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.: PACTR202005916875055 Date of Approval: 08/05/2020
Trial Status: Retrospective registration - This trial was registered after enrolment of the first participant
TRIAL DESCRIPTION
Public title Improving PRegnancy Outcomes With PReVEntive Therapy in Africa-2 (IMPROVE-2)
Official scientific title Chemoprevention with monthly IPTp with dihydroartemisinin-piperaquine for malaria in HIVinfected pregnant participants on daily cotrimoxazole in Kenya and Malawi: a multi-centre placebocontrolled trial
Brief summary describing the background and objectives of the trial 2.3.3 Short technical protocol summary Background: Pregnant women represent a vulnerable population for malaria. HIV-infected women are particularly at risk. In HIV-infected pregnant women, WHO recommends daily cotrimoxazole (CTX), an antifolate drug, for malaria chemoprevention and prophylaxis against opportunistic infection. However, there is cross-resistance with sulphadoxine-pyrimethamine (SP), and high levels of antifolate resistance threatens the antimalarial effect of CTX. Recent trials with intermittent preventive therapy (IPT) with mefloquine in HIV-infected women on daily CTX, suggested that chemoprevention with an effective antimalarial markedly improves the protection against malaria compared to daily CTX alone. However, mefloquine was not well tolerated. The long-acting combination of dihydroartemisinin-piperaquine (DP) is well tolerated and has shown great promise as IPTp in HIV-negative women in East-Africa. Chemoprevention with monthly DP has also been explored in HIV-infected pregnant women on daily CTX in Uganda. Unfortunately, the study was inconclusive because malaria transmission was too low and a clinically relevant drug interaction with efavirenz (EFV) was found reducing the exposure to DP. WHO now recommends dolutegravir (DTG) based combination antiretroviral therapy (ARTs) as the preferred firstline regimen including for pregnant women in the 2nd and 3rd trimester of pregnancy for the prevention of mother-to-child transmission of HIV. Objectives and methods: This is a 2-arm, individually-randomized, multi-centre, placebo-controlled superiority trial comparing the safety and efficacy of daily CTX plus monthly DP ('CTX--alone', control arm) to reduce malaria and the adverse effects of malaria in 898 (449 per arm) HIV-infected pregnant women on DTG-based cARTs.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) IMPROVE 2
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Prevention
Anticipated trial start date 15/06/2019
Actual trial start date 11/11/2019
Anticipated date of last follow up 15/03/2021
Actual Last follow-up date 03/08/2021
Anticipated target sample size (number of participants) 898
Actual target sample size (number of participants) 904
Recruitment status Completed
Publication URL Not yet published
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
Parallel: different groups receive different interventions at same time during study Randomised Stratified allocation where factors such as age, gender, center, or previous treatment are used in the stratification Sealed opaque envelopes Masking/blinding used Care giver/Provider,Outcome Assessors,Participants
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group sulfamethoxazole trimethoprim Daily, one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim until delivery CTX-alone: Daily, one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim plus monthly placebo-DP, given as a fixed dose of 3 placebo-DP tablets daily for three days until delivery. 449 Uncontrolled
Experimental Group sulfamethoxazole trimethoprim and dihydroartemisinin piperaquine Daily, one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim plus monthly placebo-DP, given as a fixed dose of 3 placebo-DP tablets daily for three days until delivery. until delivery Drug: Intermittent Preventive Therapy with Dihydroartemisinin-Piperaquine Monthly DP fixed dose of 3 tablets (40 mg of dihydroartemisinin and 320 mg of piperaquine) daily for three days until delivery. All participants will (continue to) receive daily cotrimoxazole (CTX) (one double-strength tablet of 160mg of sulfamethoxazole and 800mg of trimethoprim) and anti-retroviral drugs. Other Names: Monthly DP D-artepp 449
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
HIV-infected pregnant women between 16-28 weeks' gestation Viable singleton pregnancy On or eligible for cARTs and CTX A resident of the study area Willing to adhere to scheduled and unscheduled study visit procedures Willing to deliver in a study clinic or hospital Provide written informed consen Multiple pregnancies (i.e. twin/triplets) HIV-negative or HIV status unknown Known heart ailment Severe malformations or non-viable pregnancy if observed by ultrasound Participants with advanced HIV-disease at WHO clinical stage 3 and 4 Confirmed or suspected TB infection, Unable to give consent Known allergy or contraindication to any of the study drugs Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year 13 Year(s) 44 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 03/05/2019 KEMRI SERU
Ethics Committee Address
Street address City Postal code Country
Nairobi Nairobi 54840 Kenya
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 24/10/2019 LSTM REC
Ethics Committee Address
Street address City Postal code Country
Pembroke Place Liverpool 111111 United Kingdom
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Cumulative incidence of malaria infection [ Time Frame: Detected from 2 weeks after the first day of the first dose of the first course to delivery inclusive. The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months. ] The primary outcome will be the cumulative incidence of malaria infection detected from 2 weeks after the first day of the first dose of the first course to delivery inclusive, defined as the presence of peripheral (maternal) or placental (maternal) Plasmodium infection detected by either molecular diagnostics (henceforth referred to as PCR), microscopy, RDT or placental histology (active infection). The primary outcome will be the cumulative incidence of malaria infection detected from 2 weeks after the first day of the first dose of the first course to delivery inclusive, defined as the presence
Secondary Outcome Efficacy of the intervention on the following listed secondary outcomes [ Time Frame: The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old ] Incidence of malaria infection The individual components of the composite malaria infection endpoints Incidence of clinical malaria. Malaria infection at delivery Placental malaria by histology (active, past, and active and past infections pooled) Placental malaria by any measure Maternal peripheral malaria infection at delivery by any measure Placental inflammation or chorioamnionitis Adverse pregnancy outcome: the composite of foetal loss (spontaneous abortion or stillbirth), or singleton live births born small-for-gestational-age (SGA), or with low birthweight (LBW), or preterm (PT) (SGA-LBW-PT), or subsequent neonatal death by day 28. Composite of foetal loss and neonatal mortality. SGA-LBW-PT composite. The individual components of the above composites Neonatal length and stunting. Evidence of arboviral infections The total duration of the trial is 24 months
Secondary Outcome Safety: Cardiac safety, serious adverse events and MTCT of HIV [ Time Frame: The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old ] QTc-prolongation. Congenital malformations. Maternal mortality Other SAEs and AEs. Mother to child transmission of HIV The total duration of the trial is 24 months
Secondary Outcome Tolerance [ Time Frame: The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old ] History of vomiting study drug (<30 min). Dizziness. Gastrointestinal complaints. The total duration of the trial is 24 months
Secondary Outcome Antimicrobial activity and resistance [ Time Frame: The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old ] Frequency of molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery The total duration of the trial is 24 months
Secondary Outcome Pharmacokinetic parameters [ Time Frame: The total duration of the trial is 24 months. Actual participant recruitment and follow up is expected to take up to 19 months (12 months recruitment plus 7 months of mother-infant follow-up until the child is 6 weeks old ] Standard pharmacokinetic parameters for dolutegravir, piperaquine and CTX. The total duration of the trial is 24 months
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Ahero County Referral Hospital Along Kisumu Nairobi Road Kisumu 1578 Kenya
Akala Subcounty Hospital Kisumu Bondo Road Kisumu 1578 Kenya
Homabay County Referral Hospital Homabay Homabay 1578 Kenya
Rabuor Subcounty referral Hospital Along Kisumu Nairobi road Kisumu 1578 Kenya
FUNDING SOURCES
Name of source Street address City Postal code Country
European and Developing Countries Clinical Trials and Wellcome Trust of Great Britain and the United Kingdom Department of International Development Pembroke Place London 111111 United Kingdom
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Liverpool School of Tropical Medicine Pembroke Place London 111111 United Kingdom Other Collaborative Groups
COLLABORATORS
Name Street address City Postal code Country
Kenya Medical Research Institute Nairobi Nairobi 54840 Kenya
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Hellen Barsosio hellen.barsosio@lstmed.ac.uk +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 1578 Kenya Senior Research Officer
Role Name Email Phone Street address
Public Enquiries Hellen Barsosio hellen.barsosio@lstmed.ac.uk +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 1578 Kenya Senior Research Officer
Role Name Email Phone Street address
Scientific Enquiries Feiko TerKuile Feiko.TerKuile@lstmed.ac.uk +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 1578 Kenya Chief Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Requests to access the fully-anonymised, raw data would be reviewed by the investigators based at LSTM and Kenya (or their representatives if appropriate). Approval to access the data will be granted only if the request is approved by all of the investigators. The KEMRI SERU and LSTM Research Ethics Committees will be notified of any agreements to share data. Informed Consent Form Following publication of main findings Approval by investigators in UK and Kenya
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information