Rosiglitazone Adjunctive Therapy for Severe Malaria in Children (ROSI)

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

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual 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
• Actual Primary Completion Date: March 2020
• Estimated Study Completion Date: December 2021

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Locations

Mozambique

Centro de Investigação em Saude da Manhiça

Manhiça, Maputo, Mozambique, CP1929

Sponsors and Collaborators

Centro de Investigacao em Saude de Manhica

University Health Network, Toronto

Barcelona Institute for Global Health

Investigators

• Study Director: Eusebio Macete, PhD; Fundaçao Manhiça

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Centro de Investigacao em Saude de Manhica
• ClinicalTrials.gov Identifier: NCT02694874
• Other Study ID Numbers: ROSI_v03_22072015
• First Posted: March 1, 2016
• Last Update Posted: January 27, 2021
• Last Verified: January 2021

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:

Malaria; Protozoan Infections; Parasitic Diseases; Rosiglitazone; Hypoglycemic Agents; Physiological Effects of Drugs