A Study of Single Doses of MK -5475 on Pulmonary Vascular Resistance (MK-5475-002)

Study Overview
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Brief Summary
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This study of MK-5475 in participants with Group 1 pulmonary arterial hypertension (PAH) will assess the safety, tolerability and pharmacokinetics (PK) of inhaled MK-5475. There is no formal hypothesis to be tested.

Detailed Description
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In Part 1, one panel (Panel A) of up to 8 participants will dose in up to 3 dosing periods, with a minimum washout of 7 days between dosing periods. In each dosing period, 6 participants will receive MK-5475 and 2 will receive placebo, with 2 different participants receiving placebo in each of the dosing periods. Review of available safety data will occur prior to escalating to the next dose level. Participants from Part 1 may continue into Part 2, which will assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose inhaled MK-5475. Three additional panels of participants (Panels B, C and D) will be enrolled into Part 2. Participants in Panel A will participate in 2 open-label dosing periods to assess PD measures associated with right heart catherization (RHC) [Period 2] and functional respiratory imaging (FRI) [Period 3]. Participants in Panels B, C, and D will participate in 3 dosing periods: Period 1 (open-label assessment of safety/tolerability and PK), Period 2 (FRI period) and Period 3 (RHC period).

Official Title
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A Study to Assess the Effect of Single Doses of MK -5475 on Pulmonary Vascular Resistance in Patients With Moderate to Severe Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: MK-5475
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be or have suspected Group 1 pulmonary hypertension as defined by the Nice 2013 Clinical Classification, including: idiopathic PAH, heritable PAH, drug- or toxin-induced PAH, or PAH associated with connective tissue disease or congenital heart disease Have a Body Mass Index (BMI) ≤35 kg/m2, Female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: She is a woman of nonchildbearing potential (WONCBP) or is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) Male participants are eligible to participate if they agree to the following during the intervention period and for at least 14 days, corresponding to time needed to eliminate study intervention(s) after the last dose of study intervention: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception unless confirmed to be azoospermic (Vasectomized) or secondary to medical cause. Have a clinical indication for right heart catheterization (RHC) as part of initial work-up or ongoing medical management Panel A: Have history of RHC within 3 years of starting study medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and pulmonary vascular resistance (PVR) of ≥ 300 dynes/sec/cm5 Panels B/C/D: Have history of RHC within 3 years of starting study medication demonstrating mean pulmonary artery pressure of ≥ 27 mmHg and PVR of ≥ 300 dynes/sec/cm5 OR have an echocardiogram performed by the investigator at screening or within 1 year of screening demonstrating pulmonary artery systolic pressure ≥ 50 mmHg in conjunction with 1 or more of the following: tricuspid regurgitation velocity > 3.0 m/s and or significant right heart enlargement and or reduced right heart function. Exclusion Criteria: Has pulmonary hypertension subtypes including the following according to Nice 2013 Clinical Classification: human immunodeficiency (HIV) infection, portal hypertension, schistosomiasis, chronic hemolytic anemia, pulmonary veno-occlusive disease (PVOD) and or pulmonary capillary hemangiomatosis (PCH), persistent pulmonary hypertension of the newborn (PPHN), pulmonary hypertension owing to left heart diseases, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular disease, congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies, pulmonary hypertension owing to lung diseases and/or hypoxia, Chronic obstructive pulmonary disease, Interstitial lung disease, other pulmonary diseases with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental abnormalities, pulmonary hypertension defined as chronic thromboembolic pulmonary hypertension [CTEPH]), pulmonary hypertension with unclear multifactorial mechanisms, hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy, systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis, metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders, others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension Has a history of clinically significant endocrine (not including stable diabetes mellitus), gastrointestinal, cardiovascular, hematological, hepatic (not including chronic stable Hepatitis B and Hepatitis C), immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases Is mentally or legally incapacitated, has significant emotional problems History of cancer (malignancy) except nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or other malignancies which have been successfully treated 10 years prior to screening History of significant multiple and/or severe allergies Known hypersensitivity to iodine or iodine containing products Positive for HIV Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks of screening Has persistent or permanent atrial fibrillation with an uncontrolled ventricular rate Has significantly impaired gas exchange Has an active respiratory infection (e.g. common cold, bronchitis, influenza, pneumonia) with lung function outside of the normal range Is currently on monotherapy calcium channel blockers as a specific treatment for pulmonary hypertension Has taken nitrates within 24 hours of anticipated dosing Has taken inhaled prostacyclin within 24 hours of anticipated dosing (iloprost or treprostinil) Has taken diltiazem immediate release taken within 24 hours or extended release taken within 48 hours of anticipated dosing Has taken sildenafil or vardenafil within 24 hours or tadalafil within 7 days of anticipated dosing Has taken soluble guanylate cyclase (sGC) activator for PAH within 24 hours of anticipated dosing Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit Has participated in another investigational study within 4 weeks Does not agree to follow the smoking restrictions Part 2 only: Suffers from claustrophobia and would be unable to undergo computerized tomography (CT) scan Part 2 only: Has participated in a positron-emission tomography (PET) research study or other study involving administration of a radioactive substance or ionizing radiation within 12 months prior to the screening visit, or has undergone or plans to have extensive radiological examination within this period Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day Consumes excessive amounts, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks, or other caffeinated beverages per day Is a regular user of cannabis, any illicit drugs or has a history of drug (including alcohol) abuse within approximately 12 months. Participants must have a negative urine drug screen (UDS) prior to randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 of the study will evaluate safety, tolerability, and pharmacokinetics in this population using a sequential study design. Review of available safety data up to 24 hours post dose of at least the first 4 participants must occur prior to escalating to the next dose level. A break to review PK data from Periods 1 and 2 will occur after completion of Period 2. Review of safety will occur after completion of Period 3 in all participants from Panel A, prior to initiation of Part 2. An optional break to review rolling PK data from Panel A Period 3 will be dependent upon exposures observed in Periods 1 and 2.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A: MK-5475 120 ug/165 ug/240 ug/240 ug/240 ug (Parts 1 and 2)<br>Participants in Panel A will receive a single inhaled dose of MK-5475 120 ug in Period 1 of Part 1, followed by MK-5475 165 ug in Period 2, followed by MK-5475 240 ug in Period 3. Each dose will be separated by at least a 7-day washout. In Part 2 Period 2, participants will receive a single inhaled dose of MK-5475 240 ug and undergo a right heart catheterization (RHC). In Part 2 Period 3, participants will receive a single inhaled dose of MK-5475 240 ug and undergo a functional respiratory imaging (FRI). | Drug: MK-5475<br>* Single inhaled dose of MK-5475 120, 165, 240, 300, 360, or 480 ug depending upon randomization<br>|
| Experimental: Panel B: 300 ug/360 ug/360 ug (Part 2)<br>Participants in Panel B will receive a single inhaled dose of MK-5475 300 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of MK-5475 360 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of MK-5475 360 ug and undergo RHC. Each dose will be separated by at least a 7-day washout. | Drug: MK-5475<br>* Single inhaled dose of MK-5475 120, 165, 240, 300, 360, or 480 ug depending upon randomization<br>|
| Experimental: Panel C: 300 ug/360 ug/360 ug (Part 2, Expansion)<br>Participants in Panel C will receive a single inhaled dose of MK-5475 300 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of MK-5475 360 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of MK-5475 360 ug and undergo RHC. Each dose will be separated by at least a 7-day washout. | Drug: MK-5475<br>* Single inhaled dose of MK-5475 120, 165, 240, 300, 360, or 480 ug depending upon randomization<br>|
| Experimental: Panel D: 480 ug/120 ug/120 ug (Part 2)<br>Participants in Panel D will receive a single inhaled dose of MK-5475 480 ug in Period 1 of Part 2. In Period 2 of Part 2, participants will receive a single inhaled dose of MK-5475 120 ug and undergo FRI. In Period 3 of Part 2, participants receive a single inhaled dose of MK-5475 120 ug and undergo RHC. Each dose will be separated by at least a 7-day washout. | Drug: MK-5475<br>* Single inhaled dose of MK-5475 120, 165, 240, 300, 360, or 480 ug depending upon randomization<br>|
| Placebo Comparator: Placebo (Part 1)<br>Participants will receive a single inhaled dose of matching placebo in Part 1. | Drug: Placebo<br>* Single inhaled dose of placebo to match MK-5475<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced at Least 1 Adverse Event (AE): All Parts | An AE was defined as any untoward medical occurrence in a participant which may not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease that was temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The number of participants who experienced at least 1 AE was reported by dose separately for Part 1 plus Part 2 Period 1, for the RHC Period, and for the FRI Period. | Up to  14 days after last dose of treatment period (Up to  32 weeks total) | 
| Number of Participants Who Discontinued From the Study Due to an AE: All Parts | An AE was defined as any untoward medical occurrence in a participant which may not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease that was temporally associated with use of a medicinal product, regardless of whether or not it was considered related to the medicinal product. The number of participants who discontinued from the study due to an AE was reported by dose separately for Part 1 plus Part 2 Period 1, for the RHC Period, and for the FRI Period. | Up to  14 days after last dose of treatment period (Up to  32 weeks total) | 
| Percentage Change From Baseline in Minimum Pulmonary Vascular Resistance (PVR): Part 2 Right Heart Catheterization (RHC) Period | For each participant in the RHC Period, the percentage change from baseline for the minimum post-dose PVR value over the duration of the RHC procedure was calculated. The average of pre-dose measurements was set as the baseline. Mean (SD) percent change from baseline in PVR minimum were calculated and reported for each dose group that underwent RHC in Part 2. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and up to 4.5 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Heart Rate (HR) at 0.5 Hours Post-dose: Part 2 RHC Period | HR was assessed at pre-dose in the RHC Period (baseline) and at 0.5 hours post-dose. Baseline HR and change from baseline in HR was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in HR. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose | 
| Change From Baseline in Heart Rate (HR) at 4.5 Hours Post-dose: Part 2 RHC Period | HR was assessed at pre-dose in the RHC Period (baseline) and at 4.5 hours post-dose. Baseline HR and change from baseline in HR was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in HR. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose | 
| Change From Baseline in Heart Rate (HR) at 24 Hours Post-dose: Part 2 RHC Period | HR was assessed at pre-dose in the RHC Period (baseline) and at 24 hours post-dose. Baseline HR and change from baseline in HR was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in HR. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose | 
| Change From Baseline in Systolic Blood Pressure (SBP) at 0.5 Hours Post-dose: Part 2 RHC Period | SBP was assessed at pre-dose in the RHC Period (baseline) and at 0.5 hours post-dose. Baseline SBP and change from baseline in SBP was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in SBP. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose | 
| Change From Baseline in Systolic Blood Pressure (SBP) at 4.5 Hours Post-dose: Part 2 RHC Period | SBP was assessed at pre-dose in the RHC Period (baseline) and at 4.5 hours post-dose. Baseline SBP and change from baseline in SBP was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in SBP. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose | 
| Change From Baseline in Systolic Blood Pressure (SBP) at 24 Hours Post-dose: Part 2 RHC Period | SBP was assessed at pre-dose in the RHC Period (baseline) and at 24 hours post-dose. Baseline SBP and change from baseline in SBP was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in SBP. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose | 
| Change From Baseline in Diastolic Blood Pressure (DBP) at 0.5 Hours Post-dose: Part 2 RHC Period | DBP was assessed at pre-dose in the RHC Period (baseline) and at 0.5 hours post-dose. Baseline DBP and change from baseline in DBP was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in DBP. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 0.5 hours post-dose | 
| Change From Baseline in Diastolic Blood Pressure (DBP) at 4.5 Hours Post-dose: Part 2 RHC Period | DBP was assessed at pre-dose in the RHC Period (baseline) and at 4.5 hours post-dose. Baseline DBP and change from baseline in DBP was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in DBP. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 4.5 hours post-dose | 
| Change From Baseline in Diastolic Blood Pressure (DBP) at 24 Hours Post-dose: Part 2 RHC Period | DBP was assessed at pre-dose in the RHC Period (baseline) and at 24 hours post-dose. Baseline DBP and change from baseline in DBP was reported for each panel/dose group that underwent RHC in Part 2, according to treatment planned. Negative values indicate decreases from baseline in DBP. Per protocol, this outcome measure was only assessed during the Part 2 RHC Period for each panel and was not assessed during Part 1. | Baseline: Pre-dose on Day 1 of RHC Period (up to 185 days) and 24 hours post-dose | 
| Area Under the Concentration-Time Curve From Hour 0 to Infinity (AUC0-inf) of MK-5475: All Parts | Blood samples were taken at predose and at specified time points postdose to determine the AUC0-inf of MK-5475. AUC0-inf was defined as the area under the concentration-time curve of MK-5475 from time zero to infinity. MK-5475 AUC0-inf was reported by panel/dose group. Per protocol, percent geometric coefficient of variation (%GCV) values were not reported for groups with n<2 participants. | Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours) | 
| Area Under the Concentration-Time Curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-5475: All Parts | Blood samples were taken at predose and at specified time points postdose to determine the AUC0-24hr of MK-5475. AUC0-24hr was defined as the area under the concentration-time curve of MK-5475 from time zero to 24 hours. MK-5475 AUC0-24hr was reported by panel/dose group. For RHC panel/dose groups where sampling was only done up to 4.5 hours, the AUC0-24hr geometric mean represents an extrapolated AUC0-24hr value. Per protocol, %GCV values were not reported for groups with n<2 participants. | Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours) | 
| Maximum Concentration (Cmax) of MK-5475: All Parts | Blood samples were taken at predose and at specified time points postdose to determine the Cmax of MK-5475. Cmax was defined as the maximum concentration of MK-5475 reached. MK-5475 Cmax was reported by panel/dose group. Per protocol, %GCV values were not reported for groups with n<2 participants. | Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours) | 
| Concentration of MK-5475 at 24 Hours Postdose (C24): All Parts | Blood samples were taken at predose and at specified time points postdose to determine the C24 of MK-5475. C24 was defined as the concentration of MK-5475 reached at 24 hours. MK-5475 Cmax was reported by panel/dose group. Per protocol, %GCV values were not reported for groups with n<2 participants. | 24 hours postdose | 
| Time to Maximum Concentration (Tmax) of MK-5475: All Parts | 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. MK-5475 Tmax was reported by panel/dose group. | Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours) | 
| Apparent Terminal Half-life (t1/2) of MK-5475: All Parts | Blood samples were taken at predose and at specified time points postdose to determine the t½ of MK-5475. t½ was defined as the time required to divide the MK-5475 plasma concentration by two after reaching pseudo-equilibrium, following a single dose of MK-5475. MK-5475 t½ was reported by panel/dose group. | Part 1 and Part 2 Period 1: Predose and 0.1, 0.25, 0.5, 1, 2, 3, 4, 8, and 24 hours post-dose; RHC Period: predose and 0.25, 0.5, 1, 2, 3, 4, and 4.5 hours; FRI Period: predose and 1, 3, 8, and 24 hours postdose (Panel D also 0.25, 0.5, 2, 4 hours) | 
| Percentage Change From Baseline in Pulmonary Blood Volume (PBV) Over Time: Part 2 Functional Respiratory Imaging (FRI) Period | 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. | Baseline: Pre-dose on Day 1 of FRI Period (up to 227 days) and 1, 3, 8, and 24 hours post-dose |