Cardiac Safety of Dihydroartemisinin-Piperaquine Amongst Pregnant Women in Tanzania

NCT ID: NCT02909712

Last Updated: 2021-02-02

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

201 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-09-30

Study Completion Date

2020-02-29

Brief Summary

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Sulfadoxine-pyrimethamine (SP) is currently recommended by the World Health Organization for use as intermittent preventive treatment against malaria in pregnancy (IPTp) in areas of moderate to high malaria transmission. However, in some locales malaria parasites have lost sensitivity to SP, compromising its protective effect. Dihydroartemisinin-piperaquine (DP) is a candidate replacement for SP. This trial is designed to confirm the cardio-safety of DP compared to SP amongst pregnant women in Tanzania.

Detailed Description

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The trial hypothesis is that DP will increase the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle, a phenomenon referred to as QT prolongation, in the study population. However, if QT prolongation is observed, it is expected to be time-limited and of no clinical consequence.

The QT interval, measured in milliseconds (MS) will be corrected (QTc) to account for natural heart rate (HR) extremes. The Fridericia formula will also be used to correct (QTcF) for variation in cardio-contraction. As part of the electrocardiogram (ECG), the period from the beginning of the P wave to the beginning of the QRS complex (PR interval) will be measured, as well as the ST-segment which connects the QRS complex and the T wave.

Prolongation of the QT interval will be estimated when peak drug-concentrations are most likely to be found in the peripheral blood as measured using pharmacokinetic (PK) techniques. Polymerase chain reaction (PCR) methods will be used for genetic sequencing of molecular markers (A581G) associated with malaria parasite drug resistance to SP. The rapid diagnostic test (RDT) CareStart™ will be used to screen pregnant women attending antenatal care.

Conditions

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Malaria Pregnancy Malaria Cardiotoxicity Cardiac Safety Parasitemia

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

SINGLE

Outcome Assessors

Study Groups

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sulfadoxine-pyrimethamine (SP)

* Group 1 (50 CareStart™ RDT-positive women)
* Group 2 (50 CareStart™ RDT-negative women)

These 100 women will have an ECG exam, provide blood for microscopy and molecular analysis, and receive SP on day 0. On days 7, 14, 21, and 28 women will provide blood for microscopy and molecular analysis.

Group Type ACTIVE_COMPARATOR

sulfadoxine-pyrimethamine (SP)

Intervention Type DRUG

Women in Groups 1 and 2 will be provided the following SP regimen as directly observed therapy:

3 tablets total of 500 mg sulphadoxine and 25 mg pyrimethamine; 1 day of dosing.

dihydroartemisinin-piperaquine (DHA-PQP)

* Group 3 (50 CareStart™ RDT-positive women)
* Group 4 (50 CareStart™ RDT-negative women)

These 100 women will have an ECG exam, provide blood for microscopy, molecular, and PK analysis, and receive DHA-PQP day 0. On day 1, women will receive dose 2. On day 2, women will have an ECG exam, begin Holter monitoring, provide blood for PK analysis, and receive dose 3. Blood for PK analysis will be drawn at 4, 5, and 6 hours following dose 3. An ECG exam will be conducted during this period and, again, on day 7. On days 7, 14, 21, and 28, women will provide blood for microscopy and molecular analysis.

Group Type EXPERIMENTAL

dihydroartemisinin-piperaquine (DHA-PQP)

Intervention Type DRUG

Women in Groups 3 and 4 will be provided the following DHA-PQP regimen as directly observed therapy 3 tablets of 40 mg dihydroartemisinin and 320 mg piperaquine daily; 9 tablets total; 3 days of dosing.

Interventions

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sulfadoxine-pyrimethamine (SP)

Women in Groups 1 and 2 will be provided the following SP regimen as directly observed therapy:

3 tablets total of 500 mg sulphadoxine and 25 mg pyrimethamine; 1 day of dosing.

Intervention Type DRUG

dihydroartemisinin-piperaquine (DHA-PQP)

Women in Groups 3 and 4 will be provided the following DHA-PQP regimen as directly observed therapy 3 tablets of 40 mg dihydroartemisinin and 320 mg piperaquine daily; 9 tablets total; 3 days of dosing.

Intervention Type DRUG

Other Intervention Names

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Fansidar / Akacia Healthcare Ltd (South Africa) Eurartesim / Sigma-Tau (Italy)

Eligibility Criteria

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Inclusion Criteria

1. Participant presents for antenatal care at the district hospital.
2. Participant is between 18 years and 34 years of age.
3. Participant currently lives within the pre-defined catchment area of the district hospital.
4. Participant will remain within the same area through to the post-partum visit.
5. Participant agrees to deliver her child at the district hospital.
6. Participant agrees to a post-partum visit at her residence or at the district hospital.
7. Participant has no apparent severe infection or any condition that requires hospitalization.
8. Participant is not currently enrolled in another study.
9. Participant is not known to have heart disease or a known cardiac ailment.
10. Participant reports having taken no medication in the previous 28 days.
11. Participant reports having no known allergy to the study drugs or any sulphonamides.
12. Participant agrees to remain under observation for 3 hours at the district hospital and to abstain from food ingestion during the observation period in keeping with the European Medicines Agency product information for dosing with dihydroartemisinin-piperaquine.
13. Participant is willing to undergo all study procedures including sonography, ECG testing, and to provide blood samples for malaria microscopy and pharmacokinetic analysis.
14. Participant agrees to human immunodeficiency virus (HIV) testing regardless of prior results and no matter how recent.
15. Participant is not severely anaemic (haemoglobin concentration \> 5g/dL).
16. Participant provides written consent.
17. Participant has an axillary temperature \< 37.5 Celsius.
18. Participant is pregnant with a singleton determined by sonography.
19. Participant is between 16 and 35 weeks gestation determined by sonography.

Exclusion Criteria

1. Participant is younger than 18 years of age and older than 35 years of age.
2. Participant does not currently live within the pre-defined catchment area of district hospital.
3. Participant will not remain within the same area through to the post-partum visit.
4. Participant does not agree to deliver her child at the district hospital.
5. Participant does not agree to a post-partum visit at her residence or at the district hospital.
6. Participant has a severe infection or any condition that requires hospitalization.
7. Participant is currently enrolled in another study.
8. Participant is known to have heart disease or known cardiac ailment.
9. Participant reports having taken any medication in the previous 28 days.
10. Participant reports having an allergy to the study drugs or any sulphonamides.
11. Participant does not agree to abstain from food ingestion during the observation period after dosing.
12. Participant does not agree to remain under observation at the district hospital 3 hours after dosing has occurred.
13. Participant does not agree or is unwilling to undergo all study procedures including sonography, ECG testing, and to provide blood samples for malaria microscopy (and treatment group assignment) and pharmacokinetic analysis.
14. Participant does not agree to HIV testing or is diagnosed as HIV-positive during screening,
15. Participant is not severely anaemic (haemoglobin concentration \> 5g/dL).
16. Participant does not provide written consent.
17. Participant has an axillary temperature \> 37.5 Celsius or is symptomatic for malaria.
18. Participant is carrying a multiple pregnancy (e.g. twins).
19. Participant is between \< 16 weeks and \> 36 weeks gestation.
20. Participant has a QTc \> 450 milliseconds.
21. Participant has a heart rate \< 40 beats per minute.
Minimum Eligible Age

18 Years

Maximum Eligible Age

34 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

Yes

Sponsors

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Kilimanjaro Christian Medical Centre, Tanzania

OTHER

Sponsor Role collaborator

National Institute for Medical Research, Tanzania

OTHER_GOV

Sponsor Role collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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R. Matthew Chico, MPH, PhD

Role: PRINCIPAL_INVESTIGATOR

London School of Hygiene and Tropical Medicine

Jacklin Mosha, MBBS, MSc, PhD

Role: PRINCIPAL_INVESTIGATOR

Kilimanjaro Christian Medical College

Locations

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Handeni District Hospital

Handeni, Tanga, Tanzania

Site Status

Countries

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Tanzania

References

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Food and Drug Administration, HHS. International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Notice. Fed Regist. 2005 Oct 20;70(202):61134-5.

Reference Type BACKGROUND
PMID: 16237860 (View on PubMed)

Other Identifiers

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ITDCZF16

Identifier Type: -

Identifier Source: org_study_id

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