Clinical trial NCT01669941: Efficacy of Intermittent Screening and Treatment or Intermittent Preventive Treatment (IPT) With Dihydroartemisinin-Piperaquine, Versus IPT With Sulfadoxine-Pyrimethamine for the Control of Malaria in Pregnancy in Kenya
Official title: Intermittent Screening and Treatment (IST) or Intermittent Preventive Treatment (IPT) With Dihydroartemisinin-Piperaquine, Versus IPT With Sulfadoxine-Pyrimethamine for the Control of Malaria in Pregnancy in Kenya: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pregnancy
Malaria
Keywords: Pregnancy
Plasmodium
Malaria
Prevention
Kenya
Piperaquine
Dihydroartemisinin-Piperaquine
Sulfadoxine Pyrimethamine
Lead sponsor: Kenya Medical Research Institute
Sponsor class: OTHER
Collaborators: name: Centers for Disease Control and Prevention
name: Liverpool School of Tropical Medicine
name: London School of Hygiene and Tropical Medicine
First posted: 2012-08-21
Enrollment: 1546
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Malaria in pregnancy (MiP) due to Plasmodium falciparum infection is a major cause of maternal morbidity and poor birth outcomes. Intermittent preventive treatment in pregnancy (IPTp) with Sulfadoxine pyrimethamine (SP), the administration of SP at predefined intervals in the second and third trimesters of pregnancy irrespective of the presence of malaria parasitemia, is currently recommended for HIV-negative women in all areas with stable moderate to high transmission of malaria. Due to increasing resistance to SP, it is no longer used as a treatment for symptomatic malaria, and the efficacy of IPTp-SP seems to be decreased. This study aims to look at a new drug, Dihydroartemisinin-Piperaquine (DP) for IPTp, as well as to explore the strategy of intermittent screening and treatment in pregnancy (ISTp) with DP. This strategy uses increased screening at time of focused antenatal care (FANC) with treatment of women who screen positive.

The hypothesis is that the efficacy of both IPTp-DP and ISTp-DP will be associated with a reduction in malaria infection at delivery among HIV(-) women when compared to IPTp-SP, in an area with decreasing malaria transmission and high levels of SP resistance in Kenya.

Detailed description: Malaria in pregnancy (MiP) due to Plasmodium falciparum infection is a major cause of maternal morbidity and poor birth outcomes. Pregnant women are at increased risk of more frequent and severe malaria infections than are non-pregnant women. Intermittent preventive treatment in pregnancy (IPTp), the administration of treatment doses of an antimalarial at predefined intervals in the second and third trimesters of pregnancy irrespective of the presence of malaria parasitemia, is currently recommended for HIV-negative women in all areas with stable moderate to high transmission of malaria. The strategy is thought to work by providing intermittent clearance or suppression of parasites in the placenta, and preventing new infections from occurring through the prophylactic effect of the recommended drug for IPTp, sulfadoxine-pyrimethamine (SP).

SP is the only drug currently used for IPTp. Due to increasing resistance to SP, it is no longer used as a treatment for symptomatic malaria, however, IPTp with SP remains effective even in areas where SP resistance in children under five (determined by in vivo efficacy studies) is up to 26%. SP therefore continues to be used for IPTp in many countries where it is no longer used for treatment of symptomatic malaria. However, more recent data from northern Tanzania and Malawi indicate that at higher rates of resistance, IPTp-SP may no longer be effective, and could potentially be harmful.

In view of this data, a search for alternatives to IPTp-SP is warranted. One strategy would be to choose a different drug for IPTp. Of the available combinations, Dihydroartemisinin-Piperaquine (DP) remains one of the most attractive options because of the long half-life of piperaquine (PQ) and the demonstrated efficacy and safety in pregnancy. Another strategy to consider is intermittent screening and treatment in pregnancy (ISTp), whereby there is increased screening at time of focused antenatal care (FANC) with treatment of women who screen positive. The same properties (long half-life, tolerability, safety, once daily dosing) which make DP a good choice for IPTp also make it one of the best available options for ISTp.

This study aims to compare the efficacy of IPTp-SP against that of IPTp-DP and ISTp-DP to determine if these alternate strategies are associated with a reduction in malaria infection at delivery among HIV(-) women in an area with decreasing malaria transmission and high levels of SP resistance in Kenya.

Eligibility criteria: Inclusion Criteria:

1. Viable pregnancy assessed by Doppler
2. Gestational age 16 to 32 weeks (inclusive) by fundal height
3. No history of IPTp use during this pregnancy
4. Willing to participate and complete the study schedule
5. Willing to sign or thumb print informed consent
6. Resident of study area and intending to stay in the area for the duration of the follow-up
7. Willing to deliver in the labor ward of the study clinic or hospital
8. HIV negative at enrolment

Exclusion Criteria:

1. HIV positive or unknown
2. Residence outside study area or planning to move out in the 12 months following enrolment
3. High risk pregnancy, including any pre-existing illness likely to cause complication of pregnancy (hypertension, diabetes, asthma, epilepsy, renal disease, liver disease, fistula repair, leg or spine deformity)
4. Severe anemia requiring blood transfusion (Hb ≤ 7.0 g/dL) at enrolment
5. Known allergy or previous adverse reaction to any of the study drugs
6. Unable to give informed consent (for example due to mental disability)
7. Previous inclusion in the same study
8. Gestational age \>32 weeks
9. Previous IPTp during the current pregnancy
10. Participating in other malaria intervention studies
11. Known or suspected cardiac disease
12. Patients taking drugs in any of the following classes: antiarrhythmic agents, neuroleptics, macrolides, and certain antimalarial drugs such as mefloquine, chloroquine, halofantrine and lumefantrine.

Primary outcomes:
measure: Maternal malaria at delivery
timeFrame: Delivery
Secondary outcomes:
measure: Decreased fetal morbidity
timeFrame: Delivery
measure: Frequency of fetal congenital malformations
timeFrame: At delivery
measure: Pharmacokinetics- piperaquine level
timeFrame: At baseline, and day 2 and day 7 following dosing.
measure: level of antibodies to variant surface antigens (VSAs)
timeFrame: At delivery
measure: Frequency of maternal adverse events
timeFrame: At each ANC visit and at delivery
Other outcomes:
Locations:
city: Rarieda
country: Kenya
facility: Lwak Mission Hospital
state: Nyanza
city: Siaya
country: Kenya
facility: Siaya District Hospital
state: Nyanza
city: Bondo
country: Kenya
facility: Bondo District Hospital
city: Madiany
country: Kenya
facility: Madiany sub-District Hospital
Study officials:
affiliation: Centers for Disease Control and Prevention
name: Meghna Desai, PhD MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Kenya Medical Research Institute
name: Abraham Katana, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chotsiri P, Gutman JR, Ahmed R, Poespoprodjo JR, Syafruddin D, Khairallah C, Asih PBS, L'lanziva A, Otieno K, Kariuki S, Ouma P, Were V, Katana A, Price RN, Desai M, Ter Kuile FO, Tarning J. Piperaquine Pharmacokinetics during Intermittent Preventive Treatment for Malaria in Pregnancy. Antimicrob Agents Chemother. 2021 Feb 17;65(3):e01150-20. doi: 10.1128/AAC.01150-20. Print 2021 Feb 17.
citation: Desai M, Gutman J, L'lanziva A, Otieno K, Juma E, Kariuki S, Ouma P, Were V, Laserson K, Katana A, Williamson J, ter Kuile FO. Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial. Lancet. 2015 Dec 19;386(10012):2507-19. doi: 10.1016/S0140-6736(15)00310-4. Epub 2015 Sep 28.