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Trial registered on ANZCTR


Registration number
ACTRN12615000159550
Ethics application status
Approved
Date submitted
5/12/2014
Date registered
18/02/2015
Date last updated
3/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
In vivo efficacy and safety of artemether/lumefantrine and dihydroartemisinin/piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in public health facilities in Tanzania
Scientific title
In vivo efficacy and safety of artemether/lumefantrine and dihydroartemisinin/piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in public health facilities in Tanzania
Secondary ID [1] 285793 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 293685 0
Condition category
Condition code
Infection 293984 293984 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 artemether/lumefantrine (20mg/120mg: 3 day regimen of twice daily dose of 1 tablet for 5-14 kg; 2 tablets for 15-24 Kg; 3 tablets for 25-34 and 4 tablets for gretaer than or equal to 35 kg) and (ii) and dihydroartemisinin/piperaquine (4 mg/kg dihydroartemisinin and 18 mg/kg piperaquine once a day for 3 days) for the treatment of uncomplicated P. falciparum infection. The treatment will be taken orally under direct supervision by the health worker. Eligibile subjects will be treated for three days and followed up for 28 days (artemether/lumefantrine or 42 days (dihydroartemisinin/piperaquine).
Intervention code [1] 290758 0
Treatment: Drugs
Comparator / control treatment
N/A
This is a surveillance study of 2 x one-arm.
The study groups in both arms will be recruited sequentially (the first 88 patients will be enrolled in artemether+lumefantrine arm and the subsequent 88 cases will be enrolled in the DHA+PQP) and followed up prospectively.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293759 0
For artemether+lumefantrine:

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 (using microscopy), clinical responses during the 28 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 293759 0
At day 28 following initiation of artemether+lumefantrine treatment.
Primary outcome [2] 294006 0
For dihydroartemisinin/piperaquine:
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 (using microscopy), clinical responses during the 42 days follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [2] 294006 0
At day 42 following initiation of dihydroartemisinin/piperaquine treatment
Secondary outcome [1] 311769 0
Percent of adverse event will be documented. The known adverse events of artemether/lumefantrine are abdominal discomfort, nausea, headache and dizziness.

Parents or guardians of all enrolled patients 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] 311769 0
At day 28 following initiation of treatment
Secondary outcome [2] 312342 0
Percent of adverse event will be documented. The known adverse events of dihydroartemisinin/piperaquine are abdominal discomfort, nausea, headache and dizziness.

Parents or guardians of all enrolled patients 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 [2] 312342 0
At day 42 following initiation of treatment
Secondary outcome [3] 312343 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 [3] 312343 0
At Day 0 (prior initiation of treatment)

Eligibility
Key inclusion criteria
1. age six months and above, excluding female minors 12-17 years old
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000–200,000/microliter asexual forms;
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;
7.informed consent from the patient or from a parent or guardian in the case of children
8. informed assent from any minor participant aged from 12 to 17 years age of majority years; and
9. consent for pregnancy testing from female of child-bearing potential and are 18 years and above.
Minimum age
6 Months
Maximum age
No limit
Gender
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 belo 115 mm)
5. presence of febrile conditions due to diseases other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhea 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);
8. a positive pregnancy test or breastfeeding; and
9. unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age and aged 18 years and above 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)
Patients aged 6 month and above with uncomplicated malaria who meet the study inclusion criteria will be enrolled, treated on site with either artemether/lumefantrine or dihydroartemisinin/piperaquine and monitored for
42 days. The follow-up will consist of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
This surveillance study is 2 x one-arm prospective evaluation of clinical and parasitological responses to directly observed treatment for uncomplicated malaria with either
artemether/lumefantrine or dihydroartemisinin/piperaquine.

The study groups in both arms will be recruited sequentially (the first 88 patients will be enrolled in artemether+lumefantrine arm and the subsequent 88 cases will be enrolled in the dihydroartemisinin/piperaquine) and followed up prospectively.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
This is a cohort prospective study in sequential enrollment. Two artemisinin-based combinations will be tested: artemether+lumefantrine in one arm and dihydroartemisinin/piperaquine in another arm.

Patients will be enrolled first in the artemether+lumefantrine arm study and when the sample size of 88 is reached, the subsequent patients will be enrolled in the dihydroartemisinin/piperaquine arm. This will be a sequential enrollment.

Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Currently the treatment failure rate to artemether+lumefantrine or dihydroarteminin/piperaquine in the study area is less than 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included per drug test. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day (rtemether+lumefantrine) or 42-day ( dihydroarteminin/piperaquine) follow-up period, 88 patients should be included in the study per treatment arm per site.

Excel WHO tailored database will be used for data management and analysis. Data will be analysed by two methods: the Kaplan-Meier method and per-protocol analysis.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 6510 0
Tanzania, United Republic Of
State/province [1] 6510 0
Cost and Mbeya regions

Funding & Sponsors
Funding source category [1] 290356 0
Government body
Name [1] 290356 0
Ifakara Health Institute
Address [1] 290356 0
P.O. Box 78373, Plot 463, Kiko Ave, Mikocheni, Dar es Salaam
Country [1] 290356 0
Tanzania, United Republic Of
Primary sponsor type
Government body
Name
Ifakara health Institute
Address
P.O. Box 78373, Plot 463, Kiko Ave, Mikocheni, Dar es Salaam
Country
Tanzania, United Republic Of
Secondary sponsor category [1] 289080 0
None
Name [1] 289080 0
Nil
Address [1] 289080 0
Nil
Country [1] 289080 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292060 0
Institutional Review Board
Ethics committee address [1] 292060 0
P.O. Box 78373 Dar Es Salaam, Tanzania
Ethics committee country [1] 292060 0
Tanzania, United Republic Of
Date submitted for ethics approval [1] 292060 0
Approval date [1] 292060 0
23/06/2014
Ethics approval number [1] 292060 0
IHI/IRB/No:13-2014
Ethics committee name [2] 292061 0
WHO ERC
Ethics committee address [2] 292061 0
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [2] 292061 0
Switzerland
Date submitted for ethics approval [2] 292061 0
Approval date [2] 292061 0
17/11/2014
Ethics approval number [2] 292061 0
RPC681

Summary
Brief summary
Title: Invivo efficacy and safety of artemether/lumefantrine and dihydroartemisinin/piperaquine [DHA/PQP] for the treatment of uncomplicated Plasmodium falciparum malaria in public health facilities in Tanzania.

Purpose: To assess the efficacy and safety of the current first and second line treatments to support updating of the national malaria treatment policy.

Objective: To assess the efficacy and safety of artemether/lumefantrine and DHA/PQP for the treatment of uncomplicated P. falciparum malaria infections.

Study Sites: Ikwiriri and Kibiti in Rufiji district and Ipinda in Kyela district.

Study Period: The study will be conducted between December 2014 to June 2015.

Study Design: Two cohorts’ prospective study in sequential enrollments.

Patient population: Febrile patients aged 6 months and above, excluding female minors 12-17 years, with confirmed uncomplicated P. falciparum infection will be enrolled.

Sample Size: A total of 88 patients per treatment arm in each site will be enrolled.

Treatments and follow-up: artemether/lumefantrine given twice daily for three days and dihydroartemisinin/piperaquine given once daily for 3 days. Clinical and parasitological parameters will be monitored over a 28-day (artemether/lumefantrine ) or 42-day (dihydroartemisinin/piperaquine) follow-up period to evaluate drug efficacy and safety.

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. Day 3 malaria positivity rate will determined.

Secondary endpoints: The frequency and nature of adverse events

Optional exploratory endpoints:
to determine the polymorphism of molecular markers for artemisinin resistance.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 53294 0
Dr Abdunoor Mulokozi Kabanywanyi
Address 53294 0
Ifakara Health Institute
P.O. Box 78373, Plot 463, Kiko Ave, Mikocheni, Dar es Salaam
Country 53294 0
Tanzania, United Republic Of
Phone 53294 0
+255 222 774 714
Fax 53294 0
Email 53294 0
amulokozi@ihi.or.tz
Contact person for public queries
Name 53295 0
Dr Abdunoor Mulokozi Kabanywanyi
Address 53295 0
Ifakara Health Institute
P.O. Box 78373, Plot 463, Kiko Ave, Mikocheni, Dar es Salaam
Country 53295 0
Tanzania, United Republic Of
Phone 53295 0
+255 222 774 714
Fax 53295 0
Email 53295 0
amulokozi@ihi.or.tz
Contact person for scientific queries
Name 53296 0
Dr Abdunoor Mulokozi Kabanywanyi
Address 53296 0
Ifakara Health Institute
P.O. Box 78373, Plot 463, Kiko Ave, Mikocheni, Dar es Salaam
Country 53296 0
Tanzania, United Republic Of
Phone 53296 0
+255 222 774 714
Fax 53296 0
Email 53296 0
amulokozi@ihi.or.tz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary