ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618001223224

Ethics application status

Approved

Date submitted

16/07/2018

Date registered

20/07/2018

Date last updated

5/11/2019

Date data sharing statement initially provided

5/11/2019

Date results information initially provided

5/11/2019

Type of registration

Retrospectively registered

Titles & IDs

Public title

Efficacy and safety of Artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in five sites in 2017, Eritrea

Scientific title

Efficacy and safety of Artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in five sites in 2017, Eritrea

Secondary ID [1]

None

Universal Trial Number (UTN)

None

Trial acronym

None

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Malaria

Condition category

Condition code

Infection

Studies of infection and infectious agents

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The objective of the study was to assess the efficacy and safety of artemether+lumefantrine (20 mg/120 mg in each tablet) twice daily doses for three days for the treatment of uncomplicated falciparum malaria. The dose was 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. All treatments will be taken orally under direct supervision by the health worker and will be followed up for 28 days.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No comparator. It was single arm prospective study.

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Percent of treatment failures (early treatment failure + late clinical failure +late parasitological failure). This was composite primary outcome.

Timepoint [1]

Days 0, 1, 2, 3, 7, 14, 21, 28 (primary time point)

Secondary outcome [1]

Percent of adverse event following treatment of artemether+lumefantrine.
The known adverse events of artemetherr+lumefantrine are abdominal pain, asthenia, cough, diarrhoea, dizziness, fever, headache, joint and muscle pain, loss of appetite, rush, nausea, vomiting.
Patients or Parents/guardians were asked routinely about previous symptoms and about symptoms that had emerged since the previous follow-up visit. When clinically indicated, patients was evaluated and treated appropriately. All adverse events was recorded on the case report form.

Timepoint [1]

Days 0, 1, 2, 3, 7, 14, 21, 28

Secondary outcome [2]

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). The sample analysis is in process

Timepoint [2]

Day 0

Eligibility

Key inclusion criteria

1. age 6 months and above;
2. mono-infection with P. falciparum confirmed by positive blood smear (i.e. no mixed infection);
3. parasitaemia of 250-200 000 asexual forms per microliter;
4. presence of axillary temperature greater or equal to 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 18;
8. informed assent from any minor participant aged from 12 to 18 years; and
9. consent for pregnancy testing from female of child-bearing age (defined as age above 12 years and sexually active) and from their parent or guardian if under the age of 18 years.

Minimum age

6 Months

Maximum age

70 Years

Sex

Both males and females

Can healthy volunteers participate?

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. weight under 5 kg;
3. haemoglobin below 8 g per deciliter;
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 who has a mid-upper arm circumference < 115 mm).
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 or breastfeeding; and
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)

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
As the treatment failure rate to artemether+lumefantrine in the areas was estimated to 5%. At a confidence level of 95% and a precision around the estimate of 5%, a minimum of 73 patients will be included. With a 20% increase to allow loss to follow-up and withdrawals during the 28-day follow-up period, 88 patients per site will be included in the study.

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. Patients was 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

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Participant recruitment difficulties

Date of first participant enrolment

Anticipated

Actual

15/09/2017

Date of last participant enrolment

Anticipated

Actual

1/01/2018

Date of last data collection

Anticipated

Actual

28/03/2018

Sample size

Target

440

Accrual to date

Final

212

Recruitment outside Australia

Country [1]

Eritrea

State/province [1]

Gash Barka and Semenawi Keyh Bahri

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Ministry of Health, Eritrea

Address [1]

P.O. Box 212 Asmara, Eritrea

Country [1]

Eritrea

Primary sponsor type

Government body

Name

Ministry of Health, Eritrea

Address

P.O. Box 212 Asmara, Eritrea

Country

Eritrea

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health Research Proposal Review and Ethical Clearance

Ethics committee address [1]

Ararib 174, Asmara,

Ethics committee country [1]

Eritrea

Date submitted for ethics approval [1]

25/05/2017

Approval date [1]

06/06/2017

Ethics approval number [1]

HRPREC_6/6/2017

Summary

Brief summary

Title: Efficacy and safety of Artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Eritrea.
Purpose: To assess the efficacy a new antimalarial drug to support updating the national policy in introducing the drug as a second line treatment for uncomplicated malaria.
Objective: To assess the efficacy and safety of Artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria infections.
Study Sites: Tokombia, Shambuko, Goluj, Akordat and Ghindae.
Study Period: 4 months (September-December, 2017).
Study Design: This surveillance study is a one-arm 28-day in-vivo prospective study.
Patient population: Febrile patients aged between 6 months and above, with confirmed uncomplicated P. falciparum infection.
Sample Size: We will enrol 88 patients per site to reach a sample size of 440.
Treatment(s) and follow-up: Clinical and parasitological parameters was monitored over a 28-day follow-up period to evaluate drug efficacy of Artemther-lumefantrine (artemether 20 mg/lumeanine 120mg) twice daily for 3 days.
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 was distinguished from re-infection by polymerase chain reaction (PCR) analysis.
Secondary endpoints: The frequency and nature of adverse events.
Optional exploratory endpoints: to determine the polymorphism of molecular markers for artemisinin resistance

Trial website

Trial related presentations / publications

Public notes

The efficacy of the recommended antimalarial medicines are conducted at the peak of malaria season of the year. Eritrea targeted 73 cases with interpretable outcome. The study was conducted at the transmission season of Sept 2017 to December 2017. It was pushed up to March 2018. The study did not reach the target samples except one site. The reason for low sample size that malaria burden has been reduced in Eritrea which is now targeting elimination. With this back ground the study was completed not stopped.

Contacts

Principal investigator

Name

Dr Araia Berhane

Address

Ministry of Health,
P. O. Box 212 Asmara

Country

Eritrea

Phone

+2911117041

Fax

[email protected]

Contact person for public queries

Name

Dr Araia Berhane

Address

Ministry of Health,
P. O. Box 212 Asmara

Country

Eritrea

Phone

+2911117041

Fax

[email protected]

Contact person for scientific queries

Name

Dr Araia Berhane

Address

Ministry of Health,
P. O. Box 212 Asmara

Country

Eritrea

Phone

+2911117041

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea	2023	https://doi.org/10.1056/nejmoa2210956

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically