) 
Changes in the Bone disease Risk assessment (FRAX® score in persons > 40 years) during 
48 and 96 weeks of treatment. 
 
 
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n) 
Changes in the VACS Index during 48 and 96 weeks of treatment. 
o) 
Proportion of subjects experiencing a decline of renal function defined as eGFR (MDRD-6 
variables) < 60 mL/min/1.73 m2 at 48 weeks of treatment. 
p) 
Changes in eGFR-MDRD at 96 weeks of treatment 
 
  
 
7.7.1.3 
Other Efficacy Endpoint(s) 
No other efficacy endpoint(s) are planned. 
 
7.7.2 
Safety Monitoring And Assessments 
7.7.2.1 
Safety Endpoints  
 
To assess the changes in renal function (eGFR -MDRD-6 variables) during 48 and 96 weeks 
of treatment, and the frequency of experiencing a decline of renal function with an eGFR< 60 
mL/min/1.73 m2 during 48 weeks of treatment 
 
To assess laboratory alterations (liver enzymes, lipid profile) after switch from PI/r (LPV/r, 
ATV/r,  DAR/r) + TDF/FTC to RAL + NVP + 3TC during 48 and 96 weeks of treatment 
 
To assess the alterations of the tubular injury markers: b2-microglobulin (b2M), and retinol-
binding protein (RBP) and N-acetyl-b-D-glucosaminidase (NAG) during 48 and 96 weeks of 
treatment 
 
To assess metabolic bone markers changes: Serum Bone Specific Alkaline Phosphatase (s-
BSAP), , C-telopepdides of type I Collagen (s-CTx) during 48 and 96 weeks of treatment. 
 
To assess bone mineral density modifications during 48 and 96 weeks of treatment. 
 
To assess the safety (e.g. skin rash, GI disturbances) 
 
To assess the Fracture Risk (FRAX® score in persons > 40 years) during 48 and 96 weeks of 
treatment 
 
To assess the VACS Risk Index during 48 and 96 weeks of treatment 
 
7.7.2.2 
Definition of Terms 
7.7.2.2.1 
Adverse Event 
According to the International Conference on Harmonization (ICH), an adverse event (AE) is defined 
as any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to this medicinal product. 
 
 
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The onset and end dates, severity and relationship to study drug will be recorded for each adverse 
event. The severity of the adverse event will be assessed according to specific guidelines (DAIDS).  
Any action or outcome (e.g., hospitalization, discontinuation of therapy, etc.) will also be recorded for 
each adverse event. All lab abnormalities considered as clinically significant by the Investigator will be 
recorded as AEs on the CRF. 
 
7.7.2.2.2 
Serious Adverse Event 
Serious Adverse Event (SAE) is any untoward medical occurrence or effect that at any dose: 
1. Results in death 
2. Is life-threatening 
3. Requires hospitalization or prolongation of existing inpatients’ hospitalization 
4. Results in persistent or significant disability or incapacity and/or 
5. Is a congenital anomaly or birth defect 
6. Is a cancer 
7. Is associated with an overdose 
8. Is an Other Important Medical Event 
 
Life-threatening in the definition of a serious adverse event refers to an event in which the subject 
was at risk of death at the time of event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
Medical judgment should be exercised in deciding whether an adverse event/reaction is serious in 
other situations.  Important adverse events/ reactions that are not immediately life-threatening or do 
not result in death or hospitalization, but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above, should also be considered serious.  
These are considered “Other Important Medical Events”. 
7.7.2.2.3 
Events of Clinical Interest 
An "Event of Clinical Interest" (ECI) is a non-serious adverse event or occurrence that is designated 
to be of special interest and must be reported to the sponsor as though it were a serious adverse 
event – as described in Section 7.7.2.4.1. 
The following events are considered events of clinical interest for this trial: 
1. An overdose of Sponsor's product, as defined in Section 7.7.2.1.4, Overdose, that is not 
associated with clinical symptoms or abnormal laboratory results is to be reported as a non-
serious ECI, using the terminology "accidental or intentional overdose without adverse effect.” 
2. An elevated AST or ALT lab value that is 3 x the upper limit of normal (ULN) and an elevated 
total bilirubin lab value that is 2 x ULN and, at the same time, an alkaline phosphatase lab 
value that <2 x ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing is to be reported as a non-serious ECI. 
Note:  These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
 
 
 
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7.7.2.2.4 
Overdose 
An overdose is a significant variation above the recommended/scheduled dosage for a product.  In 
this current trial an overdose of the investigational products is any dose higher than the dose 
specified in Section 7.4.1.1 of this protocol or any dose specified in the  SmPC of the products of the 
experimental arm (Raltegravir dose higher than 400 mg BID, Lamivudine dose higher than 150 mg 
BID, Nevirapine dose higher than 200 mg BID). The overdose of the control arm does not need to be 
reported as an ECI or SAE. Any overdose, whether or not associated with an adverse experience, 
must be reported within 24 hours to the SPONSOR. 
7.7.2.2.5 
Clinical Supply Complaint 
A clinical supply complaint is defined as any communication concerning manufacturing, packaging, 
labeling or distribution (including adverse storage at depots) of a clinical supply that describes a 
potential defect related to its identity, strength, quality or purity after it is released and left the control 
of a Merck-approved packaging facility for distribution.  A clinical supply GCP inquiry is defined as 
any communication of an event taking place at a trial site after the product was satisfactorily received 
at the trial site, which puts product disposition in question.  Examples include adverse storage of 
product at the trial site and dosing past expiration.  The investigator shall take responsibility for and 
shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, 
distribution and usage of investigational product in accordance with the protocol and any applicable 
laws and regulations.  This responsibility includes reporting of all clinical supply complaints and/or 
clinical supply GCP inquiries to the Sponsor. 
Clinical supplies complaints and GCP inquiries, as defined above, must be reported to the Sponsor 
within 1 business day of first becoming aware of the issue.   Sponsor Contact information and related 
reporting details can be found in the Investigator Trial File Binder. 
7.7.2.2.6 
Planned Hospitalization 
A hospitalization planned by the subject prior to signing the ICF is considered a therapeutic 
intervention and not the result of a new SAE and should be recorded as medical history.  If the 
planned hospitalization or procedure is executed as planned, the record in the subject’s medical 
history is considered complete.  However, if the event/condition worsens during the trial, it must be 
reported as an AE. 
7.7.2.3 
Monitoring 
7.7.2.3.1 
Monitoring Adverse Events 
Each subject will be monitored for the occurrence of any AEs immediately after the subject has 
signed informed consent and until the last protocol specified visit (14 days post therapy follow-up) or 
discontinued the study. 
Subjects will be questioned and/or examined by the investigator or a qualified designee for evidence 
of AEs. The questioning of subjects with regard to the possible occurrence of adverse events will be 
generalized such as, "How have you been feeling since your last visit?”  The presence or absence of 
specific AEs should not be elicited from subjects. 
Subjects having AEs will be monitored with relevant clinical assessments and laboratory tests, as 
determined by the investigator. 
AEs, actions taken as a result of AEs, and follow-up results must be recorded in the electronic Case 
Report Forms (eCRF; Section 9.2), as well as in the subject's source documentation.  Follow-up 
laboratory results should be filed with the subject's source documentation. 
 
 
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For all AEs that require the subject to be discontinued from the trial and SAEs, relevant clinical 
assessments and laboratory tests will be repeated as clinically appropriate, until final resolution or 
stabilization of the event(s). 
7.7.2.3.2 
Monitoring Laboratory Assessments 
All laboratory assessments will be performed in the local laboratory.  The clinical laboratory values 
will be reported to the investigator by the laboratory and he/she will review them for significance and 
consideration as an AE(s).  
a. Safety concerns related to experimental arm: RAL-3TC-NVP about NVP related toxicity. 
Clinical care of patients randomized to experimental arm would follow recommendations stated on 
NVP label. 
Patients should be instructed that a major toxicity of nevirapine is rash. They should be advised to 
promptly notify their physician of any rash and avoid delay between the initial symptoms and medical 
consultation. The majority of rashes associated with nevirapine occur within the first 6 weeks of 
initiation of therapy. Therefore, patients should be monitored carefully for the appearance of rash 
during this period.  Nevirapine must be permanently discontinued in any patient experiencing severe 
rash or a rash accompanied by constitutional symptoms (such as fever, blistering, oral lesions, 
conjunctivitis, facial edema, muscle or joint aches, or general malaise), including Stevens-Johnson 
syndrome, or toxic epidermal necrolysis. Nevirapine must be permanently discontinued in any patient 
experiencing hypersensitivity reaction (characterized by rash with constitutional symptoms, plus 
visceral involvement, such as hepatitis, eosinophilia, granulocytopenia, and renal dysfunction). 
Monitoring of hepatic tests should be done every two weeks during the first 2 months of treatment, 
and, then regularly thereafter. Liver test monitoring should be performed if the patient experiences 
signs or symptoms suggestive of hepatitis and/or hypersensitivity.  
If AST or ALT > 2.5 ULN before or during treatment, then liver tests should be monitored more 
frequently during regular clinic visits. If AST or ALT increase to > 5 ULN during treatment, nevirapine 
should be immediately stopped. If clinical hepatitis occurs, characterized by anorexia, nausea, 
vomiting, icterus and laboratory findings (such as moderate or severe liver function test abnormalities 
(excluding GGT), nevirapine must be permanently stopped and should not be readministered 
b. Renal Safety concerns. 
MDRD 6 variables will be used to calculate the renal function in patient throughout the study period.  
According TDF/FTC’s IMP the patients treated with FTD/FTC + PI/r have to manage closely and the 
renal function (creatinine clearance and serum phosphate) should be monitored every three months. 
A safety monitoring  with more frequently visits will be ensured for the control arm. Visits each 3 
months according to the international and national guidelines for monitoring TDF safety profile have 
been planned. Test for renal safety planned each months are creatinine clearance evaluation and 
serum phosphate. If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) renal function should be re-
evaluated within one week including measurement of blood glucose, blood potassium, urine glucose 
concentrations and proteinuria 
In case of continuous deterioration of renal function (measured by eGFR-MDRD 6 variables), 
especially in patients assigned to continue baseline therapy (TDF containing regimen) we suggested 
to follow these recommendations: 
 
 
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 
The dose and administration to any subject may not be modified. If necessary, a subject must 
be discontinued. 
 
treatment with tenofovir disoproxil fumarate should be stopped in adult patients with 
creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 
mg/dl (0.32 mmol/l).  
  
 
7.7.2.4 
Assessment of Adverse Events 
7.7.2.4.1 
Assessment of Severity 
Where the determination of adverse event severity rests on medical judgment, the determination of 
severity must be made with the appropriate involvement of a medically-qualified investigator. 
The severity of (S)AEs will be graded according to the following definitions: 
MILD:  awareness of sign, symptom, or event, but easily tolerated; 
MODERATE: discomfort enough to cause interference with usual activity and may warrant 
intervention; 
SEVERE: incapacitating with inability to do normal daily living activities or significantly affects  
clinical status, and warrants intervention. 
7.7.2.4.2 
Assessment of Causality 
A medically-qualified investigator must assess the relationship of any AE (including SAEs) to the use 
of the investigational product using the guidelines listed below: 
• Yes, there is reasonable possibility of drug relationship.  There is evidence of exposure to test 
drug.  The temporal sequence of the AE onset relative to the administration of the test drug is 
reasonable.  The AE is more likely explained by the test drug than by another cause. 
• No, there is not a reasonable possibility of drug relationship.  Subject did not receive the test drug 
OR temporal sequence of the AE onset relative to administration of the test drug is not 
reasonable OR there is another obvious cause of the AE. (Also entered for a subject with 
overdose without an associated AE.) 
 
7.7.2.4.3 
Reference Safety Information (RSI) for the Assessment of Expectedness of 
Adverse Events 
The expectedness of an adverse reaction shall be determined according to the reference document. 
The reference document for this current study is to be the Investigator’s Brochure (Raltegravir),   
Summary 
of 
Product 
Characteristics 
(Lamivudine, 
Nevirapine, 
tenofovir/emtricitabine, 
lopinavir/ritonavir, darunavir, ritonavir, atazanavir). 
7.7.2.4.4 
Known Potential Toxicities of Investigational Products 
Refer for the drugs to the Summary of Product Characteristics for additional information on AEs 
expected toxicity of the study drug. 
 
 
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7.7.2.5 
Reporting Safety Observations by the Investigator to the Sponsor 
7.7.2.5.1 
 Expedited Reporting of Safety Observations by the Investigator to the Sponsor 
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
expeditiously by the investigator or qualified designee to the sponsor’s Global Safety representative 
or designee using the Global Safety Intake Form provided by the sponsor/designee – or a sponsored-
approved equivalent form – within 1 working day of becoming aware of the event, sending it to 
MSD Italy (Pharmacovigilance Office 
). 
1. SAE (including SAEs associated with overdose, pregnancy, exposure during pregnancy or 
lactation – including the pregnancy of a male subject’s female partner who has provided written 
informed consent to provide information regarding pregnancy) 
2. Death 
3. Planned hospitalizations (not previously reported in the medical history) 
4. Events of clinical interest 
5. Cancer 
 
Any occurrence of a product quality complaint in the trial must be reported expeditiously (within 1 
working day) by the investigator or qualified designee to the sponsor’s Designated Point of Contact in 
MSD Italy, either by telephone or by sending the form named “Product Quality Complaint Reporting 
Form” filed in the ITF. Contact data are: 
 
. 
 
Any occurrence of pregnancy, exposure during pregnancy or lactation NOT associated with an SAE 
in a subject in the trial must be reported expeditiously by the investigator or qualified designee to the 
sponsor or designee using the Global Safety Intake Form within 5 working days of becoming 
aware of the event.  In this trial the pregnancy of a male subject’s female partner who has provided 
written informed consent to provide information regarding pregnancy must be reported using the 
Global Safety Intake Form within 5 working days of becoming aware of the event. 
If the investigator is unsure about when to report an observation from the lists above, the event or 
outcome should be reported to the sponsor or designee using the Global Safety Intake Form within 1 
working day. 
Any observation reported to the sponsor or designee via the Global Safety Intake Form that is also an 
AE, is to be recorded in the CRF (Section 9.2), as well as in the subject's source documentation 
along with any actions taken as a result of AE and follow-up results. 
If an autopsy is performed, the de-identified autopsy report must be provided to the sponsor within 
1 working day of the results being available. 
The investigator must assess causality of the event as relative to the investigational product 
administered in the trial as describes in Section 7.7.2.3.2.   
7.7.2.5.2 Expedited Reporting by the Sponsor to a Regulatory Health Authority 
Global Safety will monitor data for safety. The Sponsor will manage the expedited reporting of 
relevant safety information to concerned health authorities, competent authorities, and IRBs/IECs in 
accordance with local laws and regulations, with reference to the guideline “Detailed guidance on the 
collection, verification and presentation of adverse event/reaction reports arising from clinical trials on 
medicinal products for human use (‘CT-3’)”. 
 
 
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7.7.2.6 Discontinuation, Treatment Interruption, and Unblinding of Blinded 
Treatment Due to Safety Observations 
7.7.2.6.1 Discontinuation 
See Section 7.3.3 for the criteria by which a subject must be discontinued.  Should a subject be 
discontinued from the trial, complete the visit activities as specified for discontinuation in the Trial 
Flow Chart in Section 2.2. 
 
7.7.2.6.2 Temporary Interruption of Treatment for a Subject 
A Subject may not temporarily interrupt and then restart treatment.  The investigator is to discontinue 
a subject as necessary according to the criteria provided in Section 7.3.3. 
 
7.7.2.6.3 Modification of Dose and/or Administration of Investigational Product for a Subject 
The dose and administration to any subject may not be modified. If necessary a subject must be 
discontinued for the reasons described in Section 7.3.3. 
 
7.7.2.6.4 Unblinding Treatment for a Subject During the Trial 
No treatments in this current trial are blinded. 
 
7.7.3 Other Endpoints  
Although no clinically relevant drug-to-drug interactions are expected according to the drugs 
metabolic pathways, no data is currently available on the pharmacokinetic compatibility of the 
raltegravir/nevirapine combination. The rather wide intra and inter-patient variability of Raltegravir 
exposure, along with the recent appraisal of its pharmacokinetic/pharmacodynamics profile, and the 
rather different elimination half-lives of the three drugs here concerned, make the development of a 
pharmacokinetic substudy of relevance in order to fully evaluate the properties of such new three-
drug regimen.     
Determination of raltegravir and nevirapine AUCs (areas under the curve) will be carried out at steady 
state according to the dosing interval with blood sampling taking place at the end of dosing interval at 
time 0 (fasted state), and  1, 2, 3, 6 and 12 h after drug intake (regardless food) in a subset of 
enrolled patients with available data in the experimental arm at week 12 (~ the first 10 patients). The 
remaining 40 patients in the experimental arm will undergo Ctrough sampling (at the end of dosing 
interval at 12 h) at week 12 and 48. Adequate documentation of drug and food intake will be required.     
Blood will be collected into 7 ml lithium heparin and plasma obtained by centrifugation (3000 rpm for 
10 minutes at 4 °C) will be stored in two criovials at -20 °C. Plasma concentrations will be analyzed 
by a validated HPLC-PDA method at the Clinical Pharmacology and Pharmacogenetics Laboratory of 
the University of Torino, Torino, Italy. 
CYP2B6 single nucleotide polymorphisms (SNPs) will be screened in both patients undergoing AUC 
determination and those being sampled for Ctrough. 
 
 
 
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7.7.4   Criteria For Early Termination Of The Trial 
The clinical trial may be stopped if the extent (incidence and/or severity) of emerging effects/clinical 
endpoints is such that the risk/benefit ratio to the trial population as a whole is unacceptable. 
In addition, further recruitment in the trial or at (a) particular site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, procedure-
related problems, or if the number of discontinuations for administrative reasons is too high. 
 
8.0 STATISTICAL AND ANALYTICAL PLAN  
 
8.0 STATISTICAL AND ANALYTICAL PLAN  
This section outlines the statistical analysis strategy and procedures for the study. The following is an 
outline of the statistical methodology that will be used to report and analyze this study. A more 
detailed description will be provided in a separate statistical analysis plan that may include additional 
exploratory analysis not explicitly mentioned in the following sections. A Statistical Analysis Plan 
(SAP) will be produced before the database lock and will contain full details of all planned summaries, 
listings and analyses. 
All analyses will be performed using SAS System software (version 9.2 or later). 
8.1 Hypotheses / Estimation  
The primary objective of the study is stated in Section 6.1.  
This randomized phase 2 study is mainly designed as an estimation study without a planned formal 
comparison between the two regimens. The control arm, not directly compared with the experimental 
arm, will be considered for assessing the internal validity of the study. 
 
It is expected that Regimen A is generally safe and well tolerated and can cause an improvement of 
the renal function. A pre vs post design will be used to examine changes in eGFR (MDRD) in the 
Regimen A arm.  
The primary endpoint of this study will be the eGFR (MDRD) change from baseline to Week 48.  
 
The secondary trial objectives are stated in section 6.2.  
8.2 Analysis Endpoints  
8.2.1 Primary Endpoint  
The primary endpoint is the eGFR (MDRD) change from baseline to week 48.  
8.2.2 Main Secondary Endpoint 
The main secondary efficacy endpoint is the proportion of subjects with HIV-RNA < 50 copies/ml at 
48 week.  
8.2.3 Other Secondary Endpoints 
a) 
Proportion of subjects with HIV-RNA < 50 copies/mL at 96 weeks of treatment.  
b) 
Time to virologic failure (HIV-1 RNA > 50 copies/mL). 
c) 
Changes of HIV-RNA absolute values at different time points.  
d) 
Changes of absolute CD4+ T-lymphocyte count at 48 and 96 weeks of treatment. 
e) 
Proportion of subjects with laboratory alterations (liver enzymes, lipid profile). 
f) 
Proportion of subjects with alterations of the tubular kidney injury markers. 
g) 
Proportion of subjects with metabolic bone markers changes  
 
 
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h) 
Proportion of patients with bone mineral density modifications  
i) 
Pharmacokinetics determination (only for RAL and NVP) (see PK paragraph). 
j) 
Proportion of subjects with genotypic resistance at virologic failure.  
k) 
Incidence of mutations associated to resistance to NRTIs, NNRTIs, PI and INI, at virological 
failure. 
l) 
Proportion of subjects with adherence to therapy during 48 and 96 weeks of treatment. 
m) 
Changes in the Bone disease Risk assessment (FRAX® score in persons > 40 years) during 
48 and 96 weeks of treatment. 
n) 
Changes in the VACS Index during 48 and 96 weeks of treatment. 
o) 
Proportion of subjects experiencing a decline of renal function defined as eGFR (MDRD-6 
variables) < 60 mL/min/1.73 m2 at 48 weeks of treatment. 
p) 
Changes in eGFR-MDRD at 96 weeks of treatment 
   
8.2.4 Safety Endpoints  
Safety and tolerability will be assessed by clinical review of all relevant parameters including:  
 
Occurrence of Adverse experiences (AEs) 
 
Laboratory tests 
 
Vital signs 
8.3 Analysis Populations  
8.3.1 Full Analysis Set (FAS)  
The primary analysis on primary and secondary end-points will be performed on the Full Analysis Set 
(FAS) which includes all randomized subjects who received at least one dose of study medications, 
and have both a baseline assessment and at least one post-baseline assessment of any primary or 
secondary endpoints, irrespective of compliance with the study protocol and procedures.  
 
In addition, a Per Protocol Set is defined as all FAS subjects who meet key eligibility criteria. 
Sensitivity analyses will be based on this Per Protocol Set. A supportive analysis using the Per-
Protocol population will be performed for the primary endpoint only in case more than 10% of patients 
are identified as protocol violators.  
 
The final determination on protocol violations, and thereby the composition of the Per-Protocol 
population, will be made and documented prior to the Data Base Lock at the Data Review Meeting.   
8.3.2 Safety Analysis Populations (SAF) 
The All Treated Set will be used for the analysis of safety data in this study.  
The All Treated Set consists of all randomized patients who received at least one dose of study 
treatment. 
8.4 Statistical Methods  
Study Day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events. Reference start date is defined as the day of the first dose of study 
medication, (Day 1 is the day of the first dose of study medication). 
If the date of the event is on or after the reference date then: Study Day = (date of event – reference 
date)+1. 
If the date of the event is prior to the reference date then: Study Day = (date of event – reference 
date). 
 
 
 
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Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
reference start date (including unscheduled assessments). In the case where the last non-missing 
measurement and the reference start date coincide, that measurement will be considered pre-
baseline, but Adverse Events (AEs) and medications commencing on the reference start date will be 
considered post-baseline. 
 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries, but will contribute to the endpoint value, or 
best/ worst case value where required (e.g. shift table). 
For quantitative measurements, change from baseline will be calculated as: Test Value at Visit X – 
Baseline Value.  
8.4.1 Statistical Methods for Primary Endpoint  
The primary endpoint for this trial is the eGFR (MDRD) change from baseline to week 48. 
The primary analysis will be conducted on the Full Analysis Set. An additional sensitivity analysis will 
be based on the Per Protocol Set.  
The primary endpoint will be analyzed using a one-group (two-sided) Student’s t test on the Regimen 
A group. Assumption of normality distribution will be checked and in case of strong deviation from 
normality, the non parametric Wilcoxon test will be used.  
For the Regimen B group, the difference from baseline to week 48 will be estimated together with its 
pertinent 95% Confidence Interval. 
No formal comparison between the two treatment arms will be carried out.  
 
If missing data on primary end-point will be ≤ 5%, a LOCF approach (Last Observation Carried 
Forward procedure) will be used. In that case, if a patient permanently discontinues the treatment 
during the 48-week treatment period or does not have an eGFR (MDRD) value at week 48, the last 
post-baseline eGFR (MDRD) measurement during the on-treatment period will be used as the eGFR 
(MDRD) value at week 48. Otherwise, missing data will be imputed by using a multiple imputation 
method considering the previous trend and/or the baseline covariates. 
8.4.2 Statistical Methods for the main secondary endpoint 
The main secondary efficacy end-point is the proportion of subjects with HIV-RNA < 50 copies/ml at 
week 48.  
Based on the above criteria, patients will be classified as responders or not responders (failures). If a 
patient permanently discontinues the treatment during the 48-week treatment period or does not have 
an HIV-RNA assessment at week 48, a conservative approach will be used: all missing values due to 
premature discontinuations will be considered failures, regardless of the reason for discontinuation. 
Counts and percentages of “Responders” and “Not Responders” and their 95% two-sided exact 
confidence intervals will be presented for both arms.  
Analysis of the main secondary end-point will be based on the Full Analysis Set.  
No formal comparison between the two arms will be carried out.  
8.4.3 Statistical Methods for other secondary endpoints  
Analysis of the secondary end-points will be based on the Full Analysis Set. No formal comparison 
between the two arms will be carried out.  
Continuous data will be summarized by treatment group by using the number of observations 
available (n), mean, SD, minimum, median, and maximum  
Categorical data will be summarized by treatment group by using counts and percentages at each 
time points. Missing data will not be categorized in the summaries. In general, descriptive statistics of 
quantitative efficacy and safety endpoints (result and change from baseline) by scheduled visit will be 
provided on observed cases, i.e., the inclusion of only patients having non-missing assessments at a 
specific visit. 
 
The secondary endpoints will be analyzed as follow:  
 
 
 
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 
Proportion of subjects with HIV-RNA < 50 copies/mL at 96 weeks of treatment.  
Based on the above criteria, patients will be classified as responders or not responders. Counts 
and percentages of “Responders” and “Not Responders” and their 95% two-sided exact 
confidence intervals will be presented for both arms.  
 
 
Time to virologic failure (HIV-1 RNA > 50 copies/mL). 
Time to virologic failure will be calculated as the difference between the date of randomization 
and the date in which HIV-1 RNA > 50 copies/mL. Summary statistics will be presented for both 
arms. 
 
 
Changes of HIV-RNA absolute values at different time points. 
Actual values and changes from baseline to each time point will be presented for each arm. 
Moreover, pertinent 95% Confidence Intervals at week 48 and 96 will be also presented. 
 
 
Incidence of mutations associated to resistance to NRTIs, NNRTIs, INI, at virological failure.  
Counts and percentages of patients classified as “Mutated” and “Not Mutated” and their 95% two-
sided exact confidence intervals will be presented for both arms.  
 
 
Changes of absolute CD4+ T-lymphocyte count at 48 and 96 weeks of treatment. 
Actual values and changes from baseline to each time point will be presented for each arm. 
Moreover, pertinent 95% Confidence Intervals at week 48 and 96 will be also presented. 
 
 
Proportion of subjects with laboratory alterations (liver enzymes, lipid profile). 
Counts and percentages of patients classified as “Having Normal value” and “Having Abnormal 
value” will be presented at each time point for both arms. 
 
 
 
Proportion of subjects with alterations of the tubular kidney injury markers. 
Counts and percentages of patients classified as “Having Normal value” and “Having Abnormal 
value” will be presented at each time point for both arms. 
 
 
Proportion of subjects with metabolic bone markers changes and change in the bone mineral 
density modifications. 
Counts and percentages of patients classified as “Having markers changes” and “Not-having 
markers changes” will be presented at each time point for both arms.  
Actual values and changes from baseline to each time point will be presented for each arm. 
 
 
PK determination (only for RAL and nevirapine).   
AUC[0-t] , c-through will be calculated using the trapezoidal method and summary statistics will 
be presented. 
 
 
Proportion of subjects with genotypic resistance at virologic failure. 
Counts and percentages of patients classified as “Showing genotypic resistance” and “Not-
showing genotypic resistance” will be presented for both arms.  
 
 
Proportion of subjects with adherence to therapy during 48 and 96 weeks of treatment. 
Adherence to therapy will be evaluated by using the Adherence Questionnaire. Summaries 
statistics will be presented for each item at each time interval for both arms.    
 
 
Changes in the Bone disease Risk assessment (FRAX® score in persons > 40 years) during 48 
and 96 weeks of treatment. 
Actual values and changes from baseline to each time point will be presented for each arm. 
Moreover, pertinent 95% Confidence Intervals at week 48 and 96 will be also presented. 
 
 
Changes in the VACS Index during 48 and 96 weeks of treatment. 
 
 
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Actual values and changes from baseline to each time point will be presented for each arm. 
Moreover, pertinent 95% Confidence Intervals at week 48 and 96 will be also presented. 
 
 
Proportion of subjects experiencing a decline of renal function defined as eGFR (MDRD-6 
variables) < 60 mL/min/1.73 m2 at week 48 and 96.  
Based on the above criteria, patients will be classified as failures or not failures. Counts and 
percentages of “Failures” and “Not Failures” and their 95% two-sided exact confidence intervals 
will be presented for both arms.  
 
Missing data on secondary endpoints will be handled as described for the primary and main 
secondary endpoint, where applicable.  
8.4.4 Statistical Methods for Safety Analyses  
AEs will be coded using MedDRA dictionary (using the most updated version). Adverse events (AEs) 
will be reported on a per subject basis. If a patient has more than one AE for a treatment that coded 
to the same preferred term (PT), the patient will be counted only once for that preferred term. 
Similarly, if a patient has more than one AE for a treatment within a system organ class (SOC) 
category, the patient will be counted only once in that system organ class category. A patient with 
multiple CTCAE grades for an AE will be summarized under the maximum CTCAE grade recorded for 
the event.  
Any Adverse Events which started at or after the first administration of study treatment will be 
considered a treatment Emergent Adverse Event (TEAE). If the start date is missing for an AE, the 
AE will be considered to be treatment emergent. 
An overview of AEs including the number of subjects with at least one AE, at least one TEAE, at least 
one drug-related TEAE, at least one serious TEAE, any SAE, any AE leading to death, any TEAE 
leading to death, any TEAE leading to drug discontinuation, at least one grade ≥ 3 TEAE, will be 
presented.  
The following AE frequency tables will be also provided:  
• 
incidence of TEAEs by primary SOC and PT; 
• 
incidence of drug-related TEAEs by primary SOC and PT; 
• 
incidence of TEAEs by maximum severity, primary SOC and PT; 
• 
incidence of TEAEs by strongest relationship maximum severity, primary SOC and PT; 
• 
incidence of TESAEs by primary SOC and PT; 
• 
incidence of TEAEs leading to study drug discontinuation by primary SOC and PT; 
• 
incidence of TEAEs leading to dose modification by primary SOC and PT. 
 
Other safety data including laboratory evaluations and vital signs assessments will be summarized 
at each time point. Descriptive statistics will be calculated for quantitative safety data as well as for 
the difference from baseline, if applicable. In addition, a shift table describing out of normal range 
shifts (low/normal/high values) will be provided for clinical laboratory results. 
8.4.5 Subject disposition, Demographics and Other Baseline Characteristics  
The number and percentage of patients screened, randomized, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  
Demographic variables (e.g., age, gender, weight, BMI), baseline characteristics and medical history 
will be summarized by treatment arm using summary statistics.  
Continuous data will be summarized by treatment group using the number of observations available 
(n), mean, SD, minimum, median, and maximum.  
Categorical data will be summarized by treatment group using counts and percentages. Missing data 
will not be categorized in the summaries. 
Medical history terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (using the most updated version) and will be presented by SOC and PT. 
 
 
 
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8.4.6 Prior and Concomitant Medications  
Prior medications are defined as those starting and ending prior to the first administration of 
investigational study drug.  
Concomitant medications are defined as those started at or after first administration of study drug and 
include those started prior to the first administration of investigational study drug but continued during 
the study.  
Prior and concomitant medications will be classified according to active drug substance using the 
WHO-DRL drug dictionary (using the most updated version). Frequency tabulations will be presented 
for prior and concomitant medication by primary therapeutic subgroup (3rd level ATC code), and 
generic name. 
 
8.5 Sample size and power calculation  
Patients to screen: 148; Patients evaluable: 100 (50 in each group). 
It is expected that Regimen A is generally safe and well tolerated and can cause an improvement of 
the renal function. A pre vs post design will be used to examine changes in eGFR (MDRD) in the 
Regimen A arm.  
For sample size calculation our data and results from a pilot tenofovir switching study recently 
published (21) were used.  
Sample size calculation was based on the primary endpoint of the study, defined as the eGFR 
(MDRD) change from baseline to week 48 with the following assumptions:  
 
Test: One group Student’s t-test (two-sided). 
Null hypothesis (H0): Expected mean change from baseline to week 48 is 0.0 ml/min. 
Alternative hypothesis (H1): Expected mean change from baseline to week 48 is 15 ml/min. 
Expected SD = 31.5 ml/min 
Alpha = 0.05; Power = 90%;   
 
When the sample size is 50, a single group Student’s t-test with a 0.05 two-sided significance level 
will have 90% power to detect a difference between a null hypothesis mean of 0.0 ml/min and an 
alternative hypothesis mean of 15.0 ml/min, assuming that the standard deviation is 31.5 ml/min. 
Overall 100 subjects (50 per arm) need to be evaluated. In order to obtain 50 subjects and assuming 
a 20% rate of non evaluable subjects the required set of patients will be approximately 63 per arm 
and considering a screen failure rate of 15%, such number should be increased to 74. Overall, 
approximately 148 subjects (74 per arm) will need to be screened to obtain 100 subjects valuables 
(50 per arm).  
 
Calculations were made by using nQuery Advisor® 7.0. 
 
8.6 Subgroup analyses and effect of baseline factors  
Not applicable for this study. 
 
8.7 Multiplicity  
Not applicable for this study. 
 
8.8 Interim Analyses  
No formal interim analyses are planned.  
 
 
 
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8.9 Data Safety Monitoring Board  
Not applicable for this study. 
 
9.0 ADHERENCE TO ETHICAL, REGULATORY AND ADMINISTRATIVE 
CONSIDERATIONS 
The trial must be conducted in accordance with Good Clinical Practice (GCP) as outlined in the 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Guidelines, E6 Good Clinical Practice:  Consolidated 
Guidance and other applicable laws and regulations.  In addition, the trial must be conducted in 
accordance with:  (i) the USA Code of Federal Regulations (CFR) if the trial is conducted under a 
USA IND, regardless of the country involved; (ii) the European Union (EU) Clinical Trial Directive 
(CTD) and local regulations if the trial is conducted in the EU; and (iii) any specific local regulations if 
the trial is conducted elsewhere. 
9.1 
Ethical Conduct of the Trial 
9.1.1 
Independent Ethics Committee or Institutional Review Board 
Prior to initiation of the trial at any site, the trial, including the protocol, informed consent, and other 
trial documents must be approved by an appropriate Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC).  The IRB/IEC must be constituted according to applicable regulatory 
requirements. As appropriate, amendments to the protocol must also be approved by the IRBs/IECs 
before implementation at the sites, unless warranted to eliminate an immediate hazard.  The IRB/IEC 
approval should be obtained in writing, clearly identifying the trial, the documents reviewed (including 
informed consent), and the date of the review.  The trial as described in the protocol (or amendment), 
informed consent, and other trial documentation may be implemented only after all the necessary 
approvals have been obtained and the sponsor has confirmed that it is acceptable for the investigator 
to do so. 
In the event that the IRB/IEC requires changes in the protocol, the sponsor shall be advised and must 
approve the changes prior to implementation.  The investigator shall not modify the trial described in 
the protocol once finalized and after approval by the IRB/IEC without the prior written approval of 
sponsor. 
In countries where the investigator submits the trial protocol and statement of informed consent to the 
IRB/IEC, the investigator or qualified designee will forward the approvals to the sponsor. 
 
9.1.2 
Subject Information and Consent 
The details of the protocol must be provided in written format and discussed with each potential 
subject, and written informed consent must be obtained for all subjects before any trial-related 
procedure is performed.  In obtaining informed consent, the information must be provided in language 
and terms understandable to the subject. The subject, or the subject's legal representative, must give 
their written consent to participate in the trial.  The signed and dated consent form itself must be 
retained by the investigator as part of the trial records.  A copy of the signed and dated consent form 
must be given to the subject.  The consent form must include all of the required elements of informed 
consent in accordance with ICH Guidelines E6 and local laws.  In addition, the sponsor specifically 
requests that the consent form identify it as the sponsor and state that use of the investigational 
product(s) is experimental and the side effects of the investigational product(s)are not completely 
 
 
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known. The consent form must be approved by the appropriate IRB/IEC and sponsor before trial 
initiation at a trial site.  Any subsequent changes to the approved informed consent form must be 
reviewed and approved by the appropriate IRB/IEC and sponsor before implementation. 
 
9.1.3 
Registration of the Trial 
The trial will be registered by the sponsor on a publicly accessible database.  The results will be 
disclosed by the sponsor on a publicly accessible database. 
9.2 Reporting Trial Data to the Sponsor 
9.2.1 Data Collection Forms 
The Sponsor will provide the site with data collection forms, be they Case Report Forms (CRF), either 
in paper format or electronic Case Report Forms (eCRF); diaries; Electronic Data Capture (EDC) 
screens or other appropriate data collection forms as the trial requires. The investigator is to provide 
subject data according to the Sponsor’s instructions, in the designated data collection form, compliant 
with GCP practices.  The Sponsor will also provide the site with instructions for assisting other parties 
- such as a central laboratory - to collect data.  As instructed by the Sponsor, a designated central 
laboratory may collect data in a database and provide the completed database to sponsor.  All data 
collection forms and the databases from the trial are the exclusive property of sponsor. 
The investigator must maintain records and data during the trial in compliance with all applicable legal 
and regulatory requirements.  Each data point must be supported by a source document at the trial 
site.  Any records or documents used as the source of information (called the “subject source data”) 
are to be retained for review by authorized representatives of the sponsor or a regulatory agency. 
The investigator will ensure that there are sufficient time, staff, and facilities available for the duration 
of the trial to conduct and record the trial as described in the protocol and according to all applicable 
guidances, laws, and regulations. 
All data collection forms (e.g., CRFs, diaries; EDC screens), electronic database entries, etc, should 
be completed as soon as possible after the evaluation has occurred.  All dates appearing on the 
sponsor's subject data collection forms for laboratory tests, cultures, and other data collected, must be 
the dates on which the specimens were obtained, or the procedures performed. 
 
9.2.2 Preparing Case Report Forms for All Subjects 
A CRF must be completed for all subjects who have given informed consent.  The Sponsor must not 
collect subject names, initials, or other personal information that is beyond the scope of the trial from 
any subject.  Subjects are not to be identified by name or initials on the CRF or any trial documents.  
The only acceptable identification for a subject who may appear on a CRF or trial document is the 
unique subject identification number. The investigator must maintain contact information for each 
participant so that all can be quickly contacted by the investigator, if necessary. 
For a Trial Using Electronic Signatures 
All entries into CRFs are the responsibility of the investigator and must be completed by the 
investigator or a qualified designee.  The investigator will attest in writing at the beginning of the trial 
that his/her electronic signature is the legally binding equivalent of a written signature and will 
 
 
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acknowledge by entering his/her electronic signature that he/she has verified the accuracy of the 
recorded data. 
9.2.3 Preparing Case Report Forms for Subjects Who Fail Screening 
Data are to be collected from the time the informed consent form is signed until the subject is 
determined to have failed screening. A CRF with a minimum of the following information must be 
completed for subjects who fail screening:  (1) demographics, (2) subject status, (3) reason for screen 
failure and (4) serious adverse events. 
 
9.3 Publications and Other Rights 
9.3.1 Rights to Publish by the Investigator 
The investigator has the right to publish or publicly present the results of the trial in accordance with 
this Section 9.3 of the protocol.  In the event that the protocol is a part of a multi-site trial, it is 
understood that it is the intent of the sponsor and the investigator to initially only publish or present 
the trial results together with the other sites, unless specific written permission is obtained in advance 
from the sponsor to publish separate results.  The sponsor shall advise as to the implications of 
timing of any publication in the event clinical trials are still in progress at sites other than the 
investigator's site. 
The investigator agrees not to publish or publicly present any interim results of the trial without the 
prior written consent of the sponsor.  The investigator further agrees to provide to the sponsor 
45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts 
for publication (including, without limitation, slides and texts of oral or other public presentations and 
texts of any transmission through any electronic media, e.g., any computer access system such as 
the Internet, World Wide Web, etc.) that report any results of the trial.  The sponsor shall have the 
right to review and comment with respect to publications, abstracts, slides, and manuscripts and the 
right to review and comment on the data analysis and presentation with regard to the following 
concerns: 
 
1. Proprietary information that is protected by the provisions contained in Section 9.3.2; 
2. The accuracy of the information contained in the publication; and 
3. To ensure that the presentation is fairly balanced and in compliance with FDA regulations. 
 
If the parties disagree concerning the appropriateness of the data analysis and presentation, and/or 
confidentiality of the sponsor's confidential information, investigator agrees to meet with the sponsor's 
representatives at the clinical trial site or as otherwise agreed, prior to submission for publication, for 
the purpose of making good faith efforts to discuss and resolve any such issues or disagreement. 
 
9.3.2 Use of Proprietary or Confidential Information in a Publication 
No publication or manuscript shall contain any trade secret information of the sponsor or any 
proprietary or confidential information of the sponsor and shall be confined to new discoveries and 
interpretations of scientific fact.  If the sponsor believes there is patentable subject matter contained 
in any publication or manuscript submitted for review, the sponsor shall promptly identify such subject 
 
 
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matter to investigator. If sponsor requests and at sponsor’s expense, investigator shall use its best 
efforts to assist sponsor to file a patent application covering such subject matter with the USA Patent 
and Trademark Office or through the Patent Cooperation Treaty prior to any publication. 
 
9.3.3 Use of Trial Information in a Publication 
Investigator is granted the right subject to the provisions of this protocol to use the results of all work 
provided by investigator under this protocol, including but not limited to, the results of tests and any 
raw data and statistical data generated for investigator's own teaching, research, and publication 
purposes only.  Investigator/Institution agrees, on behalf of itself and its employees, officers, trustees, 
and agents, not to cause said results to be knowingly used for any commercial purpose whatsoever 
except as authorized by the sponsor in writing. 
 
9.3.4 Authorship of Publications 
Authors of publications must meet the International Committee of Medical Journal Editors (ICMJE) 
guidelines for authorship and must satisfy the 3 criteria that follow: 
1. Authors must make substantial contributions to the conception and design of the trial, 
acquisition of data, or analysis of data and interpretation of results; 
2. Authors must draft the publication or, during draft review, provide contributions (data analysis, 
interpretation, or other important intellectual content) leading to significant revision of the 
manuscript with agreement by the other authors; 
3. Authors must provide written approval of the final draft version of the publication prior to 
submission. 
 
All contributors who do not meet the 3 criteria for authorship should be listed in an acknowledgments 
section within the publication, if allowed by the journal, per the ICMJE guidelines for acknowledgment. 
 
9.4 Trial Documents and Records Retention 
During the trial and after termination of the trial – including after early termination of the trial – the 
investigator must maintain copies of all documents and records relating to the conduct of the trial.  
This documentation includes, but is not limited to, protocols, CRFs and other data collection forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence with 
health authorities and IRBs/IECs, consent forms, investigator’s curricula vitae/biosketch, monitor visit 
logs, laboratory reference ranges, and laboratory certification or quality control procedures and 
laboratory director curriculum vitae.  Subject files and other source data must be kept for the 
maximum period of time permitted by the hospital, institution or private practice, or as specified 
below.  The sponsor must be consulted if the investigator wishes to assign the files to someone else, 
remove them to another location, or is unable to retain them for the specified period. 
The investigator must retain trial records for the amount of time specified by applicable laws and 
regulations.  At a minimum, trial records must be retained for the amount of time specified by ICH 
Guidelines, the EU Good Clinical Practices Directive, or applicable local laws, whichever is longer: 
 
 
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1. The ICH Guidelines specify that records must be retained for a minimum of 2 years after a 
marketing application for the indication is approved (or not approved) or 2 years after notifying 
the appropriate regulatory agency that an investigation is discontinued. 
2. The European Union (EU) Commission Directive 2003/63/EC which requires that Essential 
Documents (including Case Report Forms) other than subjects’ medical files, are retained for at 
least fifteen (15) years after completion or discontinuation of the trial, as defined in the protocol. 
 
All trial documents shall be made available if required by relevant health authorities.  The investigator 
should consult with the sponsor prior to discarding trial and/or subject files. 
Sponsor will retain all sponsor-required documentation pertaining to the trial for the lifetime of the 
investigational product.  Archived data may be held on microfiche or electronic record, provided that a 
back-up exists and that a paper copy can be obtained from it, if required. 
 
10.0 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
10.1 Sponsor 
The sponsor of this trial is indicated in Section 1, Title Page. 
10.2 Investigators 
10.2.1 Selecting Investigators 
Only investigators qualified by training and experience to perform a clinical investigation with 
raltegravir are selected. The sponsor will contact and select all investigators (i.e., the legally 
responsible party[ies] at each trial site), who, in turn, will select their staff. 
 
10.2.2 Financial Disclosure Requirement 
In connection with the clinical trial described in the protocol, the investigator certifies that, if asked, the 
investigator will read and answer the Certification/Disclosure Form or equivalent document truthfully 
and to the best of investigator's ability.  Investigator also certifies that, if asked, the investigator will 
have 
any 
other 
applicable 
party(ies) 
(e.g., 
subinvestigators) 
read 
and 
answer 
the 
Certification/Disclosure Form as a condition of their participation in the trial. 
If the financial interests reported on the Certification/Disclosure Form change during the course of the 
trial or within 1 year after the last subject has completed the trial as specified in the protocol, the 
investigator and the other applicable party(ies) are obligated to inform the sponsor of such financial 
change. 
 
10.2.3 Clinical Study Report Coordinator Investigator 
A Clinical Study Report (CSR) will be prepared by the sponsor or its qualified designee to describe 
the results of the trial.  One of the investigators shall be selected by the sponsor to review the CSR 
and provide approval of the final CSR in writing.  The investigator chosen to review and approve the 
 
 
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CSR is to be called the CSR Coordinating Investigator. The sponsor is to select the CSR 
Coordinating Investigator and using the following criteria: 
1. Must be the Principal Investigator at a trial site actively enrolling subjects and participating in the 
trial; 
2. Must be willing and capable of completing the necessary reviews and providing approval of the 
CSR in writing; 
 
 
 
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11. REFERENCES 
1. Robert Kalyesubula and Mark A. Perazella. Review Article Nephrotoxicity of HAART. AIDS 
Research and Treatment Volume 2011, Article ID 562790,11 pages. 
2. Cooper Ryan D. et al, Systematic Review and Meta-analysis: Renal Safety of Tenofovir 
Disoproxil Fumarate in HIV-Infected Patients. Clinical Infectious Diseases 2010; 51(5):496–505 
3. Rockwood N et al, A comparative analysis of risk factors associated with renal impairment and 
highly active antiretroviral therapy. J. Antiviral Antitroviral 2012, 4:2 
4. Reynes 
J 
et 
al. 
Lopinavir/ritonavir 
(LPV/r) 
Combined 
with 
Raltegravir 
(RAL) 
or 
Tenofovir/Emtricitabine (TDF/FTC) in Antiretroviral (ARV)-naïve Subjects: 96-Week Results of the 
PROGRESS Study. AIDS Res Hum Retroviruses. 2012 Aug 3  
5. Mocroft A.et al, Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug 
use in HIV-positive patients. AIDS 2010, 24:1667–1678 
6. Malika Sharma & Sharon L Walmsley. Expert Opin.Pharmacother.(2014) 15 (3):395-405 
7. Fabbiani M. Scandinavian Journal of Infectious Diseases, 2013; Early Online: 1–12 
8. Podzamczer D. Current HIV Research, 2012, 10 
9. Wit et al. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior 
treatment experience, compared with treatment-naive patients: the ATHENA cohort study. CID 
2008;46:933-940. 
10. De Lazzari E et al. Hepatotoxicity of nevirapine in virologically suppressed patients according to 
gender and CD4 cell counts. HIV Med. 2008 Apr; 9(4):221-6 
11. Podzamczer D et al, Long-terms benefits of nevirapine-containing regimens: multicenter study 
with 506 patients, followed-up a median of 9 years. Curr HIV Res 2012 Sep 1; 10(6): 513-20 
12. Reliquet V. Antiviral Therapy 2014;19:117-123 
13. Montrucchio C. 5th Italian Conference on AIDS and retrovirus (ICAR) 2013  Abstract CO10 
14. Di Giambenedetto S. J Antimicrob Chemother 2012 
15. Ryom L. HIV Medicine (2013) 14, 503–508 
16. Italian Guidelines for the use of antiretroviral drugs and the diagnostic-clinical management of 
people infected with HIV-1, Nov. 2013 
17. V.A. Johnson et al. Update of the Drug Resistance Mutations in HIV-1: March 2013; IAS-USA 
2014 Resistance Mutations Update, Topics in Antiviral Medicine, Volume 22 Issue 3 June/july 
2014 
18. Summary of Product Characteristics of Raltegravir 
19. Summary of Product Characteristics of Nevirapine 
 
 
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20. Summary of Product Characteristics of Lamivudine 
21. Bredeek F, et al. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy 
(ICAAC). September 17-20, 2011. Chicago. Abstract H1-1399b. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDICES 
 
 
 
Appendix 1 
Laboratory Analyses for Admission to Study and for Safety Assessment 
 
 
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Hematology Laboratory Test   
Blood hemoglobin test 
Whole blood hematocrit 
Red blood cell count 
White blood cell count 
White blood cell differential:  
    blood neutrophil count 
    blood monocyte count  
    blood eosinophilic leukocyte count 
    blood basophilic leukocyte 
    blood lymphocyte count  
     
Blood platelet count 
Mean corpuscular volume 
Blood helper/inducer cell lymphocyte count (absolute and %) (blood CD4 count) 
Blood suppressor/cytotoxic cell lymphocyte count (absolute and %) (blood CD8 count) 
Blood helper cell/suppressor cell lymphocyte ratio (blood CD4/CD8 ratio) 
Blood Chemistry Test  
Serum aspartate aminotransferase test (AST or SGOT)* 
Serum alanine aminotransferase test (ALT or SGPT)* 
Serum alkaline phosphatase test 
Serum gamma-glutamyl transferase (GGT) test* 
Serum lactate dehydrogenase (LDH) test 
Serum creatine kinase test 
Total serum bilirubin test * 
Direct serum bilirubin test* 
Indirect serum bilirubin test* 
Uric acid test 
Amylase 
Lipase 
Serum creatinine test 
 
 
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Serum blood urea nitrogen test 
Total serum protein test 
Serum albumin test 
Serum glucose test 
Serum sodium test 
Serum potassium test 
Serum phosphate test 
Serum chloride test 
Serum bicarbonate test 
Serum calcium test 
PTH test 
25-hydroxyvitamin D test 
*test for hepatic safety  
Fasting Lipids 
Fasting lipid profile (CDC lipids): 
 serum low-density lipoprotein cholesterol test  (serum LDL-C) 
 serum high-density lipoprotein cholesterol test (serum HDL-C) 
 serum cholesterol test     
 serum triglyceride test     
Pregnancy Test 
Serum beta-human chorionic gonadotropin test 
Hemostatic Function Test  
Prothrombin test (PT) 
Activated partial thromboplastin time (APTT) 
International Normalized Ratio (INR) 
Kidney function  
Estimated GFR measured by MDRD formula with 6 variables that is MDRD 4 variables plus 
blood urea nitrogen and albumin 
Urine test  
Urine Tubular Kidney Injury Markers (24h urine collection): b2-microglobulin (b2M), and 
N- Tubular Kidney Injury Markers: retinol-binding protein (RBP) 
 
 
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Urine Tubular Kidney Injury Markers (urine test) : acetyl-b-D-glucosaminidase (NAG) 
 
Bone Evaluation 
Metabolic bone formation markers: s-BSAP (Serum Bone Specific Alkaline Phosphatase)   
Metabolic bone resorption markers: s-CTx (C-telopepdides of Type I Collagen) 
 
Clinical Serology Test   
To be done at Screening for all patients prior to randomization.  
Serum hepatitis B surface antigen test  
Serum hepatitis B surface antibody test  
Serum hepatitis Be antigen test  
Serum hepatitis C antibody testa 
1 If results is positive, then hepatitis C virus PCR quantitative test should also be perfomed 
Virology Test 
Plasma HIV-RNA quantification test 
Viral Resistance Tests 
Blood samples for genotypic assay will be collected at virologic failure confirmation visit to 
assess resistance to the drugs.  The viral resistance tests are carried out by local qualified 
hospital laboratories. 
 
Pharmacokinetic Analysis 
Pk Intensive Blood sampling: determination of raltegravir and nevirapine AUCs 
Pk Ctrough sampling: at the end of the dose interval 12 ± 2 hours  
Pharmacogenomic Analysis 
CYP2B6 single nucleotide polymorphisms (SNPs) will be screened in both patients 
undergoing AUC determination and those being sampled for Ctrough. 
                                                 
 
 
 
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Appendix 2: 
Guidelines For Grading Severity Of Laboratory Adverse Experiences 
 For Toxicity Management 
 
 
 
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Appendix 3:  
Adherence Questionnaire
 
 
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Appendix 4:  
Merck Code Of Conduct For Clinical Trials
 
 
                                   
 
 
 
 
 
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Merck* 
Code of Conduct for Clinical Trials 
I. 
Introduction 
A. Purpose 
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and 
effectiveness of our products.  As such, we are committed to designing, implementing, 
conducting, analyzing and reporting these studies in compliance with the highest ethical and 
scientific standards.  Protection of subject safety is the overriding concern in the design of 
clinical trials.  In all cases, Merck clinical studies will be conducted in compliance with local 
and/or national regulations and in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki. 
B. Scope 
Such standards shall be endorsed for all clinical interventional investigations sponsored by 
Merck irrespective of the party (parties) employed for their execution (eg, contract research 
organizations, collaborative research efforts).  This Code is not intended to apply to studies 
which are observational in nature, or which are retrospective.  Further, this Code does not 
apply to investigator-initiated studies (eg, Medical School Grant Program), which are not 
under the control of Merck. 
II. 
Scientific Issues 
A. Trial Conduct 
1. 
Trial Design 
Except for pilot or estimation studies, clinical trial protocols will be hypothesis-driven to 
assess safety, efficacy and/or pharmacokinetic or pharmacodynamic indices of Merck or 
comparator products.  Alternatively, Merck may conduct outcomes research trials, studies to 
assess or validate various endpoint measures, or studies to determine patient preferences, 
etc. 
The design (ie, subject population, duration, statistical power) must be adequate to address 
the specific purpose of the trial.  Research subjects must meet protocol entry criteria to be 
enrolled in the trial. 
2. Site Selection 
Merck selects investigative sites based on medical expertise, access to appropriate 
patients, adequacy of facilities and staff, previous performance in Merck studies, as well 
as budgetary considerations.  Prior to trial initiation, sites are evaluated by Merck 
personnel to assess the ability to successfully conduct the trial. 
3. Site Monitoring/Scientific Integrity 
Trial sites are monitored to assess compliance with the trial protocol and general 
principles of Good Clinical Practice.  Merck reviews clinical data for accuracy, 
completeness and consistency.  Data are verified versus source documentation 
according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP non-Compliance are suspected, the issues are promptly 
investigated.  When necessary, the clinical site will be closed, the responsible regulatory 
authorities and ethics review committees notified and data disclosed accordingly. 
D. Publication and Authorship 
To the extent scientifically appropriate, Merck seeks to publish the results of studies it 
conducts.  Some early phase or pilot studies are intended to be hypothesis-generating rather 
than hypothesis testing.  In such cases, publication of results may not be appropriate since 
the trial may be underpowered and the analyses complicated by statistical issues of 
multiplicity. 
 
 
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Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good 
Clinical Practice guidelines.  In summary, authorship should reflect significant contribution to 
the design and conduct of the trial, performance or interpretation of the analysis, and/or 
writing of the manuscript.  All named authors must be able to defend the trial results and 
conclusions.  Merck funding of a trial will be acknowledged in publications. 
III. 
Subject Protection 
A. IRB/ERC Review 
All clinical trials will be reviewed and approved by an independent IRB/ERC before being 
initiated at each site.  Significant changes or revisions to the protocol will be approved by the 
IRB/ERC prior to implementation, except that changes required urgently to protect subject 
safety and well-being may be enacted in anticipation of IRB/ERC approval.  For each site, the 
IRB/ERC and Merck’s Consent Form Review department (U.S. studies) or Clinical Research 
Director (non-U.S. studies) will approve the subject informed consent form. 
B. Safety 
The guiding principle in decision-making in clinical trials is that subject welfare is of primary 
importance.  Potential subjects will be informed of the risks and benefits of, as well as 
alternatives to, trial participation.  At a minimum, trial designs will take into account the local 
standard of care.  Subjects are never denied access to appropriate medical care based on 
participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing 
informed consent for participation.  Subjects may withdraw from a Merck trial at any time, 
without any influence on their access to, or receipt of, medical care that may otherwise be 
available to them. 
C. Confidentiality 
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  
Unless required by law, only the investigator, sponsor (or representative) and/or regulatory 
authorities will have access to confidential medical records that might identify the research 
subject by name. 
D. DNA Research 
DNA sequence analyses, including use of archival specimens collected as part of a clinical 
trial, will only be performed with the specific informed consent of the subject.  With IRB 
approval, an exception to this restriction on use of archival specimens may be possible (for 
instance, if specimens are de-identified and are not referable to a specific subject). 
IV. 
Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators 
(or the sponsoring institution) in a fair manner for the work performed in support of Merck 
studies.  Merck does not pay incentives to enroll subjects in its trials.  However, when 
enrollment is particularly challenging, additional payments may be made to compensate for 
the time spent in extra recruiting efforts. 
Merck does not pay for subject referrals.  However, Merck may compensate referring 
physicians for time spent on chart review to identify potentially eligible subjects. 
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing the trial.  
However, the local IRB/ERC may wish to alter the wording of the disclosure statement to be 
consistent with financial practices at that institution.  As noted above, publications resulting 
from Merck studies will indicate Merck as a source of funding. 
C. Funding for Travel and Other Requests 
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator 
meetings, etc.) will be consistent with local guidelines and practices including, in the U.S., 
those established by the American Medical Association (AMA). 
 
 
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V. Investigator Commitment 
Investigators will be expected to review Merck’s Code of Conduct as an attachment to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards. 
 
* In this document, "Merck" refers to Merck Sharp & Dohme Corp, which is a subsidiary of Merck & 
Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."  
 
 
 
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