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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02694874
Recruitment Status : Recruiting
First Posted : March 1, 2016
Last Update Posted : October 1, 2019
Sponsor:
Collaborators:
University Health Network, Toronto
Barcelona Institute for Global Health
Information provided by (Responsible Party):
Centro de Investigacao em Saude de Manhica

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.

Condition or disease Intervention/treatment Phase
Malaria Drug: Rosiglitazone Drug: Placebo Not Applicable

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Rosiglitazone Adjunctive Therapy for Severe Malaria in Children
Study Start Date : February 2016
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: Rosiglitazone
Participants will receive rosiglitazone 0.045mg/kg/dose twice daily dosing, for 4 days
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

Placebo Comparator: Placebo
Participants will receive placebo (grounded placebo powder) at a dose of 0.045mg/kg/dose twice daily for 4 days
Drug: Placebo
This is the placebo control
Other Name: crushed powder placebo




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   12 Months to 12 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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 ClinicalTrials.gov identifier (NCT number): NCT02694874


Contacts
Layout table for location contacts
Contact: Quique Bassat, MD, PhD 0034609556300 quique.bassat@isglobal.org
Contact: Rosauro Varo, MD, MSc 00258840161540 rosauro.varo@isglobal.org

Locations
Layout table for location information
Mozambique
Centro de Investigação em Saude da Manhiça Recruiting
Manhiça, Maputo, Mozambique, CP1929
Contact: Quique Bassat, PhD         
Contact: Eusebio Macete, PhD         
Sponsors and Collaborators
Centro de Investigacao em Saude de Manhica
University Health Network, Toronto
Barcelona Institute for Global Health
Investigators
Layout table for investigator information
Study Director: Eusebio Macete, PhD Fundaçao Manhiça

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Centro de Investigacao em Saude de Manhica
ClinicalTrials.gov Identifier: NCT02694874     History of Changes
Other Study ID Numbers: ROSI_v03_22072015
First Posted: March 1, 2016    Key Record Dates
Last Update Posted: October 1, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Centro de Investigacao em Saude de Manhica:
Adjunctive treatment
Severe malaria
Additional relevant MeSH terms:
Layout table for MeSH terms
Malaria
Protozoan Infections
Parasitic Diseases
Rosiglitazone
Hypoglycemic Agents
Physiological Effects of Drugs