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Cardio‑Safety of Dihydroartemisinin‑Piperaquine and Pharmacokinetics of Piperaquine Amongst Pregnant Women in Tanzania

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ClinicalTrials.gov Identifier: NCT02909712
Recruitment Status : Unknown
Verified June 2016 by London School of Hygiene and Tropical Medicine.
Recruitment status was:  Recruiting
First Posted : September 21, 2016
Last Update Posted : September 21, 2016
Sponsor:
Collaborators:
Kilimanjaro Christian Medical Centre, Tanzania
National Institute for Medical Research, Tanzania
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

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.

Condition or disease Intervention/treatment Phase
Malaria Pregnancy Cardiotoxicity Parasitemia Drug: sulfadoxine-pyrimethamine (SP) Drug: dihydroartemisinin-piperaquine (DHA-PQP) Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Cardio‑Safety of Dihydroartemisinin‑Piperaquine and Pharmacokinetics of Piperaquine Amongst Pregnant Women in Tanzania
Study Start Date : September 2016
Estimated Primary Completion Date : March 2017
Estimated Study Completion Date : September 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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.

Drug: 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.

Other Name: Fansidar / Akacia Healthcare Ltd (South Africa)

Experimental: 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.

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.
Other Name: Eurartesim / Sigma-Tau (Italy)




Primary Outcome Measures :
  1. Proportion of participants in Groups 3-4 with an absolute QTc of > 500 milliseconds [ Time Frame: Measured on day 7 post-dose ]

Secondary Outcome Measures :
  1. Proportion of participants in Groups 1-2 with an absolute QTc of > 500 milliseconds [ Time Frame: Measured on day 0 ]
  2. Proportion of participants in Groups 1-2 with an absolute QTc of > 480 milliseconds [ Time Frame: Measured on day 0 ]
  3. Proportion of participants in Groups 1-2 with an absolute QTc of > 460 milliseconds [ Time Frame: Measured on day 0 ]
  4. Proportion of participants in Groups 3-4 with an absolute QTc of > 500 milliseconds [ Time Frame: Measured on day 2 ]
  5. Proportion of participants in Groups 3-4 with an absolute QTc of > 480 milliseconds [ Time Frame: Measured on day 2 ]
  6. Proportion of participants in Groups 3-4 with an absolute QTc of > 450 milliseconds [ Time Frame: Measured on day 2 ]
  7. Incidence of participants in Groups 1-4 with QTcF prolongation > 500 milliseconds. [ Time Frame: Measured on days 0, 2 and 7 ]
  8. Incidence of participants in Groups 1-4 with QTcF deviation from baseline > 60 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  9. Incidence of participants in Groups 1-4 with ventricular arrhythmia captured on ECG recording and/or suspected by a clinical event as palpitation, dizziness, syncope, convulsion, or sudden death [ Time Frame: Measured on days 0, 2 and 7 ]
  10. Proportion of participants in Groups 1-4 with mean heart rate < 40 beats per minute [ Time Frame: Measured on days 0, 2 and 7 ]
  11. Proportion of participants in Groups 1-4 with mean heart rate > 130 beats per minute [ Time Frame: Measured on days 0, 2 and 7 ]
  12. Proportion of participants in Groups 1-4 with PR interval > 210 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  13. Proportion of participants in Groups 1-4 with PR interval > 220 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  14. Proportion of participants in Groups 1-4 with QRS interval > 110 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  15. Proportion of participants in Groups 1-4 with QRS interval > 120 milliseconds [ Time Frame: Measured on days 0, 2 and 7 ]
  16. Proportion of participants in Groups 1-4 with change in QTcF from baseline > 60 milliseconds + Absolute QTc > 480 milliseconds (QTcF refers to the QT interval that has been corrected using the Fridericia formula) [ Time Frame: Measured on days 2 and 7 ]
  17. Proportion of participants in Groups 1-4 with QTcF > 480 milliseconds and > 500 milliseconds (QTcF refers to the QT interval that has been corrected using the Fridericia formula) [ Time Frame: Measured on days 0, 2 and 7 ]
  18. Proportion of participants in Groups 3-4 with change in QTcF between day 0 pre-dose, day 2 post dose at peak > 60 milliseconds, and day 7 (QTcF refers to the QT interval that has been corrected using the Fridericia formula) [ Time Frame: Measured on days 0, 2 and 7 ]
  19. Proportion of participants in Groups 1-4 with arrhythmias [ Time Frame: Measured on days 0, 2 and 7 ]
  20. Incidence of participants in Groups 3-4 with sinus pause / arrest > 3.0 seconds [ Time Frame: Measured on days 0, 2 and 7 ]
  21. Incidence of participants in Groups 3-4 with 2nd degree atrioventricular block (Mobitz 2) [ Time Frame: Measured on days 0, 2 and 7 ]
  22. Incidence of participants in Groups 3-4 with 3rd degree atrioventricular block [ Time Frame: Measured on days 0, 2 and 7 ]
  23. Incidence of participants with ventricular tachycardia [ Time Frame: Measured on days 0, 2 and 7 ]
  24. Incidence of participants with torsades de pointes [ Time Frame: Measured on days 0, 2 and 7 ]
  25. Incidence of participants with ventricular fibrillation [ Time Frame: Measured on days 0, 2 and 7 ]
  26. Mean piperaquine absorption at maximum observed concentrations (Cmax) in Groups 3-4 [ Time Frame: Measured on day 2 ]
  27. Incidence of participants who experience myocardial ischemia defined as: • ST-segment deviations ≥ 1 millimetre 80 millisecond after J-point, or • New Q-waves, or T-wave inversion [ Time Frame: Measured on days 0, 2 and 7 ]
  28. Incidence of participants who experience morphological changes of the T-wave [ Time Frame: Measured on days 0, 2 and 7 ]
  29. Incidence of participants who experience pathological U-wave [ Time Frame: Measured on days 0, 2 and 7 ]
  30. Incidence of participants who experience sinus pause or arrest > 3.0 seconds [ Time Frame: Measured on days 0, 2 and 7 ]
  31. Incidence of participants who experience 2nd degree atrioventricular block (Mobitz 2) [ Time Frame: Measured on days 0, 2 and 7 ]
  32. Incidence of participants who experience 3rd degree atrioventricular block [ Time Frame: Measured on days 0, 2 and 7 ]
  33. Incidence of participants who experience complete right bundle branch block [ Time Frame: Measured on days 0, 2 and 7 ]
  34. Incidence of participants who experience complete left bundle branch block [ Time Frame: Measured on days 0, 2 and 7 ]
  35. Proportion of participants in Groups 1-2 with and without parasitaemia at day 0 administered SP, who are aparasitaemic at day 7, day 14 and day 28, uncorrected and corrected by PCR methods [ Time Frame: Days 0, 7, 14, and 28 ]
  36. Proportion of participants in Groups 3-4 administered dihydroartemisinin‑piperaquine with and without parasitaemia at day 0, who are aparasitaemic at day 7, day 14 and day 28, uncorrected and corrected by PCR methods [ Time Frame: Days 0, 7, 14, and 28 ]
  37. Proportion of participants in Groups 1-4 with parasites that carry the A581G mutation and others biomarkers associated with SP resistance. [ Time Frame: Day 0 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 34 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02909712


Contacts
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Contact: R. Matthew Chico +44 207 927 2841 matthew.chico@lshtm.ac.uk
Contact: Jacklin Mosha +255 788 033 605 jfmosha@yahoo.com

Locations
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Tanzania
Handeni District Hospital Recruiting
Handeni, Tanga Region, Tanzania
Contact: George Mtove         
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
Kilimanjaro Christian Medical Centre, Tanzania
National Institute for Medical Research, Tanzania
Investigators
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Principal Investigator: R Matthew Chico London School of Hygiene and Tropical Medicine
Principal Investigator: Daniel Chandramohan London School of Hygiene and Tropical Medicine
Principal Investigator: Brian Greenwood London School of Hygiene and Tropical Medicine
Principal Investigator: Frank Mosha Kilimanjaro Christian Medical College

Study Data/Documents: Assessment report: Eurartesim - dihydroartemisinin / piperaquine phosphate EMEA/H/C/1199  This link exits the ClinicalTrials.gov site

Publications:
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Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT02909712     History of Changes
Other Study ID Numbers: 9751
First Posted: September 21, 2016    Key Record Dates
Last Update Posted: September 21, 2016
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Results will be published in a peer-reviewed journal
Keywords provided by London School of Hygiene and Tropical Medicine:
sub-Saharan
dihydroartemisinin
piperaquine
sulphadoxine-pyrimethamine
antimalarials
Additional relevant MeSH terms:
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Parasitemia
Cardiotoxicity
Parasitic Diseases
Pathologic Processes
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Radiation Injuries
Wounds and Injuries
Sepsis
Systemic Inflammatory Response Syndrome
Inflammation
Pyrimethamine
Piperaquine
Sulfadoxine
Dihydroartemisinin
Artemisinins
Fanasil, pyrimethamine drug combination
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents