| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV infection |
|
| 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 this study is to determine the proportion of subjects with HIV RNA < 50 c/mL at Week 24 in HIV-1 infected Treatment-Naive Subjects. |
|
| E.2.2 | Secondary objectives of the trial |
Determine:
1) proportion of subjects with non-response at Week (WK) 8
2) proportions of subjects with HIV RNA<50 c/mL at WK 48 & 96
3) proportions of subjects with HIV RNA<400 c/mL at WK 24, 48 & 96
4) antiretroviral activity at WK 24, 48 & 96 as measured by
−Change from baseline in CD4 cell counts
−Emergence of genotypic substitutions & phenotypic resistance among subjects
with virologic failure
Assess:
5) safety through WK 24, 48 & 96
−Frequency of AEs, SAEs, discontinuations, deaths & laboratory abnormalities
−Changes from baseline in select laboratory tests (eg, total bilirubin, fasting lipids)
−QRS widening, QT & PR prolongation from ECGs through WK 24, 48 & 96
6)Pharmacokinetics:
−estimate population mean inhibitory quotient for ATV co-administered with RAL in Group 1 & for ATV boosted with RTV in Group 2, based on trough concentration & historical population mean protein-binding corrected EC90
See Protocol Section 2.2 for additional secondary objectives
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Signed Written Informed Consent
1) Freely given informed consent must be obtained from subjects prior to clinical trial
participation, including informed consent for any screening procedures conducted to
establish subject eligibility for the trial;
Target Population
2) Screening HIV-1 RNA ≥ 5000 c/mL
3) Screening CD4 cell count meeting one of the following criteria:
a) < 350 cells/mm³
b) Screening CD4 ≥ 50 and ≤ 500 cells/mm³ ONLY if at least one of the following
conditions apply:
i) Screening HIV RNA > 100,000 c/mL , or
ii) CD4 decline > 50 - 100 cells/mm³/year, or
iii) age ≥ 55 years
c) Any CD4 cell count if subject has a history of an AIDS defining illness (see
Protocol Appendix 7)
4) Antiretroviral treatment-naive, as defined by:
a) No prior treatment with ATV or RAL or TDF/FTC or 3TC either for treatment or
prophylaxis.
b) No antiretroviral therapy with drugs ≥ 1 week (excluding ATV or RAL or
TDF/FTC or 3TC; see above)
However, in specific settings of antiretroviral treatment including: post exposure
prophylaxis (PEP), pre-exposure prophylaxis (PREP) and/or 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:
i) < 6 weeks of triple antiretroviral therapy (3 drugs of any class, except ATV or
integrase inhibitors or TDF/FTC or 3TC)
or
ii) < 4 weeks of dual antiretroviral therapy (2 drugs of any class, except ATV or
integrase inhibitors or TDF/FTC or 3TC)
or
iii) < 1 week of mono-antiretroviral therapy (1 drug of any class, except ATV or
integrase inhibitors or TDF/FTC or 3TC)
5) Medically stable to participate in the study, in the opinion of the investigator, and as determined by medical history, physical examination, and clinical laboratory
evaluations.
Age and Sex
6) Men and women, ≥ age 18 (or minimum age as determined by local regulatory or as legal requirements dictate)
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 last dose of investigational product, in such a manner that the risk of pregnancy is minimized. Since acceptable and available methods of contraception vary among
different countries, participating women may choose their preferred contraceptive
method based on physician recommendations.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement therapy
(HRT), a documented serum follicle stimulating hormone (FSH) level ≥ 35 mIU/mL.
Women who are using oral contraceptives, other hormonal contraceptives (vaginal
products, skin patches, or implanted or injectable products), or mechanical products
such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides)
to prevent pregnancy, or are practicing abstinence or where their partner is sterile (eg, vasectomy) should be considered to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity
25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product. |
|
| E.4 | Principal exclusion criteria |
Sex and Reproductive Status
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 last dose of
investigational product.
2) WOCBP using a prohibited contraceptive method. Caution is warranted with
co-administration of oral contraceptives (ethinyl estradiol and norethindrone); see
Protocol Appendix 4.
3) Women who are pregnant or breastfeeding
4) Women with a positive pregnancy test on enrollment or prior to investigational
product administration.
Target Disease Exceptions
5) Screening HIV Genotype showing resistance to any component of the study regimen, as described in Protocol Appendix 3;
6) Any antiretroviral therapy within 30 days prior to screening;
7) Presence of a newly diagnosed HIV-related opportunistic infection or any medical
condition requiring acute therapy at the time of enrollment; Suspected primary (acute) HIV infection;
Medical History and Concurrent Diseases
8) Co-infection with human hepatitis B virus (HBV), hepatitis C virus (HCV). HBV
coinfection is defined by HBsAg positive or anti- HBc positive; HCV coinfection is
defined as HCV Ab positive plus detectable HCV RNA.
9) History of or current presence of cardiac disease, defined by presence of arrhythmias, ischemic disease, or a conduction abnormality including left bundle branch block (LBB) or left anterior fascicular block (LAFB), > 1st degree atrioventricular block (AVB), 2nd/3rd degree AVB, or any cardiac abnormality deemed clinically significant by investigator. In addition, the following ECG findings are exclusionary:
a) PR Interval > 260msec (severe first degree AV block)
b) QRS Interval > 120msec
10) Gastro-esophageal reflux disease (GERD), or conditions that would lead the
investigator to believe that there is a significant likelihood that the subject will need
prohibited therapies or medications (eg, Proton Pump Inhibitors) while on study
therapy;
11) 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;
Physical and Laboratory Test Findings
12) Liver enzymes (ALT/AST) > 5 times the upper limit of normal
13) Alkaline phosphatase > 5 times the upper limit of normal
14) Serum creatinine > 1.5 times the upper limit of normal
15) Creatinine clearance < 60 cc/min
16) Bilirubin >1.5 times the upper limit of normal
17) Hemoglobin < 8.0 g/dL
18) Platelets < 50,000 cells/mm3
19) Urine protein ≥ 2+
Prohibited Treatments and/or Therapies
20) Refer to Appendix 4, which details prohibited and cautionary therapies.
Other Exclusion Criteria
21) Prisoners or subjects who are involuntarily incarcerated
22) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
* Primary: Proportion of subjects with HIV RNA < 50 c/mL at Week 24.
* Secondary:
1) Proportion of subjects with non-response at Week 8.
2) Proportions of subjects with HIV RNA < 50 c/mL at Weeks 48 and 96.
3) Proportions of subjects with HIV RNA < 400 c/mL at Weeks 24, 48 and 96.
4) Antiretroviral activity at Weeks 24, 48, and 96:
− Change from baseline in CD4 cell counts
− Emergence of genotypic substitutions and phenotypic resistance among subjects with virologic failure (HIV RNA ≥ 400 c/mL)
5) Safety through Weeks 24, 48, and 96 as measured by:
− Frequency of adverse events, SAEs, discontinuations, death, and laboratory abnormalities.
− Changes from baseline in select laboratory tests (total bilirubin, fasting lipids).
− QRS widening, QT and PR prolongation from ECGs
6) Assessment of Pharmacokinetics (Trough PK for all subjects at selected visits through Week 48; Intensive PK for 16 subjects in Group 1 at Week 2):
− To estimate the inhibitory quotient for ATV of each subject in Group 1, and for boosted ATV in Group 2, based on trough concentration and estimated protein-binding corrected EC90 at baseline.
− To explore correlations between trough concentrations of ATV and RAL (Group 1) and boosted ATV (Group 2) over time with efficacy and safety parameters.
− To characterize the PK profile of ATV and RAL co-administered in Group 1 (AUC, Cmin, Cmax).
− To estimate the ATV PK when ATV is co-administered with RAL BID (Group 1) relative to when it is co-administered with RTV + TDF/FTC QD (historical control). |
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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