Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Rosiglitazone Adjunctive Therapy for Severe Malaria in Children (ROSI)

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.
 
ClinicalTrials.gov Identifier: NCT02694874
Recruitment Status : Active, not recruiting
First Posted : March 1, 2016
Last Update Posted : January 27, 2021
Sponsor:
Collaborators:
University Health Network, Toronto
Barcelona Institute for Global Health
Information provided by (Responsible Party):
Centro de Investigacao em Saude de Manhica

Tracking Information
First Submitted Date  ICMJE December 9, 2015
First Posted Date  ICMJE March 1, 2016
Last Update Posted Date January 27, 2021
Study Start Date  ICMJE February 2016
Actual Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 24, 2016)
Change in serum Ang-2 levels in the first 96 hours of hospital admission. [ Time Frame: first 96 hours of hospital admission. ]
We will assess the effect of the intervention (vs. placebo) on Ang-2 levels as a biomarker of severe disease in severe malaria
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 24, 2016)
  • Time to clinical recovery [ Time Frame: up to 96 hours after hospital admission ]
    Time to recovery including:
    1. Time to fever resolution for at least 24h. Temperature measurements will be taken at admission and every 4h for the first 4 days, and then every 12h until 2 normal results (<37.5oC) are reported.
    2. Time to sit unsupported
    3. Time to hospital discharge
  • Time to parasitological recovery [ Time Frame: up to 96 hours after hospital admission ]
    Time to parasitological recovery: Time (in hours) to clearance of parasitemia from the blood (both 50% and 90% decrease from admission baseline value). Parasitemia will be quantified at admission and every 6h, for 4 days or until 2 negative readings are reported.
  • Mortality [ Time Frame: first 48h post-hospital admission and at 14 days post-hospital admission ]
    Mortality in the first 48h post-hospital admission and at 14 days post-hospital admission
  • Blood lactate levels, assessed at admission, every 12h for 24 hours then daily for Blood lactate levels [ Time Frame: Assessed at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups ]
    Blood lactate levels, assessed at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups
  • Change in levels of biomarkers of host response [ Time Frame: at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups ]
    Change in levels of biomarkers of host response at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups
  • Blood glucose levels [ Time Frame: up to 96 hours after hospital admission ]
    Blood glucose levels assessed at admission and every 6h for the first 48h, and then every 24h for following 2 days
  • Cardiac effects [ Time Frame: from baseline to 24h, and day 4 ]
    Monitor for cardiac effects by conducting ECG at baseline, at 24h (immediately before third doses of rosiglitazone and artesunate treatment are administered) and at the end of rosiglitazone treatment (day 4). Main outcome of interest will be changes in QTc from baseline to the two different time points.
  • Biochemical and hematological parameters [ Time Frame: up to 96 hours after hospital admission ]
    Biochemical and hematological parameters including: AST, ALT, creatinine, complete blood count (e.g. hemoglobin, WBC and differential, hematocrit, platelet count) will be assessed at admission and every 24h until day 4
  • AE/SAE [ Time Frame: up to day 14 after hospital admission ]
    AE/SAE monitored using the pediatric toxicity tables modified from the US National Institutes of Allergy and Infectious Diseases
  • Neurocognitive outcomes [ Time Frame: From baseline to 6 months post discharge, and 18 months post discharge ]
    Participants with Adverse Events that Are Related and unrelated to Treatment by a variety of standard neurocognitive tests
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rosiglitazone Adjunctive Therapy for Severe Malaria in Children
Official Title  ICMJE Rosiglitazone Adjunctive Therapy for Severe Malaria in Children
Brief Summary Even with optimal anti-malaria therapy and supportive care, severe and cerebral malaria are associated with a 10-30% mortality rate and neurocognitive deficits in up to 33% of survivors. Adjunctive therapies that modify host immune-pathological processes may further improve outcome over that possible with anti-malarials alone. Investigators aim to evaluate a PPARγ agonist ( "rosiglitazone") as adjunctive therapy for severe malaria.
Detailed Description

Although the use of artemisinin-based therapy has improved outcomes in severe malaria, the mortality rates remain high. Adjunctive therapies that target the underlying immunopathology may further reduce morbidity and mortality in severe and cerebral malaria beyond that possible with anti-malarials alone. Pre-clinical data have established a beneficial role for PPARγ agonists in experimental cerebral malaria. A proof-of-concept randomized clinical trial of uncomplicated malaria in Thailand has extended these findings to an informative patient population, showing that adjunctive treatment with the PPARγ agonist rosiglitazone improves parasite clearance, and reduces biomarkers of inflammation (IL-6 and MCP-1) and endothelial activation (Ang-2 to Ang-1 ratio), and increases neuro-protective pathways (BDNF). The previous clinical trial also established the safety and tolerability of short course rosiglitazone in adults with malaria infection. Importantly, rosiglitazone does not induce insulin release or hypoglycemia in malaria-infected patients. Based on these data, and on studies demonstrating neuro-protective effects on PPARγ agonists in CNS disease and injury, the investigators believe that PPARγ agonists are promising candidates for adjunctive therapy for severe and cerebral malaria.

In this study the efficacy of rosiglitazone vs. placebo control as adjunct to standard of care anti-malarial therapy in children with severe (including cerebral) malaria will be tested.

The underlying hypothesis is that the addition of rosiglitazone to standard antimalarial therapy in severe P. falciparum infection is safe and will result in improved clinical outcomes and lower rates of long-term neurocognitive impairment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Malaria
Intervention  ICMJE
  • Drug: Rosiglitazone
    This is the experimental drug, rosiglitazone, being tested against placebo to assess its efficacy as an adjunctive treatment for severe malaria
    Other Name: Avandia
  • Drug: Placebo
    This is the placebo control
    Other Name: crushed powder placebo
Study Arms  ICMJE
  • Experimental: Rosiglitazone
    Participants will receive rosiglitazone 0.045mg/kg/dose twice daily dosing, for 4 days
    Intervention: Drug: Rosiglitazone
  • Placebo Comparator: Placebo
    Participants will receive placebo (grounded placebo powder) at a dose of 0.045mg/kg/dose twice daily for 4 days
    Intervention: Drug: Placebo
Publications * Varo R, Crowley VM, Sitoe A, Madrid L, Serghides L, Bila R, Mucavele H, Mayor A, Bassat Q, Kain KC. Safety and tolerability of adjunctive rosiglitazone treatment for children with uncomplicated malaria. Malar J. 2017 May 23;16(1):215. doi: 10.1186/s12936-017-1858-0.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 24, 2016)
210
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2021
Actual Primary Completion Date March 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 1-12 years
  • Positive 3-band (HRPII plus pLDH) P. falciparum rapid diagnostic test (RDT) and microscopy confirmed malaria infection with parasitemia >2500 parasites/microlitre if microscopy is available in a timely manner at the time of randomization.
  • One or more features of severe malaria: repeated seizures (two or more generalized seizures in 24 h); prostration (in children 1 year and older, the child is unable to sit unsupported or stand although was able to before the illness); impaired consciousness (Blantyre Coma Score <5 in children 1 to 4 years, GCS <14 for children ≥ 5 years); respiratory distress: age related tachypnea with sustained nasal flaring, deep breathing or subcostal retractions
  • Requiring hospitalization and parenteral artesunate for their malaria infection based on admitting physician assessment

Exclusion Criteria:

  • P. falciparum RDT negative OR infection not confirmed by light microscopy or not reaching the predefined inclusion criterion parasitemia threshold according to age
  • Uncomplicated malaria infection not requiring hospitalization
  • Presenting with severe malaria anemia (SMA) alone (Hb < 50g/L)
  • Known underlying illness: neurological or neurodegenerative disorders, cardiac, renal, or hepatic disease, diabetes, epilepsy, cerebral palsy, children known to be HIV-1 positive and receiving antiretroviral treatment*
  • Previous treatment with a TZD
  • Unable to remain in research site region for the follow up period
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Months to 12 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Mozambique
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02694874
Other Study ID Numbers  ICMJE ROSI_v03_22072015
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Centro de Investigacao em Saude de Manhica
Study Sponsor  ICMJE Centro de Investigacao em Saude de Manhica
Collaborators  ICMJE
  • University Health Network, Toronto
  • Barcelona Institute for Global Health
Investigators  ICMJE
Study Director: Eusebio Macete, PhD Fundaçao Manhiça
PRS Account Centro de Investigacao em Saude de Manhica
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP