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.: PACTR202005615501026 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 Intermittent preVEntive Treatment in Africa (IMPROVE)
Official scientific title IPTp With Dihydroartemisinin-piperaquine and Azithromycin for Malaria, Sexually Transmitted and Reproductive Tract Infections in Pregnancy in High Sulphadoxine-pyrimethamine Resistance Areas in Kenya, Malawi and Tanzania: an International Multi-centre 3-arm Placebo-controlled Trial
Brief summary describing the background and objectives of the trial This study evaluates the efficacy and safety of monthly intermittent preventive treatment using dihydroartemisinin piperaquine (DP) alone or in combination with azithromycin (AZ) compared to sulphadoxine-pyrimthamine (SP) for the prevention of malaria in pregnant women in the second and third trimester. Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is one of the pillars of malaria prevention in pregnancy in sub-Saharan Africa, in addition to prompt case management and use of long lasting insecticide treated bednets. However, mounting resistance to SP by Plasmodium falciparum increasing renders IPTP-SP ineffective. Two exploratory trials in Uganda and Kenya demonstrated that IPTp with DP was superior to IPTp-SP for the prevention of malaria infection in pregnancy. However, neither study was adequately powered to look at adverse birth outcomes. This study is a confirmatory efficacy trial in Malawi, Tanzania and Kenya to determine the efficacy and safety of IPTp with DP alone or in combination with AZ. This will be a 3-arm trial, superiority, partial blinded, placebo controlled, randomized trial comparing IPTp with SP, versus IPTp with DP alone, and IPTp with DP+AZ with the following hypotheses: IPTp with DP is superior to IPTp with SP in preventing adverse pregnancy outcomes. The combination of DP with AZ further reduces adverse pregnancy outcomes compared to IPTp with DP alone.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) IMPROVE
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria,Sexually Transmitted and Reproductive Tract Infections in Pregnancy
Purpose of the trial Prevention
Anticipated trial start date 15/09/2017
Actual trial start date 15/03/2018
Anticipated date of last follow up 15/10/2019
Actual Last follow-up date 20/03/2020
Anticipated target sample size (number of participants) 4680
Actual target sample size (number of participants) 4680
Recruitment status Completed
Publication URL
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
Experimental Group dihydroartemisinin piperaquine and Azithromycin Standard 3-day course of DP (40/320mg) per day based on body weight (Eurartesim) given monthly, plus AZ, 2g as 2x500mg daily for 2 days at enrolment, followed by standard 3-day course of DP only, given monthly; Until delivery Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg) Other Name: Eurartesim plus Zithromax 1560
Experimental Group dihydroartemisinin piperaquine and placebo azithromycin Standard 3-day course of DP (40/320mg) per day based on body weight (Eurartesim) given monthly, plus placebo AZ at enrolment Dihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + placebo AZ at each scheduled antenatal visit Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo Other Name: Eurartesim 1560
Control Group sulfamethoxazole trimethoprim Women randomised to this intervention will receive stat dose of 3 tablets of 500 mg sulphadoxine and 25 mg of pyrimethamine each (total dose of 1,500mg sulphadoxine and 75mg pyrimethamine) on a single day of clinic visit Until delivery Women randomised to this intervention will receive stat dose of 3 tablets of 500 mg sulphadoxine and 25 mg of pyrimethamine each (total dose of 1,500mg sulphadoxine and 75mg pyrimethamine) on a single day of clinic visit Other Name: Fansidar 1560 Uncontrolled
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Pregnant women between 16-28 weeks' gestation Viable singleton pregnancy 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 consent Multiple pregnancies (i.e. twin/triplets) HIV-positive Known heart ailment Severe malformations or non-viable pregnancy if observed by ultrasound History of receiving IPTp-SP during this current pregnancy 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 26/05/2017 KEMRI Scientific and Ethics Review Unit
Ethics Committee Address
Street address City Postal code Country
Nairobi Nairobi 54840 Kenya
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Adverse pregnancy outcome [ Time Frame: 8 months ] 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. 8 months
Secondary Outcome Composite of foetal loss and neonatal mortality [ Time Frame: 8 months ] Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality 8 months
Secondary Outcome SGA-LBW-PT composite [ Time Frame: 6 months ] Composite of small for gestational age, low birth weight or preterm birth 6 months
Secondary Outcome SGA [ Time Frame: 6 months ] Small for gestational age using the new INTERGROWTH population reference's 10th percentile 6 months
Secondary Outcome LBW [ Time Frame: 6 months ] Low birth weight defined as a corrected birth weight below 2.5 kg 6 months
Secondary Outcome PT [ Time Frame: 6 months ] Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks 6 months
Secondary Outcome Neonatal length and stunting [ Time Frame: 8 months ] Neonatal length and stunting 8 months
Secondary Outcome Clinical malaria during pregnancy [ Time Frame: 6 months from randomisation ] Incidence of clinical malaria during pregnancy 6 months from randomisation
Secondary Outcome Malaria infection during pregnancy detected by microscopy and PCR [ Time Frame: 6 months from randomisation ] Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR 6 months from randomisation
Secondary Outcome Composite placental malaria detected by microscopy, by molecular methods or by histology [ Time Frame: 6 months from randomisation ] Prevalence of placental malaria by microscopy, PCR and placental histology 6 months from randomisation
Secondary Outcome Placental malaria detected by microscopy [ Time Frame: 6 months from randomisation ] Prevalence of placental malaria detected in maternal placental blood by microscopy 6 months from randomisation
Secondary Outcome Placental malaria detected by molecular methods (PCR) [ Time Frame: 6 months from randomisation ] Prevalence of placental malaria detected in maternal placental blood by PCR 6 months from randomisation
Primary Outcome Placental malaria detected by histology [ Time Frame: 6 months from randomisation ] Prevalence of placental malaria detected in full placental section by histology 6 months from randomisation
Secondary Outcome Maternal nutritional status [ Time Frame: 6 months from randomisation ] Changes in maternal nutritional status by MUAC and BMI. 6 months from randomisation
Secondary Outcome Maternal anaemia during pregnancy and delivery [ Time Frame: 6 months from randomisation ] Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and deivery 6 months from randomisation
Secondary Outcome Congenital anaemia [ Time Frame: 6 months from randomistion ] Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood 6 months from randomisation
Secondary Outcome Congenital malaria infection [ Time Frame: 6 months from randomistion ] Prevalence of malaria infection by microscopy or PCR from newborn cord blood 6 months from randomisation
Secondary Outcome QTc-prolongation [ Time Frame: 6 months from randomistion ] QTcF-prolongation of more than 60ms between baseline DTcF prior to first dose of DP (+/- AZ) on day 0 and repeat QTcF 4 - 6 hrs after administration of 3rd dose of DP(+/- AZ) on day 2, or QTcF > 480ms, 4 - 6 hours after on day 2 treatment administration. Only on the DP containing arms. 6
Secondary Outcome QTc-prolongation [ Time Frame: 6 months from randomistion ] QTcF-prolongation of more than 60ms between baseline DTcF prior to first dose of DP (+/- AZ) on day 0 and repeat QTcF 4 - 6 hrs after administration of 3rd dose of DP(+/- AZ) on day 2, or QTcF > 480ms, 4 - 6 hours after on day 2 treatment administration. Only on the DP containing arms. 6 months from randomisation
Secondary Outcome Maternal mortality [ Time Frame: 8 months from randomisation ] The death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes. 8 months from randomisation
Secondary Outcome Other SAEs and AEs [ Time Frame: 8 months from randomisation ] Incidence of AEs and SAEs 8 months from randomisation
Secondary Outcome Molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery [ Time Frame: 6 months from randomisation ] 6 months from randomisation
Secondary Outcome Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) [ Time Frame: 6 months from randomisation ] Prevalence and incidence of STIs/RTIs (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) at randomization and last antenatal visit prior to delivery 6 months from randomisation
Secondary Outcome Changes in macrolide resistance in Pneumococcus detected in maternal nasopharyngeal samples [ Time Frame: 6 months from randomisation ] Prevalence and incidence of carriage of macrolide resistant pneumoccocus at randomization and delivery 6 months from randomisation
Secondary Outcome Changes in the colony composition of maternal vaginal microbiota, and intestinal microbiota of mother and infant. [ Time Frame: 6 months from randomisation ] Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota 6 months from randomisation
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Ahero Sub County Hospital Kisumu Kisumu 1578 Kenya
Homabay County Referral Hospital Homabay Homabay 1578 Kenya
Rabuor Sub county Hospital Kisumu Kisumu 1578 Kenya
Akala Sub County Hospital Siaya Siaya 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 Kisumu Kisumu 1578 Kenya
CONTACT PEOPLE
Role Name Email Phone Street address
Public Enquiries Hellen 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
Role Name Email Phone Street address
Principal Investigator Simon Kariuki skariuki1578@gmail.com +254724464507 Kisumu
City Postal code Country Position/Affiliation
Kisumu 1578 Kenya Malaria Branch Chief
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