The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618001800213
Ethics application status
Approved
Date submitted
6/10/2018
Date registered
5/11/2018
Date last updated
5/11/2018
Date data sharing statement initially provided
5/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of Artemether-Lumefantrine and dihydroartimisininne-pipraquine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel site in Sudan
Scientific title
Efficacy and safety of Artemether-Lumefantrine and dihydroartimisininne-pipraquine for the treatment of uncomplicated Plasmodium falciparum malaria in different sentinel site in Sudan
Secondary ID [1] 296273 0
None
Universal Trial Number (UTN)
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 309947 0
Condition category
Condition code
Infection 308721 308721 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study aims to evaluate the efficacy and safety of artemether-lumefantrine (20 mg/120 mg in each table) twice daily doses for three days in one site and dihydroartemisinin-piperaquine (40mg/320 mg) once daily for three days in three sites for the treatment of uncomplicated falciparum. For artemether-lumefantrine, the dose regimens will be calculated based on the recommended weight bands as follows: 1 tablet to those weighing 5 to 14 kg; 2 tablets for 15 to 24 kg; 3 tablets for 25 to 34 kg and 4 tablets for equal or greater than 35 kg. For dihydroartemisinin-piperaquine, 4mg/kg body weight (bw) dihydroartemisinin+18mg/kg bw piperaquine will be given. All treatments will be taken orally under direct supervision by the health worker. The patients treated with artemether-lumefantrine will be followedup for 28 days and those treated with dihydroartemisinin-piperaquine will be followe-up for 42 days.
Intervention code [1] 312607 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307701 0
Percent of treatment failures (early treatment failure + late clinical failure + late parasitological failure). This is composite primary outcome.

Study patients will be assessed for parasitological and clinical responses during the 28 days (artemether-lumefantrine) or 42 days (dihydroartemisinin-piperaquine) follow-up and treatment outcomes will be classified according to the latest WHO protocol.
Timepoint [1] 307701 0
Days 0, 1, 2, 3, 7, 14, 21 and 28 for artemether-lumefantrine
Days 0, 1, 2, 3, 7, 14, 21, 28,35 and 42 for dihydroartemisinin-piperaquine
Primary outcome [2] 307702 0
Percent of adverse event following treatment of artemether-lumefantrine or dihydroartesmisinin-piperaquine will be investigated.
The known adverse events of atemether-lumefantrine are abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting. Those for dihydroartemisinin include asthenia, cough, diarrhoea, fever, loss of appetite, nausea, vomiting.

Patients or care takers of children will be asked on each visit about previous symptoms that have emerged since the previous follow-up visit. When clinically indicated, patients will be assessed and treated appropriately. All adverse events will be recorded on the case report form.
Timepoint [2] 307702 0
Days 0, 1, 2, 3, 7, 14, 21 and 28 artemether-lumefantrine
Days 0, 1, 2, 3, 7, 14, 21, 28, 35 and 42 artemether-lumefantrine
Secondary outcome [1] 352583 0
Prevalence of mutations in k13 gene associated with artemisinin resistance.

Parasite DNA extracted from dried blood spots will be analyzed by PCR and sequenced for the presence of mutations in k13 gene (molecular marker for artemisinin resistance)
Timepoint [1] 352583 0
Day 0 (before treatment is given)
Secondary outcome [2] 352584 0
Prevalence of amplification in plasmepsin 2 gene associated with piperaquine.

Parasite DNA extracted from dried blood spots will be analyzed by PCR for variatios of plamsepsin2 copy number (molecular marker for piperaquine resistance)
Timepoint [2] 352584 0
Day 0 (at recruitment) samples

Eligibility
Key inclusion criteria
1. Age above six months excluding female minors (from 12 years) and unmarried females.
2. mono-infection with P. falciparum confirmed by positive blood smear (i.e. no mixed infection);
3. parasitaemia of 1000 to 100000 asexual parasite per microliter blood;
4. presence of axillary temperature egual or greater than 37.5 degree centigrade 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 aged less than age of majority;
8. informed assent from any minor participant aged from 12 to below below age of majority (18 years); and
9. consent for pregnancy testing from married female of child-bearing age

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 12 years or signs of severe falciparum malaria according to the definitions of WHO;
2. unmarried female in the child bearing age
3. weight under 5 kg;
4. mixed or mono-infection with another Plasmodium species detected by microscopy;
5. presence of severe malnutrition defined as a child aged between 6-60 months whose weight-for-high is below –3 z-score
6. 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);
7. regular medication, which may interfere with antimalarial pharmacokinetics;
8. history of hypersensitivity reactions or contraindications to any of the medicine(s) being tested or used as alternative treatment(s);
9. a positive pregnancy test.
10. Unable to or unwilling to take pregnancy test or to use contraception for women of child-bearing age (defined as age above 12 years and 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)
Not applicable
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 estimation
Treatment failure rate to artemether-lumefantrine and dihydroartemisinin-piperaquine in the study areas is assumed as 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be included per drug. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day (artemether-lumefantrine) or 42-day (dihydroartemisinin-piperaquine) follow-up period, 88 patients per site will be included in the study. A total sample of 352 patients is targeted.

Analysis of data
The WHO excel software programs will be used for data management and analysis. Data will be analyzed by two methods: the Kaplan-Meier method and per-protocol analysis. Subjects 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 other species. 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, 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 28, with 95% confidence intervals, PCR-uncorrected and PCR-corrected.

Recruitment
Recruitment status
Not yet recruiting
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] 20902 0
Sudan
State/province [1] 20902 0
Sennar, South Darfur, Blue Nile and Gadaref

Funding & Sponsors
Funding source category [1] 300866 0
Government body
Name [1] 300866 0
Ministry of Health
Address [1] 300866 0
Nile street, 1111 Khartoum.
Country [1] 300866 0
Sudan
Primary sponsor type
Government body
Name
Ministry of Health
Address
Nile street, 1111 Khartoum.
Country
Sudan
Secondary sponsor category [1] 300422 0
None
Name [1] 300422 0
Address [1] 300422 0
Country [1] 300422 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301641 0
WHO ERC
Ethics committee address [1] 301641 0
20 Avenue Appia,
1211 Geneva 27
Ethics committee country [1] 301641 0
Switzerland
Date submitted for ethics approval [1] 301641 0
10/09/2018
Approval date [1] 301641 0
05/10/2018
Ethics approval number [1] 301641 0
ERC.0003106

Summary
Brief summary
Title: Efficacy and safety of artmether-lumefantrine in one site and dihydroartimisinine-pipraquin in three sites for the treatment of uncomplicated Plasmodium falciparum malaria.
Purpose: To assess the efficacy of the current first and second line treatment policy.
Objective: To assess the efficacy and safety of artmether-lumefantrine and dihydroartimisinine-pipraquine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Sennar (artemether-lumefantrine), and South Darfur,
Blue Nile and Gadaref (dihydroartimisininne/pipraquine)
Study Period: October2018 to April 2019.
Study Design: It is a one arm prospective study.
Patient population: Febrile patients aged six months and above, with confirmed uncomplicated P. falciparum infection. Unmarried females in child bearing age 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 per each antimalarial drug.
Treatment(s) and follow-up: Clinical and parasitological parameters will be monitored over a 28 days for artmether/lumefantrine efficacy or 42 days for dihydroartimisinine/pipraquine 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:
Secondary endpoints: (i) The frequency and nature of adverse events and (ii) the molecular markers for artemisinin (k13) and piperaquine (plasmepsin 2) resistance.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87634 0
Dr Mariam Adam Babiker
Address 87634 0
CNCDCD, Ministry of Health
Algassar street ,Khartoum.
Country 87634 0
Sudan
Phone 87634 0
+249915202560
Fax 87634 0
Email 87634 0
mariamadam484@gmail.com
Contact person for public queries
Name 87635 0
Dr Mariam Adam Babiker
Address 87635 0
CNCDCD, Ministry of Health
Algassar street ,Khartoum.
Country 87635 0
Sudan
Phone 87635 0
+249915202560
Fax 87635 0
Email 87635 0
mariamadam484@gmail.com
Contact person for scientific queries
Name 87636 0
Dr Marian Warsame Yusuf
Address 87636 0
University of Gothenburg,
Medicinaregatan 16
405 30 Gothenburg
Country 87636 0
Sweden
Phone 87636 0
+46760525254
Fax 87636 0
Email 87636 0
dahan2004@hotmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The Sudan National Malaria Control Programme will share the individual data with WHO.
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable