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Study Protocol Protocol: MTI-107 Protocol number: MTI-107 Document title: An open-label long-term safety study of serlopitant for the treatment of pruritus. Version numbers: Protocol Version 3.0 Date of the documents: 21 March 2019 NCT number: NCT03540160 Confidential - Proprietary Information Menlo Therapeutics Inc. Confidential Protocol MTI-107 CLINICAL STUDY PROTOCOL TITLE: AN OPEN-LABEL LONG-TERM SAFETY STUDY OF SERLOPITANT FOR THE TREATMENT OF PRURITUS IND No.: 117780 EudraCT: 2017-004211-40 ClinicalTrials.gov ID: TBD Protocol No.: MTI-107 Protocol Version/Date: FINAL 1.0 18 December 2017 Development Phase: Phase 3 Sponsor: Menlo Therapeutics Inc. 200 Cardinal Way, 2nd Floor Redwood City, CA 94063 Confidentiality Statement: This document is a confidential communication of Menlo Therapeutics Inc. As such, the recipients agree not to disclose or reproduce, without prior written approval, this document and any attachments, except to appropriate Institutional Review Boards, Ethics Committees, representatives of the US Food and Drug Administration, the European Medicines Agency, other Competent Authorities or regulatory agencies, or as otherwise required by applicable laws or regulations. FINAL 1.0 18 December 2017 Page 1 2 Menlo Therapeutics Inc. Confidential Protocol MTI-107 SIGNATURE PAGE FOR INVESTIGATOR(S) TITLE: AN OPEN-LABEL LONG-TERM SAFETY STUDY OF SERLOPITANT FOR THE TREATMENT OF PRURITUS IND No.: 117780 EudraCT: 2017-004211-40 ClinicalTrials.gov ID: TBD Protocol No.: MTI-107 Protocol Version/Date: FINAL 1.0 18 December 2017 Development Phase: Phase 3 Sponsor: Menlo Therapeutics Inc. 200 Cardinal Way, 2nd Floor Redwood City, CA 94063 I have read the protocol and agree to conduct this study in accordance with the protocol, all relevant laws and regulations in force at the time, International Conference on Harmonisation Guidelines for Good Clinical Practice, and the Declaration of Helsinki. Principal/Coordinating Investigator’s printed name Principal/Coordinating Investigator’s signature Date (DD-MMM-YYYY) FINAL 1.0 18 December 2017 Page 2 3 Menlo Therapeutics Inc. Confidential Protocol MTI-107 PROTOCOL SYNOPSIS Study Title: An Open-Label Long-Term Safety Study of Serlopitant for the Treatment of Pruritus Protocol Number: MTI-107 Sponsor: Menlo Therapeutics Inc. Development Phase: Phase 3 Study Objectives: Primary objective: • To assess the long-term safety of serlopitant in adults with pruritus associated with prurigo nodularis (PN), atopic dermatitis (AD), or psoriasis. Secondary objectives: • To assess change in severity of pruritus in subjects with PN, AD, or psoriasis using the worst-itch numeric rating scale (WI-NRS). • To assess change in severity and extent of PN using the Investigator’s Global Assessment of PN Stage (IGA PN-S), for those subjects with PN. • To assess whether serlopitant produces physical dependence. Study Design: Study MTI-107 is a multicenter, open-label study to assess the long-term safety of serlopitant in adults with pruritus associated with PN, AD, or psoriasis. Eligible subjects who have completed selected studies of serlopitant may be given the opportunity, at the investigator’s discretion, to consent to and participate in this open-label study, regardless of their treatment allocation in prior studies. If deemed necessary by Menlo Therapeutics to meet enrollment objectives, eligible subjects who have not participated in a prior serlopitant study may also be enrolled in study MTI-107. The study will consist of two periods, for a total study period of approximately 56 weeks: • Treatment period: 52 weeks • Post-drug observation period: 4 weeks During the treatment period, subjects will take one serlopitant 5 mg tablet once daily orally. Standard therapy for the concurrent skin lesions and pruritus may be employed during this study. After completion of the 52-week treatment period, all subjects will enter a 4-week post-drug observation period. Subjects who discontinue treatment early will have a post-drug observation visit 4 weeks after their last dose of serlopitant. Safety Review: An internal safety monitoring team consisting of representatives from Menlo Therapeutics Inc. and its designees will monitor safety data on a regular basis throughout the study. Planned Sample Size: Approximately 400 subjects Study Population: The study will enroll adults with pruritus due to PN, AD, or psoriasis. Inclusion Criteria (Subjects must meet the following criteria to be enrolled into the study): 1. Male or female, age 18 years or older at consent. 2. Subject reports pruritus in the 24-hour period prior to enrollment and: a. Has completed a prior applicable clinical study of serlopitant without a serious adverse event (SAE) that was assessed as likely related to the study drug FINAL 1.0 18 December 2017 Page 4 5 Menlo Therapeutics Inc. Confidential Protocol MTI-107 OR b. Has not participated in a prior clinical study of serlopitant and has a clinical diagnosis of PN, AD, or psoriasis, and Sponsor has approved enrollment. 3. All female subjects who are of childbearing potential must be willing to practice highly effective contraception (i.e., pregnancy prevention method with a failure rate of <1% per year) from the time of the Baseline visit until 2 weeks after last dose of study drug. 4. Willing and able (has adequate cognitive ability, in the investigator’s opinion) to comply with study visits and study related requirements including providing written informed consent. Exclusion Criteria (Subjects who meet any of the following criteria are not eligible for participation in the study): 1. Presence of malignancy within 5 years prior to enrollment (exception for non-melanoma cutaneous malignancies). 2. Presence of a psychiatric diagnosis (such as major depressive disorder, bipolar disorder, schizophrenia, psychotic disorder, intellectual disability, severe alcohol abuse disorder) meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria in past 3 years, history of suicidal ideation within the past 3 years or any history of suicide attempt. 3. Presence of any medical condition or disability, that, in the investigator’s opinion, could interfere with the assessment of safety in this study or compromise the safety of the subject. 4. Treatment with any investigational therapy within 4 weeks or 5-half-lives prior to enrollment (whichever is longer) or expected participation in another clinical study involving an investigational product or device during the subject’s participation in MTI-107. 5. Treatment with other neurokinin-1 receptor (NK1-R) antagonists (e.g., aprepitant, fosaprepitant, rolapitant) within 4 weeks prior to enrollment. 6. Treatment with strong cytochrome P450 3A4 inhibitors within 4 weeks prior to enrollment. 7. Currently pregnant or breastfeeding or planning to become pregnant during the study. Study Drug: Serlopitant 5 mg tablets Dosage: Serlopitant: 5 mg once daily orally for 52 weeks • Incidence of treatment-emergent adverse events (TEAEs) and SAEs Safety Endpoints: • Changes from baseline in clinical laboratory parameters following study drug exposure • Changes from baseline in vital sign and electrocardiogram (ECG) parameters following study drug exposure • Assessment of physical dependence following chronic study drug exposure, in the monitored 4-week post-drug discontinuation period • Changes from baseline in WI-NRS to Weeks 4, 8, 20, 28, 36, 44, and 52 Efficacy Endpoints: • Changes from baseline in Patient-Reported Outcomes Measurement Information System Itch Questionnaire (PROMIS-PIQ) score for Itch (General, Scratching Behavior, Mood and Sleep, Activity and Clothing) to Weeks 20, 36, and 52 • Changes from baseline in Dermatology Life Quality Index (DLQI) (symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment) to Weeks 20, 36 and 52 FINAL 1.0 18 December 2017 Page 5 6 Menlo Therapeutics Inc. Confidential Protocol MTI-107 • Changes from baseline in IGA PN-S to Weeks 4, 8, 20, 28, 36, 44, and 52 Statistical Methods: All subjects who receive at least 1 confirmed dose of study drug and have at least 1 post-baseline safety assessment will be included in the safety population. All analyses will be performed using the safety population. Data will be summarized with descriptive statistics by visit. For continuous variables, the following information will be presented: n, mean, standard deviation, median, minimum and maximum. For categorical variables, counts and percentages will be used. All adverse events (AEs) will be classified by system organ class and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA). TEAEs will be tabulated in a manner which provides information about the incidence of TEAEs for the entire treatment period as well as by specified time periods in order to understand the evolution of TEAEs over time. Additionally, the pre-specified TEAEs and SAEs that may be associated with physical dependence will be summarized separately. An overview of AEs, which includes subject incidence of TEAEs, treatment-related TEAEs, TEAEs by severity, SAEs, deaths, and AEs leading to discontinuation, will be presented. Summary statistics for actual safety laboratory values and for changes from baseline will be tabulated by scheduled visit. Subjects with clinical laboratory values outside of the normal reference range at any post-baseline assessment will be summarized. Shifts from baseline laboratory values will be tabulated. A listing of all out-of-range laboratory test results,
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