| 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 | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
|
| 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 antiviral activity of BMS-626529 following administration of selected
regimens of BMS-663068 with and without Ritonavir (RTV) administered orally to HIV infected subjects
for 8 days. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess safety and tolerability of multiple regimens of BMS-663068 with and without RTV in HIV infected subjects
• To assess the effect of BMS-626529 following multiple regimens of BMS-663068 on CD4+ and CD8+ lymphocyte counts and percents
• To assess the PK of BMS-626529 following multiple regimens of BMS-663068 with and without RTV in HIV infected subjects
• To asses the diurnal variation in the PK exposures of BMS-626529 following multiple regimens of BMS-663068 with and without RTV in HIV infected subjects
• To assess the plasma protein binding for BMS-626529
• To assess the relationships between change from baseline in log10 HIV RNA versus Inhibitory Quotient (IQ) and PK exposures for BMS-626529 following multiple regimens of BMS-663068 with and without RTV
• To assess the PK of RTV when coadministered with various regimens of BMS-663068 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
a) The signed informed consent form
2) Target Population
a) Clade B HIV-1 infected subjects meeting the following criteria at the screening visit (within 35 days of enrollment):
i) Plasma HIV RNA level ≥ 5,000 copies/mL (may be repeated for confirmation)
ii) CD4+ lymphocyte measurement ≥ 200 cells/μL (may be repeated for confirmation)
iii) Antiretroviral naive or experienced (ARV naive is defined by: No prior antiretroviral therapy of ≥ 1 week)
iv) Off all antiretroviral therapy with HIV activity for > 8 weeks
v) Have not previously received an HIV attachment inhibitor
b) Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive. BMI = weight (kg)/ [height(m)]2
c) Not currently co-infected with HCV or HBV
3) Age and Sex
a) Men and women, ≥ 18 years of age
Women of childbearing potential (WOCBP) must be using an adequate method of contraception (generally defined as two separate forms of contraception, one of
which must be an effective barrier method (eg, condom with spermicide), to avoid
pregnancy throughout the study and for up to 12 weeks after the last dose of
investigational product in such a manner that the risk of pregnancy is minimized.
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 24 hours prior to the start
of investigational product. |
|
| E.4 | Principal exclusion criteria |
-WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy generally defined as two effective forms of contraception) for the entire study period and for up to 12w after the last dose of IP
-WOCBP using a prohibited contraceptive method including oral, injectable, or implantable hormonal contraceptive agent within 12w of enrollment.
-Women who are pregnant or breastfeeding
-Women with a pos pregnancy test on enrollment or prior to IP admin
-Sexually active fertile men not using effective birth control (generally defined as two effective forms of contraception) during study participation and for at least 12w after the last dose of IP if their partners are WOCBP
- Any significant acute or chronic medical illness which is not stable or is not controlled with med or not consistent with HIV infection
-Current or recent (within 3m) GI disease that, in the opinion of the inv or Medical Monitor, may impact on drug absorption and/or put the subject at risk for GI tract irritation and/or bleeding. Exclusionary diseases include, but are not limited to GI ulcers, esophageal or gastric varicies, or hematochezia
-Acute diarrhea lasting ≥ 1 day, within 3w prior to randomization. Diarrhea will be defined as the passage of liquid feces and/or a stool frequency greater than 3 times/d
-Any major surgery within 4w of study drug admin
-Any gastrointestinal surgery that could impact upon the absorption of study drug
-Donation of blood or plasma to a blood bank or in a clinical study (except a Screening visit or follow up visit of less than 50 mL) within 4w of study drug admin
-Blood transfusion within 4w of study drug admin
-Inability to tolerate oral med
-Inability to be venipunctured and/or tolerate venous access
-A personal history of clinically relevant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes
- A personal or family history of long QT syndrome Subjects who are unwilling to practice adequate infection protection during and after study participation to minimize potential for spread of HIV infection, including HIV which may have developed resistance to HIV attachment inhibitors. Such protections could include, but are not limited to behaviors to minimize potential for exposure to the subjects’ infected bodily fluid or initiation of HAART therapy if indicated and recommended by a physician.
Recent (within 6m) drug or alcohol abuse as defined in DSM IV, Diagnostic Criteria for Drug and Alcohol Abuse (Appendix 2)
Any other medical, psychiatric and/or social reason which, in the opinion of the Inv, would make the candidate inappropriate for participation in this study
Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations or not consistent with the subject’s degree of HIV infection
Confirmed QT value >500 msec at screening or D-1
Confirmed QTc value >470 msec for women and >450 msec for men at screening or D-1
Evidence of second or third degree heart block at screening or D-1, confirmed by repeat ECG
Pos urine screen for drugs of abuse at either Screening or D-1 without a valid prescription (subjects positive for cannabinoids and amphetamines will be included, unless excluded by exclusion criteria 2m)
Pos blood screen for hepatitis B surface antigen
Pos blood screen for hepatitis C antibody and hepatitis C RNA
Any of the following screening or D-1 laboratory results outside of the ranges specified below as defined by the central laboratory, confirmed by repeat analysis
Absolute Neutrophil Count (ANC) 0.7 x lower limit of normal (LLN)
Hemoglobin 0.8 x LLN
ALT > 3 x upper limit of normal (ULN)
Creatinine clearance (as estimated by method of Cockcroft and Gault18) less than 60 mL/min
History of allergy to an HIV attachment inhibitor.
History of allergy to HIV protease inhibitor (e.g. RTV)
History of any significant drug allergy (such as anaphylaxis or hepatotoxicity).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety endpoints:
Safety assessments will be based on adverse event reports and the results of vital sign measurements, ECGs, physical examinations, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.
Pharmacokinetic endpoints:
Pharmacokinetics of BMS-626529 will be derived from plasma concentration versus time data. The pharmacokinetic parameters to be assessed include:
Cmax Maximum observed plasma concentration
Ctrough Trough observed plasma concentration
Tmax Time of maximum observed plasma concentration
AUC(TAU) Area under the concentration-time curve in one dosing interval
AUC(0-24h) Area under the concentration-time curve over a 24-hour period
following the AM dose (PM for Group 2) on Day 8
Css,avg Average steady-state plasma concentration, calculated as AUC(0-24h)/24
T-HALF Terminal half-life (after last dose only)
CLT/F Apparent total body clearance
Vss/F Apparent volume of distribution at steady-state
AI Accumulation index; ratio of AUC(TAU) at steady-state to AUC(TAU) after the first dose
Protein binding (%) Percent of BMS-626529 that are bound to total plasma proteins
IQ Inhibitory quotient, calculated as the ratio of BMS-626529 in vivo exposure to in vitro measured protein biding adjusted EC90. The following in vivo exposure measures will be used in evaluating IQ: Cmax, Ctrough and Css,avg.
Individual subject pharmacokinetic parameter values will be derived by non compartmental methods by a validated pharmacokinetic analysis program.
Pharmacodynamic Endpoint(s):
Pharmacodynamic assessment will be based on change in HIV RNA. Additionally,
CD4+ and CD8+ lymphocyte counts and percents will be assessed. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 4 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 81 |
| E.8.9.2 | In all countries concerned by the trial days | 81 |
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