Non-malarial Febrile Illness in Children in Areas of Perennial Malaria Transmission

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01043744
Recruitment Status : Completed
First Posted : January 7, 2010
Last Update Posted : March 11, 2013
Information provided by (Responsible Party):
Meredith McMorrow, Centers for Disease Control and Prevention

Brief Summary:
To evaluate the causes of non-malarial febrile illness in children living in an area of perennial malaria transmission and to determine if these children who test negative for malaria by rapid diagnostic test receive any benefit from antimalarial therapy.

Condition or disease Intervention/treatment Phase
Malaria Non-malarial Febrile Illness Drug: Artemether-Lumefantrine Not Applicable

Detailed Description:

Until recently, national and global malaria control authorities recommended clinical diagnosis—based solely on the presence or history of fever—for most malaria treatment settings in sub-Saharan Africa where malaria transmission is sustained and intense. To some extent this recommendation was based on the fact that conventional antimalarial treatments like chloroquine or sulfadoxine-pyrimethamine (SP) were relatively affordable and safe and that microscopic diagnosis was complex and difficult to maintain in remote rural settings. It was economically advantageous and logistically more feasible to treat all potential cases as malaria than to extend microscopic diagnosis to every level of the health system. This approach has resulted in extensive over-treatment, particularly among older children and adults, and may have contributed to the rapid development of antimalarial drug resistance.

Although much has been written recently on the cost-effectiveness of expanding malaria diagnosis, available information is scarce on a number of other important reasons why clinical diagnosis has been recommended for so long, especially among children living in high transmission settings. First, uncomplicated malaria can progress to severe or fatal illness within 24 to 48 hours of onset. Numerous care-seeking studies have demonstrated that caretakers seldom arrive at formal health facilities within 24 or 48 hours after the onset of uncomplicated febrile illness. If a diagnostic test imposes additional barriers—such as cost, time delay, or referral—requiring a positive parasitological diagnosis could put children whose cause of fever is malaria infection at greater risk of progressing to severe or fatal illness. Second, although the current approach based on clinical diagnosis appears to result in substantial over-treatment, it is still possible to demonstrate that children living in malaria transmission areas benefit from additional scheduled doses of antimalarial treatment, even when they are not ill. For example, a meta-analysis of six trials of sulfadoxine-pyrimethamine (SP) given to children at routine immunization visits demonstrated an average decrease of 30% in episodes of clinical malaria, 15% in anemia, and 24% in all-cause hospital admissions among children receiving SP compared to children who did not receive the drug at these visits. Finally, providers and clients may be inclined to disregard a negative blood slide or RDT, especially in situations where they have not identified an additional treatable cause of illness. Withholding antimalarial treatments from such children might adversely affect provider and client satisfaction and poor client satisfaction may reduce subsequent health facility utilization. It might also encourage disappointed clients to seek treatment in the private sector where a broad range of antimalarial drugs—most of them single drug treatments that contribute to the development of resistance and which are not recommended in the national treatment policy—can be obtained without diagnostic confirmation.

We propose a longitudinal cohort study to evaluate the identifiable causes of treatable fever among 1000 malaria-negative children presenting to outpatient health clinics in Miono, Bagamoyo District, Tanzania using a variety of clinical, microbiological and serologic methods. In addition we intend to follow these 1000 malaria-negative children for up to 91 days or until their next malaria infection to assess their clinical progress and need for further malaria treatment. To compare the relative benefit of providing antimalarial treatment even to malaria-negative children, half of the participants will be randomized to receive first-line treatment for malaria as currently recommended; the other half will receive treatment only for other identified illnesses.

Alternative Hypothesis: Febrile, parasite-negative children treated for malaria have better clinical and longitudinal outcomes (as measured by prevalence of anemia at the end of the follow up period, reticulocyte count repeat visits to the health facility, hospitalization, and time to next infection with malaria parasites) than febrile, parasite-negative children not treated for malaria in areas of high transmission.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Treatment Outcomes for Non-malarial Febrile Illness in Children Aged 6-59 Months in Areas of Perennial Malaria Transmission
Study Start Date : January 2010
Actual Primary Completion Date : December 2011
Actual Study Completion Date : December 2011

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever Malaria
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Artemether-Lumefantrine
Receive artemether-lumefantrine with direct observation of am dose on days 0, 1, and 2 of study
Drug: Artemether-Lumefantrine

Artemether-lumefantrine (Coartem; Novartis) administered twice daily for three days as tablets containing 20 mg of artemether plus 120 mg of lumefantrine at a dosage of:

  • 1 tablet (for patients weighing 5-14 kg)
  • 2 tablets (for patients weighing 15-24 kg)
Other Name: CoArtem, Novartis
No Intervention: No treatment
No antimalarial treatment given on day 0.

Primary Outcome Measures :
  1. Hematological recovery (Hb return to normal) [ Time Frame: 28, 63, 91 days ]
  2. Mean time to next infection [ Time Frame: Weekly ]

Secondary Outcome Measures :
  1. Etiologic agent of non-malarial febrile illness [ Time Frame: Day 0 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 59 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Age 6 to 59 months.
  • Present to health facility with fever (oral or rectal temperature ≥38°C or axillary temperature ≥37.5°C) or history of fever in the past 48 hours.
  • Have negative rapid diagnostic test for malaria.
  • Live within the boundaries of the officially recognized catchment area of Miono Health Center (within approximately 10 km of the health facility).

Exclusion Criteria:

  • Plan to travel or leave the area within the next 3 months.
  • Have been treated for malaria in the 2 weeks prior to enrollment.
  • Have clinical evidence or history of danger signs: convulsions, lethargy, loss of consciousness, unable to eat or drink, vomiting everything.
  • Have severe, life-threatening anemia: hemoglobin ≤5g/ dL.
  • Have very low weight for age, severe pneumonia, or very severe disease as defined in the Integrated Management of Childhood Illness algorithms.
  • Have a history of sensitivity to artemisinin derivatives or Artemether-Lumefantrine.
  • Have previously been enrolled in this study or another ongoing cohort study of malaria treatment options at these health facilities
  • Chronic disease requiring ongoing medical care (i.e HIV on cotrimoxazole).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01043744

Miono Health Center
Miono, Bagamoyo District, Tanzania
Msata Dispensary
Msata, Tanzania
Sponsors and Collaborators
Centers for Disease Control and Prevention
Principal Investigator: Meredith L McMorrow, MD, MPH Centers for Disease Control and Prevention
Study Chair: S. Patrick Kachur, MD, MPH Centers for Disease Control and Prevention
Study Chair: Larry Slutsker, MD Centers for Disease Control and Prevention
Study Director: Saumu Ahmed, MD Ifakara Health Institute
Study Chair: Salim MK Abdulla, MD, PhD Ifakara Health Institute

Responsible Party: Meredith McMorrow, Medical Officer, Centers for Disease Control and Prevention Identifier: NCT01043744     History of Changes
Other Study ID Numbers: CDC-CCID-5597
First Posted: January 7, 2010    Key Record Dates
Last Update Posted: March 11, 2013
Last Verified: March 2013

Keywords provided by Meredith McMorrow, Centers for Disease Control and Prevention:
presumptive treatment
Integrated Management of Childhood Illness

Additional relevant MeSH terms:
Protozoan Infections
Parasitic Diseases
Body Temperature Changes
Signs and Symptoms
Artemether-lumefantrine combination
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antifungal Agents
Antiplatyhelmintic Agents