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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03660839
Recruitment Status : Active, not recruiting
First Posted : September 7, 2018
Last Update Posted : October 22, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

Brief Summary:

Primary Objective:

To show the contribution of OZ439 to the clinical and parasiticidal effect of OZ439/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 AUC of OZ439 as PK predictor.

Secondary Objective(s):

  • To evaluate the dose response of OZ439 combined with FQ on PCR-corrected ACPR and crude Day 28 ACPR, and on other 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.

Condition or disease Intervention/treatment Phase
Plasmodium Falciparum Infection Drug: Artefenomel OZ439 Drug: Ferroquine SSR97193 Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open Label, Parallel-group, Single Dose Regimen, Phase 2a Study, to Investigate the Clinical and Parasiticidal Activity and the Pharmacokinetics of 3 Dose Levels of Artefenomel (OZ439) Given in Combination With Ferroquine (FQ) and FQ Alone, in African Patients With Uncomplicated Plasmodium Falciparum Malaria
Actual Study Start Date : September 5, 2018
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

Arm Intervention/treatment
Experimental: Ferroquine (FQ)
single dose FQ
Drug: Ferroquine SSR97193
Pharmaceutical form:Capsule Route of administration: Oral

Experimental: OZ439 dose 1 + ferroquine
single dose OZ439 dose 1 and FQ
Drug: Artefenomel OZ439
Pharmaceutical form:Granule for oral suspension Route of administration: Oral

Drug: Ferroquine SSR97193
Pharmaceutical form:Capsule Route of administration: Oral

Experimental: OZ439 dose 2 + ferroquine
single dose OZ439 dose 2 and FQ
Drug: Artefenomel OZ439
Pharmaceutical form:Granule for oral suspension Route of administration: Oral

Drug: Ferroquine SSR97193
Pharmaceutical form:Capsule Route of administration: Oral

Experimental: OZ439 dose 3 + ferroquine
single dose OZ439 dose 3 and FQ
Drug: Artefenomel OZ439
Pharmaceutical form:Granule for oral suspension Route of administration: Oral

Drug: Ferroquine SSR97193
Pharmaceutical form:Capsule Route of administration: Oral




Primary Outcome Measures :
  1. PCR-corrected ACPR [ Time Frame: At Day 28 ]
    Polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) at Day 28 (corresponding to absence of parasitemia without early treatment failure [ETF], late clinical failure [LCF], or late parasitological failure [LPF] and applies only to recrudescence)


Secondary Outcome Measures :
  1. PCR-crude ACPR [ Time Frame: At Day 28 ]
    PCR-crude ACPR at Day 28 (the endpoint does not distinguish between re-infection [by a new clone of parasite] and recrudescence [re-emergence of the original clone of parasite that is present at baseline])

  2. Parasitemia [ Time Frame: Baseline, 6 hours during the first 36 hours then at 48 hours and every 24 hours until Day 7 ]
    Absolute change in parasitemia count (blood smear) (/µL) at baseline then every 6 hours during the first 36 hours then at 48 hours and every 24 hours until Day 7

  3. Parasite reduction [ Time Frame: Baseline to Day 28 ]
    Number of events: Time to 99% reduction in parasite

  4. Time to Parasite Clearance [ Time Frame: Baseline to Day 28 ]
    Number of events: Time to parasite clearance

  5. Recrudescence or re-infection [ Time Frame: Baseline to Day 28 ]
    Number of events: Time to recrudescence or re-infection

  6. Elapsed below LOQ of parasitemia [ Time Frame: Baseline to Day 28 ]
    Number of events: Time elapsed below limit of quantification (LOQ) of parasitemia

  7. Observed parasite rate reduction (PRR) [ Time Frame: At 24 hours, 48 hours, and 72 hours ]
    Fold reduction in parasitaemia over one life cycle

  8. Adverse events [ Time Frame: Up to Day 28 ]
    Number of patients with adverse event (AE), including serious adverse event (SAE), AE of special interest (AESI) and treatment emergent AE (TEAE).

  9. Assessment of pharmacokinetic (PK) parameters [ Time Frame: Up to Day 28 ]
    Concentrations of OZ439 in plasma

  10. Assessment of PK parameters [ Time Frame: Up to Day 28 ]
    Concentrations of FQ and SSR97213 in blood

  11. Assessment of PK parameters for OZ439 in plasma: Cmax [ Time Frame: Up to Day 28 ]
    Maximal concentration

  12. Assessment of PK parameters for OZ439 in plasma: tmax [ Time Frame: Up to Day 28 ]
    Time to reach Cmax

  13. Assessment of PK parameters for OZ439 in plasma: C168h [ Time Frame: Up to Day 28 ]
    Concentration at 168 h post dose

  14. Assessment of PK parameters for OZ439 in plasma: AUC [ Time Frame: Up to Day 28 ]
    Area under the plasma concentration versus time curve up to infinity

  15. Assessment of PK parameters for OZ439 in plasma: t1/2 [ Time Frame: Up to Day 28 ]
    Terminal half-life

  16. Assessment of PK parameters for FQ and SSR97213 in blood: Cmax [ Time Frame: Up to Day 28 ]
    Maximal concentration

  17. Assessment of PK parameters for FQ and SSR97213 in blood: tmax [ Time Frame: Up to Day 28 ]
    Time to reach Cmax

  18. Assessment of PK parameters for FQ and SSR97213 in blood: C168h [ Time Frame: Up to Day 28 ]
    Concentration at 168 h post dose

  19. Assessment of PK parameters for FQ and SSR97213 in blood: AUC [ Time Frame: Up to Day 28 ]
    Area under the plasma concentration versus time curve up to infinity

  20. Assessment of PK parameters for FQ and SSR97213 in blood: t1/2 [ Time Frame: Up to Day 28 ]
    Terminal half-life

  21. Assessment of PK parameters for FQ and SSR97213 in blood: AUC0-Day28 [ Time Frame: At Day 28 ]
    Area under the concentration time curve from T0 to Day 28



Information from the National Library of Medicine

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Ages Eligible for Study:   14 Years to 69 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria :

Participants (14-69 years old) with body weight within 35 and 90 kg, with uncomplicated P. falciparum malaria, with a fever as defined with axillary temperature ≥37.5 degree Celsius ( C) or oral/ rectal/ tympanic temperature ≥38 C or history of fever in the previous 24 hours (history of fever must be documented), with a mono-infection with P. falciparum and parasitemia (microscopically, blood smear) ≥ 3,000 and ≤ 50,000 asexual parasites/μL 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/m² for adults and for children Z-score <-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 PQP-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 are: strong CYP2C 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 - IgM (HAV-IgM), Hepatitis B surface antigen (HBs Ag) or Hepatitis C virus antibody (HCV Ab) and/or known to have active Hepatitis C virus RNA (HCV RNA).
  • Laboratory parameters with abnormalities deemed clinically significant by the investigator.
  • Abnormal Liver Function Test (LFT): aspartate transferase (AST) >2 upper limit of normal range (ULN), or alanine transferase (ALT) >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 ms at screening or pre-dose.
  • Hypokalemia (<3.5 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
  • Patient not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or patients potentially at risk of noncompliance to study procedures or unable to drink.

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03660839


Locations
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Benin
Investigational Site Number 2040001
Cotonou, Benin
Burkina Faso
Investigational Site Number 8540001
Ouagadougou, Burkina Faso, 01 BP218
Investigational Site Number 8540002
Ouagadougou, Burkina Faso
Gabon
Investigational Site Number 2660002
Lambarene, Gabon
Investigational Site Number 2660001
Libreville, Gabon, B.P. 4009
Kenya
Investigational Site Number 4040002
Siaya County, Kenya
Uganda
Investigational Site Number 8000001
Tororo, Uganda
Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi

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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03660839     History of Changes
Other Study ID Numbers: ACT14655
U1111-1191-5573 ( Other Identifier: UTN )
First Posted: September 7, 2018    Key Record Dates
Last Update Posted: October 22, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Ferroquine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents