Safety and Efficacy Study of Adjunctive Rosiglitazone in the Treatment of Uncomplicated Falciparum Malaria

Condition(s) targeted: Falciparum Malaria

Intervention: Rosiglitazone (Drug)

Phase: Phase 1/Phase 2

Status: Completed

Sponsored by: Mahidol University

Official(s) and/or principal investigator(s):
Kevin C Kain, MD, FRCPC, Principal Investigator, Affiliation: Faculty of Medicine, University of Toronto; McLaughlin-Rotman Center for Global Health, Toronto

The purpose of this study is to examine the safety, tolerability, and efficacy of adjunctive rosiglitazone in the treatment of uncomplicated P. falciparum malaria.

Official title: A Randomized, Double-Blind, Placebo-Controlled Trial of Rosiglitazone as Adjunctive Therapy for P.Falciparum Infection

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Time to clearance (in hours) of parasitemia from blood is recorded

Secondary outcome:

Time to resolution of fever (in hours)

AST/ALT levels (U/L)

Capillary blood glucose (mmol/L)

Need for ICU admission

Tolerability of study drug/placebo as assessed by patient log

Detailed description: Study Rationale: Evidence suggests that if PPAR-RXR agonists (such as rosiglitazone) are used as adjunctive therapy in P. falciparum malaria infections they may increase phagocytic clearance of P. falciparum malaria, modulate deleterious inflammatory responses and decrease sequestration of malaria parasites in vital organs. They may therefore represent a novel immunomodulatory treatment approach for P. falciparum malaria.

Study Objectives: 1) To examine the in vivo effect of rosiglitazone on the rapidity of clearance of P. falciparum parasitemia and fever in patients with non-severe P. falciparum infections 2) To assess the safety and tolerability of adjunctive rosiglitazone treatment in non-severe cases of P. falciparum infection.

Primary Outcomes: Time to clearance of P. falciparum parasitemia

Study Design: Randomized double blind placebo-controlled trial.

Intervention: Standard antimalarial treatment (atovaquone/proguanil) to all patients combined with adjuvant rosiglitazone treatment (8mg per day) or placebo.

Setting: Hospital for Tropical Diseases at Mahidol University, Thailand.

Participants: 140 patients with non-severe P. falciparum infection.

Follow-up: 28 days

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Microscopically confirmed P. falciparum infection

- Age >18 years

- Able to tolerate oral therapy

- Able to give informed consent

Exclusion Criteria:

- Fulfillment of WHO criteria for severe/cerebral malaria

- Prior treatment with any thiazolidinedione

- Allergy to rosiglitazone

- History of diabetes mellitus

- History of severe/decompensated liver disease

- ALT level >2. 5 times normal

- Current treatment for congestive heart failure

- Pregnancy or breastfeeding

Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand

Mahidol University, Faculty of Tropical Medicine

McLaughlin Centre for Molecular Medicine, McLaughlin-Rotman Center for Global Health

Related publications:

Suh KN, Kain KC, Keystone JS. Malaria. CMAJ. 2004 May 25;170(11):1693-702. Review.

Patel SN, Serghides L, Smith TG, Febbraio M, Silverstein RL, Kurtz TW, Pravenec M, Kain KC. CD36 mediates the phagocytosis of Plasmodium falciparum-infected erythrocytes by rodent macrophages. J Infect Dis. 2004 Jan 15;189(2):204-13. Epub 2004 Jan 9.

Serghides L, Smith TG, Patel SN, Kain KC. CD36 and malaria: friends or foes? Trends Parasitol. 2003 Oct;19(10):461-9. Review. No abstract available.

Smith TG, Ayi K, Serghides L, Mcallister CD, Kain KC. Innate immunity to malaria caused by Plasmodium falciparum. Clin Invest Med. 2002 Dec;25(6):262-72. Review.

Smith TG, Serghides L, Patel SN, Febbraio M, Silverstein RL, Kain KC. CD36-mediated nonopsonic phagocytosis of erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum. Infect Immun. 2003 Jan;71(1):393-400.

Serghides L, Kain KC. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet. 2002 Apr 20;359(9315):1404-6.

Serghides L, Kain KC. Peroxisome proliferator-activated receptor gamma-retinoid X receptor agonists increase CD36-dependent phagocytosis of Plasmodium falciparum-parasitized erythrocytes and decrease malaria-induced TNF-alpha secretion by monocytes/macrophages. J Immunol. 2001 Jun 1;166(11):6742-8.

McGilvray ID, Serghides L, Kapus A, Rotstein OD, Kain KC. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood. 2000 Nov 1;96(9):3231-40.

Serghides L, Crandall I, Hull E, Kain KC. The Plasmodium falciparum-CD36 interaction is modified by a single amino acid substitution in CD36. Blood. 1998 Sep 1;92(5):1814-9.

Urquhart AD. Putative pathophysiological interactions of cytokines and phagocytic cells in severe human falciparum malaria. Clin Infect Dis. 1994 Jul;19(1):117-31. Review.

Ockenhouse CF, Ho M, Tandon NN, Van Seventer GA, Shaw S, White NJ, Jamieson GA, Chulay JD, Webster HK. Molecular basis of sequestration in severe and uncomplicated Plasmodium falciparum malaria: differential adhesion of infected erythrocytes to CD36 and ICAM-1. J Infect Dis. 1991 Jul;164(1):163-9.

Ockenhouse CF, Chulay JD. Plasmodium falciparum sequestration: OKM5 antigen (CD36) mediates cytoadherence of parasitized erythrocytes to a myelomonocytic cell line. J Infect Dis. 1988 Mar;157(3):584-8. No abstract available.

Oquendo P, Hundt E, Lawler J, Seed B. CD36 directly mediates cytoadherence of Plasmodium falciparum parasitized erythrocytes. Cell. 1989 Jul 14;58(1):95-101.

Day NP, Hien TT, Schollaardt T, Loc PP, Chuong LV, Chau TT, Mai NT, Phu NH, Sinh DX, White NJ, Ho M. The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. J Infect Dis. 1999 Oct;180(4):1288-97.

Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet. 1990 Nov 17;336(8725):1201-4.

Brown H, Turner G, Rogerson S, Tembo M, Mwenechanya J, Molyneux M, Taylor T. Cytokine expression in the brain in human cerebral malaria. J Infect Dis. 1999 Nov;180(5):1742-6.

Aitman TJ, Cooper LD, Norsworthy PJ, Wahid FN, Gray JK, Curtis BR, McKeigue PM, Kwiatkowski D, Greenwood BM, Snow RW, Hill AV, Scott J. Malaria susceptibility and CD36 mutation. Nature. 2000 Jun 29;405(6790):1015-6. No abstract available.

Omi K, Ohashi J, Naka I, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K. Polymorphisms of CD36 in Thai malaria patients. Southeast Asian J Trop Med Public Health. 2002;33 Suppl 3:1-4.

Shankar AH, Genton B, Semba RD, Baisor M, Paino J, Tamja S, Adiguma T, Wu L, Rare L, Tielsch JM, Alpers MP, West KP Jr. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomised trial. Lancet. 1999 Jul 17;354(9174):203-9.

Schoonjans K, Auwerx J. Thiazolidinediones: an update. Lancet. 2000 Mar 18;355(9208):1008-10.

Starting date: December 2004
Ending date: January 2006
Last updated: August 22, 2007