The primary objectives of this study are to assess the safety/tolerability and efficacy (by evaluating changes in pulmonary vascular resistance \[PVR\] and pulmonary blood volume \[PBV\]) of frespaciguat in participants with pulmonary hypertension associated with chronic obstructive pulmonary disease (PH-COPD). The primary hypothesis is that 28 days of frespaciguat treatment is superior to placebo treatment in reduction of PVR.
Part 1 of this study will assess safety, tolerability, and PK of frespaciguat compared to placebo. Part 2 will assess safety, tolerability, PK, and changes in PVR and PBV of frespaciguat compared to placebo.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
22
Frespaciguat 32 µg, 100 µg, 195 µg, 360 µg or 380 µg administered as dry powder inhalation according to randomization. Following review of pharmacokinetic (PK) and safety data, a second 7 days of dosing may be initiated. A dose of up to 360 μg up to twice a day may be administered based on PK data. Dosage may be adjusted downwards in Part 2, if indicated by PK results in Part 1.
Placebo administered as dry powder inhalation according to randomization
Lexington VA- Health Care System ( Site 0034)
Lexington, Kentucky, United States
Johns Hopkins - University ( Site 0003)
Baltimore, Maryland, United States
Massachusetts General Hospital ( Site 0005)
Boston, Massachusetts, United States
Percentage of Participants Who Experienced at Least 1 Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE was assessed.
Time frame: Up to approximately 139 days
Percentage of Participants Who Discontinued Study Drug Due to an AE
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed.
Time frame: Up to approximately 32 days
Percentage Change From Baseline to Day 28 in Pulmonary Vascular Resistance (PVR): Part 2
PVR was calculated in participants after MK-5475 dosing at baseline and Day 28. Based on the variables obtained by right heart catheterization (RHC), the fold change from baseline individual PVR was calculated. The difference from baseline was assessed on the log scale and then back-transformed for reporting (percent change from baseline). Per protocol, this outcome measure was only assessed during the Part 2 and was not assessed during part 1.
Time frame: Baseline (between Day -5 and Day -1) and Day 28
Plasma Area Under the Concentration Time-Curve From 0 to Infinity (AUC0-inf) of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose to determine the AUC0-inf of MK-5475. Plasma AUC0-inf was defined as the area under the concentration vs. time curve for MK-5475 from 0 to infinite hours.
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Brigham & Women's Hospital ( Site 0001)
Boston, Massachusetts, United States
University of Rochester Medical Center ( Site 0012)
Rochester, New York, United States
Medical Universtiy of South Carolina ( Site 0011)
Charleston, South Carolina, United States
Rambam Medical Center ( Site 0037)
Haifa, Israel
Rabin Medical Center ( Site 0035)
Petah Tikva, Israel
Republican Clinical Hospital of Moldova ( Site 0013)
Chisinau, Moldova
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC0-24) of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose on Day 7 to determine the AUC0-24 of MK-5475. AUC0-24 values for Day 1 correspond to extrapolated values since collection on Day 1 stopped at 8 hours.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Maximum Observed Plasma Concentration (Cmax) of MK-5475: Part 1
Plasma concentration of MK-5475 was quantified for each arm to determine Cmax.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 1
Blood samples were taken to determine the C24 of MK-5475. Data are reported as Mean with Standard Deviation. Concentration values below the lower limit of quantification were treated as having a value of 0.
Time frame: 24 hours postdose on Day 7
Time to Maximum Concentration (Tmax) of MK-5475: Part 1
Blood samples were taken at predose and at specified time points postdose to determine the Tmax of MK-5475. Tmax was defined as the time to maximum concentration of MK-5475.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Plasma Apparent Terminal Half-Life (t½) of MK-5475: Part 1
Blood samples were taken at predose and at specified time points postdose to determine the t½ of MK-5475.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
Cmax Accumulation Ratio of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose to determine the Cmax accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 Cmax to the Day 1 Cmax.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-24 Accumulation Ratio of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose to determine the AUC0-24 accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-24 to the Day 1 AUC0-24.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-inf Accumulation Ratio of MK-5475: Part 1
Blood samples were taken predose and at specified times postdose on Days 1-7 to determine the AUC0-inf accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-inf to the Day 1 AUC0-inf.
Time frame: Day 1: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4 and 8 hours postdose, Day 7: Predose, 5 minutes, 15 minutes, 0.5, 1, 2, 3, 4, 8 and 24 hours postdose
AUC0-inf of MK-5475: Part 2
Blood samples were taken pre-dose and at specified times post-dose to determine the AUC0-inf of MK-5475. Concentrations for samples collected pre-RHC in a time window of 6-8 hours postdose on Day 28 were used to derive PK parameter values on Day 28. A nominal elapsed time of 6.01 hours postdose was used in the calculation.
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
AUC0-24 of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose on Day 28 to determine the AUC0-24 of MK-5475. Concentrations for samples collected pre-RHC in a time window of 6-8 hours postdose on Day 28 were used to derive PK parameter values on Day 28. A nominal elapsed time of 6.01 hours postdose was used in the calculation. AUC0-24 was calculated using extrapolated concentration at 24 hours postdose.
Time frame: Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Cmax of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the Cmax of MK-5475.
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Plasma Concentration 24 Hours Postdose (C24) of MK-5475: Part 2
Blood samples were taken to determine the C24 of MK-5475. Data are reported as Mean with Coefficient of Variation, but due to data entry limitations the table below labels them as Geometric Mean and Geometric Coefficient of Variation. Concentration values below the lower limit of quantification were treated as having a value of 0.
Time frame: 24 hours postdose on Day 7
Tmax of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the Tmax of MK-5475.
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
t½ of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the t½ of MK-5475.
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
AUC0-3 Accumulation Ratio of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose on to determine the AUC0-3 accumulation ratio of MK-5475. Accumulation ratio is the ratio of the Day 7 AUC0-3 to the Day 1 AUC0-3.
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Cmax Accumulation Ratio of MK-5475: Part 2
Blood samples were taken predose and at specified times postdose to determine the Cmax accumulation ratio of MK-5475. Cmax accumulation ratio is the ratio of the Day 7 Cmax to the Day 1 Cmax.
Time frame: Day 1: Predose, 0.5, 1, 2 and 3 hours postdose, Day 15: 1 hour postdose, Day 28: Predose, 0.5, 1, 2 and 3 hours postdose
Percent Change From Baseline in Pulmonary Blood Volume (PBV) at Day 28: Part 2
Participants underwent a series of computed tomography (CT) scans with an intravenous (IV) iodinated contrast agent to facilitate assessment of PBV at baseline and at several times points after MK-5475 dosing. Percentage change from baseline (CFB) in PBV was calculated and reported for each dose group that underwent FRI in Part 2. As pre-specified, central tendency for PBV percentage CFB was provided as numerical values rounded to whole numbers. Per protocol, this outcome measure was only assessed during the Part 2 FRI Period for each panel and was not assessed during part 1 and part 3.
Time frame: Baseline (between Day -5 and Day -1) and Day 28