| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To describe the repeat-dose pharmacokinetics of CAB + RPV (oral and injectable) through Week 24
2. To assess the safety of the oral lead-in of CAB + RPV, and the safety of CAB + RPV (oral and injectable) through Week 24 |
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| E.2.2 | Secondary objectives of the trial |
Cohort 1:
1. Assess the safety of CAB + RPV (oral and injectable) through Weeks 48 and 72
2. Describe the repeat-dose pharmacokinetics of injectable CAB LA + RPV LA through Weeks 48 and 72
3. Assess the maintenance of viral suppression of CAB + RPV (oral and injectable) through Weeks 24, 48, and 72
4. Evaluate the tolerability and acceptability of injectable CAB LA + RPV LA through Weeks 24, 48, and 72
5. Describe HIV-1 genotypes and phenotypes for children who experience virologic failure during study treatment
6. Assess immunologic activity of CAB + RPV (oral and injectable) through Weeks 24, 48, and 72
Cohort 2:
1. Describe tolerability and acceptability of 48 weeks of CAB + RPV (oral and injectable) and 44 weeks of CAB LA + RPV LA (injectable only)
2. Describe the safety and repeat-dose pharmacokinetics of 48 weeks of CAB + RPV (oral and injectable) or 44 weeks of CAB LA + RPV LA (injectable only)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Step 1: Entry for Cohort 1, Cohort 2a, and Cohort 2b
1. Parent or legal guardian is willing and able to provide written permission for child’s study participation and, when applicable per institutional review board/ethics committee (IRB/EC) policies and procedures, child is willing and able to provide written assent for study participation.
2. Age two years old to less than 12 years old at entry
3. Body weight ≥10 kgs and <40 kgs at entry
4. At entry, willing and able to comply with the study visit schedule and other study requirements, as determined by the site investigator or designee.
5. Confirmed HIV-1-infection based on documented testing of two samples collected from two separate blood collection tubes per Sample #1 and Sample #2 requirements.
6. Has been on a stable unchanged ART regimen consisting of two or more drugs from two or more antiretroviral drug classes for at least six consecutive months (defined as 180 consecutive days) prior to entry.
7. Has no prior history of switching ART regimens for reasons related to treatment failure based on parent/guardian report and/or available medical records.
8.From a specimen collected less than six months (defined as within 179 days) prior to entry, has at least one of the following documented plasma HIV-1 RNA results:
•<50 copies/mL, or
•less than the lower limit of detection of the assay
9. From a specimen collected in the 6-18 months (defined as 180 to 545 days) prior to entry, has at least one of the following documented plasma HIV-1 RNA results:
•<50 copies/mL, or
•less than the lower limit of detection of the assay
10. At screening, a documented plasma HIV-1 RNA <50 copies/mL.
11. Has normal, Grade 1, or Grade 2 results for all the following laboratory tests at screening (i.e., within 28 days prior to entry) based on grading per the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events:
a. AST (<5.0 x ULN)
b. ALT (<5.0 x ULN)
c. Total bilirubin (<2.6 x ULN)
d. Lipase (<3 x ULN)
e. Estimated glomerular filtration rate (eGFR; ≥60 ml/min/1.73 m2)
f. Platelets (≥50,000 cells/mm3 or ≥50.00 x 109 cells/L)
g. Hemoglobin (≥8.5 g/dL or ≥5.25 mmol/L)
h. Neutrophils (≥600 cells/mm3)
12/ Has no evidence of chronic hepatitis B infection based on hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and hepatitis B surface antibody (HBsAb) testing at screening; any of the following three combinations of test results are acceptable for inclusion:
• HBsAg negative, HBcAb negative, HBsAb negative
• HBsAg negative, HBcAb negative, HBsAb positive
• HBsAg negative, HBcAb positive, HBsAb positive
13. At screening, has a mean QTc interval (based upon a triplicate reading) less than or equal to 450 msec based on an electrocardiogram (ECG) automated machine readout or calculated using the Fridericia formula.
14. For female participants of childbearing potential, not pregnant based upon negative blood or urine pregnancy test at entry. Childbearing potential is defined as nine years of age or older and:
•having reached menarche or
•engaging in sexual activity (self-reported) that could lead to pregnancy
Step 2: Continuation for Cohort 1 and Cohort 2a to injection phase
1. Currently enrolled as a participant in Step 1.
2. Has normal, Grade 1, or Grade 2 results from all of the following laboratory test results based upon specimens collected at the Week 4a study visit or from confirmatory repeat testing of Week 4a study visit laboratory tests:
a. AST (<5.0 x ULN)
b. ALT (<5.0 x ULN)
c. Lipase (< 3 x ULN)
d. Estimated glomerular filtration rate (eGFR; ≥60 ml/min/1.73 m2))
e. Platelets (≥50,000 cells/mm3 or ≥50.00 x 109 cells/L)
f. Hemoglobin (≥8.5 g/dL or ≥5.25 mmol/L)
g. CK (<10 x ULN)
3. For female participants of childbearing potential, not pregnant based upon negative blood or urine pregnancy test at the Week 4b study visit.
4. Assessed by the IoR or designee as sufficiently adherent to study products in Step 1 to permit an adequate evaluation of safety and tolerability as part of the oral lead in phase prior to entry into the injection phase. |
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| E.4 | Principal exclusion criteria |
Step 1: Entry for Cohort 1, Cohort 2a, and Cohort 2b
1. Within 6 months prior to entry, any HIV-1 RNA value >400 copies/mL OR two consecutive “viral blips,” defined as an HIV-1 RNA value ≥50 copies/mL but ≤400 copies/mL.
2. As determined by the IoR or designee, and based on available medical records, known or suspected resistance to NNRTIs.
3. As determined by the IoR or designee, and based on available medical records, known or suspected resistance to INSTIs.
4. Ongoing congestive heart failure, symptomatic arrhythmia, or any current clinically significant cardiac disease, as determined by the IoR or designee, and based on available medical records.
5. Has any of the following, as determined by the IoR or designee based on participant/parent/guardian report and available medical records:
a. Current hepatitis C infection
b. Current clinically significant hepatic disease
c. Current or anticipated need for chronic anti-coagulation
d. History of known or suspected bleeding disorder, including a history of prolonged bleeding
e. History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by the IoR or designee, based on available medical records
f. Risk factors for Torsade de Pointes (e.g., heart failure, hypokalemia, hypomagnesemia)
g. Known or suspected allergy to study product components.
h. Known phobia to needles
6. More than one seizure within one year (defined as within 365 days) prior to entry, or unstable or poorly controlled seizure disorder, as determined by the IoR or designee, and based on available medical records
7. Has the following combination of laboratory test results at screening (i.e., from specimens collected within 28 days prior to entry): ALT greater than or equal to 3 x ULN and total bilirubin greater than or equal to 1.5 x ULN and direct bilirubin greater than 35% of total bilirubin.
8. At entry, known active tuberculosis infection, as determined by the IoR or designee based on participant/parent/guardian report and available medical records.
9. At entry, any ongoing pancreatitis as determined by the IoR or designee based on participant/parent/guardian report and available medical records.
10. At entry, has symptoms suggestive of active coronavirus disease 2019 (COVID-19) or test results or contacts that require quarantine per local clinical practice, public health, and/or infection control guidelines as determined by the IoR or designee based on participant/parent/guardian report and available medical records.
11. Receipt of any prohibited medication within 7 days prior to entry, with the exception of antiviral agents that are part of the participant’s ART regimen, as determined by the site investigator based on participant/parent/guardian report and available medical records
12. Any past or current exposure to CAB LA or RPV LA
13. At entry, based on physical examination, has a current inflammatory skin condition that compromises the safety of intramuscular injections, as determined by the IoR or designee.
14. At entry, based on physical examination, has a dermatological condition overlying the buttock or upper thigh region, which, in the IoR or designee’s opinion, may interfere with the interpretation of injection site reactions.
15. Enrolled in another clinical trial of an investigational agent, device, or vaccine.
16. Has any documented or suspected clinically significant medical or psychiatric condition or any other condition or social circumstance that, in the opinion of the site investigator, would make participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.
Step 2: Continuation for Cohort 1 and Cohort 2a to injection phase
1. Has permanently discontinued oral study product.
2. Occurrence of any grade 3 or higher adverse event assessed as related to study product during Step 1.
3. Any other condition or social circumstance situation that, in the opinion of the IoR or designee, would make continued study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
COHORT 1 Primary Outcome Measures:
Safety of the CAB + RPV oral lead-in and 24 weeks of CAB + RPV (oral and injectable)
- Proportion of children who experience the following during the CAB + RPV oral lead-in period:
o drug-related safety failure event
o grade 3 or higher adverse event
o SAE
o premature permanent discontinuation study treatment due to an adverse event
- Proportion of children who experience the following during the 24 weeks of CAB + RPV (oral and injectable):
o drug-related safety failure event
o grade 3 or higher adverse event
o SAE
o premature permanent discontinuation study treatment due to an adverse event |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Cohort 1: Through Week 24 |
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| E.5.2 | Secondary end point(s) |
Cohort 1:
1. Proportion of children who experience the following through Weeks 48 and 72 of CAB + RPV (oral and injectable):
o drug-related safety failure event
o grade 3 or higher adverse event
o SAE
o premature permanent discontinuation study treatment due to an adverse event
2. Proportion of children who have HIV-1 RNA <50 and ≥50, copies/ml at Weeks 24, 48, and 72 using the FDA Snapshot algorithm
• Proportion of children who have HIV-1 RNA <200 and ≥200 copies/ml at Weeks 24, 48, and 72 using the FDA Snapshot algorithm
• Proportion of children with confirmed virologic failure at Weeks 24, 48 and 72 while on CAB + RPV
3. Tolerability: Child and/or parent/caregiver responses to questionnaires about CAB or RPV side effects, pain associated with injections, and injection site reactions at Weeks 24, 48, and 72.
Acceptability: Child and/or parent/caregiver reported attitudes about CAB or RPV, including willingness to use at Weeks 24, 48, and 72.
4. Proportion of participants who had genotypic and phenotypic resistance to CAB or RPV among children who experience virologic failure while on CAB + RPV.
5. Median for CD4 count and percentage at Weeks 24, 48 and 72. Median change from baseline CD4 count and percentage at Weeks 24, 48 and 72.
Cohort 2:
1. For children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable):
Tolerability: Child and/or parent/caregiver responses to questionnaires about CAB or RPV side effects, pain associated with injections, and injection site reactions
Acceptability: Child and/or parent/caregiver reported attitudes about CAB or RPV, including willingness to use
2. Safety of 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable)
Proportion of children who experience the following during the 48 weeks of CAB + RPV (oral and injectable) OR the 44 weeks of CAB LA + RPV LA (injectable):
o drug-related safety failure event
o grade 3 or higher adverse event
o SAE
o premature permanent discontinuation study treatment due to an adverse event
3. For children who are on 48 weeks of CAB + RPV (oral and injectable) OR 44 weeks of CAB LA + RPV LA (injectable):
Maintenance of virologic suppression
o Proportion of children who have HIV-1 RNA <50 and ≥50, copies/ml using the FDA Snapshot algorithm
o Proportion of children who have HIV-1 RNA <200 and ≥200 copies/ml using the FDA Snapshot algorithm
o Proportion of children with confirmed virologic failure while on treatment
Immunologic activity:
o Median and Interquartile Range for CD4 count and percentage
o Median and Interquartile Range change from baseline CD4 count and percentage
4. Proportion of participants who had genotypic and phenotypic resistance to CAB and RPV for children who experience virologic failure while on 48 weeks of CAB + RPV (oral and injectable) OR while on 44 weeks of CAB LA + RPV LA (injectable). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: Through Week 24, Week 48 and Week 72
Cohort 2A: Through Week 48
Cohort 2B: Through Week 44 |
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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 | 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) | 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 |
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| 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.8.3 |
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 | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Botswana |
| Brazil |
| South Africa |
| Thailand |
| United States |
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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
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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 | 4 |
| 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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