ACT With Chloroquine, Amodiaquine & Sulphadoxine-pyrimethamine in Pakistan

January 11, 2017 updated by: Brian Greenwood, London School of Hygiene and Tropical Medicine

Studies on Adding Artesunate to Existing Antimalarial Therapies With Chloroquine, Amodiaquine & Sulphadoxine-pyrimethamine in Pakistan

Chloroquine resistant falciparum malaria in Pakistan is prevalent in every malarious area examined. Resistance to the favoured second-line treatment, sulphadoxine-pyrimethamine S/P is rising fast. To avert a repetition of the resistance catastrophe that occurred in SE Asia it is critical to preserve the effective life of SP by using it in combination with artesunate. Efficacy of ACT with artesunate in combination with chloroquine, SP or amodiaquine for treatment of malaria (falciparum or vivax) will be examined in malaria patients in Pakistan.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The incidence of falciparum malaria in Pakistan has risen 6-fold over the last 15 years and chloroquine resistance is prevalent in every malarious area examined. Chloroquine's position as first line treatment must be reconsidered. Resistance to the favoured second-line treatment, sulphadoxine-pyrimethamine SP, is 10% and rising fast. It is critical to preserve the effective life of SP by using it in combination with a non-related fast-acting antimalarial such as artesunate (AS). It is conceivable that use of AS in combination with chloroquine itself might even recover the latter's effectiveness and restrain the selection of stronger levels of chloroquine resistance. To determine the tolerability and efficacy of AS combination therapy in the subcontinent, randomized controlled trials will be conducted by HealthNet International and government staff, with technical support from LSHTM, in Afghan refugee camps in Pakistan against the current therapies of chloroquine, amodiaquine and SP. Current policy is to use primaquine(PQ) as the gametocytocidal drug with CQ or SP. It is not clear whether this has any value in the face of high levels of CQ resistance. The efficacy of PQ in combination with CQ or SP will be examined in individual randomised trial in comparison with CQ or SP alone.

In the past, treatment of falciparum and vivax malaria was with chloroquine. With development of drug resistance treatment of the two species is diverging and this places higher priority on accurate differential diagnosis which cannot always be met at peripheral health posts. There may be advantage in harmonising treatment of the two species with ACT. Thus the current treatment for vivax, chloroquine, shall be compared with that of ACT with artesunate and SP, the likely ACT to be adopted for falciparum malaria.

Protocol design:

Randomised, single-blind, controlled trials comparing for falciparum malaria (1) artesunate (AS) and chloroquine (CQ), vs CQ alone, vs CQ and primaquine (PQ); (2) AS and sulphadoxine-pyrimethamine (SP), vs SP alone, vs SP and PQ; (3) AS and amodiaquine (AQ), vs AQ alone.

Randomised, single-blind, controlled trial comparing for vivax malaria: AS and sulphadoxine-pyrimethamine (SP), vs CQ alone.

Patients will be randomly assigned to one of the following treatment groups:

  • CQ (day1,2,3) + placebo (day 1, 3) vs
  • CQ (day 1,2,3) + PQ (day 1) + placebo (day 3) vs
  • CQ (day 1,2,3) + PQ (day 3) + placebo (day 1) vs
  • CQ (day 1,2,3) + AS (day 1) + placebo (day 3)
  • S/P (day 1) + placebo (day 1) vs
  • S/P (day 1) + AS (day 1) vs
  • S/P (day 1) + PQ (day 1)
  • AQ (day 1,2,3) + placebo (day 1,2,3) vs
  • AQ (day 1,2,3) + AS (day 1,2,3)

To determine the viability and transmissibility of any gametocytes (and also to detect sub-patent gametocytaemias) still present after treatment it is also proposed to carry out mosquito feeding studies directly on patients on the 7th day after the start of combination therapy with either CQ, CQ+AS, CQ+PQ., SP, SP+AS, SP+PQ and to incubate any midgut infections to the oocyst stage. To determine the genetic consequences of any selection from the different drugs (i.e. CQ, AS, or PQ), the mosquito midgut infections would be preserved for further genetic studies in UK, as would blood samples taken from initial and recrudescent infections.

To improve our understanding of the genetic basis of drug resistance we will genotype parasites from blood samples of patients with treatment failure in this study. Blood samples of 20 patients from each arm of the study who had parasitological treatment failure will be selected randomly, together with midgut infections, and analysed for genetic markers of resistance to chloroquine and sulphadoxine/pyrimethamine. These will be compared with genotypes of pre-treatment infections.

Study Type

Interventional

Enrollment (Actual)

650

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Pakistan
      • Peshawar, Pakistan
        • HealthNet International

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

5 years to 70 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • adults or children > 5 yrs
  • weight > 5 kg
  • monoinfection with P. falciparum or P. vivax
  • history of recent fever
  • consent from patient or parent.

Exclusion Criteria:

  • patients with signs of severe malaria.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Day 7 slide clearance rate (complete clearance of trophozoites) assessed by microscopists who are blind to treatment allocation.
Day 28 slide clearance rate without subsequent recrudescence.
Day 7 gametocyte prevalence.

Secondary Outcome Measures

Outcome Measure
Fever clearance time
Day 14 gametocyte prevalence
cure rate (elimination of parasitaemia without recrudescence).
Rate and time of parasite clearance.
Rate of resolution of fever.
Proportion of gametocyte carriers.
Transmissibility of gametocytes through mosquito feeding studies.
Tolerability.
Molecular characterisation of genetic diversity and resistance before and after treatment.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

London School of Hygiene and Tropical Medicine

Collaborators

World Health Organization
United Nations High Commissioner for Refugees
HealthNet TPO
Malaria Control Program, Directorate of Malaria Control, Pakistan

Investigators

  • Principal Investigator: Kate Graham, MSc, HealthNet International, Peshawar, Pakistan

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2001

Study Completion (Actual)

December 1, 2004

Study Registration Dates

First Submitted

September 8, 2005

First Submitted That Met QC Criteria

September 8, 2005

First Posted (Estimate)

September 12, 2005

Study Record Updates

Last Update Posted (Estimate)

January 12, 2017

Last Update Submitted That Met QC Criteria

January 11, 2017

Last Verified

January 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ITDCVC98
  • ITDCVV98

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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