Study to Investigate the Clinical and Parasiticidal Activity and Pharmacokinetics of Different Doses of Artefenomel and Ferroquine in Patients With Uncomplicated Plasmodium Falciparum Malaria

NCT ID: NCT03660839

Last Updated: 2022-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-11
• Study Completion Date: 2019-11-06

Brief Summary

Primary Objective:

To show the contribution of artefenomel (OZ439) to the clinical and parasiticidal effect of OZ439/Ferroquine (FQ) combination by analyzing exposure-response of OZ439 measured by Day 28 polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) for the effect and the area under the curve (AUC) of OZ439 as pharmacokinetic (PK) predictor.

Secondary Objectives:

• To evaluate the exposure-response of OZ439 combined with FQ on crude Day 28 ACPR.
• To evaluate the dose response of OZ439 combined with FQ on PCR-corrected and crude Day 28 ACPR.
• To evaluate the dose-response of OZ439 combined with FQ on selected secondary endpoints.
• To evaluate the safety and tolerability of different dosages of OZ439 in combination with FQ and FQ alone.
• To characterize the PK of OZ439 in plasma, and of FQ and its active metabolite SSR97213 in blood.

Detailed Description

The duration of the study was up to 32 days, including up to 1 day screening period before the single-dose treatment, 5 days of post-treatment surveillance (included 2 to 4 days hospitalization) and 24±2 days follow-up period.

Conditions

Plasmodium Falciparum Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ferroquine 400 milligram (mg)

On Day 0, participants received orally a single dose of FQ 400 mg (4 capsules of 100 mg) in fasted condition.

Group Type: EXPERIMENTAL

Ferroquine (SSR97193)

Intervention Type: DRUG

Pharmaceutical form: Capsule Route of administration: Oral

Ferroquine 400 mg + Artefenomel 300 mg

On Day 0, participants received orally a single dose of FQ 400 mg (4 capsules of 100 mg) in fasted condition followed by OZ439 300 mg oral suspension.

Group Type: EXPERIMENTAL

Artefenomel (OZ439)

Intervention Type: DRUG

Pharmaceutical form: Granules for oral suspension Route of administration: Oral

Ferroquine (SSR97193)

Intervention Type: DRUG

Pharmaceutical form: Capsule Route of administration: Oral

Ferroquine 400 mg + Artefenomel 600 mg

On Day 0, participants received orally a single dose of FQ 400 mg (4 capsules of 100 mg) in fasted condition followed by OZ439 600 mg oral suspension.

Group Type: EXPERIMENTAL

Artefenomel (OZ439)

Intervention Type: DRUG

Pharmaceutical form: Granules for oral suspension Route of administration: Oral

Ferroquine (SSR97193)

Intervention Type: DRUG

Pharmaceutical form: Capsule Route of administration: Oral

Ferroquine 400 mg + Artefenomel 1000 mg

On Day 0, participants received orally a single dose of FQ 400 mg (4 capsules of 100 mg) in fasted condition followed by OZ439 1000 mg oral suspension.

Group Type: EXPERIMENTAL

Artefenomel (OZ439)

Intervention Type: DRUG

Pharmaceutical form: Granules for oral suspension Route of administration: Oral

Ferroquine (SSR97193)

Intervention Type: DRUG

Pharmaceutical form: Capsule Route of administration: Oral

Interventions

Artefenomel (OZ439)

Pharmaceutical form: Granules for oral suspension Route of administration: Oral

Intervention Type: DRUG

Ferroquine (SSR97193)

Pharmaceutical form: Capsule Route of administration: Oral

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

Participants (14-69 years old inclusive) with body weight within 35 and 90 kilograms (kg), with uncomplicated Plasmodium falciparum (P. falciparum) malaria, with a fever as defined with axillary temperature greater than or equal to (>=) 37.5 degree Celsius (°C) or oral/ rectal/ tympanic temperature >=38°C or history of fever in the previous 24 hours (history of fever was documented), with a mono-infection with P. falciparum and parasitemia (microscopically, blood smear) >= 3,000 and less than or equal to (<=) 50,000 asexual parasites per microliter of blood.

Exclusion Criteria

• Presence of severe malaria.
• Known history or evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, respiratory, endocrine, immunological, infectious, neurological (in particular convulsions), malignancy, psychiatric disease or symptoms which, in the judgment of the investigator, might confuse the interpretation of the safety information.
• Severe vomiting defined as more than 3 times in the 24 hours prior to enrollment in the study or inability to tolerate oral treatment or severe diarrhea defined as 3 or more watery stools per day.
• Severe malnutrition defined as a body mass index of less than 16 kg per meter square for adults and for children Z-score less than (<) -3 or weight for age (%) of the median <60.
• Splenectomized participants or presence of surgical scar on left hypochondrium.
• Known history of hypersensitivity, allergic, or anaphylactoid reactions to FQ or other amino quinolines or to OZ439 or OZ277 or any of the excipients.
• Participant treated with anti-malarial treatment:
• With piperaquine phosphate-based compound, mefloquine, naphthoquine or sulphadoxine/pyrimethamine within the previous 6 weeks.
• With amodiaquine or chloroquine within the previous 4 weeks.
• With quinine, halofantrine, lumefantrine-based compounds and any other anti-malarial treatment or antibiotics with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones, and azithromycin) within the past 14 days.
• With any herbal products or traditional medicines, within the past 7 days.
• Previous treatment within 5 times the half-life or within the last 14 days, whichever the longest, which were: strong Cytochrome P450 (CYP) 2C or CYP3A inhibitors and/or moderate inhibitors but inhibiting both CYP2C and CYP3A and/or CYP inducers.
• Any treatment known to induce a prolongation of QT interval.
• Participated in any trial investigating OZ439 and/or FQ compounds.
• Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance.
• Enrolled in another clinical trial within the past 4 weeks or during the study period.
• Mixed Plasmodium infection.
• Presence of Hepatitis A - immunoglobulin, Hepatitis B surface antigen or Hepatitis C virus antibody and/or known to had active Hepatitis C virus ribonucleic acid.
• Laboratory parameters with abnormalities deemed clinically significant by the investigator.
• Abnormal Liver Function Test: aspartate transferase greater than (>) 2 upper limit of normal range (ULN), or alanine transferase >2 ULN or total bilirubin >1.5 ULN.
• Positive pregnancy test at study screening for female participants of childbearing potential.
• QT interval corrected using Fridericia formula (QTcF) >450 milliseconds at screening or pre-dose.
• Hypokalemia (<3.5 millimoles per liter [mmol/L]), hypocalcemia (<2.0 mmol/L) or hypomagnesemia (<0.5 mmol/L) at screening or pre-dose.
• Family history of sudden death or of congenital prolongation of the QT interval or known congenital prolongation of the QT-interval or any clinical condition known to prolong the QT interval e.g., participants with a history of symptomatic cardiac arrhythmias including atrial fibrillation or with clinically relevant bradycardia.
• Participant not suitable for participation, whatever the reason, as judged by the Investigator, included medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures or unable to drink.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

• Minimum Eligible Age: 14 Years
• Maximum Eligible Age: 69 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Medicines for Malaria Venture

OTHER

Sponsor Role: collaborator

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Investigational Site Number 2040001

Cotonou, , Benin

Investigational Site Number 8540002

Banfora, , Burkina Faso

Investigational Site Number 8540001

Ouagadougou, , Burkina Faso

Investigational Site Number 2660002

Lambaréné, , Gabon

Investigational Site Number 2660001

Libreville, , Gabon

Investigational Site Number 4040002

Siaya, , Kenya

Investigational Site Number 8000001

Tororo, , Uganda

Countries

Benin; Burkina Faso; Gabon; Kenya; Uganda

References

Gansane A, Lingani M, Yeka A, Nahum A, Bouyou-Akotet M, Mombo-Ngoma G, Kaguthi G, Barcelo C, Laurijssens B, Cantalloube C, Macintyre F, Djeriou E, Jessel A, Bejuit R, Demarest H, Marrast AC, Debe S, Tinto H, Kibuuka A, Nahum D, Mawili-Mboumba DP, Zoleko-Manego R, Mugenya I, Olewe F, Duparc S, Ogutu B. Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria. Malar J. 2023 Jan 3;22(1):2. doi: 10.1186/s12936-022-04420-2.

Reference Type: DERIVED

PMID: 36597076 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

U1111-1191-5573

Identifier Type: OTHER

Identifier Source: secondary_id

ACT14655

Identifier Type: -

Identifier Source: org_study_id