Longitudinal Antimalarial Combinations in Uganda

June 3, 2020 updated by: Philip Rosenthal, University of California, San Francisco

Longitudinal Comparison of Combination Antimalarial Therapies in Ugandan Children: Evaluation of Safety, Tolerability, and Efficacy

The purpose of this study is to compare different ways of treating uncomplicated malaria in a group of Ugandan children. The study will be divided into 2 parts. Part 1 of the study will consist of 600 children, ages 1-10, living in the Mulago III Parish of Kampala. Approximately 90 children living in the same household as children from the Phase 1 portion of the study will be enrolled in Phase II of this study. Participants in Phase II of the study will receive an insecticide treated net to cover their bed. Over the course of the study, participants will be tested for malaria when they present to the clinic with a fever or illness. Participants that test positive for malaria will be given 1 of 3 possible study drug combinations. Study procedures will include physical exams and blood samples. Children will participate for about 3 years. Protocol 05-0110 is a study related to this protocol.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Malaria is one of the most important infectious diseases worldwide. New therapies are needed, and it is generally agreed that combination therapy for uncomplicated malaria offers the best opportunity for effective therapy and for the prevention of selection of resistant parasites. Phase I of this study will be a randomized, single-blinded longitudinal clinical trial, comparing the efficacies of different combination antimalarial regimens for the treatment of uncomplicated malaria in a cohort of Ugandan children. The clinical study will be linked to an epidemiological survey and molecular analyses of parasite and human genetic polymorphisms. The aims of the study will be to: compare safety, tolerability, and efficacy of combination antimalarial therapies using a longitudinal design; follow plasmodial genetic polymorphisms as longitudinal markers of antimalarial drug resistance; and evaluate the roles of host genetic polymorphisms in antimalarial drug resistance and the incidence of clinical malaria. The clinical study will recruit participants from a defined and mapped source population in the Mulago III Parish, Kawempe District in Kampala, Uganda; conduct a survey of epidemiological factors on participants; and follow clinical care and outcomes over an extended period of time. Molecular analyses of parasite and human genetic polymorphisms will evaluate the impact of parasite mutations on treatment efficacy, the effects of repeated treatments on selection for resistance-mediating genotypes, and the impact of host polymorphisms on the incidence of malaria and responses to therapy. Phase I will include a random sample of 600 Ugandan children between the ages of 1-10 years. Participants will be followed for 3 years for all routine medical care in the study clinic at Mulago Hospital. Children presenting to the study clinic with a new episode of fever will undergo standard evaluation (history, physical examination and Giemsa-stained blood smear) for the diagnosis of malaria. Participants will be randomized to one of three combination treatment regimens at the time of their first diagnosis of uncomplicated malaria. Subsequent episodes of uncomplicated malaria will be treated with each participant's assigned treatment regimen. Clinical treatment failures occurring within 14 days of diagnosis and all episodes of complicated malaria will be treated with quinine, the standard therapy for malaria after treatment failure in Uganda. Routine home visits will be made for participants not seen in the clinic after any consecutive 30-day period. Routine home visits, made every 90 days, will include review of study protocol with the participants, assessment for any outside medical care, a focused history and physical examination and routine laboratory testing. Phase II will be a randomized, open-label, longitudinal clinical trial, comparing two combination antimalarial regimens. Following the first year of follow up, recruitment will be re-opened for children belonging to the same households previously recruited to the study, for children not previously enrolled ages 1-10 years. At this time, all participants will receive an insecticide treated bed net and phase II follow up will begin. All other aspects of subject evaluation, management, and follow-up will be the same as in Phase I, except that researchers will discontinue 30 day finger sticks (subjects will still be visited if they have not been seen in the clinic for 30 days, but finger sticks for blood smears and filter paper will only be performed during clinic evaluations, when clinically indicated or if the patient has not been evaluated in the clinic over a 90 day period). The primary outcome and endpoint (power calculations are based only on this endpoint) for this study will be treatment incidence density (treatments per time at risk) for each treatment arm. Secondary outcomes include drug efficacy and safety and tolerability. Protocol 05-0110 is a sub study of this protocol.

Study Type

Interventional

Enrollment (Actual)

601

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Uganda
      • Kampala, Uganda
        • Assessment Center - Mulago Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 10 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Phase I

  • Age 1 to 10 years.
  • Agreement to come to the study clinic for any febrile episode or other illness.
  • Agreement to avoid medications administered outside the study.
  • Willingness of parents or guardians to provide informed consent.

Phase II

  • Child and Guardian/Parent belong to household currently enrolled in the study.
  • Age 1 to 10 years.
  • Agreement to come to the study clinic for any febrile episode or other illness.
  • Agreement to avoid medications administered outside the study.
  • Willingness of parents or guardians to provide informed consent.

Exclusion Criteria:

Phase I

  • History (obtained from the parent/guardian) of any known serious chronic disease requiring frequent medical care (e.g. AIDS, sickle cell disease, malignancy).
  • Intention to move from Kampala during the follow-up period.
  • History (obtained from the parent/guardian) of serious side effects to study medications or sulfa drugs.
  • Weight < 10 kg
  • Severe malnutrition defined as weight-for-height or height-for-age Z-score <-3.
  • Homozygous hemoglobin SS (sickle cell) result by hemoglobin electrophoresis.
  • Life-threatening screening laboratory value in the absence of malaria:
  • Absolute neutrophil count: < 250/mm^3
  • Hemoglobin: < 5.0 g/dL
  • Platelet count: < 25,000/mm^3
  • Creatinine: < 2 years: > 1.5 mg/dL, greater than or equal to 2 years: > 2.0 mg/dL
  • ALT: > 15.0 x ULN
  • Bilirubin: > 7.5 x ULN Phase II
  • History of any known serious chronic disease requiring frequent medical attention (e.g. AIDS, sickle cell disease, malignancy)
  • Intention to move from Kampala during the follow-up period
  • Any history of serious side effects to study medications
  • Weight < 10 kg
  • Severe malnutrition
  • Life-threatening screening laboratory test result

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
Drug: Amodiaquine+Artesunate
Amodiaquine 10 mg/kg on day 1, then 5 mg/kg on day 2 and 3; Artesunate 4 mg/kg/d for three days
Experimental: 2
Drug: Amodiaquine+Sulfadoxine/Pyrimethamine
Amodiaquine 10 mg/kg on day 1, then 5 mg/kg on day 2 and 3; S/P at 25 mg/kg sulfadoxine and 1.25 mg/kg pyrimethamine single dose
Experimental: 3
Drug: Artemether+Lumefantrine
Artemether 20 mg + Lumefantrine 120 mg 6 dose regimen at 0 and 8 hours on day 1 and twice daily on days 2 and 3:5 kg to < 15 kg: 1 tab/dose; 15 to 24 kg: 2 tabs/dose; >35 kg:4 tabs per dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Annual incidence of malaria per treatment arm
Time Frame: duration of study
duration of study

Secondary Outcome Measures

Outcome Measure
Time Frame
Short term: clinical and parasitological outcome; rates of fever and parasite clearance; presence of gametocytes following treatment
Time Frame: 14 days
14 days
Short term: change in hemoglobin level from day 0-14; safety and tolerability of study medications
Time Frame: 14 days
14 days
Long term: risk of reinfection using Kaplan-Meier product limit estimates of risk at various time intervals
Time Frame: Beyond 14 days to end of study
Beyond 14 days to end of study
Long term: risk of recrudescence; change in hemoglobin level; safety and tolerability of study medications
Time Frame: Beyond 14 days to end of study
Beyond 14 days to end of study
Longitudinal: prevalence of asymptomatic parasitemia; mean hemoglobin
Time Frame: 4 years
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of California, San Francisco

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2004

Primary Completion (Actual)

June 1, 2006

Study Completion (Actual)

December 1, 2008

Study Registration Dates

First Submitted

July 22, 2005

First Submitted That Met QC Criteria

July 22, 2005

First Posted (Estimate)

July 25, 2005

Study Record Updates

Last Update Posted (Actual)

June 9, 2020

Last Update Submitted That Met QC Criteria

June 3, 2020

Last Verified

June 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 04-068
  • UCSF-CHR Number:H2397-25789-01

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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