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

HIV Infections Clinical Trial

— MOCHA  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03497676
• Other study ID #: IMPAACT 2017
• Secondary ID: 30070
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 19, 2019
• Est. completion date: June 17, 2025

Study information

• Verified date: April 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study was to determine the dosage for oral cabotegravir (CAB) and long-acting cabotegravir (CAB LA) and long-acting rilpiverine (RPV LA) LA and evaluate the safety, acceptability, tolerability, and pharmacokinetics (PK) of oral CAB,CAB LA, and RPV LA in virologically suppressed HIV-infected children and adolescents.

Description:

IMPAACT 2017 was a Phase I/II, multi-center, open-label, non-comparative dose-finding study with the primary objective of evaluating the safety, acceptability, tolerability, and PK of oral cabotegravir (CAB) and long acting cabotegravir (CAB LA) as well as long acting rilpivirine (RPV LA) in adolescents living with HIV-1, who are 12 to <18 years of age, ≥35kg, and virologically suppressed.

The study design included two cohorts of participants and five study steps. In Cohort 1, Step 1 participants received either oral CAB or oral rilpivirine (RPV) for at least four weeks and up to six weeks (maximum). In Cohort 1, Step 2 participants received intramuscular injectable formulations of the study products, either CAB LA or RPV LA. Cohort 1 participants were assigned either CAB (Cohort 1C) or RPV (Cohort 1R) based on their pre-study combination Antiretroviral Therapy (cART) regimen. Participants on a PI-based and/or NNRTI-based cART regimen were assigned to Cohort 1C, and participants on a non-boosted INSTI-based cART regimen were assigned to Cohort 1R. All participants continued their pre-study cART regimen during Cohort 1.

During Cohort 2, all participants discontinued their pre-study cART regimen and received both study products, CAB and RPV, at the doses established in Cohort 1. Cohort 2 participants enrolled to either Cohort 2A to receive both oral CAB + oral RPV (Step 3) followed by both CAB LA + RPV LA (Step 4) or Cohort 2B to directly receive both CAB LA + RPV LA without an oral lead-in phase (Step 5). If eligible, Cohort 1 participants were able to enroll into Cohort 2 (i.e., Cohort 1 Rollover). However, Cohort 2 participants who were not previously enrolled in Cohort 1 (i.e., Cohort 1-Naïve) were the primary group for analyses and conclusions. No participants enrolled into Cohort 2B, direct to injection (Step 5). Therefore, all references to Cohort 2 refer to Cohort 2A (Steps 3 and 4).

Two interim analyses were planned. The first interim analysis established the doses for Cohort 2 and determined whether to open Cohort 2 to Cohort 1 participants who met criteria to enter Cohort 2. The second interim analysis provided justification to open Cohort 2 to additional participants who were not previously enrolled in Cohort 1. A final analysis of Cohort 1 data was performed to confirm the final doses for Cohort 2.

Safety and PK evaluations were performed during Steps 1-5 and long-term safety follow-up (LSFU). Antiviral activity assessments were performed during Steps 1-5. Acceptability and tolerability were assessed during Steps 1-5 and LSFU, with all participants completing quantitative questionnaires and a subset of participants completing in-depth qualitative interviews. Additionally, parents/caregivers of a subset of U.S. participants from U.S. sites were also enrolled to complete a single in-depth qualitative interview. Because objectives related to parents/caregivers were exploratory, these outcomes are not described here.

Cohort 1 participants were followed for up to 64 weeks. Participants were followed for at least four weeks in Step 1 (oral phase) and at least 12 weeks in Step 2 (injection phase). All Step 2 participants were followed (on cART, off study product) for up to an additional 48 weeks as part of LSFU after their last study product injection. If eligible, Cohort 1 participants enrolled into Cohort 2 before completing LSFU. For Cohort 1, Step 1 participants not progressing to Step 2, the last visit was targeted to be completed 28 days after the participant's last oral study product use.

Cohort 2 participants were followed for up to 188 (Cohort 2B) or 192 (Cohort 2A) weeks. Participants were followed for at least four weeks in Step 3 (oral phase) and 92 weeks in Step 4/Step 5 (injection phase). After completing 92 weeks of follow-up in Step 4/Step 5 (injection phase), Cohort 2 participants who continue access to injectable study products through a mechanism external to the protocol exited the study. If it is not possible for participants to access injections of CAB LA + RPV LA from non-study sources at the completion of their Step 4 Week 96 or Step 5 Week 92 visit, participants remained in the study safety extension for up to 48 weeks. Participants who permanently discontinue injectable study product use during Cohort 2, Step 4/Step 5, or do not wish to continue to access the study products through the external mechanism after their Week 96, were followed (on cART, off study product) for an additional 48 weeks as part of LSFU after their last study product injection, except for participants in the safety extension study. Participants in the study safety extension who decide to permanently discontinue injectable study product or who have not established access to study product after the 48 weeks in the study safety extension would exit the study (not enter LSFU). For Cohort 2, Step 3 participants not progressing to the injection phase, the last visit was targeted to be completed 28 days after the participant's last oral study product use. Female participants who discontinued study product use (either oral or injectable study product) due to pregnancy during Steps 1-5 were followed for an additional 48 weeks in LSFU to assess long-term safety and washout PK of the study products, except for participants in the safety extension study. Participants who became pregnant during the safety extension were only followed until the pregnancy outcome was determined.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 168
• Est. completion date: June 17, 2025
• Est. primary completion date: February 18, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 17 Years

Eligibility

Inclusion Criteria: Cohort 1 Step 1, Cohort 2 Step 3, and Cohort 2 Step 5

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, 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.

OR

For Cohort 1 participants enrolling to Cohort 2, has documented plasma HIV-1 RNA results less than the lower limit of detection of the assay from all indicated Cohort 1 study visits with their Cohort 1 Week 16 visit completed within 28 days prior to Cohort 2 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)

• AST (u/l)

• Absolute Neutrophil Count (cells/mm3)

• 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.

• At screening, is on an atazanavir-containing (ATV) cART regimen, and 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, Cohort 2 Step 3, or Cohort 2 Step 5

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)

• AST (u/l)

• Absolute Neutrophil Count (cells/mm3)

• 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)

• AST (u/l)

• Absolute Neutrophil Count (cells/mm3)

• 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.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Oral Cabotegravir (CAB)
30 mg tablets administered orally
• Oral Rilpivirine (RPV)
25 mg tablets administered orally
• Long-Acting Injectable Cabotegravir (CAB LA)
Administered by intramuscular (IM) injection
• Long-Acting Injectable Rilpivirine (RPV LA)
Administered by intramuscular (IM) injection
• Combination Antiretroviral Therapy (cART)
Participants will continue their pre-study cART regimen. The antiretroviral drugs in participants' cART regimens were not provided through the study.

Locations

Country	Name	City	State
Botswana	Gaborone CRS	Gaborone	South-East District
Botswana	Molepolole CRS, Site 12702	Molepolole
South Africa	Wits RHI Shandukani Research Centre CRS	Johannesburg
South Africa	Soweto CRS, Site 8052	Soweto
South Africa	Famcru Crs	Tygerberg Hills	Western Cape
South Africa	Umlazi CRS	Umlazi
Thailand	Siriraj Hospital Mahidol University	Bangkok
Thailand	Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS	Chiang Mai
Thailand	Chiangrai Prachanukroh Hospital NICHD CRS	Chiang Mai
Uganda	Baylor-Uganda CRS	Kampala
Uganda	MU-JHU Care Limited CRS	Kampala
United States	Emory University School of Medicine NICHD CRS	Atlanta	Georgia
United States	Univ. of Colorado Denver NICHD CRS	Aurora	Colorado
United States	Johns Hopkins Univ. Baltimore NICHD CRS	Baltimore	Maryland
United States	Lurie Children's Hospital of Chicago (LCH) CRS	Chicago	Illinois
United States	Usc La Nichd Crs	Los Angeles	California
United States	St. Jude Children's Research Hospital CRS	Memphis	Tennessee
United States	Pediatric Perinatal HIV NICHD CRS, Site 5127	Miami	Florida

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	ViiV Healthcare

Countries where clinical trial is conducted

United States,  Botswana,  South Africa,  Thailand,  Uganda, 

References & Publications (2)

Gaur AH, Capparelli EV, Calabrese K, Baltrusaitis K, Marzinke MA, McCoig C, Van Solingen-Ristea RM, Mathiba SR, Adeyeye A, Moye JH, Heckman B, Lowenthal ED, Ward S, Milligan R, Samson P, Best BM, Harrington CM, Ford SL, Huang J, Crauwels H, Vandermeulen K — View Citation

Lowenthal ED, Chapman J, Ohrenschall R, Calabrese K, Baltrusaitis K, Heckman B, Yin DE, Agwu AL, Harrington C, Van Solingen-Ristea RM, McCoig CC, Adeyeye A, Kneebone J, Chounta V, Smith-Anderson C, Camacho-Gonzalez A, D'Angelo J, Bearden A, Crauwels H, Hu — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Participants Who Had Grade 3 or Higher Adverse Event (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. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 4
Primary	Proportion 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. The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related by the site investigator of record to study product through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 4
Primary	Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1)	Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 4
Primary	Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)	We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 4
Primary	Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)	We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 4 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 4
Primary	Proportion of Participants Who Had Grade 3 or Higher Adverse Events (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. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 16
Primary	Proportion 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. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 16
Primary	Proportion of Participants Who Had Serious Adverse Events Meeting International Conference on Harmonisation (ICH) Criteria Assessed as Related to Study Product/s (Cohort 1)	Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 16
Primary	Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)	We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 16
Primary	Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 1)	We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 16 weeks post-treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 1 Treatment Initiation through Week 16
Primary	Proportion of Participants Who Had Grade 3 or Higher Adverse Events (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. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 2 Treatment Initiation through Week 24
Primary	Proportion 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. The DAIDS grading table provides an adverse event (AE) severity grading scale ranging from grades 1 to 5 with descriptions for each AE based on the following general guidelines: grade 1 indicates a mild event, grade 2 indicates a moderate event, grade 3 indicates a severe event, grade 4 indicates a potentially life-threatening event, and grade 5 indicates death. We present the proportion of participants with at least one grade 3 or higher AE assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 2 Treatment Initiation through Week 24
Primary	Proportion of Participants Who Had Serious Adverse Events Meeting ICH Criteria Assessed as Related to Study Product/s (Cohort 2)	Adverse events (AE) were assessed as a Serious AE by ICH criteria. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details). We present the proportion of participants with at least one serious AE assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 2 Treatment Initiation through Week 24
Primary	Proportion of Participants Who Permanently Discontinued Study Product Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2)	We present the proportion of participants who permanently discontinued study product due to adverse events (AEs) assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 2 Treatment Initiation through Week 24
Primary	Proportion of Participants Who Died Due to Adverse Events Assessed as Related to Study Product/s (Cohort 2)	We present the proportion of participants who died due to adverse events assessed as related to study product by the site investigator of record through 24 weeks post-Cohort 2 treatment initiation, bounded by an exact 95% confidence interval (CI).	Cohort 2 Treatment Initiation through Week 24
Primary	Geometric Mean Area Under the Plasma Concentration-time Curve (AUC) for Step 1 Oral CAB (Cohort 1C)	AUC calculated using non-compartmental methods with linear up-log down trapezoidal rule (Phoenix WinNonlin v 8.3, Certara®). We present the geometric mean of the AUC with associated geometric coefficient of variation.	Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose
Primary	Apparent Total Body Clearance (CL/F) of Step 1 Oral CAB (Cohort 1C)	We present the geometric mean of the total body clearance of CAB and associated geometric coefficient of variation, based on analysis of intensive pharmacokinetic (PK) samples.	Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8 and (for Q4W dosing) 24 hours post-dose
Primary	Geometric Mean Maximum Plasma Concentration (Cmax) of Oral CAB (Cohort 1C)	We present the geometric mean of the maximum plasma concentration of CAB and associated geometric coefficient of variation, based on analysis of intensive PK samples	Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8 and (for Q4W dosing) 24 hours post-dose
Primary	Time of Maximum Concentration (Tmax) of Oral CAB (Cohort 1C)	We present the mean time of maximum concentration of CAB and associated standard deviation, based on analysis of intensive PK samples.	Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose
Primary	Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 1C)	We present the geometric mean pre-dose CAB concentration and associated geometric coefficient of variation, based on analysis of intensive PK samples.	Week 2: Samples collected pre-dose and 1, 2, 3, 4, 8, and (for Q4W dosing) 24 hours post-dose
Primary	Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q4W)	We present the geometric mean concentration of LA CAB/LA RPV and associated geometric coefficients of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK sample.	Week 16
Primary	Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q4W)	We present the geometric mean of the maximum plasma concentration of LA CAB/LA RPV and associated geometric coefficient of variation for the first injection in participants on the Q4W dosing regimen, based on analysis of intensive PK samples.	Samples collected at Weeks 4b, 5, 6, and 8
Primary	Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q4W)	We present the mean time of maximum concentration of LA CAB/LA RPV at the first injection and associated standard deviation for participants on the Q4W dosing regimen, based on analysis of intensive PK samples.	Samples collected at Weeks 4b, 5, 6, 8
Primary	Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q4W)	We present the geometric mean pre-dose concentrations of each injection and associated geometric coefficient of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK samples.	Week 4b, Week 8, Week 12
Primary	Geometric Mean Concentration of LA CAB/LA RPV at Week 16 (Cohort 1 Q8W)	We present the geometric mean concentration of LA CAB/LA RPV and associated geometric coefficients of variation for participants on the Q4W dosing regimen, based on analysis of the pre-dose PK sample.	Week 16
Primary	Geometric Mean Maximum Plasma Concentration (Cmax) of LA CAB/LA RPV (Cohort 1 Q8W)	We present the geometric mean of the maximum plasma concentration of LA CAB/LA RPV and associated geometric coefficient of variation for the first injection in participants on the Q8W dosing regimen, based on analysis of intensive PK samples.	Samples collected at Weeks 4b, 5, and 8
Primary	Time of Maximum Concentration (Tmax) of LA CAB/LA RPV (Cohort 1 Q8W)	We present the mean time of maximum concentration of LA CAB/LA RPV at the first injection and associated standard deviation for participants on the Q8W dosing regimen, based on analysis of intensive PK samples.	Samples collected at Weeks 4b, 5, and 8
Primary	Geometric Mean Pre-dose Concentration (C0) of LA CAB/LA RPV (Cohort 1 Q8W)	We present the geometric mean pre-dose concentration of the first injection and associated geometric coefficient of variation for participants on the Q4W dosing regimen, based on analysis of pre-dose PK samples.	Week 4b, Week 8
Secondary	Proportion of Participants With HIV-1 RNA < 50 Copies/mL (Cohort 1)	We present the proportion of participants with results of HIV-1 RNA < 50 copies/mL at Week 16	Week 16
Secondary	Proportion of Participants Who Reported "Hurts Whole Lot" or "Hurts Worst" in Regards to Being Bothered by Pain During Injection of CAB LA or RPV LA (Cohort 1)	Results collected via administration of Pain During Injection survey to participants after receiving injection. Pain during injections was assessed using the Faces Pain Scale-Revised which includes 6 visual and text options: "no hurt," "hurts little bit," "hurts little more," "hurts even more," "hurts whole lot" and "hurts worst".	Week 8
Secondary	Median Dimension of Quality of Life Scores	A commonly used 23-item Pediatric Quality of Life Inventory, the PedsQLTM, was used to measure physical, emotional, and social dimensions of health as well as school functioning. Question responses were used to generate scores from 0-100 (100 being the best quality of life) based on the PedsQLTM guidelines. The number of participants drops slightly for the school functioning result as not all participants are eligible to answer these school-related questions.	Week 16
Secondary	Number of Participants Who Had Grade 3 or Higher Adverse Events (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.	Cohort 2 treatment initiation through Week 48
Secondary	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.	Cohort 2 treatment initiation through Week 48
Secondary	Number of Participants Who Had Serious Adverse Events Meeting ICH Criteria, as Cited in References, Assessed as Related to Study Product/s (Cohort 2)	Assessed by meeting ICH criteria as related to study product/s. Per ICH, a serious AE is any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (see references for additional details).	Cohort 2 treatment initiation through Week 48
Secondary	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.	Cohort 2 treatment initiation through Week 48
Secondary	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.	Cohort 2 treatment initiation through Week 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA >= 50 Copies/mL Per the FDA Snapshot (Cohort 2)	We present the proportion of participants with HIV-1 RNA >= 50 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations.	Week 48
Secondary	Proportion of Participants With Plasma HIV-1 RNA >= 200 Copies/mL Per the FDA Snapshot (Cohort 2)	We present the proportion of participants with HIV-1 RNA >= 200 copies/mL and associated exact 95% CI (Clopper-Pearson) per the FDA snapshot, based on laboratory evaluations.	Week 24
Secondary	Geometric Mean Pre-dose Concentration (C0) of Oral CAB (Cohort 2)	We present the geometric mean of the pre-dose concentration of oral CAB and oral RPV and associated coefficient of variation, based on analysis of pre-dose PK sample.	Week 2
Secondary	Accumulation Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2)	We present the ratio of the geometric means of pre-dose CAB and RPV concentrations at Week 24:Week 8 and associated coefficient of variation, based on analysis of pre-dose PK samples.	Week 8 and Week 24
Secondary	Accumulation Ratio of Pre-dose CAB and RPV Concentrations at Week 24: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2)	We present the ratio of the geometric means of pre-dose CAB and RPV concentrations at Week 24:Week 16 and associated coefficient of variation, based on analysis of pre-dose PK samples.	Week 16 and Week 24
Secondary	Accumulation Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 8 (Cohort 2)	Based on analysis of intensive PK samples	Week 8 and Week 48
Secondary	Accumulation Ratio of Pre-dose CAB and RPV Concentrations at Week 48: Pre-dose CAB and RPV Concentrations at Week 16 (Cohort 2)	Based on analysis of intensive PK samples	Week 16 and Week 48

External Links

•   ICH Criteria for Meeting Serious Adverse Events