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

Plasmodium Falciparum Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03660839
• Other study ID #: ACT14655
• Secondary ID: U1111-1191-5573
• Status: Completed
• Phase: Phase 2
• Start date: September 11, 2018
• Est. completion date: November 6, 2019

Study information

• Verified date: March 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: November 6, 2019
• Est. primary completion date: November 6, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years to 69 Years

Eligibility

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.

Related Conditions & MeSH terms

• Malaria
• Malaria, Falciparum
• Plasmodium Falciparum Infection

Intervention

Drug:
• Artefenomel (OZ439)
Pharmaceutical form: Granules for oral suspension Route of administration: Oral
• Ferroquine (SSR97193)
Pharmaceutical form: Capsule Route of administration: Oral

Locations

Country	Name	City	State
Benin	Investigational Site Number 2040001	Cotonou
Burkina Faso	Investigational Site Number 8540002	Banfora
Burkina Faso	Investigational Site Number 8540001	Ouagadougou
Gabon	Investigational Site Number 2660002	Lambarene
Gabon	Investigational Site Number 2660001	Libreville
Kenya	Investigational Site Number 4040002	Siaya
Uganda	Investigational Site Number 8000001	Tororo

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Medicines for Malaria Venture

Countries where clinical trial is conducted

Benin,  Burkina Faso,  Gabon,  Kenya,  Uganda, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 28 (ACPR28)	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.	Day 28
Secondary	Percentage of Participants With Crude Adequate Clinical and Parasitological Response at 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.	Day 28
Secondary	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	Parasitemia (quantitative content of parasites present in the blood) at baseline until Day 7 (i.e. 168 hours) was assessed by optical microscope.	Baseline, 6, 12, 18, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
Secondary	Observed Parasite Reduction Ratio (PRR) at 24 Hours, 48 Hours, and 72 Hours	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.	Baseline, 24, 48 and 72 hours post-dose
Secondary	Time to 50% and 99% Parasite Reduction	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.	Up to Day 28
Secondary	Parasite Clearance Time (PCT)	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.	From the start of study drug administration up to the time of the first negative blood film (up to Day 28)
Secondary	Parasite Clearance Rate	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.	Up to Day 28
Secondary	Time to Re-emergence	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.	Up to Day 28
Secondary	Time to Recrudescence	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.	Up to Day 28
Secondary	Time to Re-infection	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.	Up to Day 28
Secondary	Time Elapsed Below the Limit of Quantification (LOQ) of Parasitemia	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.	Up to Day 28
Secondary	Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI)	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.	From Baseline up to Day 28
Secondary	Pharmacokinetics (PK): Concentration of OZ439 in Plasma	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.	1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
Secondary	Pharmacokinetics: Concentration of FQ and Its Active Metabolite SSR97213 in Blood	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.	1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Secondary	Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Artefenomel	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.	Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
Secondary	Pharmacokinetics: Time to Reach Maximum Plasma Concentration (Tmax) of Artefenomel	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.	Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
Secondary	Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose (C168h) of Artefenomel	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.	At 168 hours post-dose
Secondary	Pharmacokinetics: Area Under the Concentration Curve (AUC) Form Time 0 to Infinity (AUC0-inf]) of Artefenomel	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.	Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
Secondary	Pharmacokinetics: Terminal Half-life (t1/2) of Artefenomel	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.	Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
Secondary	Pharmacokinetics: Maximum Observed Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213	Cmax is the maximum observed plasma concentration of Ferroquine.	Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Secondary	Pharmacokinetics: Time to Reach Maximum Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213	tmax is the time taken by the drug to reach the maximum plasma concentration.	Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Secondary	Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose of Ferroquine and Its Active Metabolite SSR97213	The observed plasma concentration of FQ and SSR97213 post 168 hours of FQ administration.	At 168 hours post-dose
Secondary	Pharmacokinetics: Area Under the Concentration Curve Form Time 0 to Day 28 (AUC0-28) of Ferroquine and Its Active Metabolite SSR97213	Area under the plasma concentration versus time curve from time 0 to Day 28 (i.e. 672 hours).	Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Secondary	Pharmacokinetics: Area Under the Concentration Curve From Time 0 to Infinity of Ferroquine and Its Active Metabolite SSR97213	Area under the plasma concentration versus time curve from time 0 to infinity.	Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Secondary	Pharmacokinetics: Terminal Half-life of Ferroquine	Terminal t1/2 is defined as the time required for the plasma concentration of a drug to decrease by half of its initial concentration.	Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose