Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-128800 in Healthy Subjects

Safety and Tolerability Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02029482
• Other study ID #: AC-058-109
• Status: Completed
• Phase: Phase 1
• First received: January 6, 2014
• Last updated: January 6, 2014
• Start date: April 2010
• Est. completion date: June 2010

Study information

• Verified date: January 2014
• Source: Actelion
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Related Conditions & MeSH terms

• Safety and Tolerability

Intervention

Drug:
• ACT-128800

• Placebo

Locations

Country	Name	City	State
United Kingdom	Quintiles Drug Research Unit at Guy's Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
Actelion

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline to Day 18 in systolic blood pressure	Blood pressure was measured using an automatic oscillometric device, always on the leading arm (i.e., leading arm right = writing with right hand).; Measurements were recorded from the subject in the supine position after having rested for a 5-minute period.	18 days	Yes
Primary	Change from baseline to Day 18 in diastolic blood pressure	Blood pressure was measured using an automatic oscillometric device, always on the leading arm (i.e., leading arm right = writing with right hand).; Measurements were recorded from the subject in the supine position after having rested for a 5-minute period.	18 days	Yes
Primary	Change from baseline to Day 18 in pulse rate	Pulse rate was measured using an automatic oscillometric device, always on the leading arm (i.e., leading arm right = writing with right hand).; Measurements were recorded from the subject in the supine position after having rested for a 5-minute period.	18 days	Yes
Primary	Change from baseline to Day 18 in body temperature	Body temperature was measured in the supine position using the same thermometer throughout the study.	18 days	Yes
Secondary	Change from baseline to Day 10 in mean absolute lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte counts were determined with standard commercially available assay kits.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean T cell (Cluster of differentiation (CD) CD3+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean B cell (CD3-/CD19+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean natural killer (NK) cell (CD3-/CD56+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean natural killer T (NKT) cell (CD3+/CD56+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD4+ T-helper cell (CD3+/CD4+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean T-cytotoxic cell (CD3+/CD8+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD4+T-naive cell (CD45RA+/chemokine receptor type 7 (CCR7+)) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD4+ T-central memory cell (CD45RA-/CCR7+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD4+ T-effector memory cell (CD45RA-/CCR7-) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD4+ T-effector cell (CD45RA+/CCR7-) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD8+ T-naive cell (CD45RA+/CCR7+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD8+ T-central memory cell (CD45RA-/CCR7+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD8+ T-effector memory cell (CD45RA-/CCR7-) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean CD8+ T-effector cell (CD45RA+/CCR7-) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean T-regulatory cell (CD25+/Forkhead box P3 (Foxp3+)) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean skin-homing T-helper cell (Cutaneous lymphocyte antigen (CLA)+/integrin ß7-) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Change from baseline to Day 10 in mean gut-homing T-helper cell (CLA-/integrin ß7+) lymphocyte count	For each assessment, 1.5 mL of blood was collected aseptically from the subject in the supine position by venipuncture or via an intravenous. catheter placed in an antecubital vein in the arm in ethylenediaminetetraacetic acid containing tubes. Immediately following collection of the required whole blood volume, the tubes were slowly tilted backwards and forwards (no shaking) to bring the anti-coagulant into solution. The anticoagulated whole blood stored at room temperature (20-25 °C) was preferably stained within 12 hours, at the latest 24 hours, and analyzed within 24 hours. The lymphocyte subset counts were analyzed by fluorescence activated cell sorting.	10 days	Yes
Secondary	Maximum plasma concentration (Cmax) of ACT-128800 on Days 9 and 18	Blood samples for pharmacokinetic analysis were taken following drug administration on study Day 9 (Day 3 of the dosing period with 40 mg) and study Day 18 (Day 3 of the dosing period with 100 mg) and Cmax of ACT-128800 was determined by non-compartmental analysis.	18 days	No
Secondary	Area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24) of ACT-128800 on Days 9 and 18	Blood samples for pharmacokinetic analysis were taken following drug administration on study Day 9 (Day 3 of the dosing period with 40 mg) and study Day 18 (Day 3 of the dosing period with 100 mg) and AUC0-24 of ACT-128800 was determined by non-compartmental analysis.	18 days	No
Secondary	Area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity) of ACT-128800 on Day 18	Blood samples for pharmacokinetic analysis were taken following drug administration on study Day 18 (Day 3 of the dosing period with 100 mg) and AUC0-infinity of ACT-128800 was determined by non-compartmental analysis.	18 days	No
Secondary	Time to reach maximum plasma concentration (tmax) of ACT-128800 on Days 9 and 18	Blood samples for pharmacokinetic analysis were taken following drug administration on study Day 9 (Day 3 of the dosing period with 40 mg) and study Day 18 (Day 3 of the dosing period with 100 mg) and tmax of ACT-128800 was determined by non-compartmental analysis.	18 days	No
Secondary	Terminal half-life (t1/2) of ACT-128800 on Day 18	Blood samples for pharmacokinetic analysis were taken following drug administration on study Day 18 (Day 3 of the dosing period with 100 mg) and t1/2 of ACT-128800 was determined by non-compartmental analysis.	18 days	No