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Trial registered on ANZCTR


Registration number
ACTRN12616001533482
Ethics application status
Approved
Date submitted
25/10/2016
Date registered
7/11/2016
Date last updated
7/11/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in 2 sentinel sites in Indonesia
Scientific title
Efficacy and safety of dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria in 2 sentinel sites in Indonesia
Secondary ID [1] 290389 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 300709 0
Condition category
Condition code
Infection 300554 300554 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To assess the efficacy and safety of dihydroartemisinin-piperaquine (40/320 mg) for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Doses will be administered as 4 mg/kg dihydroartemisinin and 18 mg/kg piperaquine once a day for 3 days. The treatment will be given in tablets by oral. Eligible subjects will be treated for three days and followed up for 42 days. All treatments will be taken orally under direct supervision by the health worker.
Intervention code [1] 296217 0
Treatment: Drugs
Comparator / control treatment
No control group. This is a one arm cohort prospective study.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299966 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This is composite primary outcome.
Enrolled patients will be assessed for parasitological and clinical responses during the 42 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 299966 0
At days 1, 2, 3, 7, 14, 21 and 28, 35 and 42 following treatment.
Secondary outcome [1] 328716 0
Percent of adverse event following treatment of each drugs will be documented.
The known adverse events of dihydroartemisinine/piperaquine are asthenia, cough, diarrhoea, fever, loss of appetite, nausea, vomiting.
Parents or guardians of all enrolled children will be asked routinely about previous symptoms and about symptoms that have emerged since the previous follow-up visit. When clinically indicated, patients will be evaluated and treated appropriately. All adverse events will be recorded on the case report form.
Timepoint [1] 328716 0
At days 1, 2, 3, 7, 14, 21 and 28, 35 and 42 following treatment.
Secondary outcome [2] 328717 0
Prevalence of artemisinin resistance molecular markers (K13).

Parasite DNA extracted from the dried blood spots will be analyzed by PCR and sequencing for the presence of K13 (molecular marker for artemisinin resistance).
Timepoint [2] 328717 0
Day 0 (before treatment)
Secondary outcome [3] 328880 0
Piperaquine blood concentrations of the study subjects.

Piperaquine concentration will be measured by using solid phase extraction and analysis by liquid chromatography with ultraviolet detection.
Timepoint [3] 328880 0
Days 7 and day of parasite recurrence

Eligibility
Key inclusion criteria
1. age between one year to 65 years old, excluding female minors aged 12 to 17 years;
2. mono-infection with P. falciparum or P. vivax detected by microscopy;
3. parasitaemia of more than 500 asexual parasites per microliter for P. falciparum and 250 asexual parasites per microliter P.vivax
4. presence of axillary temperature greater or equal to 37.5 degrees C or history of fever during the past 24 h;
5. ability to swallow oral medication;
6. ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; and
7. informed assent from any minor participant aged from 12 to 17 years (age of majority in the country); and
8. consent for pregnancy testing from female of child-bearing potential and from their parent or guardian if under the age of majority years.
Minimum age
1 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO;
2. weight under 5 kg;
3. mixed or mono-infection with another Plasmodium species detected by microscopy;
4. presence of severe malnutrition defined as a child aged 6-60 months has a mid-upper arm circumference below 115 mm);
5. presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. cardiac, renal and hepatic diseases, HIV/AIDS);
6. regular medication, which may interfere with antimalarial pharmacokinetics;
7. history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s); and
8. a positive pregnancy test or breastfeeding (include this criterion only if adults are included)
9. unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age and who are sexually active.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
No concealment
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size: the treatment failure rate to DHP in the area is assumed to be 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included in each arm in each site. With a 20% increase to allow loss to follow-up and withdrawals during the 42-day follow-up period, a total of 88 patients per arm (P. falciparum and P. vivax study) should be included in the study per site.

Analysis of data
The WHO excel software programs and SPSS for windows will be used for data management and analysis. The data will be double entered and . Data will be analysed by two methods: the Kaplan-Meier method and per-protocol analysis. In addition to the reasons for withdrawal listed in section 3.8, patients will be considered withdrawn from the analysis if the PCR results are unclassifiable or if the results of PCR indicate that the failure is due to reinfection with P. falciparum or P. vivax.
The final analysis will include:
1. a description of all patients screened and the distribution of reasons for non-inclusion in the study;
2. a description of all the patients included in the study;
3. the proportion of adverse events and serious adverse events in all the patients included in the study;
4. the proportion of patients lost to follow-up or withdrawn, with 95% confidence intervals and a list of reasons for withdrawal;
5. the cumulative incidence of success and failure rates at day 42, PCR-uncorrected and PCR-corrected; and
6. the proportion of early treatment failure, late clinical failure, late parasitological failure and adequate clinical and parasitological response at day 42, with 95% confidence intervals, PCR-uncorrected and PCR-corrected.
7. the proportion of patients with asexual parasitaemia on day 3

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2016
Actual
Date of last participant enrolment
Anticipated
1/10/2017
Actual
Date of last data collection
Anticipated
13/11/2017
Actual
Sample size
Target
352
Accrual to date
Final
Recruitment outside Australia
Country [1] 8347 0
Indonesia
State/province [1] 8347 0
Papua and Bengkulu

Funding & Sponsors
Funding source category [1] 294780 0
Government body
Name [1] 294780 0
Ministry of Health of Indonesia
Country [1] 294780 0
Indonesia
Primary sponsor type
Government body
Name
Ministry of Health of Indonesia
Address
Jl Percetakan Negara no 29
Rawasari, Jakarta Pusat 10560
Country
Indonesia
Secondary sponsor category [1] 293626 0
None
Name [1] 293626 0
None
Address [1] 293626 0
None
Country [1] 293626 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296187 0
WHO ERC
Ethics committee address [1] 296187 0
20 Av. Appia,
1211 Geneva 27
Ethics committee country [1] 296187 0
Switzerland
Date submitted for ethics approval [1] 296187 0
14/07/2016
Approval date [1] 296187 0
19/10/2016
Ethics approval number [1] 296187 0
ERC.0002801

Summary
Brief summary
Title: Efficacy and safety of dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum and Plasmodium vivax in 2 sentinel sites in Indonesia.
Purpose: To assess the efficacy of the current first treatment policy
Objective: To assess the efficacy and safety of dihydroartemisinin-piperaquine for the treatment of uncomplicated P. falciparum and P. vivax malaria infections.
Study Sites: Papua Province and Bengkulu Province.
Study Period: December 2016 to November 2017.
Study Design: One arm prospective study.
Patient population: Febrile patients aged between one year to 65 years old, with confirmed uncomplicated P. falciparum or P. vivax infection. Young female of child bearing age (between 12-17 years) will be excluded due to culturally sensitive reasons.
Sample Size: A total of 120 patients (60 with P. falciparum and 60 with P. vivax malaria) will be enrolled in each site.
Treatment(s) and follow-up: DHA-PIP (containing 40 mg dihydroartemisinin and 320 mg piperaquine) tablets will be administered once a day for 3 days, administered as a weight per dose regimen of 2.25 and 18 mg/kg of dihydroartemisinin and piperaquine. Clinical and parasitological parameters will be monitored over a 42-day follow-up period to evaluate drug efficacy.
Primary endpoints: The proportion of patients with early treatment failure, late clinical failure, late parasitological failure or an adequate clinical and parasitological response as indicators of efficacy. Recrudescence will be distinguished from re-infection by polymerase chain reaction (PCR) analysis.
Secondary endpoints: The frequency and nature of adverse events.
Optional exploratory endpoints:
1. to determine the polymorphism of molecular markers for artemisinin resistance (K13).
2. to determine the blood concentration of piperaquine.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69926 0
Prof Din Syafruddin
Address 69926 0
Institution: Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, Jakarta 10430, Indonesia
Country 69926 0
Indonesia
Phone 69926 0
+62 21 3917131
Fax 69926 0
Email 69926 0
[email protected]
Contact person for public queries
Name 69927 0
Din Syafruddin
Address 69927 0
Institution: Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, Jakarta 10430, Indonesia
Country 69927 0
Indonesia
Phone 69927 0
+62 21 3917131
Fax 69927 0
Email 69927 0
[email protected]
Contact person for scientific queries
Name 69928 0
Din Syafruddin
Address 69928 0
Institution: Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, Jakarta 10430, Indonesia
Country 69928 0
Indonesia
Phone 69928 0
+62 21 3917131
Fax 69928 0
Email 69928 0
[email protected]

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