IMPAACT 2019

Phase I/II Study of the Pharmacokinetics, Safety, and Tolerability of Abacavir/Dolutegravir/Lamivudine Dispersible and Immediate Release Tablets in HIV-1-Infected Children Less than 12 Years of Age

Rationale

To date, DTG has only been studied as a single ARV formulation in children. ABC/DTG/3TC (immediate release tablet marketed as Triumeq®) is a safe, effective, and well-tolerated “one pill, once daily” regimen approved by the FDA and EMA for use in adults and children weighing at least 40 kg (the EMA approval for pediatric use is limited to children at least 12 years of age).

DTG has rapidly become a “preferred” agent for initial treatment of HIV in adults, and more recently, children and adolescents six years of age and older. Much of the safety, PK and dosefinding evaluation for DTG in children was completed in the ongoing IMPAACT P1093 and ODYSSEY studies. Internationally, the WHO supports harmonization of ARV regimens across populations including using the same regimen of ARVs in adult and pediatric populations. As more experience with INSTIs become available, it is presumed that this drug class will be identified as the candidate for a universal regimen for adults, pregnant women and children. To facilitate this goal, the safety and PK of dispersible tablet ABC/DTG/3TC in young children must be defined.

This Phase I/II study will investigate the PK, safety and tolerability of ABC/DTG/3TC in HIV infected children less than 12 years of age. Given that DTG has demonstrated excellent virologic activity in P1093 and has an increasing role as initial ARV therapy in adults and older children, this study will include both ART-naïve and ART-experienced children. ABC/DTG/3TC will be dosed by weight bands across the age spectrum, consistent with the intended future marketing of the product. Age-based quotas have been specified to help ensure that adequate PK, safety, and tolerability data are collected among children less than six years of age as well as children six years of age and older.

Previous experience in adults has demonstrated that the exposure to DTG, ABC and 3TC in a fixed dose combination formulation is consistent with each drug administered individually. This information was provided as part of the application for Triumeq®. Therefore, the DTG dosing recommendations from IMPAACT P1093 are not expected to differ when DTG is administered in a fixed dose combination. Nonetheless, a subset of children in each weight band will undergo intensive PK approximately one week after initiating ABC/DTG/3TC to evaluate for similar exposure to DTG. Population PK will be evaluated among all study participants.

Rationale for Initial Dose Selection

The DTG doses selected for evaluation in this study are expected to achieve DTG exposures similar to those observed with DTG 50 mg twice-daily in adults. The DTG doses are higher than those previously evaluated but consistent with doses currently being studied in IMPAACT P1093. The higher expected exposures of DTG are due to the coformulation of DTG, ABC, and 3TC in a single tablet; whereas the doses of 3TC and ABC increase in sync to each other with body weight, the increase is not the same for DTG. Safety data available from adults with higher DTG doses and exposures support the DTG doses selected for evaluation in this study (31-33).

The DTG doses selected for evaluation in this study are specified within weight bands and are expected to be applicable to children less than 12 years of age who weigh at least 6 kg. However, as of the date of this protocol, limited data are available on DTG dosing for children less than six months of age. Additional data from the IMPAACT P1093 and ODYSSEY studies are expected to become available for this age group in the near future. When these data become available, the IMPAACT 2019 Protocol Team will review them to determine whether the dosing specified for this study is appropriate for children less than six months of age. Until this review is conducted, accrual into this study will be restricted to children six months of age and older. Once this review is conducted, if the Protocol Team determines that the dosing specified for this study is appropriate for children less than six months of age, the restriction on accrual will be lifted. If the Protocol Team determines that the dosing is not appropriate for children less than six months of age, the restriction on accrual will be maintained while alternative dosing and/or other protocol modifications are developed for children less than six months of age. Study sites will be notified of the outcome of the team’s review and decision-making via email.

The doses of ABC/3TC proposed for use in this study are consistent with WHO recommended doses of ~16 mg/kg for ABC and ~8 mg/kg for 3TC in children. Exposures from these doses are expected to achieve AUCs similar to those measured in ARROW, PENTA13, and PENTA15, which examined the PK and efficacy of once-daily ABC/3TC in pediatric patients. A relative bioavailability study is planned to provide reassurance of similar exposures of ABC/3TC with use of the dispersible fixed dose combination tablet compared with the marketed immediate release fixed dose combination tablet.

Rationale for PK Targets A minimum of five children in each weight band will undergo intensive PK sampling with real time testing and review of intensive PK outcomes for ABC, DTG, and 3TC to confirm appropriate dose selection for each weight band. Dose confirmation for each weight band will be based on PK (AUC0-24h for ABC, DTG, and 3TC, in addition to C24h for DTG) and safety outcomes. Dose confirmation based on all three agents reflects ViiV’s currently agreed PIP and PSP.

The DTG targets are similar to current targets for IMPAACT P1093. These targets will continue to be evaluated and updated if needed based on new findings from P1093. The weight band target AUC0-24h target range for DTG is based on the lower and upper bounds of the 90% CIs for once and twice-daily DTG dosing in adults, respectively. The weight band target C24h target range for DTG is based on 60% of once-daily geometric mean exposures and 140% of twice-daily geometric mean exposures in adults. The ABC and 3TC AUC0-24h targets are based on the minimum lower and maximum upper bounds of the 90% CIs for predicted exposures with once daily ABC/3TC weight band dosing with the tablet formulation in children (summarized Table 3).

If the geometric mean AUC0-24h for ABC, DTG, or 3TC and/or C24h for DTG among the dose evaluable (refer to Section 3.2) children in each weight band falls outside of the targeted range, the Protocol Team will re-evaluate the dose for that weight band using all available PK data from this study in addition to PK results from previous and ongoing studies of ABC, DTG, and 3TC. Individual dose adjustments may also be performed if a child’s DTG AUC0-24h or C24h falls outside of the individual target ranges outlined in Table 5. If a child requires an individual dose adjustment, a repeat PK assessment may be performed for that child, with an appropriate sampling hstrategy determined by the Protocol Pharmacologists.

Rationale for Deferred Enrollment of Children Switching from an NNRTI-Containing Regimen

Children switching to the study drug regimen from an NNRTI-containing regimen (particularly a regimen containing etravirine, efavirenz, or nevirapine) will not be included in the intensive PK sampling as they may have decreased DTG exposure subsequent to enzymatic induction by these agents. These children, however, will have additional sparse sampling to better understand the PK of DTG when switching from an NNRTI-containing regimen. A sub-study in adult patients switched from efavirenz or nevirapine to DTG with rilpivirine (SWORD 1 and 2) examined trough levels at Weeks 2, 4, 8, 24, and 48 following the switch, and revealed that DTG trough concentrations were similar to levels in patients not on an NNRTI regimen by Week 4 (34). No dose adjustments to DTG were made following the transition from efavirenz or nevirapine to DTG with rilpivirine, and trough levels remained above the DTG IC90 at all time points examined.

Note: Under certain pre-specified conditions, and in consultation with the Study Monitoring Committee (SMC), the Protocol Team may consider expanding intensive PK sampling to children switching to the study drug regimen from an NNRTI-containing regimen; refer to Section 9.5.1 for more information regarding this potential option.

Rationale for Exploratory Evaluations

In addition to plasma PK evaluations, this study will characterize phosphorylated 3TC and ABC moieties in PBMCs and dried blood spots (DBS). The active moieties of ABC and 3TC are found intracellularly and have been shown to correlate with ARV activity in previous studies (28). Thus, examining intracellular levels of carbovir-triphosphate and lamivudine-triphosphate in PBMCs may provide additional insight into exposure-response relationships at the site of action with these agents.

DBS will be collected to characterize drug levels in this matrix and compare levels to self reported adherence. This approach has been studied with tenofovir disoproxil fumarate, tenofovir alafenamide, and emtricitabine, for which concentrations of the phosphorylated moieties can serve as measures of long- and short-term adherence to ARV therapy, respectively (35-37). Tenofovir-diphosphate concentrations increase proportionally with the number of doses taken per week, and thus this measure has been integrated as a surrogate measure of adherence and treatment outcomes in several HIV pre-exposure prophylaxis (PrEP) (25, 38-40) and treatment (41, 42) studies. This same approach could be applied with the phosphorylated moieties of ABC and 3TC.

Pharmacogenetic analyses will focus on single nucleotide polymorphisms (SNPs) in genes that encode drug transporters and metabolizing enzymes involved in the PK disposition of ABC, DTG, and 3TC. The primary focus for initial pharmacogenetic analyses will focus on SNPs that influence the PK of DTG, such as UGT1A1 (rs8175317), for which individuals with low and reduced activity (presence of *28 and/or *37 alleles) exhibit slower clearance and higher DTG exposure (43).

Rationale for Adherence Evaluations

A variety of methods will be used to evaluate adherence to daily administration of ABC/DTG/3TC in this study. For all children, questionnaires will be administered at time points designated in the Schedule of Evaluations. In addition, for children undergoing intensive PK sampling, more objective methods of assessing adherence such as texted video, video streaming, and in-person directly observed therapy will be used to confirm daily dosing between enrollment and the day of intensive PK sampling. Data obtained through these methods will assist with determining whether failure to reach PK targets is due to challenges with adherence or administration versus actual PK differences in the pediatric study population. Relationships between PK-based adherence measures and other adherence measures will be explored, which may provide useful insights into selection of adherence measures to be used in future pediatric studies.

Primary Objectives

• Determine the steady-state AUC0-24h, Cmax, and C24h of ABC, DTG, and 3TC and confirm the dosing of ABC/DTG/3TC dispersible and immediate release tablets that achieves

• Protocol-defined PK targets for ABC, DTG, and 3TC in children less than 12 years of age

• Evaluate the safety profile of 24 weeks of treatment with ABC/DTG/3TC dispersible

• Tablets and ABC/DTG/3TC immediate release tablets among children less than 12 years of age

Study Population

This study will be conducted among at least 50 and up to 75 HIV-1-infected children who will be selected At least 25 children will be less than six years of age and at least 25 will be six to less than 12 years of age.

Investigators

Dr. Faeezah Patel

Dr. Elizea Horne

Dr. Maysseb Masenya

Dr. Stacy Lee Sigamoney

Dr. Mrinmayee Dhar

Dr. Gabriella Benade

Othusitse Segalo

Tiffany Seef

Sponsors/Donors

NIAID NICHD

Latest Update: 23 August 2021

For more about IMPAACT 2019 please email rhicomms@wrhi.ac.za