search
Back to results

Cardiac Safety of Dihydroartemisinin-Piperaquine Amongst Pregnant Women in Tanzania

Primary Purpose

Malaria, Pregnancy Malaria, Cardiotoxicity

Status
Completed
Phase
Phase 2
Locations
Tanzania
Study Type
Interventional
Intervention
sulfadoxine-pyrimethamine (SP)
dihydroartemisinin-piperaquine (DHA-PQP)
Sponsored by
London School of Hygiene and Tropical Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Malaria focused on measuring Sub-Saharan Africa, Dihydroartemisinin, Piperaquine, Sulphadoxine-Pyrimethamine, Antimalarials

Eligibility Criteria

18 Years - 34 Years (Adult)FemaleAccepts Healthy Volunteers

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.

Sites / Locations

  • Handeni District Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

sulfadoxine-pyrimethamine (SP)

dihydroartemisinin-piperaquine (DHA-PQP)

Arm Description

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 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.

Outcomes

Primary Outcome Measures

Mean QTcF/QTcB change from baseline and proportion of pregnant women treated with DHA-PQP who experienced changes in RR, HR, PR, QRS, QT, QTcF and QTcB measurements from Day 0 pre-dose to Day 2 post-dose.
Mean QTcF/QTcB change from baseline and proportion of pregnant women treated with DHA-PQP who experience changes in QT, QTcF and QTcB measurements from Day 0 pre-dose to Day 7.

Secondary Outcome Measures

Proportion of pregnant women treated with DHA-PQP/SP with and without asymptomatic parasitaemia who experienced clinical symptoms that could be related with a cardiac arrhythmia.
Clinical assessment
Mean QTcF/QTcB change from baseline and proportion of pregnant women treated with SP who experience changes in QT, QTcF and QTcB measurements from Day 0 pre-dose to Day 7
Electrocardiography
Comparative analysis of the QT changes from Day 0 pre-dose to Day 7 post first dosing in pregnant women given DHA-PQP versus SP
Electrocardiography
Analysis of values and changes from baseline for the other electrocardiogram (ECG) parameters (RR, HR, PR, QRS) in pregnant women given DHA-PQP or SP
Electrocardiography
Adequate Parasitological Responses (APR) at Days 7, 14, 21 and 28 post-dose, PCR-Corrected and uncorrected
Efficacy
Proportion of participants in Groups 1-4 with parasites at Days 0, 7, 14, 21 and 28 that carry the 581G and/or K540E mutations associated with SP resistance
Parasite resistance

Full Information

First Posted
September 5, 2016
Last Updated
February 1, 2021
Sponsor
London School of Hygiene and Tropical Medicine
Collaborators
Kilimanjaro Christian Medical Centre, Tanzania, National Institute for Medical Research, Tanzania
search

1. Study Identification

Unique Protocol Identification Number
NCT02909712
Brief Title
Cardiac Safety of Dihydroartemisinin-Piperaquine Amongst Pregnant Women in Tanzania
Official Title
Cardiac Safety of Dihydroartemisinin-Piperaquine Amongst Pregnant Women in Tanzania
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
September 2016 (Actual)
Primary Completion Date
January 2020 (Actual)
Study Completion Date
February 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
London School of Hygiene and Tropical Medicine
Collaborators
Kilimanjaro Christian Medical Centre, Tanzania, National Institute for Medical Research, Tanzania

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria, Pregnancy Malaria, Cardiotoxicity, Cardiac Safety, Parasitemia
Keywords
Sub-Saharan Africa, Dihydroartemisinin, Piperaquine, Sulphadoxine-Pyrimethamine, Antimalarials

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
201 (Actual)

8. Arms, Groups, and Interventions

Arm Title
sulfadoxine-pyrimethamine (SP)
Arm Type
Active Comparator
Arm Description
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.
Arm Title
dihydroartemisinin-piperaquine (DHA-PQP)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
sulfadoxine-pyrimethamine (SP)
Other Intervention Name(s)
Fansidar / Akacia Healthcare Ltd (South Africa)
Intervention Description
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
Intervention Name(s)
dihydroartemisinin-piperaquine (DHA-PQP)
Other Intervention Name(s)
Eurartesim / Sigma-Tau (Italy)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Mean QTcF/QTcB change from baseline and proportion of pregnant women treated with DHA-PQP who experienced changes in RR, HR, PR, QRS, QT, QTcF and QTcB measurements from Day 0 pre-dose to Day 2 post-dose.
Time Frame
Measured on day 2 post-dose
Title
Mean QTcF/QTcB change from baseline and proportion of pregnant women treated with DHA-PQP who experience changes in QT, QTcF and QTcB measurements from Day 0 pre-dose to Day 7.
Time Frame
Measured on day 7 post-dose
Secondary Outcome Measure Information:
Title
Proportion of pregnant women treated with DHA-PQP/SP with and without asymptomatic parasitaemia who experienced clinical symptoms that could be related with a cardiac arrhythmia.
Description
Clinical assessment
Time Frame
Measured on day 28 post-dose
Title
Mean QTcF/QTcB change from baseline and proportion of pregnant women treated with SP who experience changes in QT, QTcF and QTcB measurements from Day 0 pre-dose to Day 7
Description
Electrocardiography
Time Frame
Measured on day 7 post-dose
Title
Comparative analysis of the QT changes from Day 0 pre-dose to Day 7 post first dosing in pregnant women given DHA-PQP versus SP
Description
Electrocardiography
Time Frame
Measured on day 7 post-dose
Title
Analysis of values and changes from baseline for the other electrocardiogram (ECG) parameters (RR, HR, PR, QRS) in pregnant women given DHA-PQP or SP
Description
Electrocardiography
Time Frame
Measured on day 7 post-dose
Title
Adequate Parasitological Responses (APR) at Days 7, 14, 21 and 28 post-dose, PCR-Corrected and uncorrected
Description
Efficacy
Time Frame
Measured on day 28 post-dose
Title
Proportion of participants in Groups 1-4 with parasites at Days 0, 7, 14, 21 and 28 that carry the 581G and/or K540E mutations associated with SP resistance
Description
Parasite resistance
Time Frame
Measured on days 28 post-dose

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
34 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Participant presents for antenatal care at the district hospital. Participant is between 18 years and 34 years of age. Participant currently lives within the pre-defined catchment area of the district hospital. Participant will remain within the same area through to the post-partum visit. Participant agrees to deliver her child at the district hospital. Participant agrees to a post-partum visit at her residence or at the district hospital. Participant has no apparent severe infection or any condition that requires hospitalization. Participant is not currently enrolled in another study. Participant is not known to have heart disease or a known cardiac ailment. Participant reports having taken no medication in the previous 28 days. Participant reports having no known allergy to the study drugs or any sulphonamides. 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. Participant is willing to undergo all study procedures including sonography, ECG testing, and to provide blood samples for malaria microscopy and pharmacokinetic analysis. Participant agrees to human immunodeficiency virus (HIV) testing regardless of prior results and no matter how recent. Participant is not severely anaemic (haemoglobin concentration > 5g/dL). Participant provides written consent. Participant has an axillary temperature < 37.5 Celsius. Participant is pregnant with a singleton determined by sonography. Participant is between 16 and 35 weeks gestation determined by sonography. Exclusion Criteria: Participant is younger than 18 years of age and older than 35 years of age. Participant does not currently live within the pre-defined catchment area of district hospital. Participant will not remain within the same area through to the post-partum visit. Participant does not agree to deliver her child at the district hospital. Participant does not agree to a post-partum visit at her residence or at the district hospital. Participant has a severe infection or any condition that requires hospitalization. Participant is currently enrolled in another study. Participant is known to have heart disease or known cardiac ailment. Participant reports having taken any medication in the previous 28 days. Participant reports having an allergy to the study drugs or any sulphonamides. Participant does not agree to abstain from food ingestion during the observation period after dosing. Participant does not agree to remain under observation at the district hospital 3 hours after dosing has occurred. 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. Participant does not agree to HIV testing or is diagnosed as HIV-positive during screening, Participant is not severely anaemic (haemoglobin concentration > 5g/dL). Participant does not provide written consent. Participant has an axillary temperature > 37.5 Celsius or is symptomatic for malaria. Participant is carrying a multiple pregnancy (e.g. twins). Participant is between < 16 weeks and > 36 weeks gestation. Participant has a QTc > 450 milliseconds. Participant has a heart rate < 40 beats per minute.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
R. Matthew Chico, MPH, PhD
Organizational Affiliation
London School of Hygiene and Tropical Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jacklin Mosha, MBBS, MSc, PhD
Organizational Affiliation
Kilimanjaro Christian Medical College
Official's Role
Principal Investigator
Facility Information:
Facility Name
Handeni District Hospital
City
Handeni
State/Province
Tanga Region
Country
Tanzania

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Results will be published in a peer-reviewed journal
Citations:
PubMed Identifier
16237860
Citation
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.
Results Reference
background
Available IPD and Supporting Information:
Available IPD/Information Type
Assessment report: Eurartesim - dihydroartemisinin / piperaquine phosphate EMEA/H/C/1199
Available IPD/Information URL
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001199/WC500118116.pdf

Learn more about this trial

Cardiac Safety of Dihydroartemisinin-Piperaquine Amongst Pregnant Women in Tanzania

We'll reach out to this number within 24 hrs