Comparison of ISTp- PYRAMAX-US-RDT to IPTp-SP to Prevent Malaria in Pregnant Women in DRC (ULTRAPYRAPREG)

NCT04783051 | Completed Phase 3

• 1 other identifier: 226/CNES/BN//PMMF/2020
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 1

Brief Summary

In endemic settings Plasmodium falciparum (Pf) can sequester in the placenta resulting in low peripheral parasitemia and false negative malaria diagnosis in pregnant women. Intermittent Preventive Treatment in pregnant women with Sulphadoxine-Pyrimethamine (IPTp-SP) is one of the World Health Organization's recommended malaria control strategies in sub-Saharan African countries. The strategy overcomes the risk of misdiagnosis of malaria in pregnant women by treating them all with SP according to predetermined schedules, but the strategy is now threatened by the spread of Plasmodium parasite resistant strains. As a necessary alternative, Intermittent Screening and Treatment in pregnancy (ISTp), aims on the monthly screening of pregnant women with a malaria rapid diagnostic test (RDT) and the treatment of positive cases with artemisinin-based combination therapy (ACT) regardless of the presence of symptoms. The ISTp depends on the performance of the diagnostic tests, and the use of ultrasensitive RDTs (us-RDTs), which have a higher analytical sensitivity than conventional RDTs, should improve the efficacy of the strategy. Unlike IPTp-SP, ISTp prevents overuse of antimalarials and thus limits drug pressure on malaria parasites. This advantage could be potentiated by using, for pregnant women, an ACT that is not yet used or should not be used in the field for other strata of the population. The recently approved new ACT combination, Pyronaridine - Artesunate (Pyramax®) is the ideal candidate for this purpose. This study will compare the effects of the ISTp using an us-RDT and Pyramax® (ISTp-US-Py) with the standard IPTp-SP on maternal malaria indicators (malaria infection, parasite density), maternal anemia, spontaneous abortions or intrauterine deaths during pregnancy, fetal morbidity (preterm birth, low birth weight, small for gestational age) and neonatal mortality at delivery in both study groups through conducting a randomized clinical trial enrolling second trimester pregnant women in Maternité Esengo Health Center, located in Kisenso, Kinshasa, the Democratic Republic of the Congo (DRC), a malaria perennial transmission area. The results generated from this study will be essential for the National Malaria Control Program in the selection and implementation of new malaria control policies and addresses the effectiveness of IPTp-SP decline among pregnant women in the DRC.

Conditions

Malaria in Pregnancy

Keywords

Malaria; Pregnancy; IPTp-SP; ISTp-Pyramax; Kinshasa; DR Congo

Outcome Measures

Primary Outcomes (7)

• The proportion of asymptomatic malaria in the 2 study arms

  Asymptomatic malaria is defined as the presence of Pf diagnosed by an us-RDT in the peripheral blood and a T°≤38°C

  6 months

• The proportion symptomatic malaria in the 2 study arms

  Symptomatic malaria is be defined as the presence of Pf diagnosed by an us-RDT in the peripheral blood and a T°≥38°C

  6 months

• The proportion of parasitic densities in the 2 study arms

  Parasite density is assessed by the quantification of Pf parasites in the peripheral blood of asymptomatic/symptomatic women by a thin blood smear examined by standard malaria microscopy

  6 months

• The proportion of anemia in the 2 study arms

  Anemia is defined as a level of hemoglobin (Hb) \<10g/dl

  6 months

• The incidence of spontaneous abortions or intrauterine deaths in the 2 study arms

  Intrauterine death is defined to describe the death of the offspring in the uterus

  6 months

• The proportion of fetal morbidities in the 2 study arms

  Fetal morbidity is defined as any of the following: Preterm birth (birth before 37 weeks gestation) and low-birth-weight (birth weight under 2,500 grams)

  6 months

• The proportion of the neonatal and early neonatal mortality of the offspring in the 2 study arms

  The early neonatal mortality is defined as infant death at birth or within 7 days of life; And the neonatal mortality is defined as infant death within the first 28 days of life

  28 days

Study Arms (2)

IPTp-SP

ACTIVE COMPARATOR

The IPTp-SP group will be pregnant women who will receive the standard regimen recommended by the Malaria National Control Program (MNCP) at week 16, 28, 32 and 36 of their pregnancy

Drug: Sulfadoxine pyrimethamine

ISTp-US-Py

EXPERIMENTAL

The ISTp-US-Py group will comprise pregnant women who will be screened monthly from the beginning of the 2nd trimester with ultra-sensitive -RDT and who will be treated with Pyramax® if the test is positive

Drug: Pyramax

Interventions

Sulfadoxine pyrimethamine DRUG

Intermittent Preventive Treatment in pregnant women with Sulfadoxine-Pyrimethamine

Also known as: IPTp-SP

IPTp-SP

Pyramax DRUG

Intermittent screening using ultra-sensitive malaria Rapid Diagnostic test and treatment using Pyronaridine - Artesunate (PYRAMAX®)

Also known as: ISTp-US-Py

ISTp-US-Py

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Pregnant women
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Gestation ≥16 weeks;
• Age: ≥18 years;
• Residence within the health facility catchment area;
• Willing to adhere to study requirements and to deliver at the health facility.
• Willing to provide written informed consent; if the woman is illiterate, she can choose an impartial witness, not related to the study, to accompany her during the informant consent process and they will both sign the informed consent form

You may not qualify if:

• Known history of allergy to SP or to an ACT
• An ongoing antibioprophylaxis with cotrimoxazole,
• Current issue requiring hospital admission (including severe malaria as defined by WHO)
• Pregnancy at high risk

Sponsors & Collaborators

• University of Kinshasa: lead
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• Novartis: collaborator

Study Sites (1)

Maternité Esengo

Kinshasa, Democratic Republic of the Congo

Location

Related Publications (18)

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  PMID: 17251082 BACKGROUND

• WHO. Guidelines for the treatment of malaria. Third edition2015. 316 p

  BACKGROUND

• Anchang-Kimbi JK, Achidi EA, Nkegoum B, Sverremark-Ekstrom E, Troye-Blomberg M. Diagnostic comparison of malaria infection in peripheral blood, placental blood and placental biopsies in Cameroonian parturient women. Malar J. 2009 Jun 8;8:126. doi: 10.1186/1475-2875-8-126.

  PMID: 19505312 BACKGROUND

• Matangila JR, Lufuluabo J, Ibalanky AL, Inocencio da Luz RA, Lutumba P, Van Geertruyden JP. Asymptomatic Plasmodium falciparum infection is associated with anaemia in pregnancy and can be more cost-effectively detected by rapid diagnostic test than by microscopy in Kinshasa, Democratic Republic of the Congo. Malar J. 2014 Apr 2;13:132. doi: 10.1186/1475-2875-13-132.

  PMID: 24690179 BACKGROUND

• van Eijk AM, Hill J, Larsen DA, Webster J, Steketee RW, Eisele TP, ter Kuile FO. Coverage of intermittent preventive treatment and insecticide-treated nets for the control of malaria during pregnancy in sub-Saharan Africa: a synthesis and meta-analysis of national survey data, 2009-11. Lancet Infect Dis. 2013 Dec;13(12):1029-42. doi: 10.1016/S1473-3099(13)70199-3. Epub 2013 Sep 18.

  PMID: 24054085 BACKGROUND

• WHO. World Malaria Report 2017. Geneva: World Health Organization; 2017

  BACKGROUND

• Harrington WE, Mutabingwa TK, Kabyemela E, Fried M, Duffy PE. Intermittent treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistance. Clin Infect Dis. 2011 Aug 1;53(3):224-30. doi: 10.1093/cid/cir376.

  PMID: 21765070 BACKGROUND

• McGready R, White NJ, Nosten F. Parasitological efficacy of antimalarials in the treatment and prevention of falciparum malaria in pregnancy 1998 to 2009: a systematic review. BJOG. 2011 Jan;118(2):123-35. doi: 10.1111/j.1471-0528.2010.02810.x.

  PMID: 21159117 BACKGROUND

• Cottrell G, Moussiliou A, Luty AJ, Cot M, Fievet N, Massougbodji A, Deloron P, Tuikue Ndam N. Submicroscopic Plasmodium falciparum Infections Are Associated With Maternal Anemia, Premature Births, and Low Birth Weight. Clin Infect Dis. 2015 May 15;60(10):1481-8. doi: 10.1093/cid/civ122. Epub 2015 Feb 18.

  PMID: 25694651 BACKGROUND

• Esu E, Berens-Riha N, Pritsch M, Nwachuku N, Loescher T, Meremikwu M. Intermittent screening and treatment with artemether-lumefantrine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in pregnancy: a facility-based, open-label, non-inferiority trial in Nigeria. Malar J. 2018 Jul 6;17(1):251. doi: 10.1186/s12936-018-2394-2.

  PMID: 29976228 BACKGROUND

• Das S, Jang IK, Barney B, Peck R, Rek JC, Arinaitwe E, Adrama H, Murphy M, Imwong M, Ling CL, Proux S, Haohankhunnatham W, Rist M, Seilie AM, Hanron A, Daza G, Chang M, Nakamura T, Kalnoky M, Labarre P, Murphy SC, McCarthy JS, Nosten F, Greenhouse B, Allauzen S, Domingo GJ. Performance of a High-Sensitivity Rapid Diagnostic Test for Plasmodium falciparum Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections. Am J Trop Med Hyg. 2017 Nov;97(5):1540-1550. doi: 10.4269/ajtmh.17-0245. Epub 2017 Aug 18.

  PMID: 28820709 BACKGROUND

• Vasquez AM, Medina AC, Tobon-Castano A, Posada M, Velez GJ, Campillo A, Gonzalez IJ, Ding X. Performance of a highly sensitive rapid diagnostic test (HS-RDT) for detecting malaria in peripheral and placental blood samples from pregnant women in Colombia. PLoS One. 2018 Aug 2;13(8):e0201769. doi: 10.1371/journal.pone.0201769. eCollection 2018.

  PMID: 30071004 BACKGROUND

• Ayyoub A, Methaneethorn J, Ramharter M, Djimde AA, Tekete M, Duparc S, Borghini-Fuhrer I, Shin JS, Fleckenstein L. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients. Antimicrob Agents Chemother. 2015 Dec 14;60(3):1450-8. doi: 10.1128/AAC.02004-15.

  PMID: 26666916 BACKGROUND

• Croft SL, Duparc S, Arbe-Barnes SJ, Craft JC, Shin CS, Fleckenstein L, Borghini-Fuhrer I, Rim HJ. Review of pyronaridine anti-malarial properties and product characteristics. Malar J. 2012 Aug 9;11:270. doi: 10.1186/1475-2875-11-270.

  PMID: 22877082 BACKGROUND

• D'Alessandro U, Hill J, Tarning J, Pell C, Webster J, Gutman J, Sevene E. Treatment of uncomplicated and severe malaria during pregnancy. Lancet Infect Dis. 2018 Apr;18(4):e133-e146. doi: 10.1016/S1473-3099(18)30065-3. Epub 2018 Jan 31.

  PMID: 29395998 BACKGROUND

• West African Network for Clinical Trials of Antimalarial Drugs (WANECAM). Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. Lancet. 2018 Apr 7;391(10128):1378-1390. doi: 10.1016/S0140-6736(18)30291-5. Epub 2018 Mar 29.

  PMID: 29606364 BACKGROUND

• Tshiongo JK, Khote FL, Kabena M, Mavoko HM, Kalonji-Mukendi T, Luzolo L, Schallig HDFH, Kayentao K, Mens PF, Lutumba P, Tinto H, Maketa V. Intermittent screening using ultra-sensitive malaria rapid diagnostic test and treatment with pyronaridine-artesunate compared to standard preventive treatment with sulfadoxine-pyrimethamine for malaria prevention in pregnant women in Kinshasa, DRC. Malar J. 2025 Feb 21;24(1):58. doi: 10.1186/s12936-025-05260-6.

  PMID: 39985024 DERIVED

• Maketa V, Kabalu J, Kabena M, Luzolo F, Muhindo-Mavoko H, Schallig HDFH, Kayentao K, Mens PF, Lutumba P, Tinto H. Comparison of intermittent screening (using ultra-sensitive malaria rapid diagnostic test) and treatment (using a newly registered antimalarial pyronaridine-artesunate-PYRAMAX(R)) to standard intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria in pregnant women living in endemic areas: ULTRAPYRAPREG. Trials. 2022 Nov 28;23(1):963. doi: 10.1186/s13063-022-06884-8.

  PMID: 36443882 DERIVED

Related Links

• The PYRAPREG project
• Clinical trials and operational research studies to optimise the use of products for poverty-related diseases in mothers, newborns, children and/or adolescents
• Pharmaceuticals R. FANSIDAR. brand of sulfadoxine and pyrimethamine TABLETS 1996

MeSH Terms

Conditions

Malaria

Interventions

fanasil, pyrimethamine drug combination; pyronaridine tetraphosphate, artesunate drug combination

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 27, 2021
• First Posted: March 4, 2021
• Study Start: May 6, 2021
• Primary Completion: June 22, 2022
• Study Completion: June 22, 2022
• Last Updated: November 4, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Starting right after the publication
• Access Criteria: Data will be shared with any researcher who will ask via any contact of the corresponding author of any publication resulting from this clinical trial

Locations

DE (1)