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Efficacy and Safety of Basimglurant As Adjunctive

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Efficacy and Safety of Basimglurant As Adjunctive 1 2 3 4 5 6 7 8 F. HOFFMANN-LA ROCHE LTD 9 CLINICAL STUDY PROTOCOL 10 PROTOCOL NUMBER NP25620 11 RO4917523 12 EUDRACT NUMBER 2011-001436-33 13 IND NUMBER 103001 14 15 Sponsor: F. HOFFMANN-LA ROCHE LTD 16 Grenzacherstrasse 124, 17 4070 Basel, Switzerland 18 19 20 21 22 23 24 25 26 27 PROTOCOL APPROVAL 28 29 NP25620 / C 30 Protocol Number / Version: 31 32 Date: See date in electronic signature manifestation below. 33 Name Reason for Signing Date and Time (UTC) Quiroz,Jorge Translational Medicine Leader 04-Apr-2012 18:04:29 34 35 36 37 38 39 40 41 42 Confidentiality Statement 43 44 The information contained in this document, especially unpublished data, is the property 45 of F. Hoffmann-La Roche Ltd (or under its control), and therefore provided to you in 46 confidence as an investigator, potential investigator or consultant, for review by you, your 47 staff and an applicable Independent Ethics Committee/Institutional Review Board. It is 48 understood that this information will not be disclosed to others without written 49 authorization from Roche except to the extent necessary to obtain informed consent from 50 those persons to whom the drug may be administered. CONFIDENTIAL Roche Protocol NP25620 C (RO4917523) - Page1 Downloaded From: https://jamanetwork.com/ on 09/29/2021 51 52 53 SYNOPSIS OF PROTOCOL NUMBER NP25620 54 55 56 TITLE A randomized, double-blind, parallel-group study of the safety and efficacy of 57 RO4917523 versus placebo, as adjunctive therapy in patients with major 58 depressive disorder with inadequate response to ongoing antidepressant 59 treatment. 60 61 SPONSOR F. Hoffmann-La Roche Ltd CLINICAL 64 IIb 62 PHASE 6563 INDICATION Major Depressive Disorder (MDD) 66 OBJECTIVES Primary 67 To evaluate the efficacy of two fixed doses of RO4917523 compared to 68 placebo in a confirmatory manner over 6 weeks as adjunctive therapy in 69 patients with MDD with inadequate response to ongoing antidepressant 70 treatment, based on mean change in the Montgomery Asberg Depression 71 Rating Scale (MADRS) total score from baseline to end of treatment. 72 73 Secondary 74 The secondary objectives are to evaluate change after 6 weeks of treatment 75 with RO4917523 versus placebo as adjunctive therapy on the following: 76 • Clinical Global Impression Scores: Severity (CGI-S) from baseline to end 77 of treatment, and Improvement (CGI-I) at end of treatment 78 • Safety and tolerability of RO4917523 79 • Proportion of patients exhibiting remission (a MADRS score of less than 80 or equal to 10) 81 • Proportion of patients exhibiting response (reduction in MADRS score 82 equal to or greater than 50% of the baseline score) 83 • Quick Inventory of Depressive Symptomatology Self Report (QIDS-SR16) 84 • Patient Global Impression of Improvement (PGI-I) score at end of 85 treatment 86 87 Exploratory 88 Key Exploratory Objective 89 To evaluate the effect size (ES) of two fixed doses of RO4917523 compared to 90 placebo over 6 weeks as adjunctive therapy in patients with MDD with 91 inadequate response to ongoing antidepressant treatment, based on mean 92 change in the Montgomery Asberg Depression Rating Scale (MADRS) total 93 score from baseline to end of treatment. 94 95 Other Exploratory Objectives 96 To investigate the differential effect of RO4917523 vs. placebo in: 97 • Proportion of patients who meet MADRS responder criteria plus CGI-I 98 score of 1) “very much improved” or 2) “much improved” 99 • Proportion of patients who meet MADRS remission criteria plus CGI-I 100 score of 1) “very much improved” or 2) “much improved 101 • Speed of onset of antidepressant effect based on change over time in any 102 of the depression symptom scales 103 • CANTAB Cognitive Test Battery subset 104 • Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q- 105 LES-Q-SF) 106 • Sheehan Disability Scale (SDS) CONFIDENTIAL Roche Protocol NP25620 C (RO4917523) - Page 2 Downloaded From: https://jamanetwork.com/ on 09/29/2021 107 108 Pharmacokinetics 109 • Pharmacokinetics of RO4917523 in the target population with the 110 objective of performing a population pharmacokinetic analysis with non- 111 linear mixed effect model 112 Biomarkers 113 • Identify biomarkers that are predictive of response to RO4917523 114 treatment 115 • Increase our knowledge and understanding of the pathogenesis, course and 116 outcome of depression and related diseases 117 • Develop biomarker or diagnostic assays, and establish the performance 118 characteristics of these assays 119 TRIAL DESIGN This is an outpatient trial consisting of three consecutive periods: screening (up 120 to 14 days), 6-week double-blind treatment, and a 21 day follow-up period. 121 122 NUMBER OF SUBJECTS Approximately 300 patients, randomized in equal proportions to the three 123 treatment arms. 124 125 TARGET POPULATION The study will include male and female outpatients from 18 to 70 years of age 126 with a primary diagnosis of major depressive disorder (MDD) without 127 psychotic features as defined by DSM-IV-TR criteria, and having inadequate 128 response to ongoing antidepressant therapy. Patients must have had at least one 129 but no more than three treatment failures (of adequate dose and duration 130 according to the Massachusetts General Hospital Antidepressant Treatment 131 History Questionnaire [MGH ATRQ]). Failure to ongoing antidepressant 132 treatment in the current episode is counted as one treatment failure. 133 134 LENGTH OF STUDY • 14 day screening period 135 • 6 week double-blind treatment 136 • 21 day follow-up 137 END OF STUDY The date of the last visit (including the follow-up period) of the last patient in 138 the study 139 INVESTIGATIONAL 143 Doses of RO4917523 0.5 mg or 1.5 mg supplied as pellets in capsules, in 140 MEDICAL PRODUCT(S)144 combinations of Ro 491-7523/F18 0.5 mg, Ro 491-7523/F19 1.0 mg, taken 141 DOSE/ ROUTE/ 145 orally once a day 146142 REGIMEN 147 148 149 COMPARATOR “DRUG”154 Matching capsules of placebo Ro 491-7523/F21, taken orally once a day 150 DOSE/ ROUTE/ 151 REGIMEN 152 ASSESSMENTS OF: 155153 156 -EFFICACY • MADRS total score 157 • Remission (a MADRS score less than or equal to 10) 158 • Response (reduction in MADRS score equal to or greater than 50% from 159 baseline) 160 • CGI-S 161 • CGI-I 162 • PGI-I 163 • QIDS-SR16 164 • Q-LES-Q-SF 165 • SDS 166 • CANTAB CONFIDENTIAL Roche Protocol NP25620 C (RO4917523) - Page3 Downloaded From: https://jamanetwork.com/ on 09/29/2021 167 168 • Adverse events (AEs) and concomitant medications will be monitored 169 -SAFETY 170 throughout the entire study (screening through follow-up). Intensity of AEs 171 will be graded on a 3 point scale (mild, moderate, or severe) 172 • A subscale (4 items) of the BPRS will be completed only to follow up on 173 treatment emergent psychotic-related and mania-related (mania or 174 hypomania) adverse events. The symptom constructs included are 175 conceptual disorganization, suspiciousness, hallucinatory behavior, and 176 unusual thought content 177 • The YMRS (item 1 only for mood elevation) will be completed only to 178 follow up on treatment emergent psychotic-related and mania-related 179 (mania or hypomania) adverse events 180 • Columbia-Suicide Severity Rating Scale (C-SSRS) 181 • Physical examination 182 • Vital signs (pulse, blood pressure) 183 • 12-lead ECG 184 • Laboratory parameters 185 o Chemistry panel 186 o Hematology panel with differential 187 o Free T4 and TSH 188 o Viral Serology 189 o Urinalysis (dipstick) 190 o Urine drug screen 191 o Pregnancy test in females 192 • Data Safety Monitoring Board (DSMB) 193 o An independent Data Safety Monitoring Board (DSMB) will review 194 potential safety signals of concern. The DSMB will be composed of 195 non-sponsor members who are not involved in the conduct of this 196 study. The DSMB will review available safety data from this trial at 197 regularly scheduled intervals as specified in the DSMB Charter 198 • Statistical Interim Analyses 199 o No statistical interim analyses are planned 200 -PHARMACOKINETICS PK sampling will be obtained from all patients according to the Schedule of 201 Assessments. 202 -EXPLORATORY - 206 Specimens for the Roche Clinical Repository (RCR) will be collected for 203 BIOMARKERS (non- 207 dynamic (non-inherited) biomarker discovery and validation. The RCR 204 inherited) 208 sampling is optional. Blood specimens will be collected as per Schedule of 205 209 Assessments, with details as follows: 210 ƒ Plasma and Serum assays: Blood samples for plasma and serum isolation 211 will be obtained at baseline and the end of treatment. A total of 4 samples 212 (2x6 mL for serum and 2x6 mL for plasma; 24 mL total) for each patient 213 will be collected during the study. These samples will be used for 214 biomarker assays for candidate depression biomarkers. 215 ƒ Blood for RNA expression profiling: Blood samples for RNA isolation 216 will be obtained at baseline and the end of treatment (5 mL each; 10 mL 217 total). 218 ƒ Blood sample for epigenetic analysis: Blood samples for DNA isolation 219 will be collected at baseline and the end of treatment (6 mL each; 12 mL 220 total). 221 222 These specimens will be stored for up to 15 years after the end of the study. CONFIDENTIAL Roche Protocol NP25620 C (RO4917523) - Page 4 Downloaded From: https://jamanetwork.com/ on 09/29/2021 223 224 -EXPLORATORY 250 Additional specimens for the Roche Clinical Repository (RCR) will be 225 BIOMARKERS (inherited)251 collected from consenting patients for genetic biomarker (inherited) discovery 226 227 252 and validation. The RCR sampling (inherited) is optional. A single blood 228 253 specimen will be collected from consenting patients, with details as follows: 229 254 ƒ Blood sample for genetic analysis: A blood sample (approx.
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