Clinical trial NCT02186002: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-451840 in Healthy Subjects (Part A)
Official title: Single-center, Double-blind, Placebo-controlled, Randomized, Single-ascending Dose, With Nested Cross-over for Food Effect, to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-451840 in Healthy Subjects (Part A)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: ACT-451840
Safety
Tolerability
Pharmacokinetics
Lead sponsor: Idorsia Pharmaceuticals Ltd.
Sponsor class: INDUSTRY
First posted: 2014-07-10
Enrollment: 40
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The primary objective of the study was to evaluate the safety and tolerability of ACT-451840 in healthy male subjects.Secondary objectives were : to investigate the pharmacokinetics (PK) of ACT-451840; to investigate the effect of food on the PK of ACT-451840; to evaluate the urinary excretion of ACT-451840 and to investigate the antimalarial activity of ACT-451840.


Eligibility criteria: Inclusion Criteria:

* Signed informed consent in the local language prior to any study-mandated procedure.
* Body mass index (BMI) of 18.0 to 28.0 kg/m2 (inclusive) at screening.
* Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (inclusive), measured on the dominant arm, after 5 min in the supine position at screening.
* 12-lead electrocardiogram without clinically relevant abnormalities, measured after 5 min in the supine position at screening.
* Hematology, coagulation, clinical chemistry, and urinalysis test results not deviating from the normal range to a clinically relevant extent at screening.
* No clinically significant findings on the physical examination at screening.
* Negative results from urine drug screen at screening.
* Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.
* Subject covered by Health Insurance system and/or in compliance with the recommendations of the National Law in force relating to biomedical research.
* If the subject's partner could become pregnant, reliable methods of contraception must be used from the time of the first administration of study medication until 3 months following administration of the last dose of study medication.

Exclusion Criteria:

* Known allergic reactions or hypersensitivity to any excipient of the drug formulation(s).
* History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
* Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
* Documented history of chronic liver or gall bladder disease.
* Documented history of hemolytic anemia.
* Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).
* Previous exposure to the study medication.
* Treatment with another investigational drug within 3 months prior to screening or participation in more than four investigational drug studies within the 12 months prior to screening.
* Subject in the exclusion period of a previous clinical study.
* Subject who had received more than 4,500 Euros as indemnities for his participation in a biomedical research within the 12 last months, including the indemnities for the present study.
* History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
* Excessive caffeine consumption, defined as 800 mg or more per day at screening.
* Smoking within 3 months prior to screening and inability to refrain from smoking during the course of the study.
* Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St. John's Wort) within 2 weeks prior to first study drug administration.
* Loss of 250 mL or more of blood within 3 months prior to screening.
* Positive results from the hepatitis (hepatitis B and C) serology, except for vaccinated subjects.
* Positive results from human immunodeficiency virus serology at screening.
* Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
* Legal incapacity or limited legal capacity at screening.

Primary outcomes:
measure: Change in systolic blood pressure from baseline up to end of study
timeFrame: 4 days
measure: Change in diastolic blood pressure from baseline up to end of study
timeFrame: 4 days
measure: Change in pulse rate from baseline up to end of study
timeFrame: 4 days
measure: Change in body weight from baseline up to end of study
timeFrame: 4 days
measure: Change in heart rate from baseline up to end of study
timeFrame: 4 days
measure: Change in PQ/PR interval from baseline up to end of study
timeFrame: 4 days
measure: Change in QRS interval from baseline up to end of study
timeFrame: 4 days
measure: Change in QTc interval (time interval from beginning of the Q wave until end of the T wave) according to Fridericia's correction (QTcF interval) from baseline up to end of study
timeFrame: 4 days
measure: Change in QTc interval (time interval from beginning of the Q wave until end of the T wave) according to Bazett's correction (QTcB interval) from baseline up to end of study
timeFrame: 4 days
measure: Number of treatment-emergent electrocardiogram abnormalities from baseline up to end of study
timeFrame: 4 days
Secondary outcomes:
measure: Maximum plasma concentration (Cmax) of ACT-451840
timeFrame: 4 days
measure: Time to maximum plasma concentration (tmax) of ACT-451840
timeFrame: 4 days
measure: Area under the plasma concentration-time curve (AUC(0-t)) of ACT-451840
timeFrame: 4 days
measure: Area under the plasma concentration-time curve (AUC(0-infinity)) of ACT-451840
timeFrame: 4 days
measure: Plasma half life (t1/2) of ACT-451840
timeFrame: 4 days
measure: Dose proportionality of single doses of ACT-451840
timeFrame: 4 days
measure: Percentage of administered ACT-451840 excreted unchanged in urine
timeFrame: 4 days
measure: Anti-malarial half-maximal inhibitory concentration (IC50) of ACT-451840
timeFrame: 4 days
Other outcomes:
Locations:
city: Gières
country: France
facility: OPTIMED Clinical Research
Study officials:
affiliation: Idorsia Pharmaceuticals Ltd.
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Bruderer S, Hurst N, de Kanter R, Miraval T, Pfeifer T, Donazzolo Y, Dingemanse J. First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity. Antimicrob Agents Chemother. 2015 Feb;59(2):935-42. doi: 10.1128/AAC.04125-14. Epub 2014 Nov 24.