| 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 | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
| E.1.2 | System Organ Class | 100000004862 |
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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 describe the incidence of Grade 3 and Grade 4 alanine aminotransferase (ALT) abnormalities defined as >5x upper limit of normal (ULN) for subjects whose baseline ALT ≤ULN, or >3.5x baseline for subjects whose baseline ALT >ULN, at Week 48 in the maraviroc versus the placebo arm. |
|
| E.2.2 | Secondary objectives of the trial |
| A number of secondary objectives through Week 144 include an assessment of the potential antifibrotic activity of maraviroc, and liver histology, as well as, virologic response, immunologic response, safety and tolerability, pharmacokinetics, and changes in HCV RNA and HBV DNA. |
|
| 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 |
| Liver biopsy substudy in approximately 24 subjects (12 per arm) |
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| E.3 | Principal inclusion criteria |
1. Men or women at least 18 years of age available for a follow-up period of at least 148 weeks;
2. Undetectable HIV-1 RNA for at least 3 months prior to the screening visit;
3. Treatment with current antiretroviral therapy (3-6 drugs excluding low-dose ritonavir) for at least 5 months;
4. Detectable HCV RNA and/or Hepatitis B surface antigen (HBsAg) positive;
5. Willing to initiate and remain on randomized treatment without any changes or additions to the background treatment, except for toxicity management or upon virologic failure;
6. HBV co-infected subjects must be taking a HAART regimen active against HBV or HBV-specific antivirals, and they must not stop any drug with anti-HBV activity
while participating in this study, due to the risk of developing life-threatening hepatic flares;
7. A negative pregnancy test for women who are of childbearing potential (WOCBP) and the results must be available and documented in the source documents prior tostudy entry at the baseline visit.
NOTE: WOCBP includes any female who has experienced menarche and who has not undergone hysterectomy, bilateral oopherectomy or tubal ligation, or is not
post-menopausal (aged >45 yrs, amenorheic for >2yrs, and serum FSH levels >30 IU/L). Even women who are using mechanical products (intrauterine devices, barrier methods) to prevent pregnancy, who are practicing abstinence, or who have a partner that is sterile (eg, vasectomy) should be considered of CBP.
8. WOCBP, males and their partners must use 2 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; |
|
| E.4 | Principal exclusion criteria |
1. Currently receiving maraviroc;
2. Suspected or documented active, untreated HIV-1 related opportunistic infections (OI) or other condition requiring acute therapy at the time of randomization. Subjects on a stable secondary OI prophylaxis regimen (>1 month) are eligible for the study, and subjects on a primary OI prophylaxis regimen of any duration are also eligible for the study;
NOTE: Trimethoprim-sulfamethoxazole may not be initiated within 30 days prior to screening but may be continued if subject is on stable therapy. The use of isoniazid is prohibited.
3. Treatment for an active opportunistic infection, or unexplained temperature >38.5°C for 7 consecutive days within 30 days prior to screening;
4. Prior treatment with maraviroc or another CCR5 antagonist for more than 14 days at any time;
5. Active alcohol consumption of not less than 30g ethanol per day in males and not less than 20g ethanol per day in females;
6. Substance abuse sufficient in the Investigator’s judgment to prevent adherence to study medication and/or follow up. Subjects receiving methadone or buprenorphine replacement therapy is allowed in the study;
7. Lactating women, or planned pregnancy during the trial period;
8. Malignancy requiring parenteral or oral chemotherapy that must be continued for the duration of the trial;
9. Subjects receiving treatment for HCV infection or who anticipate the need to initiate HCV treatment after randomization. Subjects who were previously treated for HCV and are still HCV-positive are eligible for the study;
10. Documented or suspected acute hepatitis or pancreatitis within 30 days prior to screening;
11. Renal insufficiency defined as a creatinine clearance of ≤80 mL/min (as calculated by the Cockcroft and Gault equation) (Appendix 2);
12. Any of the following laboratory abnormalities:
ALT and/or AST levels >5 times the ULN (ACTG Grade 3);
Direct bilirubin >1.5 times the ULN;
Prothrombin time prolonged >6 sec;
Serum albumin <2.8 g/dL;
Absolute neutrophil count ≤750 cells/mm3;
Platelet count ≤50,000 cells/mm3;
Hemoglobin ≤7 g/dL.
13. History of bleeding esophageal varices, ascites, encephalopathy, persistent jaundice or decompensated cirrhosis;
14. Child-Pugh Class C category (score >9) (Appendix 3);
15. Evidence of other known underlying liver disease including autoimmune hepatitis, metabolic liver disease, known biliary abnormalities (exception – Gilbert’s syndrome or asymptomatic gallstones), hemochromatosis, genetic liver disease, or drug-induced liver disease;
16. Clinically significant malabsorption syndrome (eg, not less than 6 loose stools per day for at least 7 consecutive days) within 30 days prior to screening;
17. Inability to tolerate oral medication;
18. Concomitant therapy with other investigational agents;
19. The following medications being taken by the subject at the time of randomization that must be continued during the study period, including immunomodulators (for the treatment of HIV-1 infection), isoniazid, rifampin, rifapentine, rifabutin, St. John’s Wort and/or drugs that are contraindicated with any of the antiretroviral agents in the regimen;
20. Known hypersensitivity or contraindication to any components of maraviroc, including soy lecithin, or peanuts;
21. Participation in other studies within 30 days before the current study begins and/or during study participation
22. 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 subject
inappropriate for entry into this study.
23. Subjects who are investigational site staff members or subjects who are Pfizer or ViiV employees directly involved in the conduct of the trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for subjects whose baseline ALT ≤ULN, or >3.5x baseline for subjects whose baseline ALT >ULN, at Week 48 in the maraviroc arm versus the placebo arm. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for subjects whose baseline ALT ≤ULN, or >3.5x baseline for subjects whose baseline ALT >ULN, at Weeks 96 and 144;
• Time to development of Grade 3 and Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for subjects whose baseline ALT ≤ULN, or >3.5x baseline for subjects whose baseline ALT >ULN, at Weeks 48, 96 and 144;
• Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT = or >100 IU/L at Weeks 48, 96 and 144;
• Time to development of Grade 3 and Grade 4 ALT test abnormalities associated with a change from baseline ALT = or >100 IU/L at Weeks 48, 96 and 144;
• Percentage of subjects with Hy’s law abnormalities at Weeks 48, 96 and 144;
• Percentage of subjects with plasma HIV 1 RNA concentration <40 copies/mL at Weeks 48, 96 and 144;
• Change from baseline in CD4+ and CD8+ cell counts at Weeks 48, 96 and 144;
• Frequency and severity of adverse events and laboratory abnormalities;
• Change from baseline in markers of immune activation (CD38 expression on CD4 and CD8 cells, C reactive protein, D dimer, transforming growth factor beta [TGF beta]) at Weeks 48, 96 and 144;
• Change from baseline in plasma HCV RNA at Weeks 48, 96 and 144;
• Change from baseline in plasma HBV DNA at Weeks 48, 96 and 144;
• Change from baseline in Enhanced Liver Fibrosis (ELF) test at Weeks 48, 96 and 144;
• Change from baseline in the hepatic elastography (Fibroscan) at Weeks 48, 96 and 144;
• Change from baseline in fibrosis score (Ishak) in liver biopsy samples at Week 144 (liver biopsy substudy);
• Maraviroc population pharmacokinetics (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses (to be reported separately);
• Health economic impact, as measured by the utilization of hepatic fibrosis and cirrhosis related inpatient and outpatient services and associated costs of care.
|
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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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, virology testing, immune activation markers, liver fibrosis assessment. |
|
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 30 |
| 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 |
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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
|
| End of Trial in all participating countries is defined as the last subject last visit. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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