Longitudinal comparison of combination antimalarial therapies in Ugandan children: evaluation of safety, tolerability and efficacy

ISRCTN	ISRCTN37517549
DOI	https://doi.org/10.1186/ISRCTN37517549
Protocol serial number	N/A
Sponsor	National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID) (USA)
Funder	The National Institute of Allergy and Infectious Diseases (NIAID) (USA)

Submission date: 16/05/2005
Registration date: 10/06/2005
Last edited: 09/08/2010

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Philip Rosenthal
Scientific

San Francisco General Hopital
1001 Potrero Avenue
Building 30, Room 421
San Francisco
94110
United States of America

Phone	+1 415 206 8845
Email	rosnthl@itsa.ucsf.edu

Study information

Primary study design	Interventional
Study design	Randomised controlled trial
Secondary study design	Randomised controlled trial
Scientific title
Study objectives	We will test the hypothesis that the malaria treatment incidence density (number of treatments for malaria per time at risk) will differ among patients randomised to our three treatment groups (amodiaquine and sulfadoxine-pyrimethamine versus amodiaquine and artesunate versus artemether-lumefantrine).
Ethics approval(s)	Not provided at time of registration
Health condition(s) or problem(s) studied	Uncomplicated falciparum malaria
Intervention	Amodiaquine plus sulfadoxine-pyrimethamine versus amodiaquine plus artesunate versus artemether-lumefantrine
Intervention type	Drug
Phase	Not Specified
Drug / device / biological / vaccine name(s)	Amodiaquine, sulfadoxine-pyrimethamine, artesunate, artemether-lumefantrine
Primary outcome measure(s)	The effect of antimalarial drug therapy can be measured both in terms of drug efficacy (risk of true treatment failure) and post-treatment prophylactic effect (risk of new infection). To best reflect the overall impact of therapy, our primary outcome measurement will be the treatment incidence density (treatments per time at risk) for each treatment arm. To eliminate the period not influenced by study drugs, treatment count will exclude the first episode. Follow-up time will be from the first episode to the end of the study. Treatment count will include both first-line treatments with study drugs and second-line treatments with quinine following study drug failure. It will be assumed that participants will not be at risk for repeat therapy for 14 days after treatment with quinine, for which resistance has not been reported, so this time will be excluded when calculating total time at risk.
Key secondary outcome measure(s)	1. Drug efficacy: We will examine the efficacy of the different treatment groups using each episode of malaria treated with a study drug as the unit of analysis. We will examine the risk for repeat treatment as a function of time. Short-term (14-day) assessments of treatment efficacy will provide a standard analysis that will be useful for comparisons with other studies. 1.1. Specific short-term outcomes to be assessed will include: 1.1.1. Clinical and parasitological outcome 1.1.2. Rates of fever and parasite clearance 1.1.3. Change in hemoglobin level from day zero to 14 1.1.4. Presence of gametocytes following treatment 1.1.5. Safety and tolerability of study medications 1.2. Long-term (beyond 14-day) outcomes will be: 1.2.1. Risk of recrudescence 1.2.2. Risk of new infection using Kaplan-Meier product limit estimates of risk at various time intervals (i.e. four, six, and eight weeks after initiation of therapy) In the analysis of long-term outcomes, molecular genotyping will be used to distinguish recrudescence (true treatment failure) from new infections. 2. Safety and tolerability: All adverse events will be catalogued based on their frequency, severity, and relationship to study medication using standardised protocols. These indices of safety and tolerability among treatment groups will be compared using each episode of malaria treated with a study drug as the unit of analysis. 3. Other long-term outcomes that will be assessed will include: 3.1. Incidence of asymptomatic parasitemia 3.2. Change in haemoglobin level over time 3.3. Perceived tolerability of study medications among subjects and care givers 3.4. Drug costs (comparison of total cost per patient)
Completion date	20/04/2007

Eligibility

Participant type(s)	Patient
Age group	Child
Lower age limit	1 Year
Upper age limit	10 Years
Sex	All
Target sample size at registration	601
Key inclusion criteria	1. Aged one to ten years 2. Agreement to come to the study clinic for any febrile episode or other illness 3. Agreement to avoid medications administered outside the study 4. Willingness of parents or guardians to provide informed consent
Key exclusion criteria	1. History (obtained from the parent/guardian) of any known serious chronic disease requiring frequent medical care (e.g. Acquired Immune Deficiency Syndrome [AIDS], sickle cell disease, malignancy) 2. Intention to move from Kampala during the follow-up period 3. History (obtained from the parent/guardian) of serious side effects to study medications or sulfa drugs 4. Weight less than 10 kg 5. Severe malnutrition defined as weight-for-height or height-for-age Z-score less than -3 6. Homozygous haemoglobin SS (sickle cell) result by haemoglobin electrophoresis 7. Life-threatening screening laboratory value in the absence of malaria: 7.1. Absolute neutrophil count: less than 250/mm^3 7.2. Hemoglobin: less than 5.0 g/dl 7.3. Platelet count: less than 25,000/mm^3 7.4. Creatinine: less than two years: more than 1.5 mg/dl, more than two years: more than 2.0 mg/dl 7.5. Alanine transaminase (ALT): more than 15.0 x Upper Limit of Normal (ULN) 7.6. Bilirubin: more than 7.5 x ULN
Date of first enrolment	01/11/2004
Date of final enrolment	20/04/2007

Locations

Countries of recruitment

Uganda
United States of America

Study participating centre

San Francisco General Hopital

San Francisco
94110
United States of America

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	23/05/2007		Yes	No
Results article	results	30/07/2010		Yes	No