Clinical trial NCT04235270: A Study of Macitentan and Tadalafil as a Fixed Dose Combination and the Free Combination in Healthy Adult Participants
Official title: Single-center, Open-label, Single-dose, 2-period, Randomized, Crossover Phase 1 Study to Demonstrate Bioequivalence of Tadalafil Administered as a Fixed Dose Combination Formulation of Macitentan/Tadalafil (10 mg/40 mg) and as the Free Combination of 10 mg Macitentan (Opsumit) and 40 mg Tadalafil (Adcirca), and to Assess the Effect of Food on the Pharmacokinetics of the Fixed Dose Formulation of Macitentan/Tadalafil (10 mg/40 mg) in Healthy Adult Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2020-01-21
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to demonstrate bioequivalence on the primary pharmacokinetic (PK) parameters of tadalafil administered as an fixed dose combination (FDC) (test) of macitentan/tadalafil (10 milligram \[mg\]/40 mg) and coadministered as a free combination (reference) of 10 mg macitentan (Opsumit) and 40 mg Canada-sourced tadalafil (Adcirca) in fasted conditions in healthy adult participants (Group 1) and to evaluate the effect of food on the primary PK parameters of macitentan and tadalafil administered as an FDC of macitentan/tadalafil (10 mg/40 mg) in healthy adult participants (Group 2).


Eligibility criteria: Inclusion Criteria:

* Body mass index (BMI; weight \[kilogram\]/height\^2 \[m\^2\]) between 18.5 and 30.0 kilogram per meter square (kg/m\^2), inclusive, and body weight not less than 50.0 kg at screening
* Healthy on the basis of physical examination, and medical and surgical history, performed at screening. If there are abnormalities, the participant may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator
* Healthy on the basis of clinical laboratory tests performed at screening. If the results of hematology, coagulation, or biochemistry assessments are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator
* Systolic blood pressure (SBP) between 100 and 145 millimeter of Mercury (mmHg), diastolic blood pressure (DBP) between 50 and 90 mmHg, and pulse rate between 45 and 99 beats per minute (bpm; inclusive), preferably measured on the right arm, after the participant is supine for at least 5 minutes, at screening
* 12-lead electrocardiogram (ECG) without clinically relevant abnormalities, at the discretion of the investigator, measured after the participant is supine for at least 5 minutes, at screening

Exclusion Criteria:

* Female participant who is breastfeeding at screening and plans to breastfeed throughout the study
* Known allergy, hypersensitivity, or intolerance to any active substance or drugs of the same class, or 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 treatment(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed)
* Any loss of vision in 1 or both eyes
* Known hereditary degenerative retinal disorders, including retinitis pigmentosa

Primary outcomes:
measure: Group 1: Maximum Observed Plasma Analyte Concentration (Cmax) of Tadalafil
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1: Area Under the Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Tadalafil
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC [0-infinity]) of Tadalafil
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 2: Maximum Observed Plasma Analyte Concentration (Cmax) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 2: Area Under the Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 2: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC [0-infinity]) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
Secondary outcomes:
measure: Group 1 and Group 2: Time to Reach Maximum Observed Plasma Analyte Concentration (Tmax) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1 and Group 2: Last Observed Measurable Plasma Analyte Concentration (Clast) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1 and Group 2: Area Under the Plasma Analyte Concentration-time Curve from Time of 0 to 72 Hours Post Dosing (AUC[0-72h] of Tadalafil and Macitentan
timeFrame: Up to 72 hours post dose
measure: Group 1 and Group 2: Apparent Terminal Elimination Half-life (t1/2) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1 and Group 2: Apparent Terminal Elimination Rate Constant (Lambda[z]) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1 and Group 2: Total Apparent Oral Clearance (CL/F) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1 and Group 2: Apparent Volume of Distribution (Vdz/F) of Tadalafil and Macitentan
timeFrame: Up to 216 hours post dose (Up to Day 10)
measure: Group 1 and Group 2: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: Up to 6 weeks
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Celerion
state: Arizona
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Csonka D, Fishman V, Natarajan J, Stieltjes H, Armas D, Dishy V, Perez Ruixo JJ. Bioequivalence and food effect of a fixed-dose combination of macitentan and tadalafil: Adaptive design in the COVID-19 pandemic. Pharmacol Res Perspect. 2021 Oct;9(5):e00846. doi: 10.1002/prp2.846.