More Options for Children and Adolescents (MOCHA): Oral and Long-Acting Injectable Cabotegravir and Rilpivirine in HIV-Infected Children and Adolescents (MOCHA)

More Options for Children and Adolescents (MOCHA): Oral and Long-Acting Injectable Cabotegravir and Rilpivirine in HIV-Infected Children and Adolescents

Phase I/II Study of the Safety, Acceptability, Tolerability, and Pharmacokinetics of Oral and Long-Acting Injectable Cabotegravir and Long-Acting Injectable Rilpivirine in Virologically Suppressed HIV-Infected Children and Adolescents

The purpose of this study is to determine the dosage for oral and IM Cabotegravir LA and IM Rilpiverine LA and evaluate the safety, acceptability, tolerability, and pharmacokinetics of oral and long-acting injectable cabotegravir and long-acting injectable rilpivirine in virologically suppressed HIV-infected children and adolescents.

This study will confirm the dose and evaluate the safety, acceptability, tolerability, and pharmacokinetics (PK) of oral cabotegravir (CAB), long-acting injectable cabotegravir (CAB LA), and long-acting injectable rilpivirine (RPV LA) in virologically suppressed HIV-1 infected children and adolescents aged 12 to less than 18 years. The study will include two cohorts of participants and two steps of study participation in each cohort. Cohort 1, Step 1 and Cohort 2, Step 3 are both a lead-in phase in which participants will receive oral formulations of the study products for at least 4 weeks, and up to 6 weeks (maximum). In Cohort 1, Step 2 and Cohort 2, Step 4, participants will receive injectable formulations of the study products. In each cohort, participants will enter the study in the oral lead-in phase (Step 1, or Step 3) and then transition to the injectable phase (Step 2, or Step 4) if eligibility criteria for the injectable phase are met. Cohort 1, Step 2, and Cohort 2, Step 4, participants, including those who prematurely permanently discontinue injectable study product, will continue on-study for an additional 48 weeks after their last study product injection, per the long-term safety and washout PK follow-up (LSFU) schedule. The study will open to accrual in Cohort 1, in which participants, in addition to continuing their pre-study combination antiretroviral therapy (cART) regimen, will receive either oral CAB or oral RPV (Step 1) followed by either CAB LA or RPV LA (Step 2). Cohort 1 participants will be assigned either CAB (Cohort 1C) or RPV (Cohort 1R) based on their pre-study cART regimen. Participants will not stop their cART. An interim analysis of safety and PK data will be performed, and Cohort 2 will initially open to accrual based on these interim analyses; however, accrual at this stage will be limited to Cohort 1 participants who meet criteria to enter Cohort 2. After Cohort 1 is fully enrolled and a full cohort data analysis is performed, accrual into Cohort 2 will be opened to additional participants who were not previously enrolled in Cohort 1. Upon Cohort 2 Entry (i.e. Cohort 2, Step 3), all Cohort 2 participants will discontinue their pre-study cART regimen and receive both study products - CAB and RPV - at the doses confirmed in Cohort 1. Participants in Cohort 1 will be followed for up to 64 weeks, and participants in Cohort 2 will be followed for up to 144 weeks. Enrolled parents/caregivers will complete a single qualitative phone interview (U.S. sites only).

Step 1: CAB administered orally as one 30 mg tablet once daily, beginning at the Entry visit, for 4-6 weeks. Step 2: CAB LA administered as one IM injection at Week 4b (Step 2 Entry) study visit (600 mg/3 mL), and at Week 8 (600 mg/3 mL).

Step 1: RPV administered orally as one 25 mg tablet once daily, beginning at the Entry visit, for 4-6 weeks. Step 2: RPV LA administered as one IM injection at Week 4b (Step 2 Entry) study visit (900 mg/3 mL), and at Week 8 (900 mg/3 mL).

Step 3: CAB administered orally as one 30 mg tablet once daily AND RPV administered orally as one 25 mg tablet once daily, beginning at the Entry visit for 4-6 weeks. Step 4: First injection: CAB LA administered as one 600 mg (3 mL) IM injection AND RPV LA administered as one 900 mg (3 mL) IM injection, at Week 4b (Step 4 Entry) and at Week 8. Subsequent injections: starting at Week 16, CAB LA administered as a 600 mg (3 mL) IM injection AND RPV LA administered as a 900 mg (3 mL) IM injection, every eight weeks through Week 96.

Participants will continue their pre-study cART regimen. The antiretroviral drugs in participants' cART regimens will not be provided through the study.

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who had Grade 3 or higher adverse events assessed as related to study product/s (Cohort 1)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who had serious adverse events meeting International Conference on Harmonisation (ICH) criteria assessed as related to study product/s (Cohort 1)

Number of participants who permanently discontinued study product due to adverse events assessed as related to study product/s (Cohort 1)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who died due to adverse events assessed as related to study product/s (Cohort 1)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who had Grade 3 or higher adverse events assessed as related to study product/s (Cohort 2)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who had serious adverse events meeting ICH criteria assessed as related to study product/s (Cohort 2)

Number of participants who permanently discontinued study product due to adverse events assessed as related to study product/s (Cohort 2)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who died due to adverse events assessed as related to study product/s (Cohort 2)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Tolerability measures will include measures of side effects, pain during and after injections, injection site reactions, and perceptions of injections from comprehensive surveys of adolescents

Acceptability measures will include assessments of motivation for changing regimens, satisfaction with treatment, preferences for injectable versus oral regimen, quality of life, changes in attitudes towards the study products from comprehensive surveys of adolescents

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who had Grade 3 or higher adverse events assessed as related to study product/s (Cohort 2)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who had serious adverse events meeting ICH criteria assessed as related to study product/s (Cohort 2)

Number of participants who permanently discontinued study product due to adverse events assessed as related to study product/s (Cohort 2)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Number of participants who died due to adverse events assessed as related to study product/s (Cohort 2)

Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017.

Inclusion Criteria: Cohort 1 Step 1 and Cohort 2 Step 3 All the following criteria must be met for inclusion of any adolescent participant in Step 1 of Cohort 1, or in Step 3 of Cohort 2, unless otherwise noted: At enrollment, 12 to less than 18 years of age Note: For Cohort 1 Step 2 participants, age will not be exclusionary for enrollment into Cohort 2 Step 3, if otherwise eligible. At enrollment, body weight greater than or equal to 35 kg (77 lbs) Note: For Cohort 1 Step 2 participants, body weight will not be exclusionary for enrollment into Cohort 2 Step 3, if otherwise eligible. For Cohort 1, at enrollment, body mass index (BMI) less than or equal to 31.5 kg/m^2 At enrollment, willing and able to comply with the study visit schedule and other study requirements, as determined by the site investigator or designee Confirmed HIV-1-infection based on documented testing of two samples collected at different time points. More information on this criterion can be found in the protocol. For at least 3 consecutive months (defined as 90 consecutive days) prior to screening, and prior to enrollment, has been on stable unchanged cART consisting of 2 or more drugs from 2 or more classes of antiretroviral drugs, ascertainment of this criterion may be based on parent or guardian report only, but available medical records should also be reviewed in relation to this criterion. Note: Participants undergoing dose modifications to their antiretroviral regimen for growth or who are switching medication formulation(s) are considered to be on a stable cART. Has at least one documented plasma HIV-1 RNA less than the lower limit of detection of the assay from a specimen collected 6 to 12 months (defined as 180 to 365 days) prior to entry. OR Has at least one documented plasma HIV-1 RNA less than the lower limit of detection of the assay from a specimen collected less than 6 months (defined as 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 (defined as 365 to 545 days) prior to entry. At screening, has Grade 2 or lower of all the following laboratory test results: Alanine transaminase (ALT) (u/l) Lipase (u/l) Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m^2) Platelets (cells/mm^3) Hemoglobin (g/dL) See study protocol for guidance on severity grading. Laboratory tests may be repeated during the study screening period, with the latest result used for eligibility determination. For participants enrolling into Cohort 1, Step 1 and on an atazanavir-containing (ATV) cART regimen, at screening, has total bilirubin less than or equal to 1.5 mg/dL or normal direct bilirubin At screening, has documented plasma HIV-1 RNA less than 50 copies/mL At screening, mean value of Q-T interval (QTc) interval (automated machine readout or calculated using either Bazett or Fredericia) on ECG performed in triplicate, less than or equal to 500 msec. For females, has a negative (blood or urine) human chorionic gonadotropin (hCG) laboratory test result at entry For females of childbearing potential, at entry, currently using at least one allowable effective method of contraception, and agrees to use at least one allowable effective method of contraception throughout study participation, for at least 30 days after discontinuation of oral study product, and for at least 48 weeks after discontinuation of CAB LA and/or RPV LA, and intending to delay any planned pregnancies until 30 days after last oral study product use or until 48 weeks after last injectable study product use. Note: See study protocol for details regarding contraceptive counseling, a list of the allowed effective contraceptive methods for this study, and the definition of a female of childbearing potential. Hormonal-based contraceptives must have been initiated within the prescribed time, per the respective contraceptive method, to be considered effective at the time of Entry. The site IoR or designee is responsible for ensuring that the contraceptive is used in accordance with the approved product label, and counseling participants on proper use of chosen methods of contraception, including barrier methods. For Cohort 1 participants enrolling to Cohort 2, have completed all scheduled product injections and completed Week 16 visit in Cohort 1 Step 2 Exclusion Criteria: Cohort 1 Step 1, or Cohort 2 Step 3 Adolescents will be excluded from the study if any of the following are identified during the screening period: Within 6 months (defined as within 179 days) prior to entry, two consecutive documented HIV-1 RNA values greater than the lower limit of detection of the assay Note: Unconfirmed virologic HIV-1 RNA value of greater than the lower limit of detection of the assay (transient detectable viremia, or "blip") prior to screening is not exclusionary. For Cohort 1 participants enrolling to Cohort 2, Step 3, occurrence of any Grade 3 or higher adverse event assessed as related to study product or permanent discontinuation of study product due to an adverse event of any grade assessed as related to study product during participation in Cohort 1 (including any long-term safety and washout PK follow-up visits). For participants enrolling to Cohort 1 Step 1, based on available medical records, currently on either a cART regimen containing both a protease inhibitor (PI) and an integrase strand transfer inhibitor (INSTI), or a cART regimen containing both an INSTI and a non-nucleoside reverse transcriptase inhibitor (NNRTI). As determined by the IoR or designee, and based on available medical records, known or suspected resistance to RPV As determined by the IoR or designee based on available medical records, known or suspected resistance to INSTIs History of congestive heart failure, symptomatic arrhythmia, or any clinically significant cardiac disease, as determined by the IoR or designee based on available medical records At entry, known active tuberculosis infection, requiring anti-tuberculosis treatment, as determined by the IoR or designee based on available medical records Known hepatitis B or hepatitis C infection, as determined by the IoR or designee based on available medical records Clinically significant hepatic disease, as determined by the IoR or designee based on available medical records Current or anticipated need for chronic anti-coagulation, as determined by the IoR or designee, based on available medical records History of sensitivity to heparin or heparin-induced thrombocytopenia, as determined by the IoR or designee, based on available medical records History of known or suspected bleeding disorder including history of prolonged bleeding, as determined by the IoR or designee, based on available medical records Known or suspected allergy to study product components 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, based on available medical records. At entry, participant is receiving (or has received in the last 7 days) any disallowed medication listed in the study protocol. Current inflammatory skin condition that compromises the safety of intramuscular injections as determined by the IoR or designee. Has a tattoo or other dermatological condition overlying the buttock region which, in the opinion of the IoR or designee, may interfere with interpretation of injection site reactions Surgically-placed, or planned, buttock implants, per self-report For females, lactating (per self-report and/or parent/guardian report) at entry Enrolled in another clinical trial of an investigational agent, device, or vaccine Any other condition or social circumstance situation that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives Inclusion/Exclusion Criteria, Step 2 (Cohort 1 Progression Criteria, Step 1 to Step 2) Cohort 1 Step 1 participants will be assessed for eligibility to progress from the oral lead-in phase (Step 1) to the injection phase (Step 2) primarily based on the safety assessments from the Cohort 1 Step 1 Week 4a study visit. Clinical assessments conducted prior to administering the first injection at the Week 4b visit will also be used to confirm eligibility to receive the injectable study product. See the study protocol for Week 4a and Week 4b visit scheduling, order of procedures, and visit windows, respectively. All of the following criteria must be met in order for participants to be included in Cohort 1 Step 2: Currently enrolled in Cohort 1, Step 1 At Cohort 1 Step 1 Week 4a study visit, or from confirmatory repeat testing of Cohort 1 Step 1 Week 4a study visit laboratory tests, has Grade 2 or lower of all the following laboratory test results: ALT (u/l) Lipase (u/l) Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m^2) Platelets (cells/mm^3) Hemoglobin (g/dL) Note: For a Grade 2 ALT test result from this visit, refer to the study protocol for required participant management. Abnormal laboratory test result values from the Week 4a visit may be repeated within the target visit window, and if confirmatory testing results in Grade 2 or lower, the participant may be eligible to continue onto the injection phase, should all other eligibility criteria be met. For females, at Cohort 1 Step 1 Week 4b study visit, has a negative hCG laboratory test result Assessed by the IoR or designee as sufficiently adherent 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 Participants who meet any of the following criteria will be excluded from Cohort 1 Step 2: Has permanently discontinued oral study product Occurrence of any grade 3 or higher adverse event assessed as related to study product during participation in Step 1 Any other condition or social circumstance that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives. Inclusion/Exclusion Criteria, Step 4 (Cohort 2 Progression Criteria, Step 3 to Step 4) Cohort 2 Step 3 participants will be assessed for eligibility to progress from the oral lead-in phase (Step 3) to the injection phase (Step 4) primarily based on the safety assessments from the Cohort 2 Step 3 Week 4a study visit. Clinical assessments conducted prior to administering the first injection at the Week 4b visit will also be used to confirm eligibility to receive the injectable study product. See the study protocol for Week 4a and Week 4b visit scheduling, order of procedures, and target visit windows, respectively. All of the following criteria must be met in order for participants to be included in Cohort 2 Step 4: Currently enrolled in Cohort 2, Step 3 At Cohort 2 Step 3 Week 4a study visit, or from confirmatory repeat testing of Cohort 2 Step 3 Week 4a study visit laboratory tests, has Grade 2 or lower of the following laboratory test results: ALT (u/l) Lipase (u/l) Estimated creatinine clearance (CrCl; Schwartz formula mL/min/1.73m^2) Platelets (cells/mm^3) Hemoglobin (g/dL) Note: For a Grade 2 ALT test result from this visit, refer to the study protocol for required participant management. Abnormal laboratory test result values from the Week 4a visit may be repeated, within the target visit window, and if confirmatory testing results in Grade 2 or lower, the participant may be eligible to continue onto the injection phase, should all other eligibility criteria be met. For females, at Cohort 2 Step 3 Week 4b study visit, has a negative hCG laboratory test result Assessed by the IoR or designee as sufficiently adherent in Step 3 to permit an adequate evaluation of safety and tolerability as part of the oral lead-in phase prior to entry into the injection phase Participants who meet any of the following criteria will be excluded from Cohort 2 Step 4: Has permanently discontinued oral study products Occurrence of any grade 3 or higher adverse event assessed as related to study product during participation in Cohort 2, Step 3 Any other condition or social circumstance that, in the opinion of the IoR or designee, would make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives. Inclusion/Exclusion Criteria: Parents/Caregivers Selected parents or caregivers of adolescents may be enrolled to complete qualitative phone interviews. See the study protocol for more information regarding the selection process, and coordination of scheduling the interviews. All of the following criteria must be met for the parent/caregiver to be enrolled: Selected by the protocol team for participation in the study Willing and able to provide informed (verbal or written) consent for study participation Per the adolescent participant, has knowledge of how the adolescent participant tolerated the study product, and lives with or has regular supportive contact with the adolescent participant Per parent/caregiver self-report, has knowledge of how the participant tolerated the study product, and lives with or has regular supportive contact with the adolescent participant Willing and able to complete interview in English by phone Parents and/or caregivers of participants who meet the following criterion will be excluded from study participation: Any condition or social circumstance that, in the opinion of the IoR or designee, would make study participation unsafe for either the parent/caregiver or the adolescent participant, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Beginning 3 months following publication and available throughout period of funding of the International Maternal Pediatric Adolescent AIDS Clinical Trial (IMPAACT) Network by NIH.

With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the IMPAACT Network. For what types of analyses? To achieve aims in the proposal approved by the IMPAACT Network. By what mechanism will data be made available? Researchers may submit a request for access to data using the IMPAACT "Data Request" form at: https://www.impaactnetwork.org/resources/study-proposals.htm. Researchers of approved proposals will need to sign an IMPAACT Data Use Agreement before receiving the data.