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Gametocytocidal and Transmission-blocking Efficacy of PQ in Combination With AL and TQ in Combination With SPAQ in Mali (NECTAR3)

Primary Purpose

Malaria,Falciparum

Status

Completed

Phase

Phase 2

Locations

Mali

Study Type

Interventional

Intervention

Artemether-lumefantrine

Primaquine Phosphate

Sulphadoxine-pyrimethamine with amodiaquine

Tafenoquine

About this trial

This is an interventional treatment trial for Malaria,Falciparum

Eligibility Criteria

10 Years - 50 Years (Child, Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Age ≥ 10 years and ≤ 50 years
G6PD-normal defined by Carestart rapid diagnostic test or the OSMMR2000 G6PD qualitative test
Absence of symptomatic falciparum malaria, defined by fever on enrolment
Presence of P. falciparum gametocytes on thick blood film at a density >16 gametocytes/μL (i.e. ≥ gametocytes recorded in the thick film against 500 white blood cells)
Absence of other non-P. falciparum species on blood film
Hemoglobin ≥ 10 g/dL
Individuals weighing < = 80 kg
No evidence of acute severe or chronic disease
Written, informed consent

Exclusion Criteria:

Women who are pregnant or lactating (tested at baseline). Urine and/or serum pregnancy testing (β-hCG) will be used.
Detection of a non-P. falciparum species by microscopy
Previous reaction to study drugs / known allergy to study drugs
Signs of severe malaria, including hyperparasitemia (defined as asexual parasitemia > 100,000 parasites / μL)
Signs of acute or chronic illness, including hepatitis
The use of other medication (except for paracetamol and/or aspirin)
Use of antimalarial drugs over the past 7 days (as reported by the participant)
Clinically significant illness (intercurrent illness e.g., pneumonia, pre-existing condition e.g., renal disease, malignancy or conditions that may affect absorption of study medication e.g., severe diarrhea or any signs of malnutrition as defined clinically)
Signs of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e., decompensated cirrhosis, Child Pugh stage B or C)
Signs, symptoms or known renal impairment
Clinically significant abnormal laboratory values as determined by history, physical examination or routine blood chemistries and hematology values (laboratory guideline values for exclusion are hemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age.
Blood transfusion in the last 90 days.
Consistent with the long half-life of tafenoquine, effective contraception should be continued for 5 half-lives (3 months) after the end of treatment.
History of psychiatric disorders

Sites / Locations

Malaria Research and Training Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

Arm Label

Artemether-lumefantrine (AL)

AL with 0.25mg/kg primaquine (PQ)

Sulphadoxine-pyrimethamine with amodiaquine (SPAQ)

SPAQ with 1.66mg/kg tafenoquine (TQ)

Arm Description

Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days.

Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of AL treatment.

Subjects will receive sulphadoxine-pyrimethamine with amodiaquine (SPAQ) once daily for 3 days.

Subjects will receive sulphadoxine-pyrimethamine with amodiaquine (SPAQ) once daily for 3 days and a single dose of 1.66mg/kg tafenoquine (TQ) on the first day of SPAQ treatment.

Outcomes

Primary Outcome Measures

Change in mosquito infection rate assessed through membrane feeding assays (day 2 and day 7)

Within person percent change (presented as percent reduction) in mosquito infection rate in infectious individuals from baseline (day 0, pre-treatment) to day 2 post treatment in the AL and AL-PQ arms, and day 7 post-treatment in the SPAQ and SPAQ-TQ.

Secondary Outcome Measures

Change in mosquito infection rate assessed through membrane feeding assays (all timepoints)

Within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points, with comparison within and between arms.

Mosquito infection rate assessed through membrane feeding assays

Mosquito infection rate at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Human infectivity to locally reared mosquitoes assessed through membrane feeding assays

Infectivity to mosquitoes at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Mosquito infection density assessed through membrane feeding assays

Oocyst intensity (in all/all infected mosquitoes) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Gametocyte infectivity

Infectiousness to mosquitoes for a given gametocyte density (measured as mosquito infection rate/gametocyte) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Asexual/sexual stage parasite prevalence

Male and female gametocyte prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite prevalence at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.

Asexual/sexual stage parasite density

Male and female gametocyte density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms. Asexual and total parasite density at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.

Sexual stage parasite sex ratio

Male and female gametocyte sex ratio (proportion male) at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.

Sexual stage parasite circulation time

Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.

Sexual stage parasite area under the curve (AUC)

Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.

Haemoglobin density

Haemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.

Change in haemoglobin density

Within person percent change (presented as percent reduction) in haemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.

Methaemoglobin density

Methaemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.

Change in methaemoglobin density

Within person percent change (presented as percent reduction) in methaemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.

Incidence of adverse events

The frequency and prevalence of adverse events (all AE's, treatment related AE's, and haematological AE's) observed up to and including day 2, 7, and 14 post-treatment, and at all timepoints.

Full Information

NCT ID

NCT05081089

First Posted

September 13, 2021

Last Updated

January 14, 2022

Sponsor

London School of Hygiene and Tropical Medicine

1. Study Identification

Unique Protocol Identification Number

NCT05081089

Brief Title

Gametocytocidal and Transmission-blocking Efficacy of PQ in Combination With AL and TQ in Combination With SPAQ in Mali

Acronym

NECTAR3

Official Title

A Four-arm Trial Comparing Artemether-lumefantrine With or Without Single-dose Primaquine and Sulphadoxine-pyrimethamine/Amodiaquine With or Without Single-dose Tafenoquine to Reduce P. Falciparum Transmission in Mali

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Completed

Study Start Date

October 12, 2021 (Actual)

Primary Completion Date

December 16, 2021 (Actual)

Study Completion Date

January 13, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

London School of Hygiene and Tropical Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to compare the gametocytocidal and transmission reducing activity of artemether-lumefantrine (AL) with and without a single dose of 0.25mg/kg primaquine (PQ) and sulfadoxine-pyrimethamine with amodiaquine (SPAQ) with and without single dose of 1.66mg/kg tafenoquine (TQ). Outcome measures will include infectivity to mosquitoes at 2, 5 and 7 days after treatment, gametocyte density throughout follow-up, and safety measures including haemoglobin density and the frequency of adverse events.

Detailed Description

Full protocol available on request.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malaria,Falciparum

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Masking Description

This is a single blind randomised controlled trial. The treating physician and staff involved with assessing all laboratory outcomes of the study are blinded, but no placebo will be used. The study pharmacist will be unblinded and responsible for randomisation and treatment administration.

Allocation

Randomized

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Artemether-lumefantrine (AL)

Arm Type

Active Comparator

Arm Description

Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days.

Arm Title

AL with 0.25mg/kg primaquine (PQ)

Arm Type

Experimental

Arm Description

Subjects will receive artemether-lumefantrine (AL) twice daily for 3 days and a single dose of 0.25mg/kg primaquine (PQ) on the first day of AL treatment.

Arm Title

Sulphadoxine-pyrimethamine with amodiaquine (SPAQ)

Arm Type

Active Comparator

Arm Description

Subjects will receive sulphadoxine-pyrimethamine with amodiaquine (SPAQ) once daily for 3 days.

Arm Title

SPAQ with 1.66mg/kg tafenoquine (TQ)

Arm Type

Experimental

Arm Description

Subjects will receive sulphadoxine-pyrimethamine with amodiaquine (SPAQ) once daily for 3 days and a single dose of 1.66mg/kg tafenoquine (TQ) on the first day of SPAQ treatment.

Intervention Type

Drug

Intervention Name(s)

Artemether-lumefantrine

Other Intervention Name(s)

Riamet

Intervention Description

Tablets containing 20/80 mg artemether and 120/480 mg lumefantrine will be administered according to weight as per manufacturer guidelines.

Intervention Type

Drug

Intervention Name(s)

Primaquine Phosphate

Other Intervention Name(s)

Primaquine

Intervention Description

The single dose of 0.25mg/kg PQ will be administered in an aqueous solution, according to a standard operating procedure (SOP) provided by the manufacturer.

Intervention Type

Drug

Intervention Name(s)

Sulphadoxine-pyrimethamine with amodiaquine

Other Intervention Name(s)

Supyra

Intervention Description

Sulfadoxine/pyrimethamine tablets contain 500mg sulfadoxine and 25mg pyrimethamine. Amodiaquine tablets contain 150mg amodiaquine (as hydrochloride). Tablets will be administered according to weight as per manufacturer guidelines.

Intervention Type

Drug

Intervention Name(s)

Tafenoquine

Other Intervention Name(s)

Arakoda

Intervention Description

100mg tafenoquine tablets are prepared into a 1mg/mL solution in water. Solution will be given according to weight as indicated per treatment arm in 5kg bands.

Primary Outcome Measure Information:

Title

Change in mosquito infection rate assessed through membrane feeding assays (day 2 and day 7)

Description

Time Frame

3 days (days 0, 2 and 7): 7 day span

Secondary Outcome Measure Information:

Title

Change in mosquito infection rate assessed through membrane feeding assays (all timepoints)

Description

Within person percent change (presented as percent reduction) in mosquito infection rate from baseline to all feeding time-points, with comparison within and between arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Mosquito infection rate assessed through membrane feeding assays

Description

Mosquito infection rate at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Human infectivity to locally reared mosquitoes assessed through membrane feeding assays

Description

Infectivity to mosquitoes at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Mosquito infection density assessed through membrane feeding assays

Description

Oocyst intensity (in all/all infected mosquitoes) at all feeding time-points, with comparison within treatment arms compared to baseline, and between arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Gametocyte infectivity

Description

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Asexual/sexual stage parasite prevalence

Description

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Asexual/sexual stage parasite density

Description

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Sexual stage parasite sex ratio

Description

Male and female gametocyte sex ratio (proportion male) at all time-points, determined by microscopy or molecular assays, with comparison within treatment arms compared to baseline, and between arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Sexual stage parasite circulation time

Description

Gametocyte circulation time (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Sexual stage parasite area under the curve (AUC)

Description

Gametocyte area under the curve (cumulative), determined by microscopy or molecular assays, compared within and between treatment arms.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Haemoglobin density

Description

Haemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.

Time Frame

8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Change in haemoglobin density

Description

Within person percent change (presented as percent reduction) in haemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.

Time Frame

8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Methaemoglobin density

Description

Methaemoglobin density (g/dL) at all time-points, with comparison within treatment arms compared to baseline, and between arms.

Time Frame

8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28)

Title

Change in methaemoglobin density

Description

Within person percent change (presented as percent reduction) in methaemoglobin density (g/dL) from baseline to all time-points, with comparison within and between arms.

Time Frame

8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Incidence of adverse events

Description

The frequency and prevalence of adverse events (all AE's, treatment related AE's, and haematological AE's) observed up to and including day 2, 7, and 14 post-treatment, and at all timepoints.

Time Frame

8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Other Pre-specified Outcome Measures:

Title

Parasite genomic and transcriptomic variation assessed in RNA

Description

Parasite genotype and transcriptional analysis at baseline and at post-treatment timepoints.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

The impact of plasma biomarkers on malaria transmission efficiency

Description

Plasma biomarkers (antibodies and parasite protein) at baseline and at post-treatment timepoints.

Time Frame

7 days (day 0, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

Title

Human genomic variation analysis and association with parasite measure

Description

Human genotype analysis at baseline (G6PD, CYP2D6, and HBB type)

Time Frame

day 0

Title

ALT/AST/Creatine density

Description

ALT/AST/Creatine density at all time-points with comparison within treatment arms compared to baseline, and between arms.

Time Frame

8 days (day 0, day 1, day 2, day 5, day 7, day 14, day 21, day 28): 28 day span

10. Eligibility

Sex

All

Minimum Age & Unit of Time

10 Years

Maximum Age & Unit of Time

50 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥ 10 years and ≤ 50 years G6PD-normal defined by Carestart rapid diagnostic test or the OSMMR2000 G6PD qualitative test Absence of symptomatic falciparum malaria, defined by fever on enrolment Presence of P. falciparum gametocytes on thick blood film at a density >16 gametocytes/μL (i.e. ≥ gametocytes recorded in the thick film against 500 white blood cells) Absence of other non-P. falciparum species on blood film Hemoglobin ≥ 10 g/dL Individuals weighing < = 80 kg No evidence of acute severe or chronic disease Written, informed consent Exclusion Criteria: Women who are pregnant or lactating (tested at baseline). Urine and/or serum pregnancy testing (β-hCG) will be used. Detection of a non-P. falciparum species by microscopy Previous reaction to study drugs / known allergy to study drugs Signs of severe malaria, including hyperparasitemia (defined as asexual parasitemia > 100,000 parasites / μL) Signs of acute or chronic illness, including hepatitis The use of other medication (except for paracetamol and/or aspirin) Use of antimalarial drugs over the past 7 days (as reported by the participant) Clinically significant illness (intercurrent illness e.g., pneumonia, pre-existing condition e.g., renal disease, malignancy or conditions that may affect absorption of study medication e.g., severe diarrhea or any signs of malnutrition as defined clinically) Signs of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e., decompensated cirrhosis, Child Pugh stage B or C) Signs, symptoms or known renal impairment Clinically significant abnormal laboratory values as determined by history, physical examination or routine blood chemistries and hematology values (laboratory guideline values for exclusion are hemoglobin < 10 g/dL, platelets < 50,000/μl, White Blood Cell count (WBC) < 2000/μl, serum creatinine >2.0mg/dL, or ALT or AST more than 3 times the upper limit of normal for age. Blood transfusion in the last 90 days. Consistent with the long half-life of tafenoquine, effective contraception should be continued for 5 half-lives (3 months) after the end of treatment. History of psychiatric disorders

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Alassane Dicko

Organizational Affiliation

Malaria Research and Training Centre, Mali

Official's Role

Principal Investigator

Facility Information:

Facility Name

Malaria Research and Training Centre

City

Bamako

Country

Mali

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

Anonymised individual participant data may be shared on a digital repository or upon reasonable request.

Learn more about this trial

Gametocytocidal and Transmission-blocking Efficacy of PQ in Combination With AL and TQ in Combination With SPAQ in Mali

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