Longitudinal Antimalarial Combinations in Uganda

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Philip Rosenthal, University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00123552
First received: July 22, 2005
Last updated: November 28, 2011
Last verified: November 2011
  Purpose

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.


Condition Intervention Phase
Malaria
Drug: Amodiaquine+Artesunate
Drug: Amodiaquine+Sulfadoxine/Pyrimethamine
Drug: Artemether+Lumefantrine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Caregiver)
Primary Purpose: Treatment
Official Title: Longitudinal Comparison of Combination Antimalarial Therapies in Ugandan Children: Evaluation of Safety, Tolerability, and Efficacy

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Primary Outcome Measures:
  • Annual incidence of malaria per treatment arm [ Time Frame: duration of study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Short term: clinical and parasitological outcome; rates of fever and parasite clearance; presence of gametocytes following treatment [ Time Frame: 14 days ] [ Designated as safety issue: No ]
  • Short term: change in hemoglobin level from day 0-14; safety and tolerability of study medications [ Time Frame: 14 days ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • Long term: risk of recrudescence; change in hemoglobin level; safety and tolerability of study medications [ Time Frame: Beyond 14 days to end of study ] [ Designated as safety issue: Yes ]
  • Longitudinal: prevalence of asymptomatic parasitemia; mean hemoglobin [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Enrollment: 690
Study Start Date: November 2004
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   1 Year to 10 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00123552

Locations
Uganda
Assessment Center - Mulago Hospital
Kampala, Uganda
Sponsors and Collaborators
University of California, San Francisco
  More Information

Publications:

Responsible Party: Philip Rosenthal, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00123552     History of Changes
Other Study ID Numbers: 04-068, UCSF-CHR Number:H2397-25789-01
Study First Received: July 22, 2005
Last Updated: November 28, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, San Francisco:
Uganda, malaria, combination antimalarial therapy

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Amodiaquine
Antimalarials
Pyrimethamine
Sulfadoxine
Artemether
Artesunate
Lumefantrine
Artemether-lumefantrine combination
Artemisinins
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents
Antifungal Agents
Coccidiostats
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics
Amebicides

ClinicalTrials.gov processed this record on August 21, 2014