Plasmodium Falciparum MalariaPhase 4AcoVNCT03773536
Efficacy and Safety of Artesunate + Amodiaquine With SLD of Primaquine for Treatment of Falciparum Malaria in Zanzibar
A Phase 4 study testing Artesunate-amodiaquine given with single low dose primaquine in people with Plasmodium Falciparum Malaria, run by Professor Anders Björkman at 1 site in Tanzania.
Trial summary
The general objective of this study is to assess the therapeutic efficacy and safety of artesunate + amodiaquine combined with a single low dose of primaquine (0.25 mg/kg) for the treatment of uncomplicated P. falciparum malaria patients in Zanzibar. Read more about this study
- Who is it for?
- Ages 3 months and older
- Conditions the study is for
- Plasmodium Falciparum Malaria
- What is being tested?
- Artesunate-amodiaquine given with single low dose primaquine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 146 participants
- Where
- 1 siteTanzania
- Study dates
- 9 May 2017to 25 Sep 2017
- 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 3 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Age 3 months and above;
- P. falciparum infection detected by malaria rapid diagnostic test (mRDT) and confirmed by microscopy;
- Presence of P. falciparum malaria asexual parasitaemia (any level);
- Presence of axillary ≥37.5 °C or history of fever during the past 48 hours
- Ability to swallow oral medication;
- Ability and willingness to comply with the study protocol for the duration of the study and to comply with the study visit schedule; and
- Informed consent from the patient or from a parent or guardian in the case of children.
Who cannot join
- Presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO (Appendix 1);
- Mono-infection with a Plasmodium species other than P. falciparum detected by microscopy;
- Presence of febrile conditions other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. severe malnutrition, cardiac, renal and hepatic diseases, HIV/AIDS);
- Regular medication, which may interfere with the study drugs;
- History of hypersensitivity reactions or contraindications to any of the study medicines; and
- Pregnancy
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Efficacy and Safety of Artesunate + Amodiaquine Combined With a Single Low Dose of Primaquine (0.25 mg/kg) for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Zanzibar
The general objective of this study is to assess the therapeutic efficacy and safety of artesunate + amodiaquine combined with a single low dose of primaquine (0.25 mg/kg) for the treatment of uncomplicated P. falciparum malaria patients in Zanzibar.
The specific objectives are:
- To determine the clinical and parasitological efficacy of artesunate + amodiaquine and primaquine in the treatment of uncomplicated Plasmodium falciparum infection.
- To differentiate recurrent infections during follow-up, i.e. recrudescence from new infections, by polymerase chain reaction (PCR).
- To evaluate the incidence of adverse events, particularly with regards to potential hematological adverse events of primaquine.
- To determine the polymorphism of molecular markers associated with artesunate + amodiaquine tolerance/resistance.
- To formulate recommendations, which will enable the Zanzibar Ministry of Health to make informed decisions about whether the current national antimalarial treatment guidelines should be updated or not.
- To determine efficacy rate of the first line treatment compared to the first efficacy trial thirteen years ago.
Read the detailed description
The aim of this study is to provide policymakers with updated efficacy and safety data of artesunate + amodiaquine in combination with a single low dose of primaquine (0.25 mg/kg) and data on genetic markers of tolerance/resistance to artemisinin based combination therapies (ACTs), proposed as an early warning system for development and spread of antimalarial drug resistance, in Zanzibar. The study protocol is based on the new WHO guidelines for surveillance of antimalarial drug efficacy (WHO 2014).
This surveillance study was designed as a one-arm prospective evaluation of the clinical and parasitological responses to directly observed treatment for uncomplicated malaria. Participants were recruited from febrile patients, i.e. documented axillary temperature ≥37.5 °C or history of fever during the past 48 hours, of 3 months and older, presenting at primary health care facilities in Zanzibar, with microscopy confirmed uncomplicated P. falciparum infection. Enrolled patients received directly observed treatment with artesunate + amodiaquine once daily for 3 consecutive days according to the national malaria treatment guidelines. A single low dose of primaquine (0.25 mg/kg) was administered together with the first artesunate + amodiaquine dose. Clinical and parasitological as well as safety parameters were monitored over a 28-day follow-up period. The follow-up consisted of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations. On the basis of the results of these assessments, the patients were classified as having therapeutic failure (early or late) or an adequate response. Blood samples from patients experiencing therapeutic failure during the follow-up period were used to estimate the efficacy of the study drugs based on PCR analysis to distinguish between recrudescence (treatment failures) and reinfection (new infections).
A standard physical examination was performed at baseline (day 0 before drug administration) and on days 1, 2, 3, 7, 14, 21, and 28 ,or any other day if the patient returned spontaneously and parasitological reassessment was required. This examination included measuring axillary temperature, with a thermometer that has a precision of 0.1 °C, as well as conducting a thick film for asexual and gametocyte counts and species identification. Haemoglobin was assessed systematically on all participants on days 0, 3, 7, 14 and 28 using Hemocue, and at any time in case of clinical suspicion of anaemia, i.e. pallor, according to standard case management of malaria in Zanzibar.
In order to differentiate a recrudescence (treatment failure/same parasite strain) from a newly acquired infection (reinfection/different parasite strain) among recurrent parasitemias found during follow-up, a genotype analysis was to be conducted. This analysis was based on the extensive diversity in the following P. falciparum genes: the merozoite surface protein 1 (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic profiles of pre- and post-parasite strains were to be compared in a stepwise manner to distinguish recrudescence from reinfection. In order to minimize discomfort to the patient due to repeated finger pricks, two to three drops of blood will be collected on a 3MM (Whatman) filter paper during screening or enrollment and each time blood smears are required according to the protocol from day 7.
The results of this study will be used to assist the Zanzibar Ministry of Health in assessing the current national treatment guidelines for uncomplicated P. falciparum malaria.
- Conditions
- Plasmodium Falciparum Malaria
- Being tested
- Artesunate-amodiaquine given with single low dose primaquine
- Keywords
- Artesunate-amodiaquine, Single Low Dose Primaquine, 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.
Artesunate-amodiaquine given with single low dose primaquineDrug
Three day treatment with ASAQ with SLD primaquine given with the first dose of ASAQ.
| Study group | Role | What they receive |
|---|---|---|
| ASAQ + SLD Primaquine | Experimental | Artesunate + amodiaquine (WHO prequalified Artesunate/Amodiaquine Winthrop®) was administered orally as a fixed dose combination, at a dose of approximately artesunate 4 mg/kg + amodiaquine 10mg/kg once daily for 3 consecutive days. Primaquine was administered orally, as a single dose (0.25 mg/kg) together with the first artesunate + amodiaquine dose. All doses of medicine were administered under direct supervision. Any patient who vomited within a 30 minute observation period was re-treated with the same dose of medicine and observed for an additional 30 minutes. If the patient vomited again after the second study drug administration, he/she was withdrawn and offered rescue therapy (Artesunate IV). Receives: Drug: Artesunate-amodiaquine given with single low dose primaquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
PCR corrected cure rates for assessing efficacy of artesunate + amodiaquine given together with a single low dose primaquine in the treatment of uncomplicated Plasmodium falciparum infection
PCR corrected cure rates were to be assessed by genotype analysis of the following P. falciparum genes: the merozoite surface protein 1 (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic profiles of pre- and post-parasite strains were to be compared in a stepwise manner to distinguish recrudescence from reinfection.
Measured: 42 days
Secondary outcomes (1)
Safety of artesunate + amodiaquine and primaquine: Incidence of adverse events
Incidence of adverse events, particularly with regards to potential hematological adverse events of primaquine.
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 posted12 Dec 2018
- Study start9 May 2017
- Primary completion25 Sep 2017
- Study completion25 Sep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- 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
- Not applicable
- Intervention model
- Single group
- Model description
- A one-armed prospective antimalarial drug efficacy trial.
- Masking
- None (open label)
- Enrolment
- 146 participants (actual)
Sponsor and investigators
- Lead sponsor
- Professor Anders Björkman
- Sponsor type
- University, hospital or other
- Collaborators
- Ministry of Health and Social Welfare, Zanzibar, Zanzibar Malaria Elimination Programme, Uppsala University
- Responsible party
- Sponsor-investigator, Professor Anders Björkman, Karolinska Institutet
- Investigators
- Mwinyi I Msellem, Principal investigator, Mnazi mmoja hospital, Zanzibar Ministry of HealthAbduallah S Ali, Study director, Zanzibar Malaria Elimination ProgrammeAndreas Martensson, Study chair, Uppsala University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03773536
- Sponsor's protocol ID
- Aco V
- Acronym
- AcoV
- Status last verified
- Dec 2018
- First submitted
- 3 Dec 2018
- Last updated
- 12 Dec 2018
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy and Safety of Artesunate + Amodiaquine Combined With a Single Low Dose of Primaquine (0.25 mg/kg) for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Zanzibar
- ClinicalTrials.gov ID
- NCT03773536
- Acronym / sponsor ID
- AcoV / Aco V
- Conditions
- Plasmodium Falciparum Malaria
- Keywords
- Artesunate-amodiaquine, Single Low Dose Primaquine, Zanzibar
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 146 participants (actual)
- Lead sponsor
- Professor Anders BjörkmanUniversity, hospital or other
- Collaborators
- Ministry of Health and Social Welfare, Zanzibar, Zanzibar Malaria Elimination Programme, Uppsala University
- Study start
- 9 May 2017 (actual)
- Primary completion
- 25 Sep 2017 (actual)
- Study completion
- 25 Sep 2017 (actual)
- First posted
- 12 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 general objective of this study is to assess the therapeutic efficacy and safety of artesunate + amodiaquine combined with a single low dose of primaquine (0.25 mg/kg) for the treatment of uncomplicated P. falciparum malaria patients in Zanzibar.
The specific objectives are:
- To determine the clinical and parasitological efficacy of artesunate + amodiaquine and primaquine in the treatment of uncomplicated Plasmodium falciparum infection.
- To differentiate recurrent infections during follow-up, i.e. recrudescence from new infections, by polymerase chain reaction (PCR).
- To evaluate the incidence of adverse events, particularly with regards to potential hematological adverse events of primaquine.
- To determine the polymorphism of molecular markers associated with artesunate + amodiaquine tolerance/resistance.
- To formulate recommendations, which will enable the Zanzibar Ministry of Health to make informed decisions about whether the current national antimalarial treatment guidelines should be updated or not.
- To determine efficacy rate of the first line treatment compared to the first efficacy trial thirteen years ago.
Detailed description
The aim of this study is to provide policymakers with updated efficacy and safety data of artesunate + amodiaquine in combination with a single low dose of primaquine (0.25 mg/kg) and data on genetic markers of tolerance/resistance to artemisinin based combination therapies (ACTs), proposed as an early warning system for development and spread of antimalarial drug resistance, in Zanzibar. The study protocol is based on the new WHO guidelines for surveillance of antimalarial drug efficacy (WHO 2014).
This surveillance study was designed as a one-arm prospective evaluation of the clinical and parasitological responses to directly observed treatment for uncomplicated malaria. Participants were recruited from febrile patients, i.e. documented axillary temperature ≥37.5 °C or history of fever during the past 48 hours, of 3 months and older, presenting at primary health care facilities in Zanzibar, with microscopy confirmed uncomplicated P. falciparum infection. Enrolled patients received directly observed treatment with artesunate + amodiaquine once daily for 3 consecutive days according to the national malaria treatment guidelines. A single low dose of primaquine (0.25 mg/kg) was administered together with the first artesunate + amodiaquine dose. Clinical and parasitological as well as safety parameters were monitored over a 28-day follow-up period. The follow-up consisted of a fixed schedule of check-up visits and corresponding clinical and laboratory examinations. On the basis of the results of these assessments, the patients were classified as having therapeutic failure (early or late) or an adequate response. Blood samples from patients experiencing therapeutic failure during the follow-up period were used to estimate the efficacy of the study drugs based on PCR analysis to distinguish between recrudescence (treatment failures) and reinfection (new infections).
A standard physical examination was performed at baseline (day 0 before drug administration) and on days 1, 2, 3, 7, 14, 21, and 28 ,or any other day if the patient returned spontaneously and parasitological reassessment was required. This examination included measuring axillary temperature, with a thermometer that has a precision of 0.1 °C, as well as conducting a thick film for asexual and gametocyte counts and species identification. Haemoglobin was assessed systematically on all participants on days 0, 3, 7, 14 and 28 using Hemocue, and at any time in case of clinical suspicion of anaemia, i.e. pallor, according to standard case management of malaria in Zanzibar.
In order to differentiate a recrudescence (treatment failure/same parasite strain) from a newly acquired infection (reinfection/different parasite strain) among recurrent parasitemias found during follow-up, a genotype analysis was to be conducted. This analysis was based on the extensive diversity in the following P. falciparum genes: the merozoite surface protein 1 (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic profiles of pre- and post-parasite strains were to be compared in a stepwise manner to distinguish recrudescence from reinfection. In order to minimize discomfort to the patient due to repeated finger pricks, two to three drops of blood will be collected on a 3MM (Whatman) filter paper during screening or enrollment and each time blood smears are required according to the protocol from day 7.
The results of this study will be used to assist the Zanzibar Ministry of Health in assessing the current national treatment guidelines for uncomplicated P. falciparum malaria.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- A one-armed prospective antimalarial drug efficacy trial.
| Arm | Type | Receives |
|---|---|---|
| ASAQ + SLD Primaquine | Experimental | Drug: Artesunate-amodiaquine given with single low dose primaquineArtesunate + amodiaquine (WHO prequalified Artesunate/Amodiaquine Winthrop®) was administered orally as a fixed dose combination, at a dose of approximately artesunate 4 mg/kg + amodiaquine 10mg/kg once daily for 3 consecutive days. Primaquine was administered orally, as a single dose (0.25 mg/kg) together with the first artesunate + amodiaquine dose. All doses of medicine were administered under direct supervision. Any patient who vomited within a 30 minute observation period was re-treated with the same dose of medicine and observed for an additional 30 minutes. If the patient vomited again after the second study drug administration, he/she was withdrawn and offered rescue therapy (Artesunate IV). |
Who may qualify
- Ages
- 3 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (7 listed)
- Age 3 months and above;
- P. falciparum infection detected by malaria rapid diagnostic test (mRDT) and confirmed by microscopy;
- Presence of P. falciparum malaria asexual parasitaemia (any level);
- Presence of axillary ≥37.5 °C or history of fever during the past 48 hours
- Ability to swallow oral medication;
Key exclusion criteria (6 listed)
- Presence of general danger signs in children aged under 5 years or signs of severe falciparum malaria according to the definitions of WHO (Appendix 1);
- Mono-infection with a Plasmodium species other than P. falciparum detected by microscopy;
- Presence of febrile conditions other than malaria (e.g. measles, acute lower respiratory tract infection, severe diarrhoea with dehydration) or other known underlying chronic or severe diseases (e.g. severe malnutrition, cardiac, renal and hepatic diseases, HIV/AIDS);
- Regular medication, which may interfere with the study drugs;
- History of hypersensitivity reactions or contraindications to any of the study medicines; and
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 |
|---|---|---|
| Artesunate-amodiaquine given with single low dose primaquineThree day treatment with ASAQ with SLD primaquine given with the first dose of ASAQ. | Drug | ASAQ + SLD Primaquine |
Primary outcome
PCR corrected cure rates for assessing efficacy of artesunate + amodiaquine given together with a single low dose primaquine in the treatment of uncomplicated Plasmodium falciparum infection
Time frame: 42 days
PCR corrected cure rates were to be assessed by genotype analysis of the following P. falciparum genes: the merozoite surface protein 1 (msp1) and 2 (msp2), and the glutamine-rich protein (glurp) (WHO 2008). The genotypic profiles of pre- and post-parasite strains were to be compared in a stepwise manner to distinguish recrudescence from reinfection.
1 secondary outcome
Safety of artesunate + amodiaquine and primaquine: Incidence of adverse events
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 12 Dec 2018.
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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.
Mwinyi I Msellem principal investigator
Mnazi mmoja hospital, Zanzibar Ministry of Health
Abduallah S Ali study director
Zanzibar Malaria Elimination Programme
Andreas Martensson study chair
Uppsala University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Artesunate-amodiaquine given with single low dose primaquine in people with Plasmodium Falciparum Malaria, run by Professor Anders Björkman at 1 site in Tanzania.
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 7 inclusion and 6 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 12 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Tanzania. Whether a site is taking part right now should be confirmed with that site. See every site.
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 for assessing efficacy of artesunate + amodiaquine given together with a single low dose primaquine in the treatment of uncomplicated Plasmodium falciparum infection (time frame: 42 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 12 Dec 2018.