To Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose Regimen of Ferroquine and Artefenomel in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

NCT02497612 | Terminated Phase 2 Results DMC

• 2 other identifiers: DRI12805U1111-1155-7960
• Study Type: interventional
• Target: 377
• Locations: 7 countries
• Sites: 12

Brief Summary

Primary Objective: To determine whether a single dose combination of OZ439 (Artefenomel)/FQ (Ferroquine) was an efficacious treatment for uncomplicated Plasmodium falciparum malaria in adults and children. Secondary Objectives:

• To evaluate the efficacy of OZ439/FQ:
• To determine the incidence of recrudescence and re-infection.
• To determine the time to relief of fever and parasite clearance.
• To evaluate the safety and tolerability of OZ439/FQ in adults and children.
• To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite SSR97213 in blood.
• To determine the blood/plasma ratio for FQ and SSR97213 in some participants at limited time points in selected sites.

Conditions

Plasmodium Falciparum Infection

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Polymerase Chain Reaction (PCR)-Adjusted Adequate Clinical and Parasitological Response (ACPR) at Day 28: African <=5 Years Per Protocol Population at Day 28 (PP28)

  ACPR: negative parasitemia at Day 28, irrespective of axillary temperature(AT), in participants not meeting any criteria of early therapy failure (ETF):Danger signs (DS)/severe malaria (SM) at Day 1, 2 or 3 in presence of parasitemia; or Day 2 parasite count \>Day 0 irrespective of AT; or parasitemia at Day 3 with AT \>=37.5 degree Celsius (°C); or parasite count on Day 3\>=25 percent (%) on Day 0, or late clinical failure(LCF):DS/ SM in presence of parasitemia between Day 4 and 28; or presence of parasitemia and AT\>=37.5°C between Day 4 and 28, or late parasitological failure (LPF):presence of parasitemia between Day 7 and 28 and AT\<37.5°C or having rescue therapy for malaria. PCR-adjusted ACPR applied to recrudescence (appearance of asexual parasites after clearance of initial infection with genotype identical to that present at Baseline), excluding participants with re-infection. In data table, "overall number of participants analyzed"=participants evaluable for this outcome measure.

  Day 28

Secondary Outcomes (29)

• Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 28: African >5 Years Per Protocol Population at Day 28 (A5PP28)

  Day 28

• Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 28: Asian PP Population at Day 28 (APP28)

  Day 28

• Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 42: African <=5 Years PP Population at Day 42 (PP42)

  Day 42

• Percentage of Participants With Polymerase Chain Reaction-adjusted Adequate Clinical and Parasitological Response at Day 63: African <=5 Years PP Population at Day 63 (PP63)

  Day 63

• Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 28: African <=5 Years PP28 Population

  Day 28

Study Arms (4)

Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg)

EXPERIMENTAL

On Day 0, based on the body weight (BW), participants received orally a single dose of ferroquine (FQ) capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of artefenomel (OZ439) (maximum dose up to 800 milligrams \[mg\]) oral suspension as follows: BW greater than or equal to (\>=) 35 kilograms (kg): FQ 400 mg + OZ439 800 mg; BW \>=24 kg to less than (\<) 35 kg: FQ 300 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 200 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 150 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 100 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 75 mg + OZ439 150 mg.

Drug: Ferroquine SSR97193; Drug: Artefenomel; Other: Placebo

Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg)

EXPERIMENTAL

On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 600 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 450 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 300 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 225 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 150 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 115 mg + OZ439 150 mg.

Drug: Ferroquine SSR97193; Drug: Artefenomel; Other: Placebo

Ferroquine (up to 900 mg) + Artefenomel (up to 800 mg)

EXPERIMENTAL

On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 900 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 675 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 450 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 335 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 225 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 170 mg + OZ439 150 mg.

Drug: Ferroquine SSR97193; Drug: Artefenomel; Other: Placebo

Ferroquine (up to 1200 mg) + Artefenomel (up to 800 mg)

EXPERIMENTAL

On Day 0, based on the BW, participants received orally a single dose of FQ capsules or oral suspension (along with matching placebo, as applicable to maintain blinding) and a single dose of OZ439 (maximum dose up to 800 mg) oral suspension as follows: BW \>= 35 kg: FQ 1200 mg + OZ439 800 mg; BW \>=24 kg to \<35 kg: FQ 900 mg + OZ439 600 mg; BW \>=15 kg to \<24 kg: FQ 600 mg + OZ439 400 mg; BW \>=10 kg to \<15 kg: FQ 450 mg + OZ439 300 mg; BW \>=7 kg to \<10 kg: FQ 300 mg + OZ439 200 mg; \>=5 kg to \<7kg: FQ 225 mg + OZ439 150 mg.

Drug: Ferroquine SSR97193; Drug: Artefenomel; Other: Placebo

Interventions

Ferroquine SSR97193 DRUG

Pharmaceutical form:Capsules Route of administration: oral

Ferroquine (up to 1200 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 900 mg) + Artefenomel (up to 800 mg)

Artefenomel DRUG

Pharmaceutical form:Granules for suspension Route of administration: oral

Ferroquine (up to 1200 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 900 mg) + Artefenomel (up to 800 mg)

Placebo OTHER

Capsules. Placebo capsules were used to keep the same number of capsules in each weight band while keeping the ferroquine dose blinded. No participant received placebo only.

Ferroquine (up to 1200 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg); Ferroquine (up to 900 mg) + Artefenomel (up to 800 mg)

Eligibility Criteria

• Age: 6 Months - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female participant aged greater than (\>) 6 months old and \<70 years old:
• Cohort 1 = 14 years \< age \<70 years and body weight greater than or equal to (\>=) 35 kilogram (kg).
• Cohort 2 = 5 years \< age less than or equal to (\<=) 14 years.
• Cohort 3 = 2 years \< age \<=5 years.
• Cohort 4 = 6 months \< age \<=2 years.
• Body weight \>=5 kg and \<=90 kg.
• Presence of mono-infection by Plasmodium falciparum with:
• Fever, as defined by axillary temperature \>=37.5 degrees Celsius (°C) or oral/rectal/tympanic temperature \>=38°C, or history of fever in the previous 24 hours (history of fever must be documented) and,
• Microscopically (blood smear) confirmed parasite infection, ranging from 1000 to 100 000 asexual parasites/microliter of blood.
• Informed consent form signed by the participant or by the legally acceptable representative of the minor participant.

You may not qualify if:

• Presence of severe malaria.
• Anti-malarial treatment:
• With piperaquine-based compound, mefloquine, naphthoquine or sulphadoxine/pyrimethamine (SP) within the previous 6 weeks (after their inhibition of new infections had fallen below 50%).
• 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.
• Known history or evidence of clinically significant disorders.
• Previous treatment within 5 times the half-life or within the last 14 days, whichever the longest which are: P-glycoprotein substrates, Cytochrome P450 (CYP) 2D6 main substrates and/or strong CYP2C or CYP3A inhibitors and/or moderate inhibitors but inhibiting both CYP2C and CYP3A and/or CYP inducers.
• Mixed plasmodium infection.
• Severe vomiting.
• Severe malnutrition.
• Laboratory parameters with clinically significant abnormalities and/or reaching critical values. For Liver Function Test. Aspartate aminotransferase (\>2 \[upper limit of normal\] ULN), or alanine aminotransferase (\>2 ULN) or total bilirubin \>1.5 ULN.
• Presence of Hepatitis A Immunoglobulin M, Hepatitis B surface antigen or Hepatitis C antibody.
• Had received an investigational drug within the past 4 weeks.
• Previous participation in any malaria vaccine study or received malaria vaccine in any other circumstance.

Sponsors & Collaborators

• Sanofi: lead
• Medicines for Malaria Venture: collaborator

Study Sites (12)

Investigational Site Number 204001

Cotonou, Benin

Location

Investigational Site Number 854002

Comoé, Burkina Faso

Location

Investigational Site Number 854003

Niangoloko, Burkina Faso

Location

Investigational Site Number 854001

Ouagadougou, Burkina Faso

Location

Investigational Site Number 266002

Lambaréné, Gabon

Location

Investigational Site Number 266001

Libreville, Gabon

Location

Investigational Site Number 404003

Kisumu, Kenya

Location

Investigational Site Number 404002

Siaya, Kenya

Location

Investigational Site Number 508001

Chokwé, Mozambique

Location

Investigational Site Number 800002

Tororo, Uganda

Location

Investigational Site Number 704003

Bình Phước, Vietnam

Location

Investigational Site Number 704004

Pleiku, Vietnam

Location

Related Publications (1)

• Adoke Y, Zoleko-Manego R, Ouoba S, Tiono AB, Kaguthi G, Bonzela JE, Duong TT, Nahum A, Bouyou-Akotet M, Ogutu B, Ouedraogo A, Macintyre F, Jessel A, Laurijssens B, Cherkaoui-Rbati MH, Cantalloube C, Marrast AC, Bejuit R, White D, Wells TNC, Wartha F, Leroy D, Kibuuka A, Mombo-Ngoma G, Ouattara D, Mugenya I, Phuc BQ, Bohissou F, Mawili-Mboumba DP, Olewe F, Soulama I, Tinto H; FALCI Study Group. A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria. Malar J. 2021 May 19;20(1):222. doi: 10.1186/s12936-021-03749-4.

  PMID: 34011358 DERIVED

MeSH Terms

Interventions

ferroquine; artefenomel

Limitations and Caveats

The study was terminated early because all treatment arms met the futility criteria for efficacy during the pre-planned interim analysis. On 02-August-2018, recruitment in Asia was stopped due to lack of efficacy.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 8, 2015
• First Posted: July 14, 2015
• Study Start: July 25, 2015
• Primary Completion: September 23, 2019
• Study Completion: September 23, 2019
• Last Updated: March 24, 2022
• Results First Posted: October 19, 2020

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

UG (1); BU (3); KE (2); VN (2); BE (1); MO (1); GA (2)