Contact information
Type
Scientific
Primary contact
Prof Philip Rosenthal
ORCID ID
Contact details
San Francisco General Hopital
1001 Potrero Avenue
Building 30
Room 421
San Francisco
94110
United States of America
+1 415 206 8845
rosnthl@itsa.ucsf.edu
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N/A
Study information
Scientific title
Acronym
Study hypothesis
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
Not provided at time of registration
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Other
Trial type
Treatment
Patient information sheet
Condition
Uncomplicated falciparum malaria
Intervention
Amodiaquine plus sulfadoxine-pyrimethamine versus amodiaquine plus artesunate versus artemether-lumefantrine
Intervention type
Drug
Phase
Not Specified
Drug names
Amodiaquine, sulfadoxine-pyrimethamine, artesunate, artemether-lumefantrine
Primary outcome measure
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.
Secondary outcome measures
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)
Overall trial start date
01/11/2004
Overall trial end date
20/04/2007
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Child
Gender
Both
Target number of participants
601
Participant 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
Recruitment start date
01/11/2004
Recruitment end date
20/04/2007
Locations
Countries of recruitment
Uganda
Trial participating centre
San Francisco General Hopital
San Francisco
94110
United States of America
Sponsor information
Organisation
National Institutes of Health (NIH) - National Institute of Allergy and Infectious Diseases (NIAID) (USA)
Sponsor details
c/o Philip E. Coyne
Jr.
MD
MSPH
Program Officer
Parasitology and International Programs Branch
Division of Microbiology and Infectious Diseases
NIAID
6610 Rockledge Dr.
Room 5093
MSC 6604
Bethesda
20892-6603
United States of America
Sponsor type
Government
Website
Funders
Funder type
Government
Funder name
The National Institute of Allergy and Infectious Diseases (NIAID) (USA)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
1. 2007 results in http://www.ncbi.nlm.nih.gov/pubmed/17519410
2. 2010 results in http://www.ncbi.nlm.nih.gov/pubmed/20689585
Publication citations
-
Results
Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, Dokomajilar C, Kamya MR, Rosenthal PJ, Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial., JAMA, 2007, 297, 20, 2210-2219, doi: 10.1001/jama.297.20.2210.
-
Results
Clark TD, Njama-Meya D, Nzarubara B, Maiteki-Sebuguzi C, Greenhouse B, Staedke SG, Kamya MR, Dorsey G, Rosenthal PJ, Incidence of malaria and efficacy of combination antimalarial therapies over 4 years in an urban cohort of Ugandan children., PLoS ONE, 2010, 5, 7, e11759, doi: 10.1371/journal.pone.0011759.