| 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 | 8.1 |
| 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 |
To assess the effect of multiple-dose FAM BID on the multiple-dose PK of ATV/RTV in
HIV-infected subjects when FAM is administered simultaneously (without TDF) or
temporally separated (with TDF). |
|
| E.2.2 | Secondary objectives of the trial |
• To assess the PK of RTV co-administered with ATV in the presence and absence of
FAM
• To assess the safety and tolerability of ATV/RTV when co-administered with FAM in
the presence of at least 2 NRTIs. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
* Signed written informed consent
* Either:
i) For Cohort 1, are receiving an ARV treatment regimen containing ATV/RTV 300/100 mg + at least 2 NRTIs (dosing per USPI or SmPC)(not TDF) continuously for at least 5 months prior to enrollment, or
ii) For Cohort 2, are receiving an ARV treatment regimen containing ATV/RTV 300/100 mg + at least 1 NRTI + TDF continuously for at least 5 months prior to enrollment
iii) Have had plasma HIV RNA < 400 copies/ml on at least 2 prior measurements
(6-20 weeks prior to enrollment and less than 3 wks prior to Day 1)
Also have Day -2 HIV RNA measurement of < 400 copies/ml with results
available prior to Day 11 dosing of FAM
Or:
i) For Cohort 1, are receiving an ARV treatment regimen containing ATV/RTV 300/100 mg + at least 2 NRTIs (dosing per USPI or SmPC) (not TDF) continuously for at least 3 months prior to enrollment, or
ii) For Cohort 2, are receiving an ARV treatment regimen containing ATV/RTV 300/100 mg + at least 1 NRTI + TDF continuously for at least 3 months prior to enrollment
iii) Have had plasma HIV RNA < 400 copies/ml on at least 2 prior measurements
(6-12 weeks prior to enrollment and less than 3 wks prior to Day 1). Also
have Day -2 HIV RNA measurement of < 400 copies/ml with results available
prior to Day 11 dosing of FAM
* Have CD4 Count > 200 cells/mm³
* Have no history of virologic failure on a protease inhibitor (PI) or documented
phenotypic PI resistance or primary PI mutations (according to IAS
recommendations).
* Have no documented phenotypic resistance to ATV or primary genotypic
mutations causing resistance to ATV.
* Body Mass Index (BMI) of 18 to 35 kg/m², inclusive. BMI = weight (kg)/[height
(m)]²
* Men and women, ages 18 to 65 inclusive
* WOCBP must use effective barrier contraception. Other methods of oral
contraception, in addition to barrier methods, are permitted (see Protocol Section 6.4.3; Precautions for details regarding potential interactions with ATV and some oral
contraceptives).
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.
|
|
| E.4 | Principal exclusion criteria |
*WOCBP unwilling or unable to use an acceptable method to avoid pregnancy for entire study period & for up to 8 weeks after study; acceptable method must include practice of barrier contraception
*WOCBP using oral contraceptives without a barrier method. Caution is warranted
with co-administration of oral contraceptives(ethinyl estradiol & norethindrone)
*Pregnant or breastfeeding women
*Women with positive pregnancy test on enrollment or prior to study drug administration
*Men unwilling or unable to agree to practice barrier contraception for duration of study & at least 3 months after dosing
*Any history of CD4 cell count < 50 cell/mm³
*History of virologic failure (2 consecutive plasma HIV RNA measurements >400
copies/mL) while being administered a PI
*Any significant acute illness within 6 months of Study Day 1 or chronic medical illness unless stable or controlled by non-prohibited medication
*History of gastroesophageal reflux disease, hiatal hernia, or peptic/gastric ulcer
disease
*Any major surgery within 4 weeks of Day 1 of on-study ATV
*Any gastrointestinal surgery that could impact upon the absorption of study drug
(ATV/RTV +/- FAM)
*Donation of blood or plasma to a blood bank or in a clinical study (except a
screening visit) within 4 weeks of Day 1 of on-study ATV
*Blood transfusion within 4 weeks of Day 1 of on-study ATV
*Inability to tolerate oral medication
*Inability to tolerate venipuncture and/or venous access
*Subjects with history of Gilbert’s syndrome
*Intractable diarrhea (≥ 6 loose stools/day for at least 7 consecutive days) within
30 days prior to Day 1 of on-study ATV
*History of hemophilia
*History of chronic pancreatitis
*History of hypochlorhydria or achlorhydria
*Recent (≤6 months prior to enrollment) drug or alcohol abuse as defined in
DSM IV, Diagnostic Criteria for Drug & Alcohol Abuse
*Any other sound medical, psychiatric &/or social reason as determined by
Investigator
*Evidence of organ dysfunction or any clinically significant deviation in physical
examination, vital signs, ECG or clinical laboratory determinations, not expected for the extent of HIV disease
*Positive urine screen for drugs of abuse at screening or Day -2 without valid
prescription (except for cannabinoids)
*Creatinine clearance, estimated by method of Cockcroft & Gault <60 mL/min
*Liver enzymes (AST, ALT) >3X upper limit of normal
*Total bilirubin > 10X upper limit of normal (due to ARV regimen containing
ATV/RTV)
*2nd- or 3rd-degree A-V block or clinically relevant ECG abnormalities
*Positive pregnancy test for females only(minimum sensitivity of 25 IU/L
equivalent units of HCG)
*Previously documented phenotypic PI resistance or Primary PI mutations
*Previously documented phenotypic or genotypic resistance to currently
prescribed nucleoside/nucleotide reverse transcriptase inhibitors such that subjects
are being treated with < 3 active antiretrovirals
*History of allergy to HIV protease inhibitors (ATV, RTV), HIV nucleoside or
nucleotide reverse transcriptase inhibitors or H2-receptor antagonists which the
patient will be administered during the study
*History of significant drug allergy or adverse drug reaction related to any study
drug (ATV/RTV +/- FAM) class in the study
*Prior exposure to any investigational drug or placebo within 4 weeks of Day 1 of
on-study ATV, except protocol-required pre-study minimum 5 month regimen (ATV/RTV, ≥ 2NRTIs)
*Use of any prescription or nonprescription drugs within 4 weeks prior to Day 1 of on-study ATV, however, certain drugs may be allowed within 2 weeks prior to study drug administration if approved by BMS Medical Monitor
*Use of ddI (Videx® or Videx EC®) as part of any TDF-containing regimen
*Use of ddI buffered formulation (Videx®)
*Use of any agents, within 4 weeks of Day 1 of on-study ATV, known to induce or inhibit CYP3A4, except protocol required pre-study regimen (ATV/RTV, ≥2NRTIs as described in Protocol Section 3.2)
*Use of over-the-counter or prescription acid controllers within 2 weeks prior to
Day 1 of on-study ATV (antacids, H2-receptor antagonists, PPIs)
*Previous therapy with agents with significant systemic myelosuppressive,
neurotoxic, pancreatotoxic, hepatotoxic or cytotoxic potential within 3 months of
Day 1 of on-study ATV
*Expected need for therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic or cytotoxic potential at time of enrollment
*History of non-adherence or psychosocial circumstances that preclude compliance
with study procedures
*Any other clinical conditions, prior therapy, or concurrent prescription/non-prescription medications that, in opinion of the Investigator, would make thesubject unsuitable for study or unable to comply with the dosing requirements
*Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
* Pharmacokinetic Measures:
PK for ATV and RTV will be derived from plasma concentration versus time data. The PK parameters to be assessed include:
- Atazanavir and Ritonavir:
• Cmax: Maximum observed plasma concentration on Days 10, 17 and 24
• Tmax: Time to reach Cmax on Days 10, 17 and 24
• Cmin: Trough plasma concentration 24-hours post-dose administration on Days
10, 17 and 24 (Days 11, 18 and 25, respectively)
• AUC(TAU): Area under the concentration-time curve, in one dosing interval from
time zero to 24-hours on Days 10, 17 and 24
• T-HALF: Terminal elimination half life on Days 10, 17 and 24 (RTV only)
- Famotidine plasma samples will be collected and stored for possible future
analysis of FAM levels.
* Primary Safety Outcome Measures:
Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, electrocardiograms, physical examinations, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.
|
|
| 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 | Yes |
| 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) | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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