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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 : Completed
First Posted : September 7, 2018
Results First Posted : December 2, 2020
Last Update Posted : December 2, 2020
Sponsor:
Collaborator:
Medicines for Malaria Venture
Information provided by (Responsible Party):
Sanofi

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.

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

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.

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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 11, 2018
Actual Primary Completion Date : November 6, 2019
Actual Study Completion Date : November 6, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria

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

Experimental: 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.
Drug: Artefenomel (OZ439)
Pharmaceutical form: Granules for oral suspension Route of administration: Oral

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

Experimental: 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.
Drug: Artefenomel (OZ439)
Pharmaceutical form: Granules for oral suspension Route of administration: Oral

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

Experimental: 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.
Drug: Artefenomel (OZ439)
Pharmaceutical form: Granules for oral suspension Route of administration: Oral

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




Primary Outcome Measures :
  1. Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 28 (ACPR28) [ Time Frame: Day 28 ]
    ACPR:absence of parasitemia at Day 28, irrespective of axillary temperature(AT), participants not meeting any criteria of early therapy failure(ETF):Danger signs(DS)/symptoms of complicated(SoC)/severe malaria(SM) at Day 1, 2 or 3 in presence of parasitemia, concomitant to at least 1 positive parasitemia;or parasitemia on Day 2 >Day 0 irrespective of AT;or parasitemia on Day 3 with AT>=37.5 degree Celsius (°C);or parasitemia 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,concomitant to at least one positive parasitemia;or presence of parasitemia and AT>=37.5°C on Day 4 to Day 28, or late parasitological failure(LPF):presence of parasitemia between Day 7 and 28 and AT<37.5°C and without rescue therapy. PCR-corrected ACPR applied to recrudescence (appearance of asexual parasites after clearance of initial infection with genotype identical to that present at Baseline), excluding participants with reinfection.


Secondary Outcome Measures :
  1. Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 28 [ Time Frame: Day 28 ]
    ACPR: absence of parasitemia at Day 28, irrespective of AT, in participants not meeting any criteria of ETF: DS/SoC/SM at Day 1, 2 or 3 in presence of parasitemia, concomitant to at least 1 positive parasitemia; or parasitemia on Day 2 > Day 0 irrespective of AT; or parasitemia on Day 3 with AT >=37.5°C; or parasitemia count on Day 3 >=25% on Day 0, or LCF: DS/SM in presence of parasitemia between Day 4 and 28, concomitant to at least one positive parasitemia; or presence of parasitemia and AT>=37.5°C on Day 4 to Day 28, or LPF: presence of parasitemia between Day 7 and 28 and AT<37.5°C or having rescue therapy for malaria. PCR-corrected 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, whereas crude ACPR does not distinguish reinfection (new clone of parasite) or recrudescence.

  2. Parasitemia: Change From Baseline in Number of Parasites Per Microliter of Blood at 6, 12, 18, 24, 30, 36, 48, 72, 96, 120, 144 and 168 Hours [ Time Frame: Baseline, 6, 12, 18, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post-dose ]
    Parasitemia (quantitative content of parasites present in the blood) at baseline until Day 7 (i.e. 168 hours) was assessed by optical microscope.

  3. Observed Parasite Reduction Ratio (PRR) at 24 Hours, 48 Hours, and 72 Hours [ Time Frame: Baseline, 24, 48 and 72 hours post-dose ]
    The observed PRR was defined as the ratio of the number of parasites at time t=0 (baseline) divided by the parasite count at each specified time t (post-treatment). If the post dose parasite count = 0 (due to a negative parasitemia) then a value of 1 parasite per microliter was imputed to allow a parasite reduction ratio calculation.

  4. Time to 50% and 99% Parasite Reduction [ Time Frame: Up to Day 28 ]
    Time to 50% and 99% parasite reduction was defined as time needed for the parasitemia (quantitative content of parasites present in blood) to be reduced to 50% and 99% of the initial value, respectively.

  5. Parasite Clearance Time (PCT) [ Time Frame: From the start of study drug administration up to the time of the first negative blood film (up to Day 28) ]
    PCT was defined as the time (in hours) from the start of study drug administration until the time of first negative blood film (no asexual parasites by microscopy). This first negative film was confirmed by a second negative film which was taken >=6 to <=12 hours of the first film. If the second film was performed <6 hours or >12 hours of the first film, then the parasite clearance was confirmed or invalidated by the third (thick) film following the second one, whatever the timing of this third film: If the third film was negative, then the clearance was considered confirmed and if the third film was positive, then the clearance was invalidated. Kaplan-Meier method was used for the estimation.

  6. Parasite Clearance Rate [ Time Frame: Up to Day 28 ]
    Parasite clearance rate (k) is the minus slope of the natural logarithm parasitemia versus time linear relationship, after exclusion of outliers, lag phase and Tail, using the worldwide antimalarial resistance network, Parasite Clearance Estimator.

  7. Time to Re-emergence [ Time Frame: Up to Day 28 ]
    Time to re-emergence (in days) was defined as the time to appearance of asexual parasites after clearance of initial infection irrespective of genotype. Re-emergence was confirmed by microscopy (positive blood smear). Participants with confirmed parasite clearance were included in the analysis and Kaplan-Meier method was used for estimation.

  8. Time to Recrudescence [ Time Frame: Up to Day 28 ]
    Time to recrudescence (in days) was defined as the time to appearance of asexual parasites after clearance of initial infection with a genotype identical to that of parasites present at Baseline. Recrudescence was confirmed by PCR analysis. Participants with confirmed parasite clearance were included in the analysis and Kaplan-Meier method was used for estimation.

  9. Time to Re-infection [ Time Frame: Up to Day 28 ]
    Time to re-infection (in days) was defined as the time to appearance of asexual parasites after clearance of initial infection with a genotype that differed from that of parasites present at Baseline. Re-infection was confirmed by PCR analysis. Participants with confirmed parasite clearance were involved in the analysis and Kaplan-Maier method was used for estimation.

  10. Time Elapsed Below the Limit of Quantification (LOQ) of Parasitemia [ Time Frame: Up to Day 28 ]
    The time elapsed below LOQ (LOQ expressed in parasites/microliter) of parasitemia (quantitative content of parasites present in the blood) was defined as the time (in days) for which no parasites were seen i.e., time corresponding to PCT, up to the time of occurrence of a new malaria infection or recrudescence. If there was no occurrence of a new malaria infection or recrudescence, then this was the time corresponding to the first negative thick blood film, until the end of study. PCT (k) is the minus slope of the natural logarithm parasitemia versus time linear relationship, after exclusion of outliers, lag phase and Tail, using the worldwide antimalarial resistance network, Parasite clearance estimator. Participants with confirmed parasite clearance were involved in the analysis and Kaplan-Meier method was used for estimation.

  11. Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI) [ Time Frame: From Baseline up to Day 28 ]
    An AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had to have a causal relationship with the treatment. SAEs were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were defined as AEs that developed or worsened or became serious during on-treatment phase that was defined as the time from the start of study drug up to the Day 28. AE of special interest (AESI) was an AE (serious or non-serious) of scientific and medical concern specific to the Sponsor's product or program, for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required.

  12. Pharmacokinetics (PK): Concentration of OZ439 in Plasma [ Time Frame: 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose ]
    Concentrations of OZ439 in plasma was analyzed by liquid chromatography tandem mass spectroscopy (LC-MS/MS). The lower limit of quantification (LLOQ) was 1 nanograms per milliliter for analysis of OZ439. Data for this outcome measure was not planned to be collected and analyzed for "Ferroquine 400 mg" arm, since artefenomel was not administered.

  13. Pharmacokinetics: Concentration of FQ and Its Active Metabolite SSR97213 in Blood [ Time Frame: 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose ]
    Concentrations of FQ and SSR97213 in blood was analyzed by LC-MS/MS. The LLOQ was 5 nanograms per milliliter for analysis of FQ and SSR97213.

  14. Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Artefenomel [ Time Frame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose ]
    Cmax is the maximum observed plasma concentration of Artefenomel. Data for this outcome measure was not planned to be collected and analyzed for "Ferroquine 400 mg" arm, since artefenomel was not administered.

  15. Pharmacokinetics: Time to Reach Maximum Plasma Concentration (Tmax) of Artefenomel [ Time Frame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose ]
    tmax is the time taken by the drug to reach the maximum plasma concentration. Data for this outcome measure was not planned to be collected and analyzed for "Ferroquine 400 mg" arm, since artefenomel was not administered.

  16. Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose (C168h) of Artefenomel [ Time Frame: At 168 hours post-dose ]
    The observed plasma concentration of artefenomel post 168 hours of drug administration. Data for this outcome measure was not planned to be collected and analyzed for "Ferroquine 400 mg" arm, since artefenomel was not administered.

  17. Pharmacokinetics: Area Under the Concentration Curve (AUC) Form Time 0 to Infinity (AUC0-inf]) of Artefenomel [ Time Frame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose ]
    Area under the plasma concentration versus time curve from time 0 to infinity. Data for this outcome measure was not planned to be collected and analyzed for "Ferroquine 400 mg" arm, since artefenomel was not administered.

  18. Pharmacokinetics: Terminal Half-life (t1/2) of Artefenomel [ Time Frame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose ]
    Terminal t1/2 is defined as the time required for the plasma concentration of a drug to decrease by half of its initial concentration. Data for this outcome measure was not planned to be collected and analyzed for "Ferroquine 400 mg" arm, since artefenomel was not administered.

  19. Pharmacokinetics: Maximum Observed Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213 [ Time Frame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose ]
    Cmax is the maximum observed plasma concentration of Ferroquine.

  20. Pharmacokinetics: Time to Reach Maximum Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213 [ Time Frame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose ]
    tmax is the time taken by the drug to reach the maximum plasma concentration.

  21. Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose of Ferroquine and Its Active Metabolite SSR97213 [ Time Frame: At 168 hours post-dose ]
    The observed plasma concentration of FQ and SSR97213 post 168 hours of FQ administration.

  22. Pharmacokinetics: Area Under the Concentration Curve Form Time 0 to Day 28 (AUC0-28) of Ferroquine and Its Active Metabolite SSR97213 [ Time Frame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose ]
    Area under the plasma concentration versus time curve from time 0 to Day 28 (i.e. 672 hours).

  23. Pharmacokinetics: Area Under the Concentration Curve From Time 0 to Infinity of Ferroquine and Its Active Metabolite SSR97213 [ Time Frame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose ]
    Area under the plasma concentration versus time curve from time 0 to infinity.

  24. Pharmacokinetics: Terminal Half-life of Ferroquine [ Time Frame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose ]
    Terminal t1/2 is defined as the time required for the plasma concentration of a drug to decrease by half of its initial concentration.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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.


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 8540002
Banfora, Burkina Faso
Investigational Site Number 8540001
Ouagadougou, Burkina Faso, 01 BP218
Gabon
Investigational Site Number 2660002
Lambarene, Gabon
Investigational Site Number 2660001
Libreville, Gabon, B.P. 4009
Kenya
Investigational Site Number 4040002
Siaya, Kenya
Uganda
Investigational Site Number 8000001
Tororo, Uganda
Sponsors and Collaborators
Sanofi
Medicines for Malaria Venture
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
  Study Documents (Full-Text)

Documents provided by Sanofi:
Study Protocol  [PDF] November 13, 2017
Statistical Analysis Plan  [PDF] May 29, 2020

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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03660839    
Other Study ID Numbers: ACT14655
U1111-1191-5573 ( Other Identifier: UTN )
First Posted: September 7, 2018    Key Record Dates
Results First Posted: December 2, 2020
Last Update Posted: December 2, 2020
Last Verified: November 2020
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