Rosiglitazone Adjunctive Therapy for Severe Malaria in Children

NCT ID: NCT02694874

Last Updated: 2024-02-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 210 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-02-29
• Study Completion Date: 2021-12-31

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.

Conditions

Malaria

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Rosiglitazone

Participants will receive rosiglitazone 0.045mg/kg/dose twice daily dosing, for 4 days

Group Type: EXPERIMENTAL

Rosiglitazone

Intervention Type: DRUG

This is the experimental drug, rosiglitazone, being tested against placebo to assess its efficacy as an adjunctive treatment for severe malaria

Placebo

Participants will receive placebo (grounded placebo powder) at a dose of 0.045mg/kg/dose twice daily for 4 days

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

This is the placebo control

Interventions

Rosiglitazone

This is the experimental drug, rosiglitazone, being tested against placebo to assess its efficacy as an adjunctive treatment for severe malaria

Intervention Type: DRUG

Placebo

This is the placebo control

Intervention Type: DRUG

Other Intervention Names

Avandia; crushed powder placebo

Eligibility 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

• Minimum Eligible Age: 12 Months
• Maximum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Health Network, Toronto

OTHER

Sponsor Role: collaborator

Barcelona Institute for Global Health

OTHER

Sponsor Role: collaborator

Centro de Investigacao em Saude de Manhica

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Eusebio Macete, PhD

Role: STUDY_DIRECTOR

Fundaçao Manhiça

Locations

Centro de Investigação em Saude da Manhiça

Manhiça, Maputo Province, Mozambique

Countries

Mozambique

References

Varo R, Crowley VM, Mucasse H, Sitoe A, Bramugy J, Serghides L, Weckman AM, Erice C, Bila R, Vitorino P, Mucasse C, Valente M, Ajanovic S, Balanza N, Zhong K, Derpsch Y, Gladstone M, Mayor A, Bassat Q, Kain KC. Adjunctive rosiglitazone treatment for severe pediatric malaria: A randomized placebo-controlled trial in Mozambican children. Int J Infect Dis. 2024 Feb;139:34-40. doi: 10.1016/j.ijid.2023.11.031. Epub 2023 Nov 25.

Reference Type: RESULT

PMID: 38013152 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28535809 (View on PubMed)

Other Identifiers

ROSI_v03_22072015

Identifier Type: -

Identifier Source: org_study_id