Clinical trial NCT04487145: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy
Official title: DPART Study: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Drug-Drug Interaction
HIV Infection
Keywords: Drug drug interaction
HIV
malaria
dihydroartemisinin
piperaquine
lopinavir
ritonavir
efavirenz
dolutegravir
Children
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Yale University
name: Makerere University
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2020-07-27
Enrollment: 194
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is an open-label prospective pharmacokinetic and safety study of DP and 3 different ART regimens (EFV-, LPV/r- and DTG-based ART) in non-malaria-infected 1) HIV-infected children and 2) HIV uninfected children not on ART (controls).
Primary purpose: PREVENTION

Brief summary: Open-label prospective intensive pharmacokinetic study of dihydroartemisinin-piperaquine (DP) in HIV-infected children on efavirenz (EFV)-, lopinavir/ritonavir (LPV/r)-, or dolutegravir (DTG)-based antiretroviral therapy (ART) and HIV-uninfected children not on ART. All children will be malaria-uninfected at the time of enrollment.

Detailed description: The primary goal of the study is to assess the pharmacokinetics (PK) and safety of DP in the setting of co-administration with first-line ART regimens (EFV-, LPV/r- or DTG-based ART) in children without malaria. Up to 190 children will be enrolled in one of the 5 groups: 1, HIV-infected children age 3 - 10 years on LPV/r-based ART (n=20 for signal dose DP, 30 standard 3-dose DP). 2, HIV-infected children age 3 - 10 years on EFV-based ART (n=30), 3, HIV-infected children age 11 - 17 years on DTG-based ART (n=30), 4, HIV-uninfected children age 3-10 years (standard 3-dose DP, n=20 for PK sampling after the 1st dose DP, n=30 for sampling after the 3rd dose DP), 5, HIV-uninfected children age 11-17 years (n=30 children receiving 3-dose DP).

HIV-infected participants will be enrolled from the Baylor Uganda Center of Excellence on the Mulago Hospital Complex, Kampala, Uganda. HIV-uninfected participants will be enrolled from Masafu General Hospital (MGH) complex in Busia, and other clinics in the surrounding area. DP weight-based dosing will follow World Health Organization (WHO) Treatment Guidelines for uncomplicated malaria (April 2015). All HIV-infected participants must be stabilized (i.e. no change in regimen for at least 10 days) on EFV, LPV/r, or DTG + 2 nucleoside reverse transcriptase inhibitors (NRTI). HIV-infected children on LPV/r will be enrolled in two Phases: Phase I participants (Group L1) will receive a single dose of DP to determine the magnitude (PK and safety) of the interaction before 3 doses are evaluated, Phase II participants (Group L3) will receive a 3-dose DP regimen (which consists of 3 days of a once daily DP dose). Phase I results will inform Phase II dosing, as a lower dose of DP over 3 days may be warranted. Phase II will not begin until PK and safety results from Phase I are evaluated. Participants in L1 and L3 will be encouraged to participate sequentially in Phase I and Phase II separated by a minimum 42-day washout period; however different children may be enrolled for the 2 phases. Weight-based dose of dihydroartemisinin-piperaquine (DP): 5- \<8kg, 20+160mg; 8- \<11kg, 30+240mg; 11- \<17kg, 40+320mg; 17- \<25kg, 60+480mg; 25- \<36kg, 80+640mg; 36- \<60kg, 120+960mg; 60-\<80kg, 160+1280mg; \>80kg, 200+1600mg.

Subjects will undergo an intensive PK study sampling design, which entails multiple venous blood collections in a smaller sample of individuals to accurately estimate drug exposure over time. These studies will be conducted in both HIV-infected and HIV-uninfected participants and will allow the researchers to investigate dihydroartemisinin (DHA) and piperaquine (PQ) PK exposure in the context of EFV-, LPV/r- and DTG-based ART in HIV-uninfected children. Comparisons will be based on an intensive PK design for DP area under the concentration-time curve (AUC) estimations. A sample size of 20 children/adolescents will be needed in groups L1 and C1. A sample size of 30 will be needed for each of the other arms (D3, E3, L3, C3a, and C3b). Sampling will occur up to day 42 in the 3-dose groups given the long half-life of PQ and for 14 or 28 days in the single dose groups. The generation of an AUC will permit robust comparisons so that results will inform treatment guidelines and policy.

Eligibility criteria: Inclusion Criteria:

All participants:

* Agreement to come to clinic for all follow-up PK and safety evaluations
* Provision of informed consent.

HIV-infected participants:

* Residency within 30km of Mulago Hospital.
* Confirmed HIV infection (confirmed positive rapid HIV test or HIV RNA as per
* Ugandan guidelines).
* On stable EFV-, LPV/r- or DTG-based ART for at least 10 days prior to enrollment.
* Age 3 - 10 years if on EFV-based ART or LPV/r-based ART.
* Age 11 - 17 years if on DTG-based ART.

HIV-uninfected participants:

* Residency within 30km of Masafu General Hospital
* Confirmed HIV negative test (confirmed positive rapid HIV test or HIV RNA as
* per Ugandan guidelines)
* Age 3 - 17 years.

Exclusion Criteria:

* History of significant comorbidities such as malignancy, active tuberculosis or
* other active WHO stage 4 disease
* Receipt of any medications known to affect CYP450 metabolism (except ART)
* within 14 days of study enrolment (see 4.2.1)
* Hemoglobin \< 7.0 g/dL
* Current malaria infection or recent treatment with antimalarials within 28 days of
* enrolment.
* Asymptomatic parasitemia detected by microscopy or rapid diagnostic test (RDT)
* History of side effects with DP
* Prior history of cardiac disease (personal or family), baseline corrected QT intervals (QTc) \>450msec, or
* receipt of any cardiotoxic drugs or those known to prolong QT intervals History of
* significant comorbidities such as malignancy, active tuberculosis or other WHO
* stage 4 disease
* Weight \< 6kg
* HIV-infected females on DTG-based ART and age 13-17 years who are pregnant
* or of childbearing potential and do not agree to consistent and reliable
* contraception.

The following medications are disallowed within 3 weeks prior to receiving study drug:

* Carbamazepine
* Clarithromycin
* Erythromycin (oral)
* Ketoconazole
* Phenobarbital
* Phenytoin
* Rifabutin
* Rifampicin
* Halofantrine
* Any other medication known to significantly affect CYP450 metabolism.
* Grapefruit juice should be avoided during the study due to its potential effects on CYP3A4.

Primary outcomes:
measure: AUC0-42day in 3-dose Study
timeFrame: 42 days
measure: QTcF in 3-dose Study
timeFrame: 42 days
measure: AUC0-day28 in 3-dose Study
timeFrame: day 2-28
measure: Cmax for Piperaquine in 3-dose Study
timeFrame: day 2-28
Secondary outcomes:
Other outcomes:
measure: Cmax for Piperaquine in Single-dose Study
timeFrame: <24hr
measure: AUC0-24h for Piperaquine in Single-dose Study
timeFrame: 1 day
measure: QTcF in Single-dose Safety Study
timeFrame: 28 days
measure: The Association of Malnutrition and PK Exposure of DP in HIV-infected and HIV-uninfected Children
timeFrame: 42 days
measure: Assess Auto-induction of DHA From Single Dose to 3-doses
timeFrame: 3 days
measure: CYP2B6 Pharmacogenetics and Its Impact on EFV PK
timeFrame: 4 days
measure: The Association of Anthropomorphic Indicators of Malnutrition Measured as Height-for-age (HFA) Z-score and PK Exposure of DP in HIV-infected and HIV-uninfected Children
timeFrame: 42 days
measure: The Effects of DP on EFV Pharmacokinetics as Measured by Trough-level (Cmin) of EFV
timeFrame: 4 days
measure: The Effects of DP on DTG Pharmacokinetics as Measured by Trough-level (Cmin) of DTG
timeFrame: 4 days
measure: The Effects of DP on LPV/r Pharmacokinetics as Measured by Trough-level (Cmin) of LPV/r
timeFrame: 4 days
Locations:
city: Masafu
country: Uganda
facility: Masafu General Hospital (MGH) at Busia District, Eastern Uganda
state: Busia
city: Kampala
country: Uganda
facility: Baylor-Uganda Center of Excellence on Mulago Hospital Complex and Masafu General Hospital
Study officials:
affiliation: University of California, San Francisco
name: Francesca Aweeka
role: PRINCIPAL_INVESTIGATOR
affiliation: Yale University
name: Sunil Parikh
role: PRINCIPAL_INVESTIGATOR
affiliation: Makerere University
name: Norah Mwebaza
role: PRINCIPAL_INVESTIGATOR
affiliation: Baylor College of Medicine Children's foundation Uganda
name: Adeodata Kekitiinwa
role: STUDY_CHAIR
References: