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

Falciparum Malaria Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled Trial of Rosiglitazone as Adjunctive Therapy for P.Falciparum Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00149383
• Other study ID #: 033-2004
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: September 6, 2005
• Last updated: April 10, 2015
• Start date: December 2004
• Est. completion date: January 2006

Study information

• Verified date: April 2015
• Source: Mahidol University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Thailand: Ethical Committee
• Study type: Interventional

Clinical Trial Summary

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

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: January 2006
• Est. primary completion date: November 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Falciparum Malaria
• Malaria
• Malaria, Falciparum

Intervention

Drug:
• Rosiglitazone

• Placebo

Locations

Country	Name	City	State
Thailand	Faculty of Tropical Medicine, Mahidol University	Bangkok

Sponsors (2)

Lead Sponsor	Collaborator
Mahidol University	McLaughlin-Rotman Center for Global Health, University of Toronto

Country where clinical trial is conducted

Thailand, 

References & Publications (20)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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

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. — View Citation

Serghides L, Smith TG, Patel SN, Kain KC. CD36 and malaria: friends or foes? Trends Parasitol. 2003 Oct;19(10):461-9. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to clearance (in hours) of parasitemia from blood is recorded		5 days
Secondary	Time to resolution of fever (in hours)		5 days
Secondary	AST/ALT levels (U/L)		2 days
Secondary	Capillary blood glucose (mmol/L)		2 days
Secondary	Need for ICU admission		5 days
Secondary	Tolerability of study drug/placebo as assessed by patient log		5 days

External Links

•   Mahidol University, Faculty of Tropical Medicine
•   McLaughlin Centre for Molecular Medicine, McLaughlin-Rotman Center for Global Health