Clinical trial NCT02694874: Rosiglitazone Adjunctive Therapy for Severe Malaria in Children
Official title: Rosiglitazone Adjunctive Therapy for Severe Malaria in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Malaria
Keywords: Adjunctive treatment
Severe malaria
Lead sponsor: Centro de Investigacao em Saude de Manhica
Sponsor class: OTHER
Collaborators: name: University Health Network, Toronto
name: Barcelona Institute for Global Health
First posted: 2016-03-01
Enrollment: 210
Sex: ALL
Minimum age (years): 12
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in serum Ang-2 levels in the first 96 hours of hospital admission.
timeFrame: first 96 hours of hospital admission.
Secondary outcomes:
measure: Time to clinical recovery
timeFrame: up to 96 hours after hospital admission
measure: Time to parasitological recovery
timeFrame: up to 96 hours after hospital admission
measure: Mortality
timeFrame: first 48h post-hospital admission and at 14 days post-hospital admission
measure: Blood lactate levels, assessed at admission, every 12h for 24 hours then daily for Blood lactate levels
timeFrame: Assessed at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups
measure: Change in levels of biomarkers of host response
timeFrame: at admission, every 12h for 24 hours then daily for 4 days, and once on day 14 and 6 month follow ups
measure: Blood glucose levels
timeFrame: up to 96 hours after hospital admission
measure: Cardiac effects
timeFrame: from baseline to 24h, and day 4
measure: Biochemical and hematological parameters
timeFrame: up to 96 hours after hospital admission
measure: AE/SAE
timeFrame: up to day 14 after hospital admission
measure: Neurocognitive outcomes
timeFrame: From baseline to 6 months post discharge, and 18 months post discharge
Other outcomes:
Locations:
city: Manhiça
country: Mozambique
facility: Centro de Investigação em Saude da Manhiça
state: Maputo
Study officials:
affiliation: Fundaçao Manhiça
name: Eusebio Macete, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.