Cardiac Safety of Repeated Doses of Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns

Malaria Clinical Trial

— ECG-Lihir  

Official title:

Electrocardiographic Safety Evaluation of Monthly Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns to Block Malaria Transmission

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02605720
• Other study ID #: LihirMC
• Status: Completed
• Phase: Phase 3
• First received: November 12, 2015
• Last updated: March 2, 2016
• Start date: September 2015
• Est. completion date: February 2016

Study information

• Verified date: February 2016
• Source: Lihir Medical Centre
• Contact: n/a
• Is FDA regulated: No
• Health authority: Papua New Guinea: Medical Society of Papua New Guinea
• Study type: Interventional

Clinical Trial Summary

Mass drug administration with antimalarial treatment is a tool that can potentially reduce or totally eliminate malaria parasite infections from a population. Dihydroartemisinin-piperaquine (DHA/PPQ) given monthly for 3 months to the entire population might be a good candidate for mass drug administration because the long acting PPQ exerts a long post-treatment prophylactic effect against reinfection and relapse. The use of a repeated dose of DHA/PPQ could lead to increased PPQ plasma concentrations and increased cardiotoxicity. However, there is no data on a second course of treatment or on safety of the drug administered in repeated monthly doses. The proposed project is a clinical trial to assess the electrocardiographic safety of monthly DHA/PPQ (for 3 days at a time) for 3 months. The investigators aim to assess the safety of the drug to be used monthly in mass treatment campaigns. Recommendations issued from this study will benefit health authorities on Lihir-Island by setting the stage for a possible subsequent campaign to completely eliminate malaria from the whole island. This study could be a crucial step to inform the feasibility of drug-based strategies for eliminating malaria elsewhere in PNG, other Melanesian countries and throughout the world.

Description:

Given the absence of regulatory data related to the safety of repeated dosing, the European Medicines Agency has set a conservatively long 2-month "wash-out" period before administration of subsequent courses can be recommended. Unfortunately such a recommendation would make it impossible to implement effective mass drug administration with PPQ as this probably requires a maximum interval of one month between doses (in order to ensure that drug levels remain high enough to prevent infections occurring between doses). Therefore it is important that a formal evaluation is performed to regulatory standards that can conclusively document the safety of repeated monthly doses of PPQ. The extensive previous experience from monthly PPQ administration in China suggests that such a study would pose minimal risks to study participants.

Various studies have looked at the potential of DHA/PPQ to cause prolongation of corrected QT interval (QTc) intervals in humans. In a study of 62 adults and children, in Cambodia, electrocardiographic (ECG) findings after DHA/PPQ treatment showed a lengthening of the mean QTc by 11 ms. In two randomized controlled trials in Thailand, the mean QTc prolongation of 56 patients was 14 ms after the last dose of DHA/PPQ. The degree of QT prolongation observed in these studies was therefore similar to that seen with other anti-malarial drugs (including lumefantrine, and chloroquine) generally considered to have no cardiotoxicity in conventional dosing, and substantially less than with others such as halofantrine.and quinidine that have been associated with cardiotoxicity. Study-DM09-006 compared QTc data of healthy subjects that received DHA/PPQ with respective placebo groups and found maximum mean QT Fridericia's correction (QTcF) prolongation of 45.2 ms if co-administered with high fat, and 21.0 ms if fasting (EMEA/H/C/119). Of total of 96 participants given DHA/PPQ in the three studies mentioned above, no subjects showed QTc > 500ms post-treatment or prolongations (after- vs pre-dose) >60ms.

The proposed project is a pharmacovigilance study for electrocardiographic safety evaluation of monthly DHA/PPQ (administered as a conventional 3-day course repeated monthly for 3 months). The investigators aim to assess the safety of the drug to be used monthly in mass treatment campaigns.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 78
• Est. completion date: February 2016
• Est. primary completion date: January 2016
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 3 Years to 49 Years

Eligibility

Inclusion Criteria:

1. Male or female =3 years to =50 years

2. Good general health by medical history physical examination, baseline electrocardiographs and laboratory tests.

3. No clinically relevant abnormalities in blood pressure and heart rate

4. No clinically relevant abnormalities in 12-lead ECG results*

*Patients with a QTcB or QTcF greater than 450 ms or clinically significant abnormalities of rhythm at Screening are not eligible. Patients with a pre-dose baseline value > 450 ms should be withdrawn from the study prior to dosing.

Exclusion Criteria:

5. A history of additional risk factors for Torsades-des-Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);

6. The use of concomitant medications that prolong the QT/QTc interval;

7. Any condition requiring regular concomitant medication, including herbal products and over-the-counter (OTC) medication or predicted need of any concomitant medication during the study;

8. History of relevant clinical allergic reactions of any origin;

9. Any other condition that in the opinion of the Investigator would interfere with the evaluation of the results or constitute a health risk for the subject;

10. Patients who are not willing to give informed consent (patient and/or parent/legal representative), or who withdraw consent.

11. Pregnant women in the 1st trimester of pregnancy.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Malaria

Intervention

Drug:
• Dihydroartemisinin-piperaquine
DHA/PPQ dose 2.1/17.1 mg/Kg daily for 3 days (PNG National Malaria Treatment Protocol) monthly for 3 months

Locations

Country	Name	City	State
Papua New Guinea	Lihir medical Centre	Londolovit	New ireland province

Sponsors (4)

Lead Sponsor	Collaborator
Lihir Medical Centre	Barcelona Institute for Global Health, Papua New Guinea Institute of Medical Research, Walter and Eliza Hall Institute of Medical Research

Country where clinical trial is conducted

Papua New Guinea, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in QTcF interval (Fridericia's correction QT interval) after study drugs administration compared to baseline		Day 58	Yes
Primary	Plasma piperaquine concentrations after study drugs		Day 58	No
Secondary	Change in QTcF interval after study drugs administration compared to baseline		Day 3	Yes
Secondary	Change in QTcF interval after study drugs administration compared to baseline		Day 31	Yes