| 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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020161 |
| E.1.2 | Term | HIV 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 |
1. To determine the pharmacokinetic profile and dosing schedule of the capsule formulation for BMS-232632 and BMS-232632 + ritonavir in combination with two NRTIs in HIVinfected children and adolescents.
2. To determine the pharmacokinetic profile and dosing schedule for the powder formulation of BMS-232632 and BMS-232632 + ritonavir in combination with two NRTIs in HIVinfected infants and young children.
3. To determine the safety and tolerability of BMS-232632 and BMS-232632 + ritonavir in HIV-infected infants, children, and adolescents. |
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| E.2.2 | Secondary objectives of the trial |
To assess the:
1.antiviral activity of ATV and ATV+ RTV containing regimens as measured by viral load response and duration of max response when given to prot. inhib. treat-experienced and -naive study subjects
2.development of virologic resistance as measured by genotypic and phenotypic assays during treatment with ATV and ATV + RTV
3.relationship between the results of baseline phenotypic and genotypic resistance assays and virologic response.
4.relationship between systemic exposure to ATV and ATV + RTV, subject- reported adherence, and virologic response (Only for U.S.A. subjects)
5. To evaluate the relationship of PK, as collected according to a population strategy, to pharmacodynamically-linked variables
6. changes in immunologic function as measured by T cell-subset analysis and markers of cellular activation in relation to initiating or changing ART.
7. To assess the long-term safety and tolerability of ATV and ATV + RTV in South African HIV-infected patients (Step II). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For step 1:
- Age: 91 days to 180 days of age.
- A confirmed diagnosis of HIV infection defined by the current definition of the IMPAACT Virology Core Laboratory Committee. The current (April 00) definition requires two separate peripheral blood specimens from different days, and each specimen must be positive. The two positive results may be obtained in any combination of the following:
• at any age: HIV culture, HIV-DNA PCR, or Plasma HIV RNA value > 10,000 copies/mL
• age >4 weeks: neutralizable HIV p24 antigen (regular or ICD)
• age >18 months: licensed ELISA with confirmatory Western Blot
This definition may be updated by the IMPAACT Virology Core Laboratory Committee at any time. The IMPAACT P1020A will update the sites if these assays or their combination is modified. The protocol will always use the current definition of confirmed HIVinfection.
- Viral load ≥ 5,000 copies/mL
- Any CDC clinical classification and immune status.
- Antiretroviral treatment naïve or experienced study candidates must be able to add two new NRTIs as part of their new therapy in this protocol, or have genotypic evidence of sensitivity to two NRTIs (the NRTIs must be used in combinations recommended in the Guidelines for the Use of Antiretroviral Agents in Pediatric and Adolescent HIV
Infection).
If the study candidate has previously received treatment with ddC, ddI will not be considered a new NRTI for his/her new regimen under this protocol, and vice-versa.
Abacavir sulfate (ABC, Ziagen®) and tenofovir disoproxil fumarate (TDF, Viread®) will be excluded as NRTI options for the subject’s regimen.
Sites must send an e-mail to the protocol team at actg.teamp1020@fstrf.org , establishing the candidate's PID#, date of
birth (DOB), and ART-history. This information is required to determine if genotypic testing is needed. Sites must receive
authorization, for each candidate, from the protocol team before proceeding with screening.
- Study candidates must show evidence of retained phenotypic sensitivity to BMS-232632 (resistance index ratio of less than 10) when the subject has failed (after at least 12 weeks of therapy) two or more courses of PI containing regimens.
Sites must send an e-mail to the protocol team at actg.teamp1020@fstrf.org , establishing the candidate's PID#, date of
birth (DOB), and ART-history. This information is required to determine if phenotypic testing is needed to confirm eligibility. Sites must receive authorization, for each candidate, from the protocol team before proceeding with screening.
- Demonstrated ability and willingness to swallow study medications.
- Study candidate, parent or legal guardian able and willing to provide signed informed consent.
- Female participants who are sexually active and able to become pregnant must use two methods of birth control. Hormonal birth control alone (e.g. pills, shots, or slow release inserts placed under the skin) would not be considered adequate. An effective, medically accepted barrier method of contraception [e.g., female/male condoms, diaphragm or cervical cap with a cream or gel that kills sperm, intrauterine device (IUD), others] must also be used during
the study. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV transmission. Use of an IUD may increase the risk of pelvic inflammatory disease.
- Males participating in the study must not attempt to impregnate a female, or participate in sperm donation programs. Males engaging in sexual activity that could lead to pregnancy must use a condom.
- Study candidates with a history of undefined syncope will require a complete cardiac conduction evaluation at screening [e.g., ECG, 24-hour monitoring (Holter), and exercise test (if age appropriate)].
This evaluation must rule-out any cardiac conduction abnormalities.
For step 2:
- Any South African subject enrolled into either part of Step I, who is virologically successful by Week 96 of the last study subject enrolled into the respective part of Step I.
- Female participants who are sexually active and able to become pregnant must continue using two methods of birth control.
Hormonal birth control alone (e.g., pills, shots, or slow release inserts placed under the skin) would not be considered adequate. An effective, medically accepted barrier method of contraception [e.g., female/male condoms, diaphragm or cervical cap with a cream or gel that kills sperm, intrauterine device (IUD), others] must also be used during the study. Condoms are recommended because their appropriate use is the only contraception method effective for preventing HIV transmission. Use of an IUD may increase the risk of pelvic inflammatory disease.
- Males who continue participation in the study must not attempt to impregnate a woman, or participate in sperm donation programs.
Males engaging in sexual activity that could lead to pregnancy must use a condom. |
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| E.4 | Principal exclusion criteria |
For Step 1:
- Active hepatitis.
- Presence of an acute serious/invasive infection requiring therapy at the time of enrollment.
- Hypersensitivity to any component of the formulation of BMS-232632.
- Chemotherapy for active malignancy.
- Pregnancy or breastfeeding.
- Any clinically significant diseases (other than HIV infection) or clinically significant findings during the screening medical history or physical examination that, in the clinician's opinion, would compromise the outcome of this study.
- Any laboratory or clinical toxicity > Grade 2 at entry
- Documented history of cardiac conduction abnormalities, or significant cardiac dysfunction.
- History of undefined syncope that can not be ruled out as related to cardiac conduction abnormalities6.
- Family history of prolonged QTc-interval syndrome, Brugada syndrome, or right-ventricular (RV) dyplasia.
- Corrected QTc-Interval > 440 msec at screening.
- Prolonged PR-Interval >0.200 seconds (200 ms) on ECG at screening (Study candidates ≥13 years of age).
- PR-Interval > 98th percentile on ECG at screening (Study candidates <13 years of age). Use Appendix VIII “Table to Determine 98th Percentile for PR-Intervals in Subjects < 13 of Age”.
- Cardiac rhythm abnormalities:
• A type I second-degree atrioventricular (AV) block (Mobitz type I heart-block) occurring during waking hours on ECG at
screening.
• A type II second-degree AV-block (Mobitz type II heart-block) at any time on ECG at screening.
• A complete AV-block at any time on ECG at screening.
• A heart rate less than the 2nd percentile for age of the normal heart rate range (See Appendix IX) on ECG at screening.
- Prolonged therapy with intravenous pentamidine for acute Pneumocystis Carinii Pneumonia (PCP) within three months of entry.
For Step 2:
- A South African subject who meets any of the criteria for treatment discontinuation by Week 96 of the last subject enrolled into either part of Step I (see Section 6.4 Criteria for Treatment Discontinuation).
- A South African subject who meets any of the exclusion criteria (Section 4.2) from Step I by Week 96 of the last subject enrolled into either part of Step 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints for analytic purposes only:
1- Grade 3 or 4 toxicity attributed to study treatment
2- Failure to achieve a 1 Log(10) reduction in RNA at Week 16
3- Plasma HIV RNA level that is increased by greater than or equal to 1 log from baseline at any time, confirmed by a second specimen
4- Plasma HIV RNA level confirmed to be greater than 10,000 copies/mL at Week 24
5- Plasma HIV RNA level confirmed to rebound at or after Week 24 by greater than 1 log from the lowest HIV RNA level achieved, provided the lowest level was greater than 1,000
If the lowest level was less than 1,000 copies/mL, then a confirmed plasma HIV RNA rebound to greater than 10,000 copies/mL.
Endpoints defining increasing levels of virologic success:
6- 1 Log(10) drop from baseline RNA at Week 16
7- RNA less than 400 copies/mL (standard assay)
8- RNA less than 50 copies/mL (ultra-sensitive assay)
Primary response variables:
9- Safety data: Grade 3 or 4 toxicities
10- Pharmacokinetic parameters, as specified in the protocol |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3-5-7-8-9-10- Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96
2-6- Measured at Week 16
4- Measured at Week 24 |
|
| E.5.2 | Secondary end point(s) |
Secondary Response Variables:
•Viral load, as measured by RNA PCR
•CD4 count and percent
•CD8 count and percent
•Markers of cellular activation |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Measured through participant's last study visit, which will occur every 8 to 12 weeks until the last study participant has reached Week 96
|
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Pharmacokinetic and Safety Study |
|
| 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 | No |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 9 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| South Africa |
| United States |
|
| 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
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| LPLV - Step II: South Africa, this step will end when BMS-232632 is approved in South Africa, and it is available for distribution to subjects. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 13 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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