| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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| 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 |
| To assess whether maraviroc (SelzentryTM, Celsentri®) administered once daily (QD) is non inferior to a reference regimen of emtricitabine/tenofovir administered QD each in combination with darunavir/ritonavir in the treatment of antiretroviral naïve HIV 1 infected subjects as measured by the proportion of subjects with HIV 1 RNA below the limits of assay detection (<50 copies of HIV 1 RNA per milliliter of plasma) at Week 48. |
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| E.2.2 | Secondary objectives of the trial |
1. To assess the safety and tolerability of maraviroc when administered in combination with darunavir/ritonavir.
2. To assess the utility of genotype testing or the enhanced Trofile assay (ESTA) for tropism testing in predicting virologic outcomes of a maraviroc containing regimen.
3. To compare the proportion of subjects with HIV 1 RNA below the limits of assay detection at Week 96 for maraviroc versus emtricitabine/tenofovir.
4. To compare the differences in the magnitude of changes in CD4+ and CD8+ cell counts and CD4+/CD8+ ratio from baseline through Weeks 48 and 96 for maraviroc versus emtricitabine/tenofovir.
5. To examine tropism change and the evolution of viral resistance in virologic failure subjects.
6. To compare the effects on peripheral fat distribution and trunk to limb fat ratio of maraviroc versus emtricitabine/tenofovir.
7. To compare the effects on bone mineral density of maraviroc versus emtricitabine/tenofovir
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| 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 |
Title: The Dual Energy X-ray Absorptiometry (DEXA) Scan Sub-Study
Date: 20 September 2011
Objectives: (i) To compare the effects on peripheral fat distribution and trunk to limb fat ratio (using DEXA scan) of maraviroc versus emtricitabine/tenofovir
(ii) To compare the effects on bone mineral density (using DEXA scan and serum markers) of maraviroc versus emtricitabine/tenofovir |
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| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study
2. At least 18 years of age at the Screening Visit.
3. Plasma HIV 1 RNA equal to or more than 1,000 copies/mL measured at the Screening Visit.
4. CD4 count equal to or more than 100 cells/mm3 at Screening.
5. Have only R5 HIV 1 at Screening as verified by a randomized tropism assay.
6. A negative urine pregnancy test at Screening and at the Baseline Visit, prior to receiving the first dose of study medication, for Women of Child Bearing Potential (WOCBP).
NOTE: WOCBP include any female who has experienced menarche and who has not undergone hysterectomy, bilateral oophorectomy or tubal ligation or any other successful surgical sterilization or is not post menopausal (age >45 years, amenorrheic for >2 years, and serum FSH levels >30 IU/L). Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products (intrauterine devices; barrier methods: eg. condom or diaphragm with spermicidal) to prevent pregnancy, who are practising abstinence, or who have a partner that is sterile (eg, vasectomy), should be considered to be of child bearing potential.
7. WOCBP, male study subjects and their partners must use two forms of contraception one of which is effective barrier contraception throughout the study and for at least 28 days following the last dose of study medication. WOCBP must use another acceptable method of contraception from screening to at least 28 days after the trial. Acceptable contraception includes the following:
• Oral, transdermal, implantable, or injectable hormone therapy;
• Effective intrauterine devices;
• Vasectomized partner;
• Double barrier contraceptive methods.
8. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
9. Subjects who have consented to participate in the DEXA scan sub study must be equal to or less than 136 kg (300 lb) in weight and equal to or less than 1.95 m (6ft. 4.8 inches) in height and have a body mass index equal to or less than 40 kg/m2
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| E.4 | Principal exclusion criteria |
1. Suspected or documented active, untreated HIV 1 related Opportunistic Infection (OI) or other condition requiring acute therapy (eg, acute hepatitis C virus infection) at the time of randomization to treatment. [Subjects on a stable (>1 month) secondary OI prophylaxis regimen or chronic treatment with stable disease (eg, for hepatitis C virus infection) are eligible for the study; subjects on a primary OI prophylaxis regimen of any duration are also eligible for the study].
2. Treatment for an active opportunistic infection, or unexplained temperature >38.5°C (101.3º F) for 7 consecutive days, within 30 days prior to screening.
3. Prior treatment with any other HIV antiretroviral therapy for more than 14 days at any time.
4. Active alcohol consumption equal to or more than 30 g ethanol per day in males and equal to or more than 20 g per day in females.
5. Substance abuse sufficient, in the Investigator’s judgment, to prevent adherence to study medication and/or Follow Up.
6. Lactating women or planned pregnancy during the study period.
7. Initiation of therapy with a potentially myelosuppressive, neurotoxic, hepatotoxic and/or cytotoxic agent within 60 days prior to screening or the expected need for such therapy during the study period.
8. Malignancy requiring parenteral or oral chemotherapy that must be continued for the duration of the study.
9. Documented or suspected acute hepatitis or pancreatitis within 30 days prior to Randomization
10. Renal insufficiency defined as a serum creatinine greater than 3 times the upper limit of normal or a creatinine clearance of less than 50 mL/min, as calculated by the Cockcroft and Gault equation.
11. Potentially life threatening (Grade 4) laboratory abnormality or medical condition (according to the Division of AIDS table for grading severity of adult adverse experiences.
12. ALT equal to or more than 5.0xULN;
13. Subjects with chronic Hepatitis B (HBsAg positive).
14. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
15. Clinically significant malabsorption syndrome (eg, equal to or more than 6 loose stools per day for at least 7 consecutive days) within 30 days prior to Screening.
16. Inability to tolerate oral medication.
17. Concomitant therapy with other investigational agents.
18. The following medications being taken by the subject at the time of randomization to treatment that must be continued during the study period, including immunomodulators (for the treatment of HIV 1 infection), and any contraindicated medication described in the package inserts of maraviroc (Selzentry, Celsentri), darunavir (Prezista), ritonavir (Norvir) and emtricitabine/tenofovir (Truvada).
19. Any evidence of genotypic/phenotypic resistance to darunavir, tenofovir, and emtricitabine.
20. CXCR4 using virus detected using randomized tropism determination or repeated failure to obtain an interpretable tropism result.
21. Any safety, behavioral, clinical, or administrative reasons that, in the Investigator’s judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy.
22. Have a known hypersensitivity to darunavir, ritonavir, tenofovir, emtricitabine, to maraviroc or any of its excipients, including soy lecithin or dyes of those drugs as described in the package inserts, or known hypersensitivity or allergy to peanuts.
23. Participation in other interventional studies within 30 days before the current study begins and/or during study participation
24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patientsubject inappropriate for entry into this study.
25. Subjects who are investigational site staff members or subjects who are the Sponsor’s employees directly involved in the conduct of the trial.
26. Subjects who have consented to participate in the DEXA scan sub study who have implants in the lumbar spine or have multiple vertebral fracture or severe degenerative disease (eg, scoliosis, osteophytes, sclerosis, etc.) in the range L1 L4 which prevents reliable spine bone mineral density measurement
27. Subjects who have consented to participate in the DEXA scan sub study who have implants in both hips or bilateral disease or deformity which prevents reliable hip bone mineral density measurement
28. Subjects who have consented to participate in the DEXA scan sub study who are receiving osteoporosis drug treatment within 30 days prior to Screening and/or during study participation. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The proportion of subjects with plasma HIV 1 RNA <50 copies/mL at Week 48. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Safety: Frequency, severity and relationship of adverse events to test drug; serious adverse events; discontinuations due to adverse events; and frequency and severity of abnormal laboratory values.
2. The relationship between the proportion of subjects with plasma HIV 1 RNA <50 copies/mL at the Week 48 and Week 96 visits and the screening tropism test (Genotype test or ESTA) in the maraviroc-containing regimen..
3. Virologic Response:
Proportion of subjects with plasma HIV RNA <50 copies/mL at Week 96.
4. Immunological Response at Week 48 and Week 96:
a. Changes in CD4+ T lymphocyte (CD4) cell counts and percent change from Baseline;
b. Changes in CD8+ T lymphocyte (CD8) cell counts and percent change from Baseline;
c. Changes in CD4+/CD8+ ratio and changes from Baseline.
5. Evolution of viral resistance and tropism change between Screening or Baseline and the time of confirmation of virologic failure or the last on treatment time point:
a. HIV 1 tropism (Genotype test)
b. For virologic failure with R5 virus, viral resistance to maraviroc (maraviroc treated subjects only).
c. Viral resistance (Genotype and Phenotype) to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) and non nucleoside reverse transcriptase inhibitors (NNRTI) [reverse transcriptase inhibitors, RTI] and protease inhibitors (PI).
6. Changes in peripheral fat distribution and trunk to limb fat ratio (using DEXA scan) from Baseline and at Weeks 48 and 96 (approximately 109 subjects per treatment arm).
7. Changes in bone mineral density (using DEXA scan and serum markers) from Baseline and at Weeks 48 and 96 (approximately 109 subjects per treatment arm).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| 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 | No |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Colombia |
| Mexico |
| United States |
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| 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
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| 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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