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

Malaria in Pregnancy Clinical Trial

— ULTRAPYRAPREG  

Official title:

Comparison of IST Using Ultra-sensitive Malaria Rapid Diagnostic Test and Pyronaridine - Artesunate - PYRAMAX®) to Standard IPT Sulfadoxine-pyrimethamine to Prevent Malaria in Pregnant Women Living in Endemic Areas

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04783051
• Other study ID #: 226/CNES/BN//PMMF/2020
• Status: Completed
• Phase: Phase 3
• Start date: May 6, 2021
• Est. completion date: June 22, 2022

Study information

• Verified date: November 2022
• Source: University of Kinshasa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

1. Introduction Malaria is a threat for pregnant women and their offspring in endemic settings (1, 2). Plasmodium falciparum (Pf) can sequester in the placenta during pregnancy, resulting in low peripheral parasitemia. As a consequence, malaria diagnostic tests are often false negative in pregnant women who actually do have a Pf malaria infection (3, 4).

Intermittent Preventive Treatment in pregnant women with Sulfadoxine-Pyrimethamine (IPTp-SP) is one of the World Health Organization (WHO)'s recommended malaria control strategies in sub-Saharan African countries (2). The IPTp-SP strategy surmounts the potential misdiagnosis of malaria in pregnant women by treating them all with SP at pre-determined schedules during the antenatal care (ANC) visits. The efficacy of IPTp-SP is dose dependent and relies on ANC coverage. However, the spread of Plasmodium SP resistant strains now threatens the efficacy of the IPTp-SP and can lead to the proliferation of placental resistant parasites in pregnant women (5-9).

As an alternative for IPTp-SP, Intermittent Screening and Treatment in pregnancy (ISTp) may be considered as an option (10). ISTp comprises of monthly screening of pregnant women with a malaria RDT and treatment of positive cases with an 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 sensitivity than conventional RDTs (11, 12), can avoid false negative that would prevent the method from being effective.

Unlike IPTp-SP, ISTp prevents overuse of antimalarials and, thus, limits drug pressure on malaria parasites (10). This advantage could be potentiated by using an ACT that is not yet used or should not be used by the national malaria control for other strata of the population than pregnant women. Pyronaridine - Artesunate (Pyramax®), a newly approved antimalarial is the ideal candidate for this purpose in Democratic Republic of Congo (DRC). Pyramax®, approved for use in malaria endemic countries since 2015, is used in the field to treat malaria in children and adults (13). There is little information on the safety of Pyramax® during pregnancy, however, Pyronaridine unintentionally administered successfully treated at least 40 cases of malaria in late pregnancy (14) and, a review reported that ACTs, although Pyramax® was not included in, are generally very effective and well tolerated during the second and third trimesters (15).

The hypothesis of this study is that the ISTp using Pyramax® for the treatment and performed with the us-RDT (ISTp-US-Py) is non inferior than IPTp-SP for the prevention of maternal malaria (malaria infection, parasite density), maternal anemia, spontaneous abortions or intrauterine death during pregnancy, fetal morbidity (premature birth, low birth weight, small for gestational age) and neonatal mortality at childbirth.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 250
• Est. completion date: June 22, 2022
• Est. primary completion date: June 22, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Gestation =16 weeks;

2. Age: =18 years;

3. Residence within the health facility catchment area;

4. Willing to adhere to study requirements and to deliver at the health facility.

5. 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

Exclusion Criteria:

1. Known history of allergy to SP or to an ACT

2. An ongoing antibioprophylaxis with cotrimoxazole,

3. Current issue requiring hospital admission (including severe malaria as defined by WHO)

4. Pregnancy at high risk

Related Conditions & MeSH terms

• Malaria
• Malaria in Pregnancy

Intervention

Drug:
• Sulfadoxine pyrimethamine
Intermittent Preventive Treatment in pregnant women with Sulfadoxine-Pyrimethamine
• Pyramax
Intermittent screening using ultra-sensitive malaria Rapid Diagnostic test and treatment using Pyronaridine - Artesunate (PYRAMAX®)

Locations

Country	Name	City	State
Congo, The Democratic Republic of the	Maternité Esengo	Kinshasa

Sponsors (3)

Lead Sponsor	Collaborator
University of Kinshasa	European and Developing Countries Clinical Trials Partnership (EDCTP), Novartis

Country where clinical trial is conducted

Congo, The Democratic Republic of the, 

References & Publications (16)

Anchang-Kimbi JK, Achidi EA, Nkegoum B, Sverremark-Ekström 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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Matangila JR, Lufuluabo J, Ibalanky AL, Inocêncio 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. — View Citation

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. Review. — View Citation

Nosten F, McGready R, Mutabingwa T. Case management of malaria in pregnancy. Lancet Infect Dis. 2007 Feb;7(2):118-25. Review. — View Citation

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. Review. — View Citation

Vásquez AM, Medina AC, Tobón-Castaño A, Posada M, Vélez GJ, Campillo A, González 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. — View Citation

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. — View Citation

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

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

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	The proportion of anemia in the 2 study arms	Anemia is defined as a level of hemoglobin (Hb) <10g/dl	6 months
Primary	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
Primary	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
Primary	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

External Links

•   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
•   The PYRAPREG project