A Study to Compare the Macitentan-tadalafil Fixed Dose Combination Tablet Relative to the Concomitant Administration of the Reference Tablets of Macitentan and Tadalafil in Healthy Subjects

Single-center, Open-label, Single-dose, Two-period, Randomized, Crossover, Phase I Study to Demonstrate Bioequivalence Between a Fixed Dose Combination Product Formulation of Macitentan/Tadalafil (10 mg/40 mg) and the Free Combination of 10 mg Macitentan (Opsumit®) and 40 mg Tadalafil (Adcirca®) in Healthy Male and Female Subjects

The primary objective of this study is to demonstrate that macitentan and tadalafil administered as a fixed combination is bioequivalent to both compounds given as separate tablets given at the same doses as in the fixed combination (i.e. whether the amounts of macitentan and tadalfil which reach the blood are comparable).

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Combination product: Macitentan / tadalafil FDC; Drug: Macitentan (Opsumit®); Drug: Tadalafil (Adcirca®)

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Mannheim, Germany, 68167
    • CRS Clinical Research Services Mannheim

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Signed informed consent
• Male and female subjects aged between 18 and 55 years (inclusive) at screening
• Healthy on the basis of the physical examination, vital signs, 12-lead ECG, and laboratory tests performed at screening
• Women must have a negative serum pregnancy test at screening and a negative urine pregnancy test on Day-1 or must be of non-childbearing potential.
• Body mass index (BMI) of 18.0 to 30.0 kg/m2 (inclusive) at screening
• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 bpm (inclusive)

Key Exclusion Criteria:

• Known hypersensitivity to any active substance or drugs of the same class, or any excipients 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 treatment(s)
• Values of hepatic aminotransferase (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) > 3 X upper limit of normal at screening
• Loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy
• Known hereditary degenerative retinal disorders, including retinitis pigmentosa
• Priapism and anatomical deformation of the penis
• Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions
• Treatment with another investigational drug within 3 months prior to screening or participation in more than 4 investigational drug studies within 1 year prior to screening
• Excessive caffeine consumption, defined as > or = 800 mg per day at screening.
• Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) within 3 months prior to screening and inability to refrain from nicotine intake from screening until end-of-study (EOS; washout period included)
• Previous treatment with any prescribed medications (including vaccines) or over the counter (OTC) medications within 3 weeks prior to first study treatment administration.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence A/B; Subjects receive one tablet of macitentan / tadalafil FDC (fixed dose combination) during Period 1, then after a washout period of at least 7 days they receive one tablet of macitentan (Opsumit®) and two tablets of tadalafil (Adcirca®) during Period 2	Combination product: Macitentan / tadalafil FDC; Tablets for oral administration containing 10 mg of macitentan and 40 mg of tadalafil; Drug: Macitentan (Opsumit®); Film-coated tablets for oral administration formulated at a strength of 10 mg; Other Names: ACT-064992; Drug: Tadalafil (Adcirca®); Film-coated tablets for oral administration formulated at a strength of 20 mg
Experimental: Sequence B/A; Subjects receive one tablet of macitentan (Opsumit®) and two tablets of tadalafil (Adcirca®) during Period 1, then after a washout period of at least 7 days, they receive one tablet of macitentan / tadalafil FDC (fixed dose combination) during Period 2	Combination product: Macitentan / tadalafil FDC; Tablets for oral administration containing 10 mg of macitentan and 40 mg of tadalafil; Drug: Macitentan (Opsumit®); Film-coated tablets for oral administration formulated at a strength of 10 mg; Other Names: ACT-064992; Drug: Tadalafil (Adcirca®); Film-coated tablets for oral administration formulated at a strength of 20 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax) of macitentan and tadalafil	The measured individual plasma concentrations of macitentan and tadalafil are used to directly obtain Cmax	Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period
Area under the plasma concentration-time curve from 0 to time t [AUC(0-t)] of macitentan and tadalafil	AUC(0-t) is the area calculated from the concentration-time profile of macitentan and tadalafil, from time 0 to to time t of the last measured concentration above the limit of quantification	Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period
Area under the plasma concentration-time curve to infinitiy [AUC(0-inf)] of macitentan and tadalafil	AUC(0-inf) is the area calculated from the concentration-time profile of macitentan and tadalafil, from time 0 to extrapolated infinite time	Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
maximal plasma concentration (Cmax) of ACT-132577	Cmax of the active metabolite of macitentan, ACT-132577, is measured directly from the plasma concentrations of ACT-132577	Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period
Area under the plasma concentration-time curve from 0 to time t [AUC(0-t)] of ACT-132577	AUC(0-t) of the active metabolite of macitentan, ACT-132577, is calculated from the concentration-time profile of ACT-132577 from time 0 to time t of the last measured concentration above the limit of quantification	Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period
Area under the plasma concentration-time curve to infinity [AUC(0-inf)] of ACT-132577	AUC(0-inf) of the active metabolite of macitentan, ACT-132577, is calculated from the concentration-time profile of ACT-132577 from time 0 to extrapolated infinite time	Blood samples for pharmacokinetic evaluations are collected at selected time points from Baseline (pre-dose) to 216 hours post-dose of each study period

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: JP Jones, Actelion

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2017
• Primary Completion (Actual): September 24, 2017
• Study Completion (Actual): September 24, 2017

Study Registration Dates

• First Submitted: July 11, 2017
• First Submitted That Met QC Criteria: July 11, 2017
• First Posted (Actual): July 12, 2017

Study Record Updates

• Last Update Posted (Actual): November 9, 2017
• Last Update Submitted That Met QC Criteria: November 8, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: bioequivalence
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Tadalafil; Macitentan
• Other Study ID Numbers: AC-077-103

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No