MalariaPhase 3ECG-LihirNCT02605720
Cardiac Safety of Repeated Doses of Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns
A Phase 3 study testing Dihydroartemisinin-piperaquine in people with Malaria, run by Lihir Medical Centre at 1 site in Papua New Guinea.
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… Read more about this study
- Who is it for?
- Ages 3 to 49 yearsHealthy volunteers can take part
- Conditions the study is for
- Malaria
- What is being tested?
- Dihydroartemisinin-piperaquine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 1 sitePapua New Guinea
- Study dates
- Sep 2015to Feb 2016
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 3 to 49 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- Male or female ≥3 years to ≤50 years
- Good general health by medical history physical examination, baseline electrocardiographs and laboratory tests.
- No clinically relevant abnormalities in blood pressure and heart rate
- 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 450 ms should be withdrawn from the study prior to dosing.
Who cannot join
- A history of additional risk factors for Torsades-des-Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
- The use of concomitant medications that prolong the QT/QTc interval;
- 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;
- History of relevant clinical allergic reactions of any origin;
- 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;
- Patients who are not willing to give informed consent (patient and/or parent/legal representative), or who withdraw consent.
- Pregnant women in the 1st trimester of pregnancy.
Trial locations and contacts
1 site in 1 country.
Papua New Guinea1 site
Lihir medical Centre
Londolovit, New Ireland Province
About this study
Official title: Electrocardiographic Safety Evaluation of Monthly Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns to Block Malaria Transmission
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.
Read the detailed 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.
- Conditions
- Malaria
- Being tested
- Dihydroartemisinin-piperaquine
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dihydroartemisinin-piperaquineDrug
Also called Eurartesim
DHA/PPQ dose 2.1/17.1 mg/Kg daily for 3 days (PNG National Malaria Treatment Protocol) monthly for 3 months
| Study group | Role | What they receive |
|---|---|---|
| Dihydroartemisinin-piperaquine | Experimental | Not described Receives: Drug: Dihydroartemisinin-piperaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in QTcF interval (Fridericia's correction QT interval) after study drugs administration compared to baseline
Measured: Day 58
Plasma piperaquine concentrations after study drugs
Measured: Day 58
Secondary outcomes (2)
Change in QTcF interval after study drugs administration compared to baseline
Measured: Day 3
Change in QTcF interval after study drugs administration compared to baseline
Measured: Day 31
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Nov 2015 (estimated)
- Study startSep 2015
- Primary completionJan 2016
- Study completionFeb 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 78 participants (actual)
Sponsor and investigators
- Lead sponsor
- Lihir Medical Centre
- Sponsor type
- University, hospital or other
- Collaborators
- Walter and Eliza Hall Institute of Medical Research, Papua New Guinea Institute of Medical Research, Barcelona Institute for Global Health
- Responsible party
- Principal investigator, Oriol Mitja, Lihir Medical Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02605720
- Sponsor's protocol ID
- LihirMC
- Acronym
- ECG-Lihir
- Status last verified
- Feb 2016
- First submitted
- 12 Nov 2015
- Last updated
- 3 Mar 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Millat-Martinez P, Salman S, Moore BR, Baro B, Page-Sharp M, Batty KT, Robinson LJ, Pomat W, Karunajeewa H, Laman M, Manning L, Mitja O, Bassat Q. Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin-Piperaquine. Antimicrob Agents Chemother. 2022 Aug 16;66(8):e0018522. doi: 10.1128/aac.00185-22. Epub 2022 Jul 6.
PubMed 35862743
Study at a glance
From the registry record, last updated by the sponsor on 3 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Electrocardiographic Safety Evaluation of Monthly Dihydroartemisinin-Piperaquine for the Use in Mass Treatment Campaigns to Block Malaria Transmission
- ClinicalTrials.gov ID
- NCT02605720
- Acronym / sponsor ID
- ECG-Lihir / LihirMC
- Conditions
- Malaria
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 78 participants (actual)
- Lead sponsor
- Lihir Medical CentreUniversity, hospital or other
- Collaborators
- Walter and Eliza Hall Institute of Medical Research, Papua New Guinea Institute of Medical Research, Barcelona Institute for Global Health
- Study start
- Sep 2015
- Primary completion
- Jan 2016 (actual)
- Study completion
- Feb 2016 (actual)
- First posted
- 16 Nov 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dihydroartemisinin-piperaquine | Experimental | Drug: Dihydroartemisinin-piperaquine |
Who may qualify
- Ages
- 3 to 49 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Male or female ≥3 years to ≤50 years
- Good general health by medical history physical examination, baseline electrocardiographs and laboratory tests.
- No clinically relevant abnormalities in blood pressure and heart rate
- 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.
Key exclusion criteria (7 listed)
- A history of additional risk factors for Torsades-des-Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
- The use of concomitant medications that prolong the QT/QTc interval;
- 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;
- History of relevant clinical allergic reactions of any origin;
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dihydroartemisinin-piperaquineAlso: EurartesimDHA/PPQ dose 2.1/17.1 mg/Kg daily for 3 days (PNG National Malaria Treatment Protocol) monthly for 3 months | Drug | Dihydroartemisinin-piperaquine |
Primary outcome
Change in QTcF interval (Fridericia's correction QT interval) after study drugs administration compared to baseline
Time frame: Day 58
Plasma piperaquine concentrations after study drugs
Time frame: Day 58
2 secondary outcomes
Change in QTcF interval after study drugs administration compared to baseline
Time frame: Day 3
Change in QTcF interval after study drugs administration compared to baseline
Time frame: Day 31
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Mar 2016.
- Derived from this study: PubMed 35862743Millat-Martinez P, Salman S, Moore BR, Baro B, Page-Sharp M, Batty KT, Robinson LJ, Pomat W, Karunajeewa H, Laman M, Manning L, Mitja O, Bassat Q. Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin-Piperaquine. Antimicrob Agents Chemother. 2022 Aug 16;66(8):e0018522. doi: 10.1128/aac.00185-22. Epub 2022 Jul 6.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Dihydroartemisinin-piperaquine in people with Malaria, run by Lihir Medical Centre at 1 site in Papua New Guinea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Papua New Guinea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in QTcF interval (Fridericia's correction QT interval) after study drugs administration compared to baseline (time frame: Day 58). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02605720, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Mar 2016.