Chloroquine and Post Malaria Anaemia Study - Full Text View

Sponsored by:	Medical Research Council Laboratories, Gambia
Information provided by:	Medical Research Council Laboratories, Gambia
ClinicalTrials.gov Identifier:	NCT00473837

Purpose

The pathogenesis of post-malaria anaemia is multifactorial. Iron supplementation remains the mainstay of management of moderate and severe anaemia; however the management of mild anaemia (Hb 80-110g/l) is problematic as population supplementation studies of children in malaria endemic areas demonstrate adverse effects in children with mild anaemia. We hypothesize that the anti-inflammatory, anti-malarial and anti-macrophageal iron loading effects of chloroquine could make it a useful drug in the management of mild post malaria anaemia To test this hypothesis, we plan to randomize children (aged 12 months to 6 years) with post malaria anaemia (Hb 70-110g/l) to receive either standard anti-malarial treatment (chloroquine plus sulphadoxine/pyrimethamine) or artemisinine combination therapy. Three days after commencement of antimalarial treatment, the children in each of the two arms will be further randomised to receive either weekly chloroquine or weekly placebo. By comparing the curve of haemoglobin change between day 3 and one month follow-up in the placebo arms of the two groups, we will test the effect of chloroquine vs. ACT treatment on macrophageal iron loading and release in acute clinical malaria. By comparing the haemoglobin change between day 3 and 3 months follow-up between the weekly chloroquine arms and the weekly placebo arms we will test the longer-term anti-inflammatory and anti- malarial effects of weekly chloroquine prophylaxis. In addition to the primary endpoint, we plan to assess potential mechanisms of action by determining parasite clearance, peripheral cytokine production and iron flux

Condition	Intervention
Malaria Anaemia	Drug: Chloroquine Drug: Placebo

MedlinePlus related topics: Anemia Malaria

Drug Information available for: Pyrimethamine Sulfadoxine Artemether Chloroquine Chloroquine diphosphate Chloroquine hydrochloride Co-artemether

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	Chloroquine as a Therapeutic Option for Mild Post Malaria Anaemia

Further study details as provided by Medical Research Council Laboratories, Gambia:

Primary Outcome Measures:

Changes in haemoglobin concentration from day 3 post treatment of malaria episode to day 90 in the weekly chloroquine and placebo arms [ Time Frame: 90 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Curve of Hb change between day 3 and day 30 in the two placebo arms; changes in markers of iron status, measures of inflammation, and Hb response between day 3 and day 30, and between day 3 and day 90 [ Time Frame: 90 days ] [ Designated as safety issue: No ]

Estimated Enrollment:	260
Study Start Date:	July 2007
Estimated Study Completion Date:	April 2009
Estimated Primary Completion Date:	April 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
S1: Experimental Subjects are initially treated with chloroquine plus sulphadoxine-pyrimethamine to clear the parasiteamia then continued with weekly chloroquine till day 90	Drug: Chloroquine Chloroquine: 10mg/kg once daily for three days, followed by weekly treatment of 7.5mg/kg for three months Sulphadoxine/Pyrimethamine: ½ tablets per 10kg body weight given once on Day 1 Co-artemether: A total of six doses given over 3 days - a stat dose, then 8 hours later followed by twice daily dose for the next two days. The number of tablets will depend on the weight of the child as follows: 5 to 14.99 kg - one tablet per dose; 15 to 24.99kg - 2 tablets per dose; and 25 to 34.99kg - 3 tablets per dose.
A1: Experimental Subjects initially treated with Co-arthemeter, and then continued on weekly chloroquine till day 90	Drug: Chloroquine Chloroquine: 10mg/kg once daily for three days, followed by weekly treatment of 7.5mg/kg for three months Sulphadoxine/Pyrimethamine: ½ tablets per 10kg body weight given once on Day 1 Co-artemether: A total of six doses given over 3 days - a stat dose, then 8 hours later followed by twice daily dose for the next two days. The number of tablets will depend on the weight of the child as follows: 5 to 14.99 kg - one tablet per dose; 15 to 24.99kg - 2 tablets per dose; and 25 to 34.99kg - 3 tablets per dose.
S0: Placebo Comparator Subjects initially treated with chloroquine plus sulphadoxine-pyrimethamine and then continued on weekly placebo till day 90	Drug: Placebo
A0: Placebo Comparator Subjects initially treated with Co-arthemeter, and then continued on weekly placebo till day 90	Drug: Placebo

Show Detailed Description

Eligibility

Ages Eligible for Study:	12 Months to 72 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

All children aged 12 months to 6 years in the 13 study villages will be enrolled in the study and followed up for the duration of the study. The inclusion criteria for randomization will be:

Children aged 12 months to 6 years; and
History of fever in the preceding 48 hours or a measured temperature > 37.5oC plus asexual forms of P. falciparum in the peripheral blood film of 500/μl or above; and
Hb <110g/l and >69g/l (Our choice of the upper limit of moderate anaemia (70 - 79g/l) is to enable us assess the response to our interventions of severer forms of anaemia while at the same time reducing the risk of adverse events which might occur with lower levels of Hb).

Exclusion Criteria:

Refusal of parent or guardian to give consent to the child's participation in the study
Inability of the subjects to take oral medications
Presence of features of severe malaria as defined by WHO50, with the exception of anaemia and parasite density
Children who have urgent need for blood transfusion as indicated by the presence of tachypnoea, tachycardia & gallop rhythm, tender hepatomegaly
Children with known haemoglobinopathy
Children with a weight for height Z score below -3SD of WHO/NCHS standard
Enrolment in another research project

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00473837

Contacts

Contact: Chidi V Nweneka, MSc

+2209957634

cnweneka@mrc.gm

Locations

Gambia, West Kiang District
Keneba Field Station	Recruiting
Banjul, West Kiang District, Gambia, 00000
Contact: Chidi V Nweneka, MSc. +220 9957634 cnweneka@mrc.gm
Contact: Sophie Moore, PhD +220 9963991 sophie.moore@lshtm.ac.uk
Principal Investigator: Chidi V Nweneka, MSc
Sub-Investigator: Conor P Doherty, MRCP, MD
Sub-Investigator: Lawrence T Weaver, DSc, FRCP
Sub-Investigator: Andrew Prentice, PhD
Sub-Investigator: Sharon Cox, PhD
Sub-Investigator: Sophie Moore, PhD
Sub-Investigator: Tony Fulford, PhD
Sub-Investigator: Climent Casals, PhD

Sponsors and Collaborators

Medical Research Council Laboratories, Gambia

Investigators

Principal Investigator:	Chidi V Nweneka, MSc.	Medical Research Council Laboratories, Gambia
Study Director:	Sophie Moore, PhD	Medical Research Council Laboratories, Gambia

More Information

Medical Research Council Laboratories, The Gambia web site This link exits the ClinicalTrials.gov site

Publications:

1. Weatherall DJ, Abdalla S. The anaemia of Plasmodium falciparum malaria. Br Med Bull 1982;38(2):147-51. 2. Schwartz RS, Olson JA, Raventos-Suarez C, et al. Altered plasma membrane phospholipid organization in Plasmodium falciparum-infected human erythrocytes. Blood 1987;69(2):401-7. 4. Looareesuwan S, Davis TM, Pukrittayakamee S, et al. Erythrocyte survival in severe falciparum malaria. Acta Trop 1991;48(4):263-70. 5. Abdalla SH, Wickramasinghe SN. A study of erythroid progenitor cells in the bone marrow of Gambian children with falciparum malaria. Clin Lab Haematol 1988;10(1):33-40. 6. Jootar S, Chaisiripoomkere W, Pholvicha P, et al. Suppression of erythroid progenitor cells during malarial infection in Thai adults caused by serum inhibitor. Clin Lab Haematol 1993;15(2):87-92. 7. Jason J, Archibald LK, Nwanyanwu OC, et al. Cytokines and malaria parasitemia. Clin Immunol 2001;100(2):208-18. 8. Clark IA, Chaudhri G. Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis. Br J Haematol 1988;70(1):99-103. 9. Biemba G, Gordeuk VR, Thuma P, Weiss G. Markers of inflammation in children with severe malarial anaemia. Trop Med Int Health 2000;5(4):256-62. 10. Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V. A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis 1999;179(1):279-82. 11. Luty AJ, Perkins DJ, Lell B, et al. Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect Immun 2000;68(7):3909-15. 12. Camacho LH, Gordeuk VR, Wilairatana P, Pootrakul P, Brittenham GM, Looareesuwan S. The course of anaemia after the treatment of acute, falciparum malaria. Ann Trop Med Parasitol 1998;92(5):525-37. 13. Kwiatkowski D, Cannon JG, Manogue KR, Cerami A, Dinarello CA, Greenwood BM. Tumour necrosis factor production in Falciparum malaria and its association with schizont rupture. Clin Exp Immunol 1989;77(3):361-6. 15. Wenisch C, Parschalk B, Narzt E, Looareesuwan S, Graninger W. Elevated serum levels of IL-10 and IFN-gamma in patients with acute Plasmodium falciparum malaria. Clin Immunol Immunopathol 1995;74(1):115-7. 17. Helleberg M, Goka BQ, Akanmori BD, Obeng-Adjei G, Rodriques O, Kurtzhals JA. Bone marrow suppression and severe anaemia associated with persistent Plasmodium falciparum infection in African children with microscopically undetectable parasitaemia. Malar J 2005;4(1):56. 18. Knutson M, Wessling-Resnick M. Iron metabolism in the reticuloendothelial system. Crit Rev Biochem Mol Biol 2003;38(1):61-88. 23. Abdalla S, Weatherall DJ, Wickramasinghe SN, Hughes M. The anaemia of P. falciparum malaria. Br J Haematol 1980;46(2):171-83. 24. Bojang KA, Palmer A, Boele van Hensbroek M, Banya WA, Greenwood BM. Management of severe malarial anaemia in Gambian children. Trans R Soc Trop Med Hyg 1997;91(5):557-61. 30. Moore HP, Gumbiner B, Kelly RB. Chloroquine diverts ACTH from a regulated to a constitutive secretory pathway in AtT-20 cells. Nature 1983;302(5907):434-6. 31. Agarwal SL, Deshmankar BS. The in vitro antihistaminic and anti-anaphylactic actions of chloroquine. Arch Int Pharmacodyn Ther 1963;143:401-7. 32. Ayitey-Smith E, Boye GL. Effect of chloroquine on histamine-induced bronchial asthma in the guinea-pig. J Pharm Pharmacol 1974;26(3):208-9. 33. Moss RB. Alternative pharmacotherapies for steroid-dependent asthma. Chest 1995;107(3):817-25. 34. Lancz GJ, McLaren LC, James CG, Scaletti JV. Chloroquine mediated alterations in mammalian cell metabolism and viral replication. Proc Soc Exp Biol Med 1971;136(4):1289-93. 35. Tsai WP, Nara PL, Kung HF, Oroszlan S. Inhibition of human immunodeficiency virus infectivity by chloroquine. AIDS Res Hum Retroviruses 1990;6(4):481-9. 36. Boelaert JR, Appelberg R, Gomes MS, et al. Experimental results on chloroquine and AIDS-related opportunistic infections. J Acquir Immune Defic Syndr 2001;26(3):300-1. 37. Neale ML, Fiera RA, Matthews N. Involvement of phospholipase A2 activation in tumour cell killing by tumour necrosis factor. Immunology 1988;64(1):81-5. 39. Cash JM, Klippel JH. Second-line drug therapy for rheumatoid arthritis. N Engl J Med 1994;330(19):1368-75. 40. Legssyer R, Ward RJ, Crichton RR, Boelaert JR. Effect of chronic chloroquine administration on iron loading in the liver and reticuloendothelial system and on oxidative responses by the alveolar macrophages. Biochem Pharmacol 1999;57(8):907-11. 41. Salihu HM, Naik EG, Tchuinguem G, Bosny JP, Dagne G. Weekly chloroquine prophylaxis and the effect on maternal haemoglobin status at delivery. Trop Med Int Health 2002;7(1):29-34. 42. Cot M, le Hesran JY, Miailhes P, et al. Effect of chloroquine prophylaxis during pregnancy on maternal haematocrit. Ann Trop Med Parasitol 1998;92(1):37-43.

Responsible Party:	Medical Research Council Labs, The Gambia ( Dr Chidi V Nweneka, Research Clinician )
Study ID Numbers:	SCC1076
Study First Received:	May 15, 2007
Last Updated:	April 23, 2008
ClinicalTrials.gov Identifier:	NCT00473837
Health Authority:	Gambia: MRC Ethics Committee

Keywords provided by Medical Research Council Laboratories, Gambia:

malaria
anaemia
chloroquine
iron delocalisation
macrophages

Study placed in the following topic categories:

Pyrimethamine
Protozoan Infections
Hematologic Diseases
Chloroquine diphosphate
Anemia
Chloroquine

Parasitic Diseases
Malaria
Sulfadoxine
Iron
Artemether

Additional relevant MeSH terms:

Anti-Inflammatory Agents
Anti-Infective Agents
Antiprotozoal Agents
Filaricides
Coccidiosis
Physiological Effects of Drugs
Anthelmintics
Pharmacologic Actions
Antimalarials
Antiparasitic Agents

Analgesics, Non-Narcotic
Sensory System Agents
Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal
Peripheral Nervous System Agents
Amebicides
Analgesics
Antirheumatic Agents
Central Nervous System Agents
Antinematodal Agents

ClinicalTrials.gov processed this record on January 16, 2009