Plasmodium Falciparum InfectionPhase 2NCT03660839
Study to Investigate the Clinical and Parasiticidal Activity and Pharmacokinetics of Different Doses of Artefenomel and Ferroquine in Patients With Uncomplicated Plasmodium Falciparum Malaria
A Phase 2 study testing Artefenomel (OZ439) and Ferroquine (SSR97193) in people with Plasmodium Falciparum Infection, run by Sanofi at 7 sites in 5 countries.
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… Read more about this study
- Who is it for?
- Ages 14 to 69 years
- Conditions the study is for
- Plasmodium Falciparum Infection
- What is being tested?
- Artefenomel (OZ439) and Ferroquine (SSR97193)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 140 participants
- Where
- 7 sitesin 5 countries
- Study dates
- 11 Sep 2018to 6 Nov 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 14 to 69 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 26Show fewer
- 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.
Trial locations and contacts
7 sites in 5 countries.
7 sites in 5 countries
Burkina Faso2 sites
Investigational Site Number 8540002
Banfora
Investigational Site Number 8540001
Ouagadougou, 01 BP218
Gabon2 sites
Investigational Site Number 2660002
Lambaréné
Investigational Site Number 2660001
Libreville, B.P. 4009
About this study
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
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.
Read more
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.
Read the 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.
- Conditions
- Plasmodium Falciparum Infection
- Being tested
- Artefenomel (OZ439), Ferroquine (SSR97193)
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Artefenomel (OZ439)Drug
Pharmaceutical form: Granules for oral suspension Route of administration: Oral
Ferroquine (SSR97193)Drug
Pharmaceutical form: Capsule Route of administration: Oral
| Study group | Role | What they receive |
|---|---|---|
| Ferroquine 400 milligram (mg) | Experimental | On Day 0, participants received orally a single dose of FQ 400 mg (4 capsules of 100 mg) in fasted condition. Receives: Drug: Ferroquine (SSR97193) |
| Ferroquine 400 mg + Artefenomel 300 mg | Experimental | 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. Receives: Drug: Artefenomel (OZ439); Drug: Ferroquine (SSR97193) |
| Ferroquine 400 mg + Artefenomel 600 mg | Experimental | 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. Receives: Drug: Artefenomel (OZ439); Drug: Ferroquine (SSR97193) |
| Ferroquine 400 mg + Artefenomel 1000 mg | Experimental | 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. Receives: Drug: Artefenomel (OZ439); Drug: Ferroquine (SSR97193) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Day 28
Secondary outcomes (24)
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.
Measured: Day 28
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.
Measured: Baseline, 6, 12, 18, 24, 30, 36, 48, 72, 96, 120, 144 and 168 hours post-dose
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.
Measured: Baseline, 24, 48 and 72 hours post-dose
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.
Measured: Up to Day 28
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.
Measured: From the start of study drug administration up to the time of the first negative blood film (up to Day 28)
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.
Measured: Up to Day 28
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.
Measured: Up to Day 28
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.
Measured: Up to Day 28
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.
Measured: Up to Day 28
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.
Measured: Up to Day 28
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.
Measured: From Baseline up to Day 28
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.
Measured: 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
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.
Measured: 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
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.
Measured: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
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.
Measured: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
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.
Measured: At 168 hours post-dose
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.
Measured: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
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.
Measured: Pre-dose, 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
Pharmacokinetics: Maximum Observed Plasma Concentration of Ferroquine and Its Active Metabolite SSR97213
Cmax is the maximum observed plasma concentration of Ferroquine.
Measured: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
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.
Measured: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
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.
Measured: At 168 hours post-dose
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).
Measured: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
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.
Measured: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
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.
Measured: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Sep 2018
- Study start11 Sep 2018
- Primary completion6 Nov 2019
- Study completion6 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Plasmodium Falciparum InfectionStudies of the same condition, open and under way.
- More trials run by SanofiThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 140 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sanofi
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Medicines for Malaria Venture
- Responsible party
- Sponsor
- Investigators
- Clinical Sciences & Operations, Study director, Sanofi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03660839
- Sponsor's protocol ID
- ACT14655
- Other IDs
- U1111-1191-5573
- Status last verified
- Mar 2022
- First submitted
- 20 Aug 2018
- Last updated
- 21 Mar 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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://vivli.org
Publications
Gansane A, Lingani M, Yeka A, Nahum A, Bouyou-Akotet M, Mombo-Ngoma G, Kaguthi G, Barcelo C, Laurijssens B, Cantalloube C, Macintyre F, Djeriou E, Jessel A, Bejuit R, Demarest H, Marrast AC, Debe S, Tinto H, Kibuuka A, Nahum D, Mawili-Mboumba DP, Zoleko-Manego R, Mugenya I, Olewe F, Duparc S, Ogutu B. Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria. Malar J. 2023 Jan 3;22(1):2. doi: 10.1186/s12936-022-04420-2.
PubMed 36597076
Study at a glance
From the registry record, last updated by the sponsor on 21 Mar 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03660839
- Acronym / sponsor ID
- ACT14655
- Conditions
- Plasmodium Falciparum Infection
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 140 participants (actual)
- Lead sponsor
- SanofiIndustry (pharma, biotech, devices)
- Collaborators
- Medicines for Malaria Venture
- Study start
- 11 Sep 2018 (actual)
- Primary completion
- 6 Nov 2019 (actual)
- Study completion
- 6 Nov 2019 (actual)
- First posted
- 7 Sep 2018 (actual)
- Results
- Posted 2 Dec 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Ferroquine 400 milligram (mg) | Experimental | Drug: Ferroquine (SSR97193)On Day 0, participants received orally a single dose of FQ 400 mg (4 capsules of 100 mg) in fasted condition. |
| Ferroquine 400 mg + Artefenomel 300 mg | Experimental | Drug: Artefenomel (OZ439), Drug: Ferroquine (SSR97193)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. |
| Ferroquine 400 mg + Artefenomel 600 mg | Experimental | Drug: Artefenomel (OZ439), Drug: Ferroquine (SSR97193)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. |
| Ferroquine 400 mg + Artefenomel 1000 mg | Experimental | Drug: Artefenomel (OZ439), Drug: Ferroquine (SSR97193)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. |
Who may qualify
- Ages
- 14 to 69 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (26 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Artefenomel (OZ439)Pharmaceutical form: Granules for oral suspension Route of administration: Oral | Drug | Ferroquine 400 mg + Artefenomel 1000 mg, Ferroquine 400 mg + Artefenomel 300 mg, Ferroquine 400 mg + Artefenomel 600 mg |
| Ferroquine (SSR97193)Pharmaceutical form: Capsule Route of administration: Oral | Drug | Ferroquine 400 mg + Artefenomel 1000 mg, Ferroquine 400 mg + Artefenomel 300 mg, Ferroquine 400 mg + Artefenomel 600 mg, Ferroquine 400 milligram (mg) |
Primary outcome
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.
24 secondary outcomes
Percentage of Participants With Crude Adequate Clinical and Parasitological Response at Day 28
Time frame: Day 28
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
Observed Parasite Reduction Ratio (PRR) at 24 Hours, 48 Hours, and 72 Hours
Time frame: Baseline, 24, 48 and 72 hours post-dose
Time to 50% and 99% Parasite Reduction
Time frame: Up to Day 28
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)
Parasite Clearance Rate
Time frame: Up to Day 28
Time to Re-emergence
Time frame: Up to Day 28
Time to Recrudescence
Time frame: Up to Day 28
Time to Re-infection
Time frame: Up to Day 28
Time Elapsed Below the Limit of Quantification (LOQ) of Parasitemia
Time frame: Up to Day 28
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
Pharmacokinetics (PK): Concentration of OZ439 in Plasma
Time frame: 1, 2, 4, 6, 12, 24, 48, 72, 120, 168 and 336 hours post-dose
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
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
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
Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose (C168h) of Artefenomel
Time frame: At 168 hours post-dose
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
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
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
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
Pharmacokinetics: Plasma Concentration at 168 Hours Post-dose of Ferroquine and Its Active Metabolite SSR97213
Time frame: At 168 hours post-dose
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
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
Pharmacokinetics: Terminal Half-life of Ferroquine
Time frame: Pre-dose, 1, 4, 6, 8, 12, 24, 72, 168, 336 and 672 hours post-dose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Mar 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36597076Gansane A, Lingani M, Yeka A, Nahum A, Bouyou-Akotet M, Mombo-Ngoma G, Kaguthi G, Barcelo C, Laurijssens B, Cantalloube C, Macintyre F, Djeriou E, Jessel A, Bejuit R, Demarest H, Marrast AC, Debe S, Tinto H, Kibuuka A, Nahum D, Mawili-Mboumba DP, Zoleko-Manego R, Mugenya I, Olewe F, Duparc S, Ogutu B. Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria. Malar J. 2023 Jan 3;22(1):2. doi: 10.1186/s12936-022-04420-2.
- Individual participant dataSharing planned: Yes. 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://vivli.org
Related trials for Plasmodium Falciparum Infection
RecruitingPhase 1
Safety, Tolerability and Efficacy of PfSPZ-LARC2 Vaccine Against CHMI in Malaria-Naïve Adults
Malaria Falciparum
Not yet recruiting
Three-arm Cluster Randomised Control Trial Evaluation of Guardian Spatial Emanator as a Complimentary Vector Control Tool in Papua New Guinea
Malaria
Active, not recruitingPhase 4
Improving Neonatal Health Through Rapid Malaria Testing in Early Pregnancy With High-Sensitivity Diagnostics
Malaria,Falciparum, Malaria in Pregnancy
Not yet recruiting
Permethrin-Treated Baby Wraps for Malaria Prevention in Refugee Settings
Malaria (Plasmodium Falciparum), Malaria Incidence
RecruitingPhase 1/2
DON in Pediatric Cerebral Malaria
Malaria, Cerebral
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Sciences & Operations study director
Sanofi
7 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Artefenomel (OZ439) and Ferroquine (SSR97193) in people with Plasmodium Falciparum Infection, run by Sanofi at 7 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in Burkina Faso, Gabon, Benin, Kenya, Uganda. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With Polymerase Chain Reaction (PCR)-Corrected Adequate Clinical and Parasitological Response (ACPR) at Day 28 (ACPR28) (time frame: Day 28). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03660839, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Mar 2022.