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Trial registered on ANZCTR


Registration number
ACTRN12617000276358
Ethics application status
Approved
Date submitted
7/02/2017
Date registered
22/02/2017
Date last updated
22/02/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether+lumefantrine & dihydroartemisinin+piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel site in Sudan
Scientific title
Efficacy and safety of artemether+lumefantrine & dihydroartemisinin+piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel site in Sudan
Secondary ID [1] 291097 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 301913 0
Condition category
Condition code
Infection 301575 301575 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 (given twice a day for 3 days) and dihydroartemisinin+piperaquine (given daily for 3 days) for the treatment of uncomplicated P. falciparum infection. Doses of artemether-lumefantrine (20/120) will be administered according to the recommended weight bands as follows: 1 tablet to those weighing 5 to 14kg; 2 tablets for 15 to 24 kg;3 tablets for 25 to34 kg and 4 tablets for equal or greater than 35 kg. For dihydroartemisinin+piperaquine, 4 mg/kg DHA and 18 mg/kg piperaquine once a day for 3 days. The treatment will be given in tablets by oral under direct supervision. Eligible subjects will be treated for three days and followed up for 28 days for artemether+lumefantrine or dihydroartemisinin+pipearquine for 42 days..
Intervention code [1] 297086 0
Treatment: Drugs
Comparator / control treatment
No control group. It is one arm study. Patients will be enrolled sequentially for the two drugs.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300982 0
Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure) for each drug.. This is a composite primary outcome.

Enrolled patients will be assessed for parasitological (using microscopy) and clinical responses and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 300982 0
Primary outcome (treatment failures) will be assessed on days 1, 3, 7, 14, 21, 28 for artemether+lumefantrine and days 1, 3, 7, 14, 21, 28, 35 and 42 for dihydroartemisinin+piperaquine
Secondary outcome [1] 331328 0
Percent of adverse events.
Known adverse events of Dihydroartemisinin+Piperaquine are asthenia, cough, diarrhoea, fever, loss of appetite, nausea, vomiting.
Adverse events of artemether-lumefantrine include abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.


Patients or parents/guardians of children enrolled in the study 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] 331328 0
Secondary outcome (adverse events) will be assessed on days 1, 2, 3, 7, 14, 21 and 28 for artemether+lumefantrine or days 1, 2, 3, 7, 14, 21, 28, 35, 42 for dihydroartemisinin+piperaquine.
Secondary outcome [2] 331329 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] 331329 0
At day 0 (prior to initiation of the treatment.

Eligibility
Key inclusion criteria
1. age above six months with the exception of 12-17 years old female minors and unmarried females above 18 years and above;
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 1000-100,000/microL 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; and
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 age of majority years; and
9. Consent for pregnancy testing from married female of 18 years and above.
Minimum age
6 Months
Maximum age
60 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 who has a mid-upper arm circumference below 110 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.
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)
As this a single arm study, no concealment.
Patients aged between 6 month and 60 years with uncomplicated malaria who meet the study inclusion criteria will be enrolled, treated on site with artemether+lumefantrive of dihydroartemisinin+piperaquine and monitored for 28 and 42 days, respectively. 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)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
None
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Minimum sample size
As the treatment failure rate to artemether+lumefantrine and dihydroartemisin+piperaquine in the area is 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients must be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day (for artemether+lumefantrine) or 42 (for dihydroartemisinin+piperaquine) follow-up period, 88 patients should be included in the study per SITE.

Analysis of data
The WHO Excel software programs last version will be used for data management and analysis. 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 28 (for artemether+lumefantrine) or 42 (for dihydroartemisinin+piperaquine), PCR-uncorrected and PCR-corrected; and
the proportion of early treatment failure, late clinical failure, late parasitological failure and adequate clinical and parasitological response at day 28 (for artemether+lumefantrine) or 42 (for dihydroartemisinin+piperaquine), with 95% confidence intervals, PCR-uncorrected and PCR-corrected.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
16/12/2016
Date of last participant enrolment
Anticipated
23/03/2017
Actual
Date of last data collection
Anticipated
4/05/2017
Actual
Sample size
Target
440
Accrual to date
Final
Recruitment outside Australia
Country [1] 8632 0
Sudan
State/province [1] 8632 0
Gadaref, Sinnar, Kassala, Darfur

Funding & Sponsors
Funding source category [1] 295537 0
Government body
Name [1] 295537 0
Fderal Minsitry of Health
Country [1] 295537 0
Sudan
Primary sponsor type
Government body
Name
Federal Ministry of Health
Address
National Malaria control programme
P.O. Box 1204
Khartoum, SUDAN
Country
Sudan
Secondary sponsor category [1] 294355 0
None
Name [1] 294355 0
Nil
Address [1] 294355 0
Nil
Country [1] 294355 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296858 0
WHO ERC
Ethics committee address [1] 296858 0
World Health Organization
20 Av. Appia,
1211 Geneva 27 Switzerland
Ethics committee country [1] 296858 0
Switzerland
Date submitted for ethics approval [1] 296858 0
10/10/2016
Approval date [1] 296858 0
19/01/2017
Ethics approval number [1] 296858 0
ERC.0002829

Summary
Brief summary
Title: Efficacy and safety of artemether+lumefantrine and dihydroartemisinin+piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel sites in Sudan
Purpose: To assess the efficacy and safety of the current second line treatment policy as well as a new antimalarial drug to support updating the national policy;
Objective: To assess the efficacy and safety of artemether+lumefantrine and dihydroartemisin+piperaquine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Geneina and Kerink, (West Dafur), Sinnar, Gadaref, and Kassala.
Study Period: December 2016 to April 2017.
Study Design: One arm prospective study.
Patient population: Febrile patients aged six months with confirmed uncomplicated P. falciparum infection. Female minors aged 12-17 years and unmarried females aged 18 years and above will be excluded as subjecting them to pregnancy testing is unacceptable according to the local customs and cultures.
Sample Size: A total of 88 patients will be enrolled in each site
Treatment(s) and follow-up: artemether (20mg)/lumefantrine (120mg) of six-dose course over 3 days according to weight bands (1 tab: 5 to 14kg, 2 tabs: 15 to 24kg, 3 tabs: 25 to 34kg and 4 tabs: greater than or equal to 35kg) or Dihydroartemisin/pipepraquine (4mg/kg bw dihydroartemisin and 18mg/kg bw piperaquine once a day for three days. Clinical and parasitological parameters will be monitored over a 28 days (for artemether+lumefantrine) or 42 days (for dihydroartemisin+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.
Secondary endpoints:
1. The frequency and nature of adverse events
2. To determine the molecular markers for artemisinin (K13) resistance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72246 0
Dr Mariam Adam Babiker
Address 72246 0
National Malaria control programme
P.O. Box 1204
Khartoum, SUDAN
Country 72246 0
Sudan
Phone 72246 0
+249915202560
Fax 72246 0
Email 72246 0
[email protected]
Contact person for public queries
Name 72247 0
Mariam Adam Babiker
Address 72247 0
National Malaria control programme
P.O. Box 1204
Khartoum, SUDAN
Country 72247 0
Sudan
Phone 72247 0
+249915202560
Fax 72247 0
Email 72247 0
[email protected]
Contact person for scientific queries
Name 72248 0
Mariam Adam Babiker
Address 72248 0
National Malaria control programme
P.O. Box 1204
Khartoum, SUDAN
Country 72248 0
Sudan
Phone 72248 0
+249915202560
Fax 72248 0
Email 72248 0
[email protected]

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