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Trial registered on ANZCTR


Registration number
ACTRN12616001478404
Ethics application status
Approved
Date submitted
22/08/2016
Date registered
24/10/2016
Date last updated
2/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy and safety of artemether-lumefantrine (AL) combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in 4 Tribal dominating states in India: Madhya Pradesh, Maharashtra, Chhattisgarh and Odisha
Scientific title
Efficacy and safety of artemether-lumefantrine (AL) combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in 4 Tribal dominating states in India: Madhya Pradesh, Maharashtra, Chhattisgarh and Odisha
Secondary ID [1] 289980 0
None
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record
Nil

Health condition
Health condition(s) or problem(s) studied:
Malaria 299986 0
Condition category
Condition code
Infection 299879 299879 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 artemether+120mg lemefantrine given (twice a day for 3 days) for the treatment of uncomplicated P. falciparum infection. Doses 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. The treatment will be given in tablets by oral. Eligible subjects will be treated for three days and followed up for 28 days. The twice daily doses of the study medicine will be administered under direct supervision.
Intervention code [1] 295675 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 299356 0
Percentage of treatment failures (early treatment failure + late clinical failure + late parasitological failure). 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 WHO protocol 2009.
Timepoint [1] 299356 0
Primary outcome (treatment failures) will be assessed on Days 1, 3, 7, 14, 21, 28 following initiation of treatment.
Secondary outcome [1] 326912 0
Percentage of adverse event will be documented.

Known adverse events of artemether+lumefantrine are 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] 326912 0
Secondary outcome (adverse events) will be assessed on Days 1, 2, 3, 7, 14, 21, 28 following initiation of treatment.
Secondary outcome [2] 326913 0
Prevalence of artemisinin resistance molecular markers (K13) among the study patients.

Parasite DNA extracted from the dried blood spots will be analyzed by PCR and sequencing for the presence of mutations of K13 (molecular marker for artemisinin resistance).
Timepoint [2] 326913 0
At day 0 (prior to initiation of the treatment).

Eligibility
Key inclusion criteria
1. age over 6 months to 60 years old
2. mono-infection with P. falciparum detected by microscopy;
3. parasitaemia of 500–100,000/micro liter asexual forms;
4. presence of axillary or tympanic temperature greater than or equal 37.5 degrees 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 18 years;
8. informed assent from any minor participant aged from 12 years to less than 18 years; and
9. consent for pregnancy testing from female of child-bearing potential 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 aged 6-60 months whose weight-for-height is below –3 z-score, has symmetrical oedema involving at least the feet or has a mid-upper arm circumference <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);
8. a positive pregnancy test or breastfeeding;
9. unable to or unwilling to take a pregnancy test or to use contraception for women of child-bearing age and who are sexually active; and
10. females minors of 12 to less than 18 years old.

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 falciparum malaria, who meet the study inclusion criteria will be enrolled, treated on site with artemether-lumefantrine and monitored for 28 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)
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
The treatment failure rate to artemether-lumefantrine in the area is assumed 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be required. With a 20% increase to allow loss to follow-up and withdrawals during the 28 day follow-up period, 88 patients should be included in the study per site.

WHO Excel programme and SPSS for windows 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, 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
Completed
Date of first participant enrolment
Anticipated
15/11/2016
Actual
1/03/2017
Date of last participant enrolment
Anticipated
31/07/2017
Actual
1/12/2017
Date of last data collection
Anticipated
31/08/2017
Actual
31/01/2018
Sample size
Target
352
Accrual to date
Final
376
Recruitment outside Australia
Country [1] 8117 0
India
State/province [1] 8117 0
Madhya Pradesh, Maharshtra, Chhattisgarh and Odisha

Funding & Sponsors
Funding source category [1] 294351 0
Government body
Name [1] 294351 0
Indian Council of Medical Research, (ICMR) Ministry of Health & Family welfare.
Country [1] 294351 0
India
Primary sponsor type
Government body
Name
Indian Council of Medical Research, (ICMR) Ministry of Health & Family welfare.
Address
P.O. Box No. 4911
Ansari Nagar, New Delhi – 110029
Country
India
Secondary sponsor category [1] 293189 0
None
Name [1] 293189 0
Address [1] 293189 0
Country [1] 293189 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295768 0
WHO ethics and research committee
Ethics committee address [1] 295768 0
20 Av. Appia,
1211 Geneva 27
Ethics committee country [1] 295768 0
Switzerland
Date submitted for ethics approval [1] 295768 0
19/05/2016
Approval date [1] 295768 0
15/07/2016
Ethics approval number [1] 295768 0
ERC.0002757

Summary
Brief summary
Title: Efficacy and safety of artemether-lumefantrine (AL) combination therapy for the treatment of uncomplicated Plasmodium falciparum malaria in 4 Tribal dominating states in India: Madhya Pradesh, Maharashtra, Chhattisgarh and Odisha.

The objective of the study is assess the efficacy and safety artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria infections. The study will be conducted in 4 sentinel sites (Balaghat district, Madhya Pradesh; Gondia district, Maharashtra; Bastar district, Chhattisgarh; and Koraput district, Odisha). The study will be started in Sept 2016 and will be completed in August 2017. It is a one arm prospective study.

The study population is febrile patients aged between 6 months and 60 years, inclusive, 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. A target sample of 88 patients will be enrolled in each site.

Artemether-lumefantrine (twice daily dose for 3 days) will be given under direct supervision. Clinical and parasitological parameters will be monitored over a 28-day follow-up period to evaluate drug efficacy and safety.

As primary outcomes, 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. The secondary endpoints include the frequency of adverse events and frequency of molecular markers for artemisinin resistance (K13).
Trial website
Nil
Trial related presentations / publications
Nil
Public notes
Nil

Contacts
Principal investigator
Name 68422 0
Dr Neeru Singh
Address 68422 0
National Institute for Research in Tribal Health, Jabalpur, Madhya Pradesh (NIRTH, ICMR)
NIRTH (ICMR) Campus, Nagpur Road, Garha
Jabalpur - 482003, Madhya Pradesh
Country 68422 0
India
Phone 68422 0
+91761-2370800
Fax 68422 0
+91761-2672835
Email 68422 0
[email protected]
Contact person for public queries
Name 68423 0
Neeru Singh
Address 68423 0
National Institute for Research in Tribal Health, Jabalpur, Madhya Pradesh (NIRTH, ICMR)
NIRTH (ICMR) Campus, Nagpur Road, Garha
Jabalpur - 482003, Madhya Pradesh
Country 68423 0
India
Phone 68423 0
+91761-2370800
Fax 68423 0
+91761-2672835
Email 68423 0
[email protected]
Contact person for scientific queries
Name 68424 0
Neeru Singh
Address 68424 0
National Institute for Research in Tribal Health, Jabalpur, Madhya Pradesh (NIRTH, ICMR)
NIRTH (ICMR) Campus, Nagpur Road, Garha
Jabalpur - 482003, Madhya Pradesh
Country 68424 0
India
Phone 68424 0
+91761-2370800
Fax 68424 0
+91761-2672835
Email 68424 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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