Clinical trial NCT02029482: Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-128800 in Healthy Subjects
Official title: Single-center, Double-blind, Placebo-controlled, Randomized, Parallel-group, Up-titration Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Increasing Doses of ACT-128800 in Healthy Male and Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Safety and Tolerability
Keywords: ACT-128800
Lead sponsor: Actelion
Sponsor class: INDUSTRY
First posted: 2014-01-08
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: This was a single-center, randomized, double-blind, placebo-controlled, up-titration Phase 1 study. Sixteen subjects in two groups (at least 40% of subjects of either male or female sex), with 12 subjects in the active treatment group with an up-titration scheme from 10 to 100 mg, and 4 subjects in the placebo treatment group. Subjects were administered ascending doses of ACT-128800/placebo once daily for 3 days at each dose level: 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, and 100 mg.


Eligibility criteria: Inclusion Criteria:

* Signed informed consent in the local language prior to any study-mandated procedure.
* Age between 18 and 65 years (inclusive) at screening.
* Body mass index (BMI) between 18 and 30 kg/m\^2 (inclusive).
* Women of childbearing potential were required to have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to first drug intake and have agreed to use two methods of contraception from the screening visit until 2 months after study drug discontinuation.
* Systolic blood pressure 100-150 mmHg, diastolic blood pressure 50-90 mmHg measured on the leading arm, and heart rate 50-95 beats per minute (inclusive) measured by electrocardiography (ECG) after 5 minutes in the supine position at screening.
* ECG without clinically relevant abnormalities at screening.
* Hematology and clinical chemistry results not deviating from the normal range to a clinically relevant extent at screening.
* Negative results from urine drug screen at screening.
* Ability to communicate well with the investigator and to understand and comply with the requirements of the study.

Exclusion Criteria:

* ECG recording; PQ/PR interval \> 200 ms at screening.
* Pregnant or lactating women.
* Known hypersensitivity to any excipients of the drug formulation.
* Known hypersensitivity to beta2 adrenergic receptor agonists.
* 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).
* Treatment with another investigational drug within 3 months prior to screening.
* Excessive caffeine consumption, defined as ≥ 800 mg per day at screening. History or clinical evidence of any disease and/or existence of any surgical or medical condition that might interfere with the absorption, distribution, metabolism or excretion of the study drug.
* Smoking within the last month prior to screening.
* Any immunosuppressive treatment within 6 weeks before study drug administration.
* Previous treatment with any prescribed or over-the-counter medications (including herbal medicines such as St John's Wort) within 2 weeks prior to screening or 5 half-lives of the drug, whichever is longer.
* Loss of 250 mL or more of blood within 3 months prior to screening.
* Lymphopenia (\< 1,000 cells/μL).
* Viral, fungal, bacterial or protozoal infection within 4 weeks before study drug administration (e.g., active herpes and/or cytomegalovirus infection).
* History or clinical evidence suggestive of active or latent tuberculosis at screening.
* Positive results from the hepatitis serology, except for vaccinated subjects, at screening.
* Positive results from the human immunodeficiency virus serology at screening.
* Forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) \< 80% of the predicted value, or FEV1/FVC ratio \< 0.7 at screening.
* History of asthma or chronic obstructive pulmonary disease.
* Any cardiac condition or illness (including ECG abnormalities) with a potential to increase the cardiac risk of the subject in the standard 12-lead ECG and 24-hour 3-lead Holter ECG at screening.
* History of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
* Familial history of sick-sinus syndrome.
* History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening. Alcohol abuse is defined as regular weekly intake of more than 21 units.
* Legal incapacity or limited legal capacity at screening.
* Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Primary outcomes:
measure: Change from baseline to Day 18 in systolic blood pressure
timeFrame: 18 days
measure: Change from baseline to Day 18 in diastolic blood pressure
timeFrame: 18 days
measure: Change from baseline to Day 18 in pulse rate
timeFrame: 18 days
measure: Change from baseline to Day 18 in body temperature
timeFrame: 18 days
Secondary outcomes:
measure: Change from baseline to Day 10 in mean absolute lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean T cell (Cluster of differentiation (CD) CD3+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean B cell (CD3-/CD19+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean natural killer (NK) cell (CD3-/CD56+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean natural killer T (NKT) cell (CD3+/CD56+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD4+ T-helper cell (CD3+/CD4+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean T-cytotoxic cell (CD3+/CD8+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD4+T-naive cell (CD45RA+/chemokine receptor type 7 (CCR7+)) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD4+ T-central memory cell (CD45RA-/CCR7+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD4+ T-effector memory cell (CD45RA-/CCR7-) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD4+ T-effector cell (CD45RA+/CCR7-) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD8+ T-naive cell (CD45RA+/CCR7+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD8+ T-central memory cell (CD45RA-/CCR7+) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD8+ T-effector memory cell (CD45RA-/CCR7-) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean CD8+ T-effector cell (CD45RA+/CCR7-) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean T-regulatory cell (CD25+/Forkhead box P3 (Foxp3+)) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean skin-homing T-helper cell (Cutaneous lymphocyte antigen (CLA)+/integrin β7-) lymphocyte count
timeFrame: 10 days
measure: Change from baseline to Day 10 in mean gut-homing T-helper cell (CLA-/integrin β7+) lymphocyte count
timeFrame: 10 days
measure: Maximum plasma concentration (Cmax) of ACT-128800 on Days 9 and 18
timeFrame: 18 days
measure: Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) of ACT-128800 on Days 9 and 18
timeFrame: 18 days
measure: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity) of ACT-128800 on Day 18
timeFrame: 18 days
measure: Time to reach maximum plasma concentration (tmax) of ACT-128800 on Days 9 and 18
timeFrame: 18 days
measure: Terminal half-life (t1/2) of ACT-128800 on Day 18
timeFrame: 18 days
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Quintiles Drug Research Unit at Guy's Hospital
Study officials:
affiliation: Quintiles Drug Research Unit
name: Darren Wilbraham, MBBS, DCPSA
role: PRINCIPAL_INVESTIGATOR
References: