Plasmodium Falciparum MalariaPhase 4AcoINCT03764527
Tolerability and Efficacy of Artemether-Lumefantrine Versus Artesunate + Amodiaquine in Zanzibar
A Phase 4 study testing Artemether-lumefantrine and Coadministered Artesunate plus Amodiaquine in people with Plasmodium Falciparum Malaria, run by Professor Anders Björkman.
Trial summary
The primary objective of the study was to determine PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine or Coartem®. Secondary objectives were to determine safety and possible selection of mutations related to the resistance of the tested drugs. Read more about this study
- Who is it for?
- Ages 6 to 59 months
- Conditions the study is for
- Plasmodium Falciparum Malaria
- What is being tested?
- Artemether-lumefantrine and Coadministered Artesunate plus Amodiaquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 408 participants
- Where
- No sites listed yet
- Study dates
- 1 Nov 2002to 17 Feb 2003
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 59 months
- All sexes
- Child
Who may be able to join
- Children age 6-59 months and body weight ≥6 kg (AQ+AS); 9-59 months and body weight ≥9 kg (AL)
- Fever or history of fever in the preceding 24 hours
- Parasitemia ≥2000 ≤200.000 parasites per µl
- Informed consent given by the child's parent or other adult guardian
Who cannot join
- Signs of severe malaria or other danger signs, such as: 1.Unconsciousness; 2. Not able to sit or stand; 3.Severe anaemia (Hb ≤ 5 g/dl); 4.Convulsions; 5. Shock (systolic BP<50 mmHg); 6. Not able to drink or breastfeed; 7. Vomiting 3 times or more the past 24 hrs
- Other diseases associated with fever
- History of allergy to test drugs
- History of intake of any drugs other than paracetamol and aspirin within 3 days
About this study
Official title: Randomized Study of the Tolerability and Efficacy of Artemether-Lumefantrine Versus Artesunate Plus Amodiaquine Coadministered for the Treatment of Uncomplicated Falciparum Malaria in Zanzibar
The primary objective of the study was to determine PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine or Coartem®.
Secondary objectives were to determine safety and possible selection of mutations related to the resistance of the tested drugs.
Read the detailed description
Combination therapy, the new strategy for malaria treatment, is based on the hypothesis that two (or more) components of different mechanisms of action protect each other from development of resistance. Artemisinin as well as its two derivatives, e.g. artemether and artesunate, constitute a family of compounds with several attractive features for such a combination, due mainly to their rapid onset of effective action against multidrug-resistant P. falciparum and their gametocytocidal effect, which potentially reduces transmission of resistant alleles. There also appears to be no cross-resistance with other known anti-malarials. Because of the short half-life of this family of compounds, their use as mono-therapy requires multiple daily doses over a period of 7 days. Combining them with longer acting partner -drugs allows for a reduction in treatment duration while simultaneously enhancing the efficacy and reducing the likelihood of resistance development.
As of October 2001 the following anti-malarial drugs were recommended for malaria treatment in Zanzibar:
- Artesunate (AS)+ Amodiaquine (AQ) - "first line" (AA)
- Lumefantrine-artemether (Co-artem®) (CO) - "second line"
- Quinine, if failure or contra indication of 1 \& 2, or for treatment of severe malaria
- Sulfadoxine-pyrimethamine (SP) for Intermittent Presumptive Treatment in pregnancy (IPT)
The move that the Zanzibar Ministry of Health has taken with this new treatment policy/strategy provided a unique opportunity to investigate the potential value of combination therapy when introduced on a large scale. Using artemisinine derivatives in combination with anti-malarials with longer half-lives is thought to be highly effective and considerably prevent the development of parasite resistance to the individual drugs. This study therefore provided baseline data on the efficacy of the new treatment policy and also for future monitoring of the policy in Zanzibar.
All children presenting with clinical signs of malaria at the study site were considered possible study subjects. The guardians of these children were informed about the study orally in Swahili for providing informed consent. Those who were willing to participate in the study were treated according to local standard procedure. The patient was tested for parasites using light microscopy on Giemsa stained blood films. A detailed clinical history, a clinical examination including an axillary temperature, was assessed. Haemoglobin was assessed and blood samples were collected on filter paper for each child for genotyping of the parasites as well as for determining blood levels of different antimalarial drugs.
The children included in the study were assigned to one of the two treatment options according to randomisation schedule, except children <9 months weighing <9 kg who were assigned AA because AL was registered for treatment of children <9 months weighing <9 kg. The drugs were given in standard doses according to bodyweight: artesunate 4 mg/kg bodyweight + amodiaquine 10 mg/kg bodyweight, once daily for 3 days, Coartem: 9 to <15 kg: 1 tablet; 15-25 kg: 2 tablets, twice daily for 3 days. All drugs were administrated under direct supervision of a study nurse. Full drug doses were re-administered if a patient spits out or vomits within 30 minutes. Drug treatment was provided free of charge.
The guardian was asked to bring their child back to the study site on day 1, 2, 3, 7, 14, 21, 28, 35 and 42. If they failed to do so they were visited in their homes to assure proper follow-up. At each follow-up the investigator asked about concomitant medication and adverse events, carefully filling out the clinical report form (CRF). If, during the follow-up between day 14 and 42, a child presented with fever, all tests and examinations were run as on day 0. If the child was clinically and parasitologically diagnosed with malaria again, he was treated as a new infection as of the national recommended guidelines. If diagnosed with severe malaria during the follow-up period the patient was given rescue treatment (oral or intravenous Quinine) and taken out of the study. Each time an enrolled child presented at the site the CRF was completed with regards to clinical and laboratory status, treatment given and possible adverse events.
The study drugs were obtained from the respective companies with the assistance of WHO/TDR and RBM.
- Conditions
- Plasmodium Falciparum Malaria
- Being tested
- Artemether-lumefantrine, Coadministered Artesunate plus Amodiaquine
- Keywords
- Artemether-Lumefantrine, Coartem, Artesunate, Amodiaquine, Zanzibar
- Medical subject headings
- Malaria, Falciparum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Artemether-lumefantrineDrug
Also called Coartem®
Two doses a day for 3 days, under supervision
Coadministered Artesunate plus AmodiaquineDrug
One dose a day for 3 days, under supervision
| Study group | Role | What they receive |
|---|---|---|
| Artemether-lumefantrine (AL) | Active comparator | One tablet of artemether-lumefantrine (Coartem®) was administered twice daily for 3 days to children with a body weight of 9 to <15 kg, and 2 tablets were administered twice daily for 3 days to children with a body weight of >15 to 25 kg. All doses were taken under direct observation. Receives: Drug: Artemether-lumefantrine |
| Artesunate + Amodiaquine (AA) | Active comparator | Artesunate + amodiaquine (ASAQ) was administered as follows: 4 mg/kg body weight of artesunate plus 10 mg/kg body weight of amodiaquine once daily for 3 days under direct observation. Receives: Drug: Coadministered Artesunate plus Amodiaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine (AA) or Coartem® (CO)
Comparing PCR adjusted parasitological cure rate (PCR-APCR) between the two treatment options up to day 42. Parasitological cure will be adjusted using PCR genotyping of msp2 marker. Recrudescence is defined as the presence of at least one matching allelic band, and reinfection as the absence of any matching allelic band on day 0 and day of recurring parasitaemia. Patients with recurrent parasitaemia having missing filter paper sample or negative PCR results will be considered uncertain with regards to PCR adjusted outcome.
Measured: 42 days
Secondary outcomes (6)
Safety of treatment with Artesunate + Amodiaquine (AA) or Coartem® (CO): Proportion of subjects with adverse events
Proportion of subjects with adverse events, including early vomiting and mean values of white blood cells (WBC) and neutrophils
Measured: 42 days
Parasite clearance
Proportion of patients with microscopy detectable parasitaemia at each time point
Measured: 42 days
Gametocyte carriage
Proportion of patients with microscopy detectable gametocytes at each time point
Measured: 42 days
Fever clearance
Proportion of patients with fever at each time point
Measured: 42 days
Hemoglobin
Mean and individual hemoglobin values at different time points during follow up
Measured: 42 days
Selection of mutations in P. falciparum related to the resistance of the study drugs
Change in possible selections of mutations related to quinoline resistance. Percentage of pfcrt and pfmdr1 mutations on day 0 and day of recurrent infection.
Measured: 42 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Dec 2018
- Study start1 Nov 2002
- Primary completion17 Feb 2003
- Study completion17 Feb 2003
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Plasmodium Falciparum MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A comparative randomised study comparing oral treatment with AQ + AS and CO of uncomplicated falciparum malaria in children.
- Masking
- None (open label)
- Enrolment
- 408 participants (actual)
Sponsor and investigators
- Lead sponsor
- Professor Anders Björkman
- Sponsor type
- University, hospital or other
- Collaborators
- Zanzibar Malaria Control Programme, World Health Organization
- Responsible party
- Sponsor-investigator, Professor Anders Björkman, Karolinska Institutet
- Investigators
- Abdullah Ali, Principal investigator, Zanzibar Malaria Control Programme
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03764527
- Sponsor's protocol ID
- Aco-study
- Acronym
- AcoI
- Status last verified
- Dec 2018
- First submitted
- 3 Dec 2018
- Last updated
- 6 Dec 2018
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Bjorkman A. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005 Oct 15;41(8):1079-86. doi: 10.1086/444460. Epub 2005 Sep 13.
PubMed 16163624Sisowath C, Ferreira PE, Bustamante LY, Dahlstrom S, Martensson A, Bjorkman A, Krishna S, Gil JP. The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Trop Med Int Health. 2007 Jun;12(6):736-42. doi: 10.1111/j.1365-3156.2007.01843.x.
PubMed 17550470Holmgren G, Hamrin J, Svard J, Martensson A, Gil JP, Bjorkman A. Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. Infect Genet Evol. 2007 Sep;7(5):562-9. doi: 10.1016/j.meegid.2007.03.005. Epub 2007 Mar 31.
PubMed 17467344
Study at a glance
From the registry record, last updated by the sponsor on 6 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Study of the Tolerability and Efficacy of Artemether-Lumefantrine Versus Artesunate Plus Amodiaquine Coadministered for the Treatment of Uncomplicated Falciparum Malaria in Zanzibar
- ClinicalTrials.gov ID
- NCT03764527
- Acronym / sponsor ID
- AcoI / Aco-study
- Conditions
- Plasmodium Falciparum Malaria
- Keywords
- Artemether-Lumefantrine, Coartem, Artesunate, Amodiaquine, Zanzibar
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 408 participants (actual)
- Lead sponsor
- Professor Anders BjörkmanUniversity, hospital or other
- Collaborators
- Zanzibar Malaria Control Programme, World Health Organization
- Study start
- 1 Nov 2002 (actual)
- Primary completion
- 17 Feb 2003 (actual)
- Study completion
- 17 Feb 2003 (actual)
- First posted
- 5 Dec 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary objective of the study was to determine PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine or Coartem®.
Secondary objectives were to determine safety and possible selection of mutations related to the resistance of the tested drugs.
Detailed description
Combination therapy, the new strategy for malaria treatment, is based on the hypothesis that two (or more) components of different mechanisms of action protect each other from development of resistance. Artemisinin as well as its two derivatives, e.g. artemether and artesunate, constitute a family of compounds with several attractive features for such a combination, due mainly to their rapid onset of effective action against multidrug-resistant P. falciparum and their gametocytocidal effect, which potentially reduces transmission of resistant alleles. There also appears to be no cross-resistance with other known anti-malarials. Because of the short half-life of this family of compounds, their use as mono-therapy requires multiple daily doses over a period of 7 days. Combining them with longer acting partner -drugs allows for a reduction in treatment duration while simultaneously enhancing the efficacy and reducing the likelihood of resistance development.
As of October 2001 the following anti-malarial drugs were recommended for malaria treatment in Zanzibar:
- Artesunate (AS)+ Amodiaquine (AQ) - "first line" (AA)
- Lumefantrine-artemether (Co-artem®) (CO) - "second line"
- Quinine, if failure or contra indication of 1 \& 2, or for treatment of severe malaria
- Sulfadoxine-pyrimethamine (SP) for Intermittent Presumptive Treatment in pregnancy (IPT)
The move that the Zanzibar Ministry of Health has taken with this new treatment policy/strategy provided a unique opportunity to investigate the potential value of combination therapy when introduced on a large scale. Using artemisinine derivatives in combination with anti-malarials with longer half-lives is thought to be highly effective and considerably prevent the development of parasite resistance to the individual drugs. This study therefore provided baseline data on the efficacy of the new treatment policy and also for future monitoring of the policy in Zanzibar.
All children presenting with clinical signs of malaria at the study site were considered possible study subjects. The guardians of these children were informed about the study orally in Swahili for providing informed consent. Those who were willing to participate in the study were treated according to local standard procedure. The patient was tested for parasites using light microscopy on Giemsa stained blood films. A detailed clinical history, a clinical examination including an axillary temperature, was assessed. Haemoglobin was assessed and blood samples were collected on filter paper for each child for genotyping of the parasites as well as for determining blood levels of different antimalarial drugs.
The children included in the study were assigned to one of the two treatment options according to randomisation schedule, except children <9 months weighing <9 kg who were assigned AA because AL was registered for treatment of children <9 months weighing <9 kg. The drugs were given in standard doses according to bodyweight: artesunate 4 mg/kg bodyweight + amodiaquine 10 mg/kg bodyweight, once daily for 3 days, Coartem: 9 to <15 kg: 1 tablet; 15-25 kg: 2 tablets, twice daily for 3 days. All drugs were administrated under direct supervision of a study nurse. Full drug doses were re-administered if a patient spits out or vomits within 30 minutes. Drug treatment was provided free of charge.
The guardian was asked to bring their child back to the study site on day 1, 2, 3, 7, 14, 21, 28, 35 and 42. If they failed to do so they were visited in their homes to assure proper follow-up. At each follow-up the investigator asked about concomitant medication and adverse events, carefully filling out the clinical report form (CRF). If, during the follow-up between day 14 and 42, a child presented with fever, all tests and examinations were run as on day 0. If the child was clinically and parasitologically diagnosed with malaria again, he was treated as a new infection as of the national recommended guidelines. If diagnosed with severe malaria during the follow-up period the patient was given rescue treatment (oral or intravenous Quinine) and taken out of the study. Each time an enrolled child presented at the site the CRF was completed with regards to clinical and laboratory status, treatment given and possible adverse events.
The study drugs were obtained from the respective companies with the assistance of WHO/TDR and RBM.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- A comparative randomised study comparing oral treatment with AQ + AS and CO of uncomplicated falciparum malaria in children.
| Arm | Type | Receives |
|---|---|---|
| Artemether-lumefantrine (AL) | Active comparator | Drug: Artemether-lumefantrineOne tablet of artemether-lumefantrine (Coartem®) was administered twice daily for 3 days to children with a body weight of 9 to <15 kg, and 2 tablets were administered twice daily for 3 days to children with a body weight of >15 to 25 kg. All doses were taken under direct observation. |
| Artesunate + Amodiaquine (AA) | Active comparator | Drug: Coadministered Artesunate plus AmodiaquineArtesunate + amodiaquine (ASAQ) was administered as follows: 4 mg/kg body weight of artesunate plus 10 mg/kg body weight of amodiaquine once daily for 3 days under direct observation. |
Who may qualify
- Ages
- 6 to 59 months
- Sex
- All
- Age groups
- Child
Key inclusion criteria (4 listed)
- Children age 6-59 months and body weight ≥6 kg (AQ+AS); 9-59 months and body weight ≥9 kg (AL)
- Fever or history of fever in the preceding 24 hours
- Parasitemia ≥2000 ≤200.000 parasites per µl
- Informed consent given by the child's parent or other adult guardian
Key exclusion criteria (4 listed)
- Signs of severe malaria or other danger signs, such as: 1.Unconsciousness; 2. Not able to sit or stand; 3.Severe anaemia (Hb ≤ 5 g/dl); 4.Convulsions; 5. Shock (systolic BP<50 mmHg); 6. Not able to drink or breastfeed; 7. Vomiting 3 times or more the past 24 hrs
- Other diseases associated with fever
- History of allergy to test drugs
- History of intake of any drugs other than paracetamol and aspirin within 3 days
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Artemether-lumefantrineAlso: Coartem®Two doses a day for 3 days, under supervision | Drug | Artemether-lumefantrine (AL) |
| Coadministered Artesunate plus AmodiaquineOne dose a day for 3 days, under supervision | Drug | Artesunate + Amodiaquine (AA) |
Primary outcome
PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine (AA) or Coartem® (CO)
Time frame: 42 days
Comparing PCR adjusted parasitological cure rate (PCR-APCR) between the two treatment options up to day 42. Parasitological cure will be adjusted using PCR genotyping of msp2 marker. Recrudescence is defined as the presence of at least one matching allelic band, and reinfection as the absence of any matching allelic band on day 0 and day of recurring parasitaemia. Patients with recurrent parasitaemia having missing filter paper sample or negative PCR results will be considered uncertain with regards to PCR adjusted outcome.
6 secondary outcomes
Safety of treatment with Artesunate + Amodiaquine (AA) or Coartem® (CO): Proportion of subjects with adverse events
Time frame: 42 days
Parasite clearance
Time frame: 42 days
Gametocyte carriage
Time frame: 42 days
Fever clearance
Time frame: 42 days
Hemoglobin
Time frame: 42 days
Selection of mutations in P. falciparum related to the resistance of the study drugs
Time frame: 42 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Dec 2018.
- Results publication: PubMed 16163624Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS, Bjorkman A. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005 Oct 15;41(8):1079-86. doi: 10.1086/444460. Epub 2005 Sep 13.
- Results publication: PubMed 17550470Sisowath C, Ferreira PE, Bustamante LY, Dahlstrom S, Martensson A, Bjorkman A, Krishna S, Gil JP. The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Trop Med Int Health. 2007 Jun;12(6):736-42. doi: 10.1111/j.1365-3156.2007.01843.x.
- Results publication: PubMed 17467344Holmgren G, Hamrin J, Svard J, Martensson A, Gil JP, Bjorkman A. Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. Infect Genet Evol. 2007 Sep;7(5):562-9. doi: 10.1016/j.meegid.2007.03.005. Epub 2007 Mar 31.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Abdullah Ali principal investigator
Zanzibar Malaria Control Programme
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Artemether-lumefantrine and Coadministered Artesunate plus Amodiaquine in people with Plasmodium Falciparum Malaria, run by Professor Anders Björkman.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PCR corrected cure-rates up to day 42 in children with uncomplicated malaria, treated with either Artesunate + Amodiaquine (AA) or Coartem® (CO) (time frame: 42 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03764527, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2018.