Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy

Study Overview
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Brief Summary
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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
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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.

Official Title
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DPART Study: Dihydroartemisinin-Piperaquine in the Context of Antiretroviral Therapy

Conditions
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Drug-Drug Interaction, HIV Infection

Intervention / Treatment
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* Drug: Dihydroartemisinin-piperaquine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV-infected children on EFV-based ART (E3)<br>30 HIV-infected children age 3 - 10 years on EFV-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|
| Experimental: HIV-infected children on DTG-based ART (D3)<br>30 HIV-infected children age 11 - 17 years on DTG-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|
| Experimental: HIV-infected children on LPV/r-based ART (L1)<br>20 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take one oral dose DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|
| Experimental: HIV-infected children on LPV/r-based ART (L3)<br>30 HIV-infected children age 3 - 10 years on LPV/r-based ART for at least 10 days will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|
| Active Comparator: HIV-uninfected children (C1)<br>20 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 1st dose. Control group for L1. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|
| Active Comparator: HIV-uninfected children (C3a)<br>30 HIV-uninfected children age 3-10 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. PK samples are collected after the 3rd dose. Control group for E3 and L3. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|
| Active Comparator: HIV-uninfected children (C3b)<br>30 HIV-uninfected children age 11-17 years not on ART will take standard 3 consecutive once-daily oral doses of DP (20/120mg tablets) based on weight per 2015 WHO guidelines for DP. The brand name Duocotexin will be used. Control group for D3. | Drug: Dihydroartemisinin-piperaquine<br>* It is expected that efavirenz (EFV), lopinavir/ritonavir (LPV/r), and/or dolutegravir (DTG) will alter DP exposure.<br>* Other names: DHA-PQ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve for all drug analytes | AUC 0-8hr or AUC 0-24hr for dihydroartemisinin and AUC 0-infinity for piperaquine | 42 days | 
| Safety of single dose DP in HIV-infected children on LPV/r-based ART determined via assessment of mean change in QT intervals from baseline | Cardiotoxicity associated with PQ is QT interval prolongation. Electrocardiogram (ECG) will be performed to provide data on QT intervals in msec. | 28 days | 
| Safety of 3-dose DP regimens determined via-assessment of mean change in QT intervals from baseline | Safety determined via assessment of mean change in QT intervals from baseline in HIV-infected children on LPV/r- EFV-, and DTG-based ART and HIV-uninfected controls | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effects of DP on EFV pharmacokinetics as measured by mid-level of EFV | Pre-ART sample to quantify mid-level of EFV, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of EFV level. | 4 days | 
| The association of anthropomorphic indicators of malnutrition measured as weight-for age (WFA) z-score and PK exposure of DP in HIV-infected and HIV-uninfected children | Children will be characterized as a) stunted but not underweight [i.e. weight for age (WFA) z-score>-2); b) underweight, but not stunted (WFA z-score ≤-2); or c) of normal nutritional status (WFA z-scores >-1). | 42 days | 
| Assess auto-induction of DHA from single dose to 3-doses | DHA AUC after 1st dose will be compared to AUC after 3rd dose. | 4 days | 
| CYP2B6 pharmacogenetics and its impact on EFV PK. | To assess prevalence of CYP2B6 pharmacogenetic variants and their impact on EFV PK | 4 days | 
| 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 | Children will be characterized as a) stunted but not underweight [i.e. height for age (HFA) z-score ≤-2); b) underweight, but not stunted (HFA z-score>-2); or c) of normal nutritional status (HFA z-scores >-1). | 42 days | 
| The effects of DP on DTG pharmacokinetics as measured by trough-level (Cmin) of DTG | Pre-ART sample to quantify trough of DTG, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of DTG level. | 4 days | 
| The effects of DP on LPV/r pharmacokinetics as measured by trough-level (Cmin) of LPV/r | Pre-ART sample to quantify trough of LPV/r, sampled collected via venipuncture on Day 0, 2, & 3 to allow for comparisons of LPV/r level. | 4 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Children, efavirenz, dolutegravir, Drug drug interaction, malaria, dihydroartemisinin, piperaquine, lopinavir, ritonavir, HIV