| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Virologically Suppressed Children, 6 to less than 12 years of age, Living with HIV-1 |
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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 |
•To estimate steady state PK (AUC0-24h) of DTG and RPV through 24 weeks of treatment
•To assess safety and tolerability at Week 24
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| E.2.2 | Secondary objectives of the trial |
•To summarize virologic efficacy [maintenance of human immunodeficiency virus (HIV)-1 RNA less than 50 copies/mL] at weeks 24 and 48 weeks of treatment
•To summarize immunologic response (CD4+ cell count and percentage) at Weeks 24 and 48
•To summarize safety and tolerability assessments (including monitoring of serum creatinine) at Week 48
•To estimate the DTG and RPV pharmacokinetics; Steady-state Cmin of DTG and RPV through 24 weeks of treatment (Pharmacokinetic assessments; Cmin)
•Viral load monitoring at Baseline and at weeks 4, 8, 12, 16, 20, 24, 36, 48
•To summarize possible resistance mutations in participants with confirmed HIV-1 RNA greater than or equal to 50 copies/mL at any visit after Baseline/Day 1.
For more details, check pages 37 to 39 of protocol document
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age and Weight
1.HIV-1 infected child 6 years to less than 12 years of age at the time of signing the informed consent form.
2.Body weight greater than or equal to 25 kg at entry.
Type of Participant and Disease Characteristics
3.Confirmed HIV-1-infection
4.Has taken the same ART regimen in the 6 months (180 days) prior to Screening, as determined by the site investigator based on participant/parent/guardian report and available medical records.
Note: See also exclusion criterion 3. The regimen may include DTG or RPV but may not include both agents.
Note: Dose and formulation changes (e.g., for growth) are permitted.
5.Has a plasma HIV-1 RNA result less than 50 copies/mL at Screening
Note: Laboratory test may be repeated once during the screening period (i.e., within 30 days prior to Baseline/Day 1), with the latest results used for eligibility determination.
6.Has at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected in the 6-12 months (180-365 days) prior to Screening
OR
Has at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected less than 6 months (within 179 days) prior to entry and at least one documented plasma HIV-1 RNA result less than the lower limit of detection of the assay from a specimen collected in the 12-18 months (365-545 days) prior to Screening
Note: For both options in this criterion, the lower limit of detection of the assay must be 50 copies/mL or lower for undiluted specimens or 200 copies/mL or lower for diluted specimens.
Sex
7.For participants of reproductive potential (defined as having reached menarche), not pregnant based on testing performed at Screening (i.e., from a specimen collected within 30 days prior to entry) and at Baseline/Day 1.
8.For participants of reproductive potential who are engaging in sexual activity that could lead to pregnancy, willing to use two methods of contraception while receiving study drug and for approximately one month after permanently discontinuing study drug, based on participant/parent/guardian report at entry.
One of the two methods must be highly effective; highly effective methods include surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy) and the following:
•Contraceptive intrauterine device or intrauterine system
•Subdermal contraceptive implant
•Progestogen injections
•Combined estrogen and progestogen oral contraceptive pills
•Percutaneous contraceptive patch
•Contraceptive vaginal ring
The highly effective method must be initiated at least seven days prior to the Baseline/Day 1 visit. The second method should ideally be a barrier method. Condom use is recommended with all other methods of contraception for dual protection against pregnancy and to avoid transmission of HIV and other sexually transmitted infections.
9.For participants of reproductive potential, not breastfeeding based on participant/parent/ guardian report at Baseline/Day 1.
General
10.At Screening, expected to be able to swallow the 14x7 mm film coated JULUCA tablets, as determined by the site investigator
11.At Screening, has access to at least one meal per day, as determined by the site investigator based on discussion with the participant/parent/guardian
12.A legal guardian or primary caregiver must be available to help the study-site personnel ensure follow up; accompany the participant to the study site on each assessment day according to the SOA (e.g., able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures); consistently and consecutively be available to provide information on the participant during the scheduled study visits; accurately and reliably dispense study intervention as directed
Informed Consent
13.Parent or legal guardian is willing and able to provide written informed consent for potential participant’s study participation and, when applicable per IRB/EC policies and procedures, potential participant is willing and able to provide written assent for study participation
Note: All sites must follow all applicable IRB/EC policies and procedures.
Note: See also exclusion criterion 17
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| E.4 | Principal exclusion criteria |
Medical History
1.Documented resistance (ever) to NNRTIs or integrase inhibitors
Note: Prior receipt of NNRTIs for prophylaxis or treatment is not exclusionary.
2.Documented HIV-1 RNA result greater than or equal to the lower limit of detection of the assay based on a specimen collected in the 12 months (365 days) prior to Screening
Note: The lower limit of detection of the assay must be 50 copies/mL or lower for undiluted specimens or 200 copies/mL or lower for diluted specimens.
3.Any change (ever) of any ARV agent due to virologic failure, as determined by the site investigator based on participant/parent/guardian report and available medical records
Note: See also inclusion criterion 4; participants must have taken the same ART regimen in the 6 months preceding study entry. In addition to that requirement, this exclusion criterion refers to any change of any ARV agent at any time due to virologic failure. Prior to the 6 months preceding study entry, ARV changes due to toxicity, intolerability, or changes in local standard treatment guidelines or formularies are permitted.
4.Has a history (ever) of allergy to DTG, RPV, or any other component of JULUCA as determined by the site investigator based on participant/parent/guardian report and available medical records
5.Has a history (ever) of congestive heart failure, symptomatic arrhythmia, or any clinically significant cardiac disease as determined by the site investigator based on participant/ parent/guardian report and available medical records
6.Has a history (ever) of unstable liver disease (defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), cirrhosis, or known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) as determined by the site investigator based on participant/parent/guardian report and available medical records
7.Has any of the following as determined by the site investigator based on participant/ parent/guardian report and available medical records:
•Current clinical evidence of pancreatitis
•Current or planned treatment for active hepatitis C infection
•Currently active AIDS-defining (WHO Clinical Stage 4) opportunistic infection
•Currently active TB and/or current rifamycin-containing TB treatment
Exclusionary Treatments
8.Has an anticipated need for any HCV therapy during the first 24 weeks of study and for HCV therapy based on interferon or any drugs that have a potential for adverse drug: drug interactions with study treatment throughout the entire study period.
9.Receipt of the following as determined by the site investigator based on participant/ parent/guardian report and available medical records:
•Any investigational agent within 90 days prior to entry
•Any prohibited medication (see Section 6.10.1) within 30 days prior to entry
•Any medication with a known risk of Torsades de Pointes (see Section 10.9) within seven days prior to entry
10.Receipt (ever) of an ART regimen that included both DTG and RPV, as determined by the site investigator based on participant/parent/guardian report and available medical records
11.Exposure to an experimental drug or experimental or approved vaccine within either 28 days (including EUA/emergency use approved COVID-19 vaccine as applicable), 5 half- lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of study treatment.
Laboratory Values and ECG
12.Any ≥ grade 3 result for the following based on grading per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (refer to Section 10.10 for guidance on severity grading):
•Haemoglobin (<8.5 g/dL or <5.25 mmol/L)
•Absolute neutrophil count (<600 cells/mm3 or <0.600 x 109 cells/L)
•Platelet count (<50,000cells/mm3 or <50.00 x 109 cells/L)
•Estimated glomerular filtration rate (eGFR: <60ml/min/1.73m2)
•ALT (≥5.0 x ULN)
•AST (≥5.0 x ULN)
Note: See also exclusion criterion 8.
Note: Laboratory tests may be repeated once during the screening period (i.e., within 30 days prior to Baseline/Day 1), with the latest results used for eligibility determination.
13.Has the following combination of laboratory test results at screening: 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
Note: Laboratory test may be repeated once during the screening period (i.e., within 30 days prior to entry), with the latest results used for eligibility determination.
For more details, check pages 47-50 of protocol document
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Steady-state AUC0-24h of DTG through 24 weeks of treatment based on population PK including all available PK data through Week 24
•Steady-state AUC0-24h of RPV through 24 weeks of treatment based on population PK including all available PK data through Week 24
•All adverse events occurring at Week 24
•The occurrence of the following adverse events at Week 24:
-Grade 3 or higher adverse events
-Grade 3 or higher adverse events assessed as related to study drug
-Fatal adverse events assessed as related to study drug
-Serious adverse events assessed as related to study drug
•The occurrence at Week 24 of adverse events assessed as related to study drug that led to permanent discontinuation of study drug
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
•The proportion of participants with HIV-1 RNA less than 50 copies/mL at Week 24 and Week 48 using the snapshot algorithm
•CD4+ cell counts and percentages at Week 24 and Week 48
•Occurrence of all adverse events at Week 48
•Participants with the following at Week 48:
-Grade 3 or higher adverse events
-Grade 3 or higher adverse events assessed as related to study drug
-Fatal adverse events assessed as related to study drug
-Serious adverse events assessed as related to study drug
•The occurrence at Week 48 of adverse events assessed as related to study drug that lead to permanent discontinuation of study drug
•Cmin (Minimum drug concentrate) of DTG through 24 weeks of treatment based on population PK including all available PK data through Week 24
•Cmin of RPV through 24 weeks of treatment based on population PK including all available PK data through Week 24
•Cmin of DTG and of RPV assessed using intensive PK collected in all participants at Week 4
•HIV-1 RNA at Baseline, and at Weeks 4, 8, 12, 16, 20, 24, 36 and 48
•HIV-1 subtype
•HIV-1 genotypes at baseline and at time of virologic failure
•HIV-1 phenotypes at time of virologic failure (for virus with HIV-1 RNA greater than or equal to 200 copies/mL)
•HIV-1 genotypes at Baseline, Week 24, Week 48 or at study withdrawal
•Reported acceptability of study drug at Weeks 4, 24, and 48
•Reported adherence to study drug through Weeks 4, 24, and 48
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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) | 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 | 1 |
| 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 |
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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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| The end of the study is defined as the last subject's last visit. |
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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 | 3 |
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