Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week. Change from Baseline was calculated as the post-Baseline score minus the Baseline score.

Full Analysis Set: all participants who were randomized and took at least 1 dose of randomized study drug. Participants were analyzed according to randomized treatment assignment. Only participants with available data were analyzed. MMRM=mixed effects model for repeated measures.

The 5-D Itch Scale is a multidimensional (degree, duration, direction, disability, and distribution) questionnaire measuring changes in pruritis. The duration, degree, and direction domain scores range from 1 (no pruritus) to 5 (most severe pruritus). The disability domain includes 4 items assessing itching impact on daily activities: sleep, leisure/social activities, housework/errands, and work/school. Disability domain score=highest score on any of the 4 categories (1 [no pruritis] to 5 [most severe pruritis]). For the distribution domain, 16 body parts are listed to determine the distribution of itching over the last 2 weeks; the number of affected body parts is tallied (potential sum=0-16); the sum is sorted into 5 thresholds: 0-2 is assigned a score of 1; 3-5, a score of 2; 6-10, a score of 3; 11-13, a score of 4; 14-16, a score of 5. Higher scores indicate more severe pruritis. The 5 domain scores are summed to get a total 5-D score: 5 (no pruritus) to 25 (most severe pruritus).

Full Analysis Set. Only participants with available data were analyzed. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Participants were asked to rate their impression of overall change in pruritus in the past 7 days compared to before they started taking study drug using the PGI-C, a 7-point scale ranging from "much improved" to "much worse," with higher scores indicating less improvement in pruritus. Participants that reported a change in their itch of "minimally improved" or better were considered to be responders in terms of "improvement in pruritus."

Full Analysis Set. Only participants with available data were analyzed. Exact binomial (Clopper-Pearson) confidence intervals have been reported.

Participants were asked to rate the severity of their pruritus in the past 7 days using the PGI-S, a 4-point scale ranging from "none" to "severe." Participants that reported a positive shift in their categorical assessment of itch compared to their Baseline level (e.g., "severe" at Visit 2 [Day 1] with a shift to "moderate" at Visit 6 [Week 6]) were considered to be responders in terms of "improvement in pruritus."

Full Analysis Set. Only participants with available data were analyzed. Exact binomial (Clopper-Pearson) confidence intervals have been reported.

Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week.

Full Analysis Set. Only participants with available data were analyzed. Exact binomial (Clopper-Pearson) confidence intervals have been reported.

Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week.

Full Analysis Set. Only participants with available data were analyzed. Exact binomial (Clopper-Pearson) confidence intervals have been reported.

Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week.

Full Analysis Set. Only participants with available data were analyzed. Exact binomial (Clopper-Pearson) confidence intervals have been reported.

Participants were asked to rate the severity of their worst level of itching in the past 24 hours using the daily WI-NRS, an 11-point scale ranging from 0 (no itching) to 10 (worst itching imaginable). Itching severity scores collected via the WI-NRS have been categorized in the as mild (<4), moderate (≥4 to <7), or severe (≥7). The average WI-NRS score using the daily values from the week before the first dose of study drug (including the WI-NRS score captured on Study Day 1 of dosing) served as the Baseline score. A weekly score was determined based on the average of all available daily scores of the week.

Full Analysis Set. Only participants with available data were analyzed. Exact binomial (Clopper-Pearson) confidence intervals have been reported.

An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The investigator assessed whether the TEAEs were related or unrelated to the study drug.

Safety Analysis Set: All participants who were randomized and took at least 1 dose of randomized study drug. Analysis was based on the treatment actually received.

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable or unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the TEAEs were related or unrelated to the study drug.

Open-label Extension Analysis Set: all participants who completed the Double-Blind Treatment Period and received at least 1 dose of study drug in the Open-Label Extension Period

TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. A serious TEAE is any untoward medical occurrence, that at any dose: results in death; is life threatening; requires hospital admission or prolongs hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly/birth defect; or is a medically significant event that, based on appropriate medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the previously listed outcomes. Serious TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the serious TEAEs were related or unrelated to the study drug.

Safety Analysis Set

TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. A serious TEAE is any untoward medical occurrence, that at any dose: results in death; is life threatening; requires hospital admission or prolongs hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly/birth defect; or is a medically significant event that, based on appropriate medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent one of the previously listed outcomes. Serious TEAEs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the serious TEAEs were related or unrelated to the study drug.

Open-label Extension Analysis Set

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. AESI were considered to be any clinically meaningful new, worsening from Baseline, or abnormal laboratory findings or symptoms suggestive of acute kidney injury (AKI) (e.g., "blood urea increased" or "protein urine present" AEs as identified by the Standardized Medical Dictionary for Regulatory Activities [MedDRA] Query [SMQ] "Acute renal failure"). TE AESIs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the AE AESIs were related or unrelated to the study drug.

Safety Analysis Set

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs are AEs with an onset after the first dose of study drug or existing events that worsened after the first dose during the study. AESI were considered to be any clinically meaningful new, worsening from Baseline, or abnormal laboratory findings or symptoms suggestive of acute kidney injury (AKI) (e.g., "blood urea increased" or "protein urine present" AEs as identified by the Standardized Medical Dictionary for Regulatory Activities [MedDRA] Query [SMQ] "Acute renal failure"). TE AESIs were graded for severity (mild [Grade 1], moderate [Grade 2], severe [Grade 3], life threatening [Grade 4], death [Grade 5]) using CTCAE, version 5.0. The investigator assessed whether the AE AESIs were related or unrelated to the study drug.

Open-label Extension Analysis Set

Clinical laboratory test results included results for clinical hematology, chemistry, coagulation, and thyroid function parameters . The investigator determined if changes were clinically meaningful.

Safety Analysis Set

Vital sign measurements included measurements for blood pressure, pulse rate, oxygen saturation, body temperature, and respiratory rate. The investigator determined if changes were clinically meaningful.

Safety Analysis Set

ECG parameters included heart rate, RR interval, PR interval, QRS duration, or QT interval. The investigator determined if changes were clinically significant.

Safety Analysis Set

The lower level of quantitation = 0.01 micrograms per milliliter (µg/mL) for EP547 and 0.005 μg/mL for EP3583.

Pharmokinetic Set: all participants who received at least 1 dose of EP547 and provided adequate blood samples for bioanalysis