Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR201910580840196 Date of Approval: 04/10/2019
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title IMPROVE DDI sub-study: Dihydroartemisinin piperaquine (DP)-Dolutegravir-based ART drug-drug interactions in pregnancy
Official scientific title Impact of dolutegravir-based antiretroviral therapy on the pharmacokinetic profile of piperaquine administered as dihydroartemisinin-piperaquine for intermittent preventive treatment of malaria in pregnant women living with human immunodeficiency virus in Malawi: a fixed sequence cohort study
Brief summary describing the background and objectives of the trial Dihydroartemisinin-piperaquine (DP) is being studied as an alternative to sulfadoxine-pyrimethamine (SP) in Malawi in pregnant women not living with HIV (the IMPROVE I trial) and in pregnant living with HIV (the IMPROVE II trial). Although unexpected, any possible effect of dolutegravir on piperaquine concentrations, or of piperaquine on dolutegravir concentrations in the blood, is not yet known. This needs to be investigated to make sure that these drugs do not impact on each other’s blood levels,and potentially change their effectiveness or tolerability. The aim of this pharmacokinetic IMPROVE DDI sub-study is to understand whether the malaria preventive treatment, DP, and the HIV treatment, dolutegravir-based ART, impact on each other’s blood levels when administered together in pregnant women living with HIV . The primary objective is to compare the mean trough plasma concentrations and pharmacokinetic parameters of piperaquine, administered as standard 3-day treatment course of dihydroarteminin-piperaquine, when coadministered with dolutegravir-based ART regimen, and when co-administered with efavirenz-based ART regimen in pregnant women living with HIV in Malawi. The secondary objectives is to compare steady-state trough and pharmacokinetic parameters of dolutegravir when administered alone as dolutegravir based-ART, and when co-administered with dihydroartemisinin-piperaquine for IPTp in pregnant women living with HIV in Malawi
Type of trial CCT
Acronym (If the trial has an acronym then please provide) IMPROVE DDI
Disease(s) or condition(s) being studied Infections and Infestations,Pregnancy and Childbirth
Sub-Disease(s) or condition(s) being studied HIV/AIDS,Malaria
Purpose of the trial Prevention
Anticipated trial start date 14/10/2019
Actual trial start date 30/11/2019
Anticipated date of last follow up 31/07/2020
Actual Last follow-up date 10/07/2020
Anticipated target sample size (number of participants) 22
Actual target sample size (number of participants) 16
Recruitment status Completed
Publication URL https://journals.asm.org/doi/full/10.1128/aac.01562-22
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Crossover: all participants receive all interventions in different sequence during study Non-randomised Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Dihydroartemisinin piperaquine 40 mg dihydroartemisinin and 320 mg piperaquine (fixed dose combination) daily 3 days Intermittent preventive treatment of malaria in pregnancy (IPTp) 22
Control Group NA NA NA NA 0 Uncontrolled
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Living with HIV, on efavirenz-based ART regimen for at least 3 months or dolutegravir based ART for at least a month Adult pregnant women (≥18 years of age) without any impaired decision-making capacity At or after 22 ± 6 weeks of gestation estimated by ultrasound scan Willing to adhere to scheduled and unscheduled study visit procedures and to attend follow up visits Resident of the study area Willing to deliver at the study hospital and have a maternal plasma, placental and cord blood samples collected at delivery Virologically suppressed (viral load <50 copies/mL) CD4 cell count > 100 cells/mm3 Able to provide written consent Haemoglobin value of <8.0 g/dL Multiple pregnancies (i.e. twin/triplets) Severe malformations or non-viable pregnancy observed by ultrasound Known allergy or contraindication to any of the study drugs On other medications that are known to have clinically significant interactions with efavirenz, dolutegravir or piperaquine such as rifampicin. Medical history of comorbidities that can influence the pharmacokinetic parameters of a study drug, such as clinically significant renal, liver or cardiac diseases Adult: 19 Year-44 Year,Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 50 Year(s) Female
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 23/09/2019 University of Malawi College of Medicine Research and Ethics Committee
Ethics Committee Address
Street address City Postal code Country
3rd Floor, John Chiphangwi Learning Resource Centre Blantyre 1234 Malawi
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Geometric mean and geometric mean ratios (90% confidence interval) of piperaquine pharmacokinetic parameters when DP-IPTp is co administered with 50 mg dolutegravir based ART compared to 600 mg efavirenz-based ART AUC 0 to 14 days, Cmax and tmax, apparent clearance and volume of distribution, observed piperaquine concentrations on days 7, 14 and 28
Secondary Outcome Geometric mean and geometric mean ratios (90% confidence interval) of piperaquine pharmacokinetic parameters of exposure when dolutegravir-based ART is administered alone compared with co-administration with DP-IPTp AUC 0-24 h, Cmax, tmax, Cmin
Secondary Outcome Geometric Mean Ratios (90% confidence interval) of maternal piperaquine concentrations in women living with HIV on 50 mg dolutegravir based ART compared to women not living with HIV (so not on ART) and not on azithromycin, matched for time since last DP dose and body weight and umbilical cord piperaquine concentration ratios in women living with HIV on 50 mg dolutegravir-based ART compared to women not living with HIV (so not on ART) At birth
Secondary Outcome Mean maternal and umbilical cord plasma dolutegravir concentrations in women living with HIV on 50 mg dolutegravir-based ART At birth
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Zomba Central Hospital Chipembere Highway Zomba Malawi
FUNDING SOURCES
Name of source Street address City Postal code Country
European and Developing Countries Clinical Trials Partnership Anna van Saksenlaan 51 The Hague 2593 Netherlands
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Liverpool School of Tropical Medicine Pembroke Place Liverpool 1234 United Kingdom University
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Karen Barnes karen.barnes@uct.ac.za +27216504070 K45 Old Main Building, Groote Schuur Hospital, Observatory
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Professor of Clinical Pharmacology
Role Name Email Phone Street address
Scientific Enquiries Clifford Banda cgbanda@mlw.mw +2651871911 University of Malawi College of Medicine, Chichiri
City Postal code Country Position/Affiliation
Blantyre 1234 Malawi Clinical Fellow
Role Name Email Phone Street address
Public Enquiries Karen Barnes karen.barnes@uct.ac.za +27216504070 K45 Old Main Building, Groote Schuur Hospital, Observatory
City Postal code Country Position/Affiliation
Cape Town 7925 South Africa Professor of Clinical Pharmacology
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Inclusion of these individual participant data in future related individual participant data meta-analyses will be made possible through the secure WorldWide Antimalarial Resistance Network repository and its independent Data Access Committee Analytic Code,Clinical Study Report,Informed Consent Form,Statistical Analysis Plan,Study Protocol Within 12 months of the publication A PhD, early career researcher or beyond and can demonstrate being part of a group or team with the necessary skills to carry out the proposed research
URL Results Available Results Summary Result Posting Date First Journal Publication Date
https://www.wwarn.org/accessing-data Yes 16/08/2024 15/03/2022
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result - 16/08/2024 Result - 16/08/2024 Result - 16/08/2024
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information