Artemisinin-Based Antimalarial Combinations and Clinical Response in Cameroon

Sponsor

University of Yaounde 1 (Other)

Overall Status

Completed

CT.gov ID

NCT01845701

Collaborator

World Health Organization (Other), Gates Malaria Partnership (Other)

720

Enrollment

Locations

Arms

Duration (Months)

360

Patients Per Site

5.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To assess the efficacy of artesunate-amodiaquine, dihydroartemisinin-piperaquine, in comparison with artemether-lumefantrine during 42 days follow up period in 720 children with acute uncomplicated P. falciparum malaria, in two different endemic ecological areas - Savanna and equatorial forest regions of Cameroon.

We have set as specific objectives:

To assess the efficacy of artesunate-amodiaquine, dihydroartemisinin-piperaquine, in comparison with artemether-lumefantrine during 14 and 28 days follow up period in children with acute uncomplicated P. falciparum malaria in two different endemic areas.
To evaluate the safety of artesunate-amodiaquine, dihydroartemisinin-piperaquine, in comparison with artemether-lumefantrine during 42 days follow up period in children with acute uncomplicated P. falciparum malaria.
To determine parasite clearance time (PCT) and fever clearance time (FCT) following the administration of the three trial regimens.
To investigate the treatment response based on WHO criteria (WHO, 2003) in patients in all groups after trial.
To investigate the Single Nucleotide Polymorphisms (SNPs) and microsatellite markers of genes associated with drug resistance

Condition or Disease	Intervention/Treatment	Phase
Malaria	Drug: Artesunate-Amodiaquine Drug: Dihydroartemisinine-Piperaquine Drug: Artemether-lumefantrine combination	Phase 3

Detailed Description

Methodology Children of either gender, between 6 months (> 5kg) and 10 years of age, with acute uncomplicated P. falciparum infection, who fulfil all of the inclusion and have none of exclusion criteria will be enrolled in the study. They will be randomised to receive the three trial arms, i.e, Study Arm-A: artesunate-amodiaquine, Study Arm-B: dihydroartemisinin-piperaquine and Study Arm-C: artemether-lumefantrine at the ratio of 2:2:1 and will be hospitalised over a 3-day period to facilitate the supervised administration of the study drugs and full clinical and laboratory assessment and observation of early adverse effects. On discharge, participants will be required to report to the study clinic on days 7, 14, 21,28, 35 and 42 or at any other time when clinical sign(s)/symptom(s) of malaria is suspected. The number of participants is about 720 children

Inclusion Criteria

Children of either gender, aged between 6 months (> 5kg) and 10 years.
Suffering from acute uncomplicated P. falciparum malaria confirmed by microscopy using Giemsa-stained thick film with an asexual parasite density of 1,000 to 100,000 parasites/μl.
Presenting with fever (axillary temperature ≥ 37.5oC) or having a history of fever in the preceding 24 hours.
Able to ingest tablets orally (either suspended in water or uncrushed with food).
Willing to participate in the study with written assent from parent/guardian. Parental authorization will be obtained for children less than 8 years old and documented assent of parents/guardians for children 8-10 years.
Willing and able to attend the clinic on stipulated regular follow-up visits.

Exclusion Criteria

• Any of the following "danger signs of severe malaria": Not able to drink or breast feed Persistent vomiting (>2 episodes within previous 24 hours) Convulsions (>1 episode within previous 24 hours) Lethargic/unconscious

Signs/symptoms indicating severe/complicated malaria according to WHO criteria (WHO definition).
Concomitant illnesses, underlying chronic hepatic or renal disease, abnormal cardiac rhythm, hypoglycaemia, jaundice, respiratory distress,
Serious gastrointestinal disease, severe malnutrition (W/H < 70%) or severe anaemia (haemoglobin < 5 g/dl).
Known hypersensitivity to the study drugs.

Study Design

Study Type:

Interventional

Actual Enrollment :

720 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Care Provider)

Primary Purpose:

Treatment

Official Title:

Phase III Study to Study the Clinical Response to ACT Fixed Dose Combination in 42 Days in Uncomplicated Malaria in Cameroon

Study Start Date :

Mar 1, 2010

Actual Primary Completion Date :

Apr 1, 2014

Actual Study Completion Date :

Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Artesunate-Amodiaquine As a fixed-dose combination of artesunate-amodiaquine developed by Sanofi-Aventis (France). It has the advantage of being a 3-day regimen usable by all age groups and potentially low cost. tablets are administered per every day at dose of 25mg/67.5mg for those between 4,5kg and 9kg for 48H	Drug: Artesunate-Amodiaquine Pharmacology: Amodiaquine is effective against the erythrocytic stages of all four species of P. falciparum. Amodiaquine accumulates in the parasite's lysosomes and prevents breakdown of haemoglobin on which the parasite depends for its survival. Artesunate is a water-soluble hemisuccinate derivative of artemisinin. Artesunate and its active metabolite dihydroartemisinin are potent blood schizonticides, active against the ring stage of the parasite. The fixed-dose combination dihydroartemisinin-piperaquine has a cost advantage over other ACTs that brings it within reach of many, making it a potential best candidate for deployment in Africa and other poor countries. The drug is currently produced in China (Duo-cotecxin®). Other Names: CoArsucam
Experimental: Dihydroartemisinine_Piperaquine As a fixed-dose combination of dihydroartemisinin-piperaquine which is produced by Fouley (China). It is a potentially low cost 2-day regimen that has been used in children between 5-10kg as half a tablet of 40mg/320mg every day for 48H	Drug: Dihydroartemisinine-Piperaquine It is a bisquinoline antimalarial drug (1,3-bis[1-(7-chloro-4 quinolyl)-4- piperazinyl]-propane) that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria. With the development of piperaquine-resistant strains of P. falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. Other Names: Duo-Cotecxin
Active Comparator: Artemeter-Lumefantrine This is the active comparator as a fixed-dose combination of artemether and lumefantrine which is produced by Novartis (Switzerland). The drug will be used as the comparator because it is the only fixed-dose combination with artemether currently available. Administered in children as tablets containing Artemether-Lumefantrine at (20mg/120mg) for body weights of 5-10kg every 12H within 48H.	Drug: Artemether-lumefantrine combination CoArtem® is an oral, fixed combination of artemether- a derivative of artemisinin and lumefantrine- a novel molecule developed by the Academy of Military Medical Sciences (AMMS) in Beijing. It is the only co-formulated ACT approved by WHO and is currently available through WHO at a negotiated public sector price. Both compounds are effective as single agents. However, recrudescence is common with artemether and lumefantrine has a slow onset of action. A fixed combination tablet (20 mg artemether/120 mg lumefantrine) has therefore been developed. Fixed combination therapy improves compliance and has the advantage of carrying a lower risk of selecting drug resistant strains. No resistance to either component has been observed to date. Other Names: CoArtem

Arm

Intervention/Treatment

Experimental: Artesunate-Amodiaquine

As a fixed-dose combination of artesunate-amodiaquine developed by Sanofi-Aventis (France). It has the advantage of being a 3-day regimen usable by all age groups and potentially low cost. tablets are administered per every day at dose of 25mg/67.5mg for those between 4,5kg and 9kg for 48H

Drug: Artesunate-Amodiaquine

Pharmacology: Amodiaquine is effective against the erythrocytic stages of all four species of P. falciparum. Amodiaquine accumulates in the parasite's lysosomes and prevents breakdown of haemoglobin on which the parasite depends for its survival. Artesunate is a water-soluble hemisuccinate derivative of artemisinin. Artesunate and its active metabolite dihydroartemisinin are potent blood schizonticides, active against the ring stage of the parasite. The fixed-dose combination dihydroartemisinin-piperaquine has a cost advantage over other ACTs that brings it within reach of many, making it a potential best candidate for deployment in Africa and other poor countries. The drug is currently produced in China (Duo-cotecxin®).

Other Names:

CoArsucam

Experimental: Dihydroartemisinine_Piperaquine

As a fixed-dose combination of dihydroartemisinin-piperaquine which is produced by Fouley (China). It is a potentially low cost 2-day regimen that has been used in children between 5-10kg as half a tablet of 40mg/320mg every day for 48H

Drug: Dihydroartemisinine-Piperaquine

It is a bisquinoline antimalarial drug (1,3-bis[1-(7-chloro-4 quinolyl)-4- piperazinyl]-propane) that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria. With the development of piperaquine-resistant strains of P. falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative.

Other Names:

Duo-Cotecxin

Active Comparator: Artemeter-Lumefantrine

This is the active comparator as a fixed-dose combination of artemether and lumefantrine which is produced by Novartis (Switzerland). The drug will be used as the comparator because it is the only fixed-dose combination with artemether currently available. Administered in children as tablets containing Artemether-Lumefantrine at (20mg/120mg) for body weights of 5-10kg every 12H within 48H.

Drug: Artemether-lumefantrine combination

CoArtem® is an oral, fixed combination of artemether- a derivative of artemisinin and lumefantrine- a novel molecule developed by the Academy of Military Medical Sciences (AMMS) in Beijing. It is the only co-formulated ACT approved by WHO and is currently available through WHO at a negotiated public sector price. Both compounds are effective as single agents. However, recrudescence is common with artemether and lumefantrine has a slow onset of action. A fixed combination tablet (20 mg artemether/120 mg lumefantrine) has therefore been developed. Fixed combination therapy improves compliance and has the advantage of carrying a lower risk of selecting drug resistant strains. No resistance to either component has been observed to date.

Other Names:

CoArtem

Outcome Measures

Primary Outcome Measures

Clinical Efficacy [42 days]
Patient's trial outcome will be classified according to the WHO guidelines (WHO 2003) with application as follows: Early Treatment Failure (ETF); Late Clinical Failure (LCF); Late Parasitological Failure (LPF); Adequate Clinical and Parasitological Response (ACPR) - Absence of parasitaemia on day 42 irrespective of temperature without previously meeting any of the criteria of early treatment failure or late clinical failure or late parasitological failure

Secondary Outcome Measures

Safety by measure of changes in Physiologic, Blood, Liver and Kidney functions to define AE & SAEs [42 days]
Prevalence of adverse events (AEs) and serious adverse events (SAEs): proportion of patients who experience AEs or SAEs during the follow up period of 42 days. Changes in vital Physiologic parameters (blood pressure, pulse rate): proportion of patients who have significant changes in vital signs comparing to baseline during the follow up period of 42 days. Prevalence of abnormal laboratory tests: proportion of patients who have abnormal values of laboratory tests (ALAT, ASAT, Bilirubin, Creatinine, Glucose, Urea etc), during the follow up period of 42 days.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months to 120 Months

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Children of either gender, aged between 6 months (> 5kg) and 10 years.
Suffering from acute uncomplicated P. falciparum malaria confirmed by microscopy using Giemsa-stained thick film with an asexual parasite density of 1,000 to 100,000 parasites/μl.
Presenting with fever (axillary temperature ≥ 37.5oC) or having a history of fever in the preceding 24 hours.
Able to ingest tablets orally (either suspended in water or uncrushed with food).
Willing to participate in the study with written assent from parent/guardian. Parental authorization will be obtained for children less than 8 years old and documented assent of parents/guardians for children 8-10 years.
Willing and able to attend the clinic on stipulated regular follow-up visits.

Exclusion Criteria:

•Any of the following "danger signs of severe malaria": Not able to drink or breast feed Persistent vomiting (>2 episodes within previous 24 hours) Convulsions (>1 episode within previous 24 hours) Lethargic/unconscious

Signs/symptoms indicating severe/complicated malaria according to WHO criteria (WHO definition).
Concomitant illnesses, underlying chronic hepatic or renal disease, abnormal cardiac rhythm, hypoglycaemia, jaundice, respiratory distress,
Serious gastrointestinal disease, severe malnutrition (W/H < 70%) or severe anaemia (haemoglobin < 5 g/dl).
Known hypersensitivity to the study drugs.