Accute Falciparum MalariaNCT02645604
Artemether-lumefantrine Resistance Monitoring in Children With Uncomplicated Plasmodium Falciparum Malaria in Mali
An observational study of Accute Falciparum Malaria, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in Mali.
Trial summary
Background: Malaria is a disease caused by a parasite. People get malaria if they are bitten by an parasite-infected mosquito. A drug called artemether-lumefantrine (AL) can treat malaria. Read more about this study
- Who is it for?
- Ages 2 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Accute Falciparum Malaria
- How many people
- 154 participants
- Where
- 1 siteMali
- Study dates
- 1 Jan 2016to 14 Dec 2018
- Phase
- Observational
- 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 2 to 65 years
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Subject Inclusion Criteria: AL Resistance Monitoring Study
- Resident of Kenieroba
- Age 2 to 17 years
- Uncomplicated falciparum malaria, confirmed by the presence of asexual P. falciparum parasites on blood film
- Asexual P. falciparum count between 2,000 and 200,000/ microliters (inclusive) at screening
- Tympanic or axillary temperature greater than or equal to 37.5 (Infinite)C or history of fever in the previous 24 hours
Show all 15Show fewer
- Written informed consent from the child s parent or guardian, and assent from children aged 14-17 years
- Subject Inclusion Criteria: Parasite Clearance Substudy
- Enrolled in the AL Resistance Monitoring Study
- Asexual P. falciparum count greater than or equal to 10,000/ microliters at screening
- Hb level greater than or equal to 7 g/dL
- Subject Inclusion Criteria: Blood Collection Study
- Age 18 to 65 years or 5 to 65 years old for the mosquito infectivity study
- Healthy-appearing
- Hb level greater than or equal to 7 g/dL
Who cannot join
- Subject Exclusion Criteria: AL Efficacy Study
- Signs of severe malaria, defined as one or more of the following:
- Blantyre Coma Scale less than or equal to 3/5 in children
- Witnessed convulsions
- Severe prostration
- Shock (poor perfusion, cool peripheries)
Show all 28Show fewer
- Hb <5 g/dL
- Jaundice
- Respiratory distress (labored breathing, nasal flaring, intercostal retraction)
- Anuria for 24 hours or more
- Repetitive vomiting
- Cessation of eating and drinking
- Acute illness other than uncomplicated falciparum malaria requiring treatment
- Presence of P. ovale or P. malariae parasites on blood film
- Severe malnutrition: http://www.who.int/childgrowth/standards/Technical_report.pdf
- Pregnancy or breastfeeding an infant
- Planning to become pregnant in the next 1 month
- History of taking an ACT in the previous 14 days
- Known hypersensitivity to artemether or LF
- Co-administration of strong inducers of CYP3A4 such as rifampin, carbamazepine, phenytoin, and St. John s wort
- Splenectomy
- Any condition that in the opinion of the investigator would render the patient unable to comply with the protocol (e.g., psychiatric disease)
- Any health condition that in the opinion of the investigator would confound data analysis (e.g., HIV infection) or pose unnecessary exposure risks to the subject
- Subject Exclusion Criteria: Parasite Clearance Substudy
- -Prior enrollment in the Parasite Clearance Substudy in current transmission season
- Subject Exclusion Criteria: Blood Collection Study
- P. falciparum infection, as determined by thick blood smear examination (unless the subject is being screened for inclusion in the mosquito infectivity study, in which case parasitemia, as detected by RDT or smear, is an inclusion criteria)
- History of taking an ACT in the previous 28 days
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Artemether-Lumefantrine Resistance Monitoring in Children With Uncomplicated Plasmodium Falciparum Malaria in Mali
Background: Malaria is a disease caused by a parasite. People get malaria if they are bitten by an parasite-infected mosquito. A drug called artemether-lumefantrine (AL) can treat malaria. Although iAL has helped make the malaria problem less severe in the African country of Mali, researchers want to find out if malaria parasites are becoming resistant to this drug.
Objective: To test for AL-resistant parasites in children with malaria in Mali.
Read more
Eligibility:
AL resistance monitoring study: children aged 2 17 years who live in Kenieroba, Mali, and have malaria.
Blood collection substudy: healthy volunteers aged 18 65 years.
Design:
Volunteers for the substudy will have blood taken up to 6 times a year.
Study participants will be screened with 1 finger-prick blood sample. Girls may have a pregnancy test.
Baseline visit: Participants will have a physical exam. Their vital signs and temperature will be measured. They will answer questions about their symptoms. They will give a blood sample.
Participants will get 6 doses of AL over 3 days. They will take it in tablet form with milk.
Some participants will also stay at the clinic for 2 days. They will have a catheter placed in a vein. They will have blood taken frequently.
Participants will have follow-up visits for about 1 month. They may have:
Physical exam performed
Vital signs and temperature measured
Symptom questionnaire administered
Finger-prick blood sample and/or a regular blood sample taken
Pregnancy test given
Antimalarial medications other than AL provided.
Read the detailed description
Artemether-lumefantrine (AL) has replaced artesunate + amodiaquine as the frontline artemisinin (ART) combination therapy (ACT) for uncomplicated Plasmodium falciparum malaria in Mali. It is not known whether parasites are developing resistance to AL in Mali, where we are studying how naturally-acquired immunity and sickle-cell trait reduce malaria risk and parasite density in our pediatric study population. AL Resistance Monitoring Study: To monitor for emerging AL resistance in vivo and lumefantrine (LF) resistance ex vivo, we will conduct a standard WHO-recommended protocol to measure AL resistance rates over the next 4 years. We will enroll all children aged 2-17 years with uncomplicated falciparum malaria and parasite count between 2,000 and 200,000 parasites per microliter, treat them with AL on D0, D1, and D2, confirm adequate LF plasma concentrations on Day 7, and monitor for malaria symptoms and recurrent parasitemias on D0, D1, D2, D3, D7, D14, D21, and D28. In related laboratory studies, we will use blood samples taken at the times of enrollment and recrudescence to measure parasite susceptibility to LF and other antimalarial drugs ex vivo; investigate genetic and transcriptional determinants of parasite response to AL in vivo and LF ex vivo; and prepare cryopreserved parasites for future work on drug action and resistance mechanisms. Parasite Clearance Substudy: We have recently discovered an agedependent acceleration of parasite clearance rates in Malian children, and postulate that it is mediated by IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite s main virulence factor on the surface of infected red blood cells (iRBCs). We hypothesize that ART exposure induces the premature expression of PfEMP1 on the surface of circulating ring-iRBCs in vivo. To test this hypothesis, we will calculate parasite clearance rates in a subset of subjects with relatively high parasite densities, and relate these rates to the ability of autologous IgG to recognize ring-iRBCs over the first 8 hours of ART exposure in vivo. In this same subset of patients, we will also explore whether AL induces parasite dormancy in vivo by removing parasites at H0, H6, H24, H48, D3, D7, and D14 following AL therapy, and cloning them to quantify the number of viable parasites. Blood Collection Study: We have found that sickle-cell trait (HbAS), like naturally-acquired humoral immunity, reduces both malaria risk and parasite density in our study population, and that this protection is associated with abnormal PfEMP1 display on the iRBC surface. To elucidate the molecular mechanism of this phenotype and explore how it may synergize with naturally-acquired IgG responses, we will investigate whether the development of PfEMP1 trafficking machinery is impaired in HbAS compared to normal homozygous hemoglobin A (HbAA) red blood cells (RBCs). To test this, we will purify parasite isolates from children with malaria, inoculate them into HbAA and HbAS RBCs from healthy adult donors, and follow their intraerythrocytic development using flow cytometry and electron microscopy.
- Conditions
- Accute Falciparum Malaria
- Keywords
- Artemisinin Combination Therapy (ACT)
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment failure up to Day 28. A subject will be defined as a treatment failure if the subject has developed P. falciparum parasitemia detected by thick blood smear (not by PCR) between the time that parasitemia becomes undetectable and Day 28,...
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jan 2016 (estimated)
- Study start1 Jan 2016
- Primary completion14 Dec 2018
- Study completion14 Dec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Accute Falciparum MalariaStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- 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
- Observational
- Observational model
- Case only
- Time perspective
- Cross-sectional
- Enrolment
- 154 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Rick M Fairhurst, M.D., Principal investigator, National Institute of Allergy and Infectious Diseases (NIAID)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02645604
- Sponsor's protocol ID
- 999916033
- Other IDs
- 16-I-N033
- Status last verified
- 14 Dec 2018
- First submitted
- 1 Jan 2016
- Last updated
- 17 Dec 2019
- Results posted
- No
Publications
Lopera-Mesa TM, Doumbia S, Chiang S, Zeituni AE, Konate DS, Doumbouya M, Keita AS, Stepniewska K, Traore K, Diakite SA, Ndiaye D, Sa JM, Anderson JM, Fay MP, Long CA, Diakite M, Fairhurst RM. Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity. J Infect Dis. 2013 Jun 1;207(11):1655-63. doi: 10.1093/infdis/jit082. Epub 2013 Feb 28.
PubMed 23448727Ndour PA, Lopera-Mesa TM, Diakite SA, Chiang S, Mouri O, Roussel C, Jaureguiberry S, Biligui S, Kendjo E, Claessens A, Ciceron L, Mazier D, Thellier M, Diakite M, Fairhurst RM, Buffet PA. Plasmodium falciparum clearance is rapid and pitting independent in immune Malian children treated with artesunate for malaria. J Infect Dis. 2015 Jan 15;211(2):290-7. doi: 10.1093/infdis/jiu427. Epub 2014 Sep 2.
PubMed 25183768Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect Dis. 2015 Jun;15(6):692-702. doi: 10.1016/S1473-3099(15)70024-1. Epub 2015 Mar 16.
PubMed 25788162Petersen JEV, Saelens JW, Freedman E, Turner L, Lavstsen T, Fairhurst RM, Diakite M, Taylor SM. Sickle-trait hemoglobin reduces adhesion to both CD36 and EPCR by Plasmodium falciparum-infected erythrocytes. PLoS Pathog. 2021 Jun 11;17(6):e1009659. doi: 10.1371/journal.ppat.1009659. eCollection 2021 Jun.
PubMed 34115805
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Artemether-Lumefantrine Resistance Monitoring in Children With Uncomplicated Plasmodium Falciparum Malaria in Mali
- ClinicalTrials.gov ID
- NCT02645604
- Acronym / sponsor ID
- 999916033
- Conditions
- Accute Falciparum Malaria
- Keywords
- Artemisinin Combination Therapy (ACT)
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 154 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- 1 Jan 2016
- Primary completion
- 14 Dec 2018 (actual)
- Study completion
- 14 Dec 2018 (actual)
- First posted
- 5 Jan 2016 (estimated)
- 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.
Background: Malaria is a disease caused by a parasite. People get malaria if they are bitten by an parasite-infected mosquito. A drug called artemether-lumefantrine (AL) can treat malaria. Although iAL has helped make the malaria problem less severe in the African country of Mali, researchers want to find out if malaria parasites are becoming resistant to this drug.
Objective: To test for AL-resistant parasites in children with malaria in Mali.
Eligibility:
AL resistance monitoring study: children aged 2 17 years who live in Kenieroba, Mali, and have malaria.
Blood collection substudy: healthy volunteers aged 18 65 years.
Design:
Volunteers for the substudy will have blood taken up to 6 times a year.
Study participants will be screened with 1 finger-prick blood sample. Girls may have a pregnancy test.
Baseline visit: Participants will have a physical exam. Their vital signs and temperature will be measured. They will answer questions about their symptoms. They will give a blood sample.
Participants will get 6 doses of AL over 3 days. They will take it in tablet form with milk.
Some participants will also stay at the clinic for 2 days. They will have a catheter placed in a vein. They will have blood taken frequently.
Participants will have follow-up visits for about 1 month. They may have:
Physical exam performed
Vital signs and temperature measured
Symptom questionnaire administered
Finger-prick blood sample and/or a regular blood sample taken
Pregnancy test given
Antimalarial medications other than AL provided.
Detailed description
Artemether-lumefantrine (AL) has replaced artesunate + amodiaquine as the frontline artemisinin (ART) combination therapy (ACT) for uncomplicated Plasmodium falciparum malaria in Mali. It is not known whether parasites are developing resistance to AL in Mali, where we are studying how naturally-acquired immunity and sickle-cell trait reduce malaria risk and parasite density in our pediatric study population. AL Resistance Monitoring Study: To monitor for emerging AL resistance in vivo and lumefantrine (LF) resistance ex vivo, we will conduct a standard WHO-recommended protocol to measure AL resistance rates over the next 4 years. We will enroll all children aged 2-17 years with uncomplicated falciparum malaria and parasite count between 2,000 and 200,000 parasites per microliter, treat them with AL on D0, D1, and D2, confirm adequate LF plasma concentrations on Day 7, and monitor for malaria symptoms and recurrent parasitemias on D0, D1, D2, D3, D7, D14, D21, and D28. In related laboratory studies, we will use blood samples taken at the times of enrollment and recrudescence to measure parasite susceptibility to LF and other antimalarial drugs ex vivo; investigate genetic and transcriptional determinants of parasite response to AL in vivo and LF ex vivo; and prepare cryopreserved parasites for future work on drug action and resistance mechanisms. Parasite Clearance Substudy: We have recently discovered an agedependent acceleration of parasite clearance rates in Malian children, and postulate that it is mediated by IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), the parasite s main virulence factor on the surface of infected red blood cells (iRBCs). We hypothesize that ART exposure induces the premature expression of PfEMP1 on the surface of circulating ring-iRBCs in vivo. To test this hypothesis, we will calculate parasite clearance rates in a subset of subjects with relatively high parasite densities, and relate these rates to the ability of autologous IgG to recognize ring-iRBCs over the first 8 hours of ART exposure in vivo. In this same subset of patients, we will also explore whether AL induces parasite dormancy in vivo by removing parasites at H0, H6, H24, H48, D3, D7, and D14 following AL therapy, and cloning them to quantify the number of viable parasites. Blood Collection Study: We have found that sickle-cell trait (HbAS), like naturally-acquired humoral immunity, reduces both malaria risk and parasite density in our study population, and that this protection is associated with abnormal PfEMP1 display on the iRBC surface. To elucidate the molecular mechanism of this phenotype and explore how it may synergize with naturally-acquired IgG responses, we will investigate whether the development of PfEMP1 trafficking machinery is impaired in HbAS compared to normal homozygous hemoglobin A (HbAA) red blood cells (RBCs). To test this, we will purify parasite isolates from children with malaria, inoculate them into HbAA and HbAS RBCs from healthy adult donors, and follow their intraerythrocytic development using flow cytometry and electron microscopy.
Study design
- Observational model
- Case only
- Time perspective
- Cross-sectional
Who may qualify
- Ages
- 2 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (15 listed)
- Subject Inclusion Criteria: AL Resistance Monitoring Study
- Resident of Kenieroba
- Age 2 to 17 years
- Uncomplicated falciparum malaria, confirmed by the presence of asexual P. falciparum parasites on blood film
- Asexual P. falciparum count between 2,000 and 200,000/ microliters (inclusive) at screening
Key exclusion criteria (28 listed)
- Subject Exclusion Criteria: AL Efficacy Study
- Signs of severe malaria, defined as one or more of the following:
- Acute illness other than uncomplicated falciparum malaria requiring treatment
- Presence of P. ovale or P. malariae parasites on blood film
- Severe malnutrition: http://www.who.int/childgrowth/standards/Technical_report.pdf
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Treatment failure up to Day 28. A subject will be defined as a treatment failure if the subject has developed P. falciparum parasitemia detected by thick blood smear (not by PCR) between the time that parasitemia becomes undetectable and Day 28,...
Time frame: 28 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 17 Dec 2019.
- Background: PubMed 23448727Lopera-Mesa TM, Doumbia S, Chiang S, Zeituni AE, Konate DS, Doumbouya M, Keita AS, Stepniewska K, Traore K, Diakite SA, Ndiaye D, Sa JM, Anderson JM, Fay MP, Long CA, Diakite M, Fairhurst RM. Plasmodium falciparum clearance rates in response to artesunate in Malian children with malaria: effect of acquired immunity. J Infect Dis. 2013 Jun 1;207(11):1655-63. doi: 10.1093/infdis/jit082. Epub 2013 Feb 28.
- Background: PubMed 25183768Ndour PA, Lopera-Mesa TM, Diakite SA, Chiang S, Mouri O, Roussel C, Jaureguiberry S, Biligui S, Kendjo E, Claessens A, Ciceron L, Mazier D, Thellier M, Diakite M, Fairhurst RM, Buffet PA. Plasmodium falciparum clearance is rapid and pitting independent in immune Malian children treated with artesunate for malaria. J Infect Dis. 2015 Jan 15;211(2):290-7. doi: 10.1093/infdis/jiu427. Epub 2014 Sep 2.
- Background: PubMed 25788162Worldwide Antimalarial Resistance Network (WWARN) AL Dose Impact Study Group. The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data. Lancet Infect Dis. 2015 Jun;15(6):692-702. doi: 10.1016/S1473-3099(15)70024-1. Epub 2015 Mar 16.
- Derived from this study: PubMed 34115805Petersen JEV, Saelens JW, Freedman E, Turner L, Lavstsen T, Fairhurst RM, Diakite M, Taylor SM. Sickle-trait hemoglobin reduces adhesion to both CD36 and EPCR by Plasmodium falciparum-infected erythrocytes. PLoS Pathog. 2021 Jun 11;17(6):e1009659. doi: 10.1371/journal.ppat.1009659. eCollection 2021 Jun.
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.
Rick M Fairhurst, M.D. principal investigator
National Institute of Allergy and Infectious Diseases (NIAID)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Accute Falciparum Malaria, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in Mali.
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 15 inclusion and 28 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 17 Dec 2019. 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 Mali. 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.
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?
Treatment failure up to Day 28. A subject will be defined as a treatment failure if the subject has developed P. falciparum parasitemia detected by thick blood smear (not by PCR) between the time that parasitemia becomes undetectable and Day 28,... (time frame: 28 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 NCT02645604, which also lists 4 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 17 Dec 2019.