Comparison of Two Antimalarial Drugs Regimens in Patient With Plasmodium Vivax Malaria in Thailand

An Open Label Randomized Comparison of Two Antimalarial Drugs Regimens in Patient With Plasmodium Vivax Malaria in Thailand

In Thailand, the proportion of P.vivax infection has now been increasing and is equal to Plasmodium falciparum since 1998. The incidence of P.vivax has recently been reported as 20 per 1000 population per year. Unlike Plasmodium falciparum, P.vivax infection rarely develops into complicated malaria and death is unusual. However, P.vivax has a dormant stage (the hypnozoite) that persists in the human liver and may cause relapse weeks, months, or even years later. Therefore, P.vivax infection is considered to have greater impact on morbidity than mortality, resulting in significant social and economic burden. Moreover, it is very difficult to control P.vivax transmission, because gametocytes appear almost simultaneously with schizonts.

Radical treatment of the infection, therefore, normally consists of a blood schizontocidal course of chloroquine and a course primaquine for the elimination of the hypnozoites as anti-relapse therapy. In Thailand, chloroquine and primaquine have remained the mainstay chemotherapeutics for the treatment of P.vivax for more than 60 years and resistance has not yet been reported . The relapse rates at day 28 are about 50% without primaquine therapy and about 20% with standard primaquine therapy. Relapse has not been observed among patients receiving high dose primaquine therapy (30 mg daily for 14 days).

Since January 2007, the evidence of reduced susceptibility of Plasmodium falciparum to artemisinins in Western Cambodia at Thai-Cambodia border was first presented and confirmed in a subsequent detailed pharmacokinetic-pharmacodynamic study. Nevertheless, a trend of gradual decline of in vitro sensitivity to chloroquine has been documented in some areas of the country, particularly Thai-Myanmar border. There has been no clinical-parasitological evidence of chloroquine resistant P.vivax in Thai-Cambodia border, Thailand.

The objectives of the present study are to assess in vivo efficacy of first line regimen of chloroquine given with primaquine, and in vitro susceptibility of P.vivax isolates in areas along Thai-Cambodia border, Thailand.

Study Overview

• Status: Unknown
• Conditions: Acute Uncomplicated Malaria With P.Vivax Infection
• Intervention / Treatment: Drug: Artesunate; Drug: Chloroquine

Detailed Description

Plasmodium vivax affects 70-80 million cases of malaria worldwide annually, is the major cause of human malaria in parts of Pacific region and South America. In Thailand, the proportion of P.vivax infection has increased and it is now equal to Plasmodium falciparum since 1998. The incidence of P.vivax has recently been reported as 20 per 1000 population per year. Unlike Plasmodium falciparum, P.vivax infection rarely develops into complicated malaria and death is unusual. However, P.vivax has a dormant stage (the hypnozoite) that persists in the human liver and may cause relapse weeks, months, or even years later. Therefore, P.vivax infection is considered to have greater impact on morbidity than mortality, resulting in significant social and economic burden. Moreover, it is very difficult to control P.vivax transmission, because gametocytes appear almost simultaneously with schizonts.

Radical treatment of the infection, therefore, normally consists of a blood schizontocidal course of chloroquine and a course primaquine for the elimination of the hypnozoites as antirelapse therapy. However, chloroquine-resistant P.vivax (CRPv) has been emer-ging in different parts of the world. The first report of chloroquine resistant Plasmodium vivax was in 2 Australian soldiers returning from Papua New Guinea in Indonesia and is now spreading over Asia and the Pacific region. In Thailand, chloroquine and primaquine have remained the mainstay chemotherapeutics for the treatment of P.vivax for more than 60 years and resistance has not yet been reported. Occasional failure of the standard primaquine therapy (15 mg daily for 14 days) to prevent relapse has been observed. However, primaquine resistance has not been confirmed. In Thailand, the relapse rates at day 28 are about 50% without primaquine therapy, and about 20% with standard primaquine therapy. Relapse has not been observed among patients receiving high dose primaquine therapy (30 mg daily for 14 days).

A number of factors are reportedly associated with relapse, or the reappearance of P.vivax, including inadequate primaquine dosage, high parasitaemia at diagnosis, and short duration of symptoms prior to diagnosis, presence of gametocytes on admission, age, and gender. Because the radical cure of P.vivax hypnozoites requires 14 days of primaquine therapy, adherence to the drug regimen may greatly affect the prevention of relapse. Unfortunately, the effect of patient adherence on 14 day primaquine treatment, and its relation to preventing parasite reappearance, is not well-document.

Since January 2007, the evidence of reduced susceptibility of Plasmodium falciparum to artemisinins in Western Cambodia at Thai_Cambodia border was first presented and confirmed in a subsequent detailed pharmacokinetic-pharmacodynamic study. Nevertheless, a trend of gradual decline of in vitro sensitivity to chloroquine has been documented in some areas of the country, particularly Thai-Myanmar border. There has been no clinical-parasitological evidence of chloroquine resistant P.vivax in Thai-Cambodia border, Thailand.

The objectives of the present study are to assess in vivo efficacy of first line regimen of chloroquine given with primaquine, and in vitro susceptibility of P.vivax isolates in areas along Thai-Cambodia border, Thailand.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 4

Contacts and Locations

Study Locations

• Thailand
  • Ranong, Thailand
    • Recruiting
    • Kraburi Hospital
    • Contact: Thongchai Keeratihatayagorn, MD; Phone Number: +6681 8952244
    • Contact: Prakaykaew Charunwatthana, MD; Phone Number: +6681-844 9678; Email: jib@tropmedres.ac
    • Sub-Investigator: Thongchai Keeratihatayagorn, MD
  • Srisaket, Thailand
    • Recruiting
    • Khunhan Hospital
    • Contact: Prakaykaew Charunwatthana, MD; Phone Number: +6681-844 9678; Email: jib@tropmedres.ac
    • Contact: Ratchadaporn Runchareon, MD; Phone Number: +6681-790-9275
    • Sub-Investigator: Ratchadaporn Runchareon, MD
  • Srisaket, Thailand
    • Recruiting
    • Phusing Hospital
    • Contact: Kitipumi Chutasmit, MD; Phone Number: +6687 9654139
    • Contact: Prakaykaew Charunwatthan, MD; Phone Number: +6681-844 9678; Email: jib@tropmedres.ac
    • Sub-Investigator: Kitipumi Chutasmit, MD
  • Surin, Thailand
    • Recruiting
    • Kap Choeng Hospital
    • Contact: Prakaykaew Charunwatthana, MD; Phone Number: +6681-844 9678; Email: jib@tropmedres.ac
    • Contact: Satawat Sinprasitkul, MD; Phone Number: +6681 7601087
    • Sub-Investigator: Satawat Sinprasitkul, MD
    • Sub-Investigator: Worawun Kopkitngam, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female, aged from 18 years to 65 years old who can come to the study hospital for follow up in case of re-infection
• Acute uncomplicated malaria with P.vivax infection, confirmed by positive blood smear with asexual forms of P. vivax with parasitaemia > 1,000 parasites/microliters
• Fever defined as temperature > 37.5 degree celsius or a history of fever within the last 24 hours
• Written informed consent
• Willingness and ability of the patients/guardians to comply with the study protocol for the duration of the study
• Communicate with Thai language

Exclusion Criteria:

• Mixed infection with other plasmodium species
• For females: pregnancy, breast feeding
• History of allergy or known contraindication to chloroquine, artesunate or primaquine
• Any criteria of severe / complicated malaria (WHO 2010)
• Presence of febrile condition caused by disease other than malaria.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AS2; Artesunate 2 mg/kg/day for 5 days Combine with; Primaquine 15 mg is given daily for 14 days.; Or primaquine 45 mg is given once a week for 8 weeks in G6PD deficiency patients.	Drug: Artesunate
Active Comparator: Chloroquine; CH25: Chloroquine 25 mg/kg: 15 mg base/kg on the first days (D0), followed by 5 mg base/kg daily on the second and third day (day1-2) (total 25 mg base/ kg). Combine with; Primaquine 15 mg is given daily for 14 days.; Or primaquine 45 mg is given once a week for 8 weeks in G6PD deficiency patients.	Drug: Chloroquine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite Clearance Rate	Parasite clearance rate as defined by the slope of the linear portion of the natural logarithm parasite clearance curve	7 days
Relapse rate of P. vivax	Incidence of relapse in P.vivax infection	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite clearance time	Parasite clearance time assessed by microscopy	7 days
Parasite density time	Time of parasite count to fall to 50%, 90% and 99% of initial parasite density	7 days
Fever clearance time	Fever clearance time (i.e. the time taken for temperature to fall below 37 degrees celsius and remain there for at least 24 hrs)	7 days
Proportion of patients with gametocytemia	Proportion of patients with gametocytemia before, during and after treatment, assessed at admission, on day 3 stratified by presence of gametocytes at enrolment	7 days
In vitro antimalarial drug susceptibility	IC0, IC90, IC99 of Plasmodium vivax responses to antimalarial drugs ( ex vivo)	7 days

Collaborators and Investigators

• Sponsor: Mahidol University

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Anticipated): December 1, 2014

Study Registration Dates

• First Submitted: August 8, 2012
• First Submitted That Met QC Criteria: August 8, 2012
• First Posted (Estimate): August 10, 2012

Study Record Updates

• Last Update Posted (Estimate): January 25, 2013
• Last Update Submitted That Met QC Criteria: January 24, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Chloroquine; Artesunate; Primaquine; P. vivax infection
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Vivax; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Amebicides; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Chloroquine; Artesunate
• Other Study ID Numbers: FTM1202