Clinical trial NCT03660839: Study to Investigate the Clinical and Parasiticidal Activity and Pharmacokinetics of Different Doses of Artefenomel and Ferroquine in Patients With Uncomplicated Plasmodium Falciparum Malaria
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Plasmodium Falciparum Infection
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Medicines for Malaria Venture
First posted: 2018-09-07
Enrollment: 140
Sex: ALL
Minimum age (years): 14
Maximum age (years): 69
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 28 (ACPR28)
timeFrame: Day 28
Secondary outcomes:
measure: Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 28
timeFrame: Day 28
measure: 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
timeFrame: Baseline, 6, 12, 18, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
measure: Observed Parasite Reduction Ratio (PRR) at 24 Hours, 48 Hours, and 72 Hours
timeFrame: Baseline, 24, 48 and 72 hours post-dose
measure: Time to 50% and 99% Parasite Reduction
timeFrame: Up to Day 28
measure: Parasite Clearance Time (PCT)
timeFrame: From the start of study drug administration up to the time of the first negative blood film (up to Day 28)
measure: Parasite Clearance Rate
timeFrame: Up to Day 28
measure: Time to Re-emergence
timeFrame: Up to Day 28
measure: Time to Recrudescence
timeFrame: Up to Day 28
measure: Time to Re-infection
timeFrame: Up to Day 28
measure: Time Elapsed Below the Limit of Quantification (LOQ) of Parasitemia
timeFrame: Up to Day 28
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Event of Special Interest (AESI)
timeFrame: From Baseline up to Day 28
measure: Pharmacokinetics (PK): Concentration of OZ439 in Plasma
timeFrame: 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
measure: Pharmacokinetics: Concentration of FQ and Its Active Metabolite SSR97213 in Blood
timeFrame: 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
measure: Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Artefenomel
timeFrame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
measure: Pharmacokinetics: Time to Reach Maximum Plasma Concentration (Tmax) of Artefenomel
timeFrame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
measure: Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose (C168h) of Artefenomel
timeFrame: At 168 hours post-dose
measure: Pharmacokinetics: Area Under the Concentration Curve (AUC) Form Time 0 to Infinity (AUC0-inf]) of Artefenomel
timeFrame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
measure: Pharmacokinetics: Terminal Half-life (t1/2) of Artefenomel
timeFrame: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
measure: Pharmacokinetics: Maximum Observed Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213
timeFrame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
measure: Pharmacokinetics: Time to Reach Maximum Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213
timeFrame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
measure: Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose of Ferroquine and Its Active Metabolite SSR97213
timeFrame: At 168 hours post-dose
measure: Pharmacokinetics: Area Under the Concentration Curve Form Time 0 to Day 28 (AUC0-28) of Ferroquine and Its Active Metabolite SSR97213
timeFrame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
measure: Pharmacokinetics: Area Under the Concentration Curve From Time 0 to Infinity of Ferroquine and Its Active Metabolite SSR97213
timeFrame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
measure: Pharmacokinetics: Terminal Half-life of Ferroquine
timeFrame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Other outcomes:
Locations:
city: Cotonou
country: Benin
facility: Investigational Site Number 2040001
city: Banfora
country: Burkina Faso
facility: Investigational Site Number 8540002
city: Ouagadougou
country: Burkina Faso
facility: Investigational Site Number 8540001
city: Lambarene
country: Gabon
facility: Investigational Site Number 2660002
city: Libreville
country: Gabon
facility: Investigational Site Number 2660001
city: Siaya
country: Kenya
facility: Investigational Site Number 4040002
city: Tororo
country: Uganda
facility: Investigational Site Number 8000001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: