| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HIV-1 Infected Treatment Naive Subjects |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of the study is to compare the proportion of subjects with HIV
RNA < 50 c/mL at Week 48 between the ATV/RTV/TDF/FTC and LPV/RTV/TDF/FTC treatment regimens.
|
|
| E.2.2 | Secondary objectives of the trial |
To assess:
-proportion of subjects with HIV RNA<400 c/mL at Week 48
-proportions of subjects with HIV RNA<50 c/mL and <400 c/mL at Week 96
-time to loss of virologic response
-reduction of log10 HIV RNA from baseline through Weeks 48 and 96
-change in CD4 cell count from baseline through Weeks 48 and 96
-safety and tolerability of the regimens
-changes from baseline in fasting lipids over time and proportion of subjects with NCEP-guided categories of fasting lipids over time
-changes from baseline in fasting glucose and insulin
-antiretroviral resistance profiles of subjects experiencing virologic failure
-trough concentrations of ATV, LPV, and RTV and to explore correlations
with efficacy and safety parameters
To evaluate:
-quality of life (as by MOS-HIV)
-impact of gastro-intestinal toxicity on the quality of life (as by IBS-QOL questionnaire)
-adherence to each drug and to the regimen (as by MACS adherence questionnaire) |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
* LIPODYSTROPHY SUBSTUDY (Appendix 1 to Protocol v4.0, Dated 09-Oct-2006)
Primary objective:
To compare the changes in body fat redistribution, as assessed by the change from baseline in trunk-to-limb fat ratio measured by DEXA at Week 96.
Secondary objectives:
1) To assess the change in body fat redistribution using the change from baseline in trunk-to-limb fat ratio measured by DEXA at Week 48;
2) To assess the changes from baseline in limb, trunk and total body fat measured by DEXA at Weeks 48 and 96;
3) To assess the changes from baseline in VAT, SAT and total adipose tissue (TAT) measured by CT at Weeks 48 and 96;
4) To assess the changes from baseline in spinal and hip bone mineral density measured by DEXA at Weeks 48 and 96;
5) To evaluate changes from baseline in physical measurements at Weeks 48 & 96; 6) To evaluate changes from baseline in exploratory markers including adipocytokines, hormones and inflammatory proteins including adiponectin, leptin, resistin, TNF-alpha, IL-6, PAI-1, Hs-CRP, HbA1c and fibrinogen over time.
* INTENSIVE PHARMACOKINETIC SUBSTUDY (Appendix 1 to Protocol v4.0, Dated 09-Oct-2006)
Objectives: The following objectives will be evaluated at Week 4:
• To assess the steady state pharmacokinetics of ATV/RTV in ARV naïve HIV-infected subjects in the presence of an ARV regimen including TDF.
• To assess the steady state pharmacokinetics of LPV/RTV in ARV naïve HIV-infected subjects in the presence of an ARV regimen including TDF.
• To assess the differential effect of ATV/RTV and LPV/RTV on the pharmacokinetics of tenofovir.
• To compare inhibitory quotient (IQ) of ATV and LPV (when dosed with RTV) using the concentration at the end of the dosing interval relative to the protein binding-corrected HIV EC90 values for the respective protease inhibitor derived from individual subject clinical isolates collected at baseline.
* METABOLIC PHARMACOGENETIC SUBSTUDY (Protocol Amendment 2, v1.0, Dated 21-Sep-2005):
To explore the relationship between the changes from baseline at Weeks 48 and 96 in fasting lipid profiles, insulin resistance, fat redistribution, and atherogenic and inflammatory markers associated with variant alleles of APOC3, APOE, TNFα in HIV-infected individuals treated with ATV/RTV or LPV/RTV, both in combination with TDF/FTC. |
|
| E.3 | Principal inclusion criteria |
1) Provide written informed consent and assess whether the subject is capable of reading and comprehending the informed consent;
2) Qualifying plasma HIV RNA ≥ 5000 c/mL obtained at screening;
3) Men and women, ages 18 years and older (or minimum age as determined by local regulatory or as legal requirements dictate).
4) Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized. Both females and males must utilize effective barrier contraception. |
|
| E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the study;
2) WOCBP using a prohibited contraceptive method (see Protocol Appendix 8);
3) Women who are pregnant or breastfeeding;
4) Women with a positive pregnancy test on enrollment or prior to study drug administration;
5) Presence of a newly diagnosed HIV-related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment;
6) Suspected primary (acute) HIV infection;
7) Any antiretroviral therapy within 30 days prior to screening
8) Prior antiretroviral therapy ≥ 1 week.
However in specific settings of antiretroviral treatment including
a/ post exposure prophylaxis (PEP)
b/ pre-exposure prophylaxis (PREP) and/or
c/ HAART exposure for reduction of risk of mother-to-child transmission,
the following prior antiretroviral exposure exceptions will apply, allowing the subject entry into the study:
•< 6 weeks of triple antiretroviral therapy (3 drugs of any class)
or
•< 4 weeks of dual antiretroviral therapy (2 drugs of any class)
or
•<1 week of mono-antiretroviral therapy (1 drug of any class)
9) Subjects with Cushing’s syndrome;
10) Untreated hypothyroidism or hyperthyroidism;
11) Recent therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment; or therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect CYP3A4 (see Protocol Section 6.4 and Appendix 8);
12) Subjects with obstructive liver disease;
13) Active alcohol or substance use sufficient, in the investigator’s opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis;
14) Proven or suspected acute hepatitis in the 30 days prior to study entry;
Note: Chronic co-infection with hepatitis C and/or B are not exclusion criteria.
Subjects with acute hepatitis infection may have the option to be screened after the
event has evolved into a chronic infection.
HBV co-infected subjects participating in this trial; and interrupting study therapy are
at an increased risk of developing elevations in hepatic transaminases due to prior
reports of exacerbations of hepatitis in patients after the discontinuation of
TDF/FTC.15 Subjects with HBV co-infection are required to have an additional
6 months of follow-up after stopping study medications.
15) Intractable diarrhea (≥ 6 loose stools/day for at least 7 consecutive days) within 30 days prior to study entry;
16) Inability to swallow capsules;
17) Active peripheral neuropathy;
18) Presence of cardiomyopathy or any significant cardiovascular disease;
19) Known, clinically significant cardiac conduction system disease. This includes severe first degree atrioventricular block (PR interval > 0.26 seconds) as well as second and third-degree atrioventricular block;
20) Moderate to Severe hepatic insufficiency
• If hepatic insufficiency is demonstrated at screening then the subject will have the
Child-Pugh Score calculated.
• Subject will not meet eligibility if the screening Child-Pugh Score = > 6 (Classes B or
C) (Appendix 13);
21) Screening laboratory values measured as follows;:
a) Calculated creatinine clearance < 60 mL/min as estimated by the Cockcroft-Gault equation:
For men, (140 – age in years) x (body weight in kg) ÷ (serum
creatinine in mg/dL x 72) = CrCl (mL/min)
For women, multiply the result by 0.85
b) total serum lipase ≥ 1.4 times the upper limit of normal,
c) liver enzymes (AST, ALT) ≥ 5 times the upper limit of normal,
d) total serum bilirubin ≥ 1.5 times the upper limit of normal.
22) Hypersensitivity to any component of the formulation of study drug;
23) Prohibited therapies and/or medication (see Protocol Appendix 8);
24) Subjects who have conditions that would lead the investigator to believe that there is
a significant likelihood that the subject will need prohibited therapies or medications
(e.g. Proton Pump Inhibitors) while on study therapy;
25) Any other clinical conditions or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for study or unable to comply with the dosing requirements;
26) Prisoners or subjects who are compulsorily detained. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects with HIV RNA < 50 c/mL at Week 48. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Outcomes Research Assessments (QoL); Tolerability of the regimens |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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