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| Name | Class |
|---|---|
| Kamuzu University of Health Sciences | OTHER |
| Kenya Medical Research Institute | OTHER |
| Malawi-Liverpool-Wellcome Trust Clinical Research Programme | OTHER |
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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-pyrimethamine (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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IPTp-SP | Active Comparator | Stat course of 3 tablets of quality-assured SP (tablets of 500 mg of sulphadoxine and 25 mg of pyrimethamine) at each scheduled antenatal visit |
|
| IPTp-DP | Experimental | 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 |
|
| IPTp-DPAZ | Experimental | 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] + AZ tablet [1.5g over 3 days as 500mg per day] at each scheduled antenatal visit. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| dihydroartemisinin-piperaquine | Drug | Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse pregnancy outcome | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Composite of foetal loss and neonatal mortality | Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality | 8 months |
| SGA-LBW-PT composite | Composite of small for gestational age, low birth weight or preterm birth |
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Inclusion Criteria:
Exclusion Criteria:
Pregnant female
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| Name | Affiliation | Role |
|---|---|---|
| Simon K Kariuki, PhD | Kenya Medical Research Institute | Principal Investigator |
| Frank Mosha, PhD | Kilimanjaro Christian Medical University College | Principal Investigator |
| John Lusingu, PhD | National Institute for Medical Research | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ahero Sud-countyHospital | Ahero | Kisumu County | Kenya | |||
| Homa Bay County Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40018559 | Derived | Gore-Langton GR, Madanitsa M, Barsosio HC, Minja DTR, Mosha J, Kavishe RA, Mtove G, Gesase S, Msemo OA, Kariuki S, Otieno K, Phiri KS, Lusingu JPA, Mukerebe C, Manjurano A, Ikigo P, Saidi Q, Onyango ED, Schmiegelow C, Dodd J, Hill J, Hansson H, Alifrangis M, Gutman J, Hunter PJ, Klein N, Ashorn U, Khalil A, Cairns M, Ter Kuile FO, Chico RM. Prevalence and risk factors of curable sexually transmitted and reproductive tract infections and malaria co-infection among pregnant women at antenatal care booking in Kenya, Malawi and Tanzania: a cross-sectional study of randomised controlled trial data. BMJ Public Health. 2024 Sep 18;2(2):e000501. doi: 10.1136/bmjph-2023-000501. eCollection 2024 Dec. | |
| 36913959 |
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Individual, de-identified participant data will be made available for meta-analyses as soon as the data analysis is completed, with the understanding that results of the meta-analysis will not be published prior to the results of the individual trial without prior agreement of the investigators. No later than 5 years after the publication of the trial a fully de-identified data set will be available for sharing purposes
No later than 5 years after publication
Open access
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| National Institute for Medical Research, Tanzania |
| OTHER_GOV |
| Kilimanjaro Christian Medical Centre, Tanzania | OTHER |
| University of Copenhagen | OTHER |
| Centers for Disease Control and Prevention | FED |
| London School of Hygiene and Tropical Medicine | OTHER |
| University College, London | OTHER |
| Tampere University | OTHER |
| University of Bergen | OTHER |
| University of Massachusetts, Worcester | OTHER |
| University of Toronto | OTHER |
| University of Melbourne | OTHER |
| Foundation for Innovative New Diagnostics, Switzerland | OTHER |
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The study will be a partially placebo-controlled involving a single placebo for AZ. To further minimise bias, an objective primary outcome measure will be used and all staff will be masked to the treatment assignment of individual women. The trial statistician will also be masked in regard to the treatment code when he develops the statistical analysis plan and writes the statistical programmes, which will be validated and completed using dummy randomisation codes. The actual allocation will only be provided to the study team after locking of the database and approval of the statistical analysis plan by the independent Data Monitoring and Ethics Committee (DMEC) before they review any trial results. The study statistician conducting the interim analysis will remain masked throughout the analysis.
|
| sulphadoxine-pyrimethamine | Drug | 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 |
|
|
| dihydroartemisinin-piperaquine plus azithromycin | Drug | Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg) |
|
|
| 6 months |
| SGA | Small for gestational age using the new INTERGROWTH population reference's 10th percentile | 6 months |
| LBW | Low birth weight defined as a corrected birth weight below 2.5 kg | 6 months |
| PT | Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks | 6 months |
| Neonatal length and stunting | Neonatal length and stunting | 8 months |
| Clinical malaria during pregnancy | Incidence of clinical malaria during pregnancy | 6 months from randomisation |
| Malaria infection during pregnancy detected by microscopy and PCR | Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR | 6 months from randomisation |
| Composite placental malaria detected by microscopy, by molecular methods or by histology | Prevalence of placental malaria by microscopy, PCR and placental histology | 6 months from randomisation |
| Placental malaria detected by microscopy | Prevalence of placental malaria detected in maternal placental blood by microscopy | 6 months from randomisation |
| Placental malaria detected by molecular methods (PCR) | Prevalence of placental malaria detected in maternal placental blood by PCR | 6 months from randomisation |
| Placental malaria detected by histology | Prevalence of placental malaria detected in full placental section by histology | 6 months from randomisation |
| Maternal nutritional status | Changes in maternal nutritional status by MUAC and BMI. | 6 months from randomisation |
| Maternal anaemia during pregnancy and delivery | Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery | 6 months from randomisation |
| Congenital anaemia | Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood | 6 months from randomisation |
| Congenital malaria infection | Prevalence of malaria infection by microscopy or PCR from newborn cord blood | 6 months from randomisation |
| QTc-prolongation | 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 |
| Congenital malformations | Any visible external congenital abnormality on surface examination | 6 months from randomisation |
| Maternal mortality | 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 |
| Other SAEs and AEs | Incidence of AEs and SAEs | 8 months from randomisation |
| (History of) vomiting study drug | Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit | 6 months from randomisation |
| Dizziness | Prevalence of dizziness after a course of IP | 6 months from randomisation |
| Gastrointestinal complaints | Prevalence of gastrointestinal complaints after a course of IP | 6 months from randomisation |
| Molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery | Prevalence and incidence of SP and artemisinin resistance markers from infection isolates after enrollment and at delivery | 6 months from randomisation |
| Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) | 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 |
| Changes in macrolide resistance in Pneumococcus detected in maternal nasopharyngeal samples | Prevalence and incidence of carriage of macrolide resistant pneumococcus at randomization and delivery | 6 months from randomisation |
| Changes in the colony composition of maternal vaginal microbiota, and intestinal microbiota of mother and infant. | 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 |
| Homa Bay |
| Kenya |
| Rabour Sub-county Hospital | Kisumu | Kenya |
| Chikwawa District Hospital | Chikwawa | Malawi |
| Mangochi District Hospital | Mangochi | Malawi |
| Handeni District Hospital | Handeni | Tanzania |
| Korogwe District Hospital | Korogwe | Tanzania |
| Derived |
| Madanitsa M, Barsosio HC, Minja DTR, Mtove G, Kavishe RA, Dodd J, Saidi Q, Onyango ED, Otieno K, Wang D, Ashorn U, Hill J, Mukerebe C, Gesase S, Msemo OA, Mwapasa V, Phiri KS, Maleta K, Klein N, Magnussen P, Lusingu JPA, Kariuki S, Mosha JF, Alifrangis M, Hansson H, Schmiegelow C, Gutman JR, Chico RM, Ter Kuile FO. Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial. Lancet. 2023 Mar 25;401(10381):1020-1036. doi: 10.1016/S0140-6736(22)02535-1. Epub 2023 Mar 10. |
| 35156190 | Derived | Mtove G, Abdul O, Kullberg F, Gesase S, Scheike T, Andersen FM, Madanitsa M, Ter Kuile FO, Alifrangis M, Lusingu JPA, Minja DTR, Schmiegelow C. Weight change during the first week of life and a new method for retrospective prediction of birthweight among exclusively breastfed newborns. Acta Obstet Gynecol Scand. 2022 Mar;101(3):293-302. doi: 10.1111/aogs.14323. Epub 2022 Feb 13. |
| ID | Term |
|---|---|
| D008288 | Malaria |
| ID | Term |
|---|---|
| D011528 | Protozoan Infections |
| D010272 | Parasitic Diseases |
| D007239 | Infections |
| D000096724 | Mosquito-Borne Diseases |
| D000079426 | Vector Borne Diseases |
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| ID | Term |
|---|---|
| C001205 | fanasil, pyrimethamine drug combination |
| D017963 | Azithromycin |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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