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

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.

- If not of legal age or otherwise not able to provide independent informed consent as
determined by site Standard Operating Procedures (SOPs) and consistent with site
Institutional Review Board (IRB)/Ethics Committee (EC) policies and procedures: Parent
or legal guardian is willing and able to provide written informed consent for study
participation and potential participant is willing and able to provide written assent
for study participation

- If of legal age or otherwise able to provide independent informed consent as
determined by site SOPs and consistent with site IRB/EC policies and procedures:
Willing and able to provide written informed consent for study participation

- 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 6 consecutive months (defined as 180 consecutive days) prior to
screening, and prior to enrollment, has been on stable cART consisting of 2 or more
drugs from 2 or more classes of antiretroviral drugs, as determined by the site
investigator of record (IoR) or designee, and based on participant or parent/guardian
report and/or available medical records.

- 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 50 copies/mL from a specimen
collected 6 to 12 months (defined as 180 to 365 days) prior to screening.

- Has at least one documented plasma HIV-1 RNA less than 50 copies/mL from a specimen
collected within 6 months (defined as within 179 days) prior to screening.

- 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, corrected Q-T interval (QTc) interval (automated machine readout or
calculated using either Bazett or Fredericia) less than or equal to 500 msec

- For females, has a negative 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 study
visits 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 screening, two consecutive
documented HIV-1 RNA values greater than or equal to 50 copies/mL

- Note: Unconfirmed virologic HIV-1 RNA value of greater than or equal to 50
copies/mL (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 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.