| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062237 |
| E.1.2 | Term | Renal impairment |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| 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 |
Primary objectives:
• Characterize the pharmacokinetics of MVC (150 mg) in the presence of Saquinavir/Ritonavir (SQV/r, a potent CYP3A4 inhibitor) in both healthy subjects and subjects with mild and moderate renal impairment.
• Characterize the pharmacokinetics of MVC (300 mg) in healthy subjects, subjects with severe renal impairment and those receiving chronic hemodialysis.
• Calculate the hemodialysis clearance of MVC in subjects with end stage renal disease (ESRD) undergoing hemodialysis. |
|
| E.2.2 | Secondary objectives of the trial |
Assess the safety and tolerability of MVC in the absence and presence of a potent
CYP3A4 inhibitor in subjects with various degrees of renal impairment or undergoing
hemodialysis. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects (female subjects must be of non childbearing potential, between the ages of 18 and 85 years, inclusive.
2. Body Mass Index (BMI) of approximately 18 to 40 kg/m2 inclusive; and a total body weight >50 kg (110 lbs) determined at screening.
3. Subjects must meet one of the following renal function categories:
• Normal renal function (CLCR >80 mL/min).
• Mild renal impairment (CLCR >50 and ≤80 mL/min).
• Moderate renal impairment (CLCR ≥30 and ≤50 mL/min).
• Severe renal impairment (CLCR <30 mL/min).
• End stage renal disease receiving chronic hemodialysis 3 times a week for at least 6 weeks prior to screening.
4. Stable renal function defined as ≤20% (25% for normal renal function) difference
between 2 measurements of serum creatinine obtained on 2 occasions separated by at least 2 weeks; the second determination must have been obtained within the 28-day period prior to the start of study medication administration [this definition does not apply to subjects with end stage renal disease receiving chronic hemodialysis].
5. Subjects in the normal renal function group must be healthy (healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests) and not be receiving chronic treatment with any prescription or non-prescription medication.
6. Willing and able to provide written informed consent and to be confined to the CRU as required by the protocol.
7. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Women who are pregnant or nursing or women of childbearing potential.
2. Subjects with known contraindications to maraviroc (and/or boosted saquinavir for
subjects with normal, mild or moderate renal impairment) according to local labeling.
3. Subjects with recent (within the last 3 months) history of myocardial infarction, unstable angina, coronary revascularization, stroke or TIA.
4. Subjects with severe heart failure (New York Heart Association Functional Class IV) at screening.
5. Subjects with acute renal disease.
6. Subjects with a history of renal transplant. However, subjects with a history of renal transplant who have rejected the organ and are no longer receiving immunosuppressive drugs are eligible for the study provided that the graft has been non-functional for at least one year.
7. For subjects receiving hemodialysis, subjects who have been hemodynamically unstable during or at the conclusion of dialysis, during the 2 weeks prior to dosing, as marked by symptomatic hypotension.
8. Subjects with liver disease as assessed by clinical evaluation or subjects with an ALT or AST at Screening that is >2.5 x-upper limit of the reference range (ULRR) or a total bilirubin that is >1.5 x-ULRR at Screening.
9. Subjects with any prior history of malignancy except for:
• Basal cell carcinoma of the skin.
• Squamous cell carcinoma of the skin that has been cancer free for >5 years.
• Other malignancies (regardless of site) that have been cancer free for >10 years.
10. Healthy subjects: Use of prescription drugs, vitamins and dietary supplements within seven days or 5 half-lives (whichever is longer) prior to the first dose of study medication.
11. Herbal supplements and hormone replacement therapy must be discontinued 28 days prior to the first dose of study medication. As an exception, acetaminophen may be used at doses of ≤1 g/day. Other exceptions may be granted by a qualified member of the Pfizer study management.
12. Renal Impaired subjects: Received any of the following medications/supplements within 7 days or 5 half-lives (whichever was longer) prior to the first dose of study medication or during the study. These medications and supplements are prohibited for the duration of the study.
• Any drug known to be a potent inhibitor of CYP3A, including erythromycin,
clarithromycin, telithromycin, systemic azole antifungal therapy (including
ketoconazole, itraconazole, voriconazole and fluconazole), nefazodone, fluvoxamine.
• Any immunosuppressive drugs, including cyclosporine, tacrolimus, sirolimus.
• Any protease inhibitors (with the exemption of boosted saquinavir as scheduled as part of the Study Design).
• Any potent enzyme-inducing drug, including rifampin, phenytoin, St John’s Wort and
carbamazepine.
• Cimetidine, trimethoprim and cibenzoline.
• Grapefruit juice.
13. Positive urine (or saliva; for subjects with ESRD) drug screen for drugs of abuse or recreational drugs. Subjects with renal impairment will be eligible to participate if their urine drug screen is positive for a prescribed medication (eg, benzodiazepine, opioid, etc).
14. History of regular alcohol consumption exceeding 7 drinks/week for women or 14
drinks/week for men (1 drink = 5 ounces (150 mL) of wine, 12 ounces (360 mL) of beer, or 1.5 ounces (45 mL) of hard liquor) within 6 months of study medication.
15. Treatment with an investigational drug within 28 days prior to the dose of study
medication.
16. Screening 12-lead ECG demonstrating a QTc >480 msec for subjects with renal
impairment.
17. Screening 12-lead ECG demonstrating a QTc >450 msec for subjects with normal renal function.
18. Supine BP at Screening ≥160mm Hg systolic or ≥95mm Hg diastolic, on at least two occasions following at least 10 minutes of rest.
19. Supine BP at Screening </=80mm Hg systolic or </=40mmg Hg diastolic, on at least two occasions following at least 10 minutes of rest.
20. Any condition possibly affecting drug absorption, eg, gastrectomy or clinically
significant diabetic gastroenteropathy.
21. Donation of blood in excess of 500 mL within 56 days prior to dosing.
22. History of sensitivity to heparin or heparin-induced thrombocytopenia if heparin was used to flush catheters.
23. Unwilling to comply with the Life Style guidelines presented in the protocol.
24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results, and in the judgment of the investigator, would make the subject inappropriate for entry into this study.
25. Subjects with urinary incontinence.
26. Subjects with AIDS/HIV. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
AUCtlast/tau and Cmax for all subjects, secondary pharmacokinetic endpoints for MVC will be plasma protein binding, AUCinf, Tmax, and half-life (t1/2), as data permits.
In addition, renal clearance (CLr) will be determined for subjects with normal, mild,
moderate, and severe renal function and hemodialysis clearance will be determined for subjects with ESRD on hemodialysis |
|
| 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 | 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) | 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 | No |
| 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) | No |
| 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 | 2 |
| 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 | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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