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It isIt illegal to post this copyrighted PDF on any website. 16.N655, Grenzacherstrasse 124, 4070 Basel, Switzerland ([email protected]) 124, Switzerland 4070 Basel, 16.N655, Grenzacherstrasse Bldg 1/Room Ltd, Roche F. Basel, Hoffmann-La Center Innovation Roche Development, Partially Refractory MajorPartially Refractory Depressive Disorder New York, F. Hoffmann-La Roche Ltd, New York, New New New York Ltd, York, Roche F. York, New Hoffmann-La J Clin Psychiatry 2020;81(4):18m12470 J ClinPsychiatry Trial Registration: ClinicalTrials.gov NCT01457677 identifier: antidepressant orprocognitive effects. Conclusions: Decoglurant was well tolerated overall any butdidnotexert adverse events. treatmentdetect effects. Nodeaths occurred; few patientsserious reported placebo response whichmay was observed, have constrained to theability measuresscores ofmoodandfunctioning. Arelatively oronsecondary high Test Automated cognitive Battery andcognitive accuracy speedcomposite Decoglurant exertednosignificant effects onCambridge Neuropsychological reducing MADRS total score orresponse orremission rates were observed. no significant differences between any treatment active andplacebo arm in 310completed 357participants, 6weeks’Results: Of treatment. At 6weeks, centralized raters. assessments by were fullyblinded Primary treatment. performed to endof outcome variablewas changeinMADRS totalprimary score from baseline analysis 30patients after ineachgroup hadreceived 6weeks’ treatment. The treatment with1SSRI/SNRI.An adaptive design was usedwithaninterim (n SNRI bloodlevels, were randomized to decoglurant 5mg(n adequate ofanSSRI/SNRIandcompliance trials confirmed by positive SSRI/ scalescore ofIllness ≥ Clinical GlobalImpressions–Severity (MADRS) Scale with Montgomery-Åsberg Depression score Rating ≥ weeks’ follow-up between September2011andJune2014.Individuals consistedphase 2trial of4weeks’ screening, 6weeks’ treatment, and8 Methods: This randomized, multicenter placebo-controlled, double-blind, (MDD), diagnosed usingDSM-IV-TR criteria. majordepressive refractory disorder (SSRIs/SNRIs) inpatients withpartially reuptake inhibitors and/orserotonin-norepinephrine reuptake inhibitors negative allosteric modulator, treatment asadjunctive to serotonin selective Lauren Boak, PhD Lauren © Copyright 2020Physicians Postgraduate Press, Inc. To https://doi.org/10.4088/JCP.18m12470 share: majorpartially refractory depressive disorder. Psychiatry JClin J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ d c b a mGlu the of trial placebo-controlled cite: To decoglurant, metabotropic aselective glutamate receptor 2/3(mGlu type Objective: To assessputative antidepressant andprocognitive effectsof Daniel Umbricht, MD mGlu the Trial Double-Blind, Placebo-Controlled Randomized, of Research Original Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland Basel, Ltd, Roche F.Basel, Hoffmann-La Dennis Deptula, PhD * Switzerland ABSTRACT Roche Pharmaceutical Research and Early Development, Roche Innovation Center Center Innovation Roche Development, Early and Research Pharmaceutical Roche Roche Pharmaceutical Research and Early Development, Roche Innovation Center Center Innovation Roche Development, Early and Research Pharmaceutical Roche Roche Product Development Neuroscience, F. Hoffmann-La Roche Ltd, Basel, Basel, Ltd, Roche F. Hoffmann-La Neuroscience, Development Product Roche Roche Product Development Biometrics, F. Hoffmann-La Roche Ltd, Basel, Switzerland Basel, Ltd, Roche F. Hoffmann-La Biometrics, Development Product Roche Corresponding author: = 102), or30mg(n Umbricht D, Niggli M, Sanwald-Ducray P, et al. Randomized, double-blind, double-blind, P, Randomized, al. et Sanwald-Ducray M, D, Niggli Umbricht 2/3 Daniel Umbricht, MD, Roche Pharmaceutical Research and Early Early and Research Pharmaceutical MD, Roche Umbricht, Daniel = d ; andPaulo Fontoura, MD, PhD 55) dailyorplacebo (n Negative Modulator Allosteric in Decoglurant c a, ; Rema Moore, MS ; Rema * ; Markus Niggli, PhD; Markus 2/3 negative modulator allosteric in decoglurant = 99) as adjunct to ongoing 99) asadjunct c ; Waltraud Grünbauer, PhD b ; Patricia Sanwald-Ducray, PhD . 2020;81(4):18m12470. 4, despite upto 2 d = 101), 15mg 25 and 2/3 ) . © 2020Copyright Physicians Postgraduate Press, Inc. a ; M memory inpreclinicalmemory assays. induced cognitive deficits and improved long-term burden. modulator, decoglurant (RG1578), of dysregulated glutamate neurotransmission. supports treatment the of MDD through modulation primarily through monoamines, growing evidence associated with MDD are needed. that effectively also ameliorate cognitive deficits by depressive symptoms. Novel antidepressants cognitive deficits beyond accounted those for that mGlu accumbens—with preclinical research suggesting PFC,the hippocampus, amygdala, and nucleus inhibitory receptors that are expressed highly in potent non-competitive mGlu vortioxetine antidepressants—with possible the exception of selective mGluselective type 2(mGlutype MDD, are metabotropic the glutamate receptor interest,Of specific as therapeutic targets in of classical depressive symptoms. of MDD that severity is largelythe independent of contrary to previous represent beliefs, akey feature impairments incognitive functions, which, We therefore hypothesized that in individuals human primates (D.U., unpublished data, 2015). deficits inexecutive and function attention innon- in ratsmodel and to scopolamine-induced rescue reduce anhedonia the index inachronic stress mild procognitive effects. not respond to first- or second-line treatment. However, asubstantial proportion of patients do antipsychotics, inconjunction with psychotherapy. reuptake inhibitors [SNRIs]), and atypical inhibitors [SSRIs], serotonin-norepinephrine inhibitors serotonin selective (eg, reuptake involves treatment with monoamine reuptake used as a tool compoundused reversed mGlu

While classic antidepressants mediate effect their The clinical presentation of MDD includes a ; significant personal, economic, and societal ajor depressive disorder (MDD) a exerts 1–3

Pharmacologic intervention currently 2 antagonists have antidepressant and 9 —have notshown been to improve 2/3 2 ) receptors—presynaptic auto- antagonist (RO4432717) that was 10,14–17 Indeed, ahighly 2/3 5 Another selective, selective, Another

negative allosteric 5–8 18 Most available was found to 2/3 agonist agonist

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You are prohibited from making this PDF publicly available. were scores of ≥ and/or records. pharmacy key inclusion Other criteria anddose duration were from verified treating the physician had to have within started 1 year of screening, and treatment Questionnaire, HospitalGeneral Antidepressant Treatment Response greater than accepted the according dose to Massachusetts the 2 adequate with an SSRI trials or SNRI at to equal or doses continuedwho to have depressive symptoms despite 1or IV-TR Mental Disorders, Fourth Edition, Text Revision ( each site. participants All gave written informed consent. authoritieshealth of and eachcountry committees ethics of Umbricht etal e2 For [email protected]. reprints orpermissions, contact ♦ Practice. Clinical Good and UnitedSouth the Africa, States following Guidelines for sites Austria, inCanada, Germany, Russia, Ukraine, Slovakia, conducted September 2011and between June 2014at 72 (ClinicalTrials.gov NCT01457677). It identifier: was 6-week treatment and 8-week period, follow-up period consistedphase 2trial of a4-week screening period, Trial Design andPatients no more than 2previous treatments. with relatively those specifically recent–onset failing disease of responding to a novel adjunctive treatment option, onfocus patients considered to have an optimum chance response to antidepressant treatment. The aim was to SNRI therapy inindividuals with MDD and inadequate decoglurant versus as placebo adjunctive treatment to SSRI/ assess putative antidepressant and procognitive of effects 2009–014678-17). cognitive deficits inhealthy volunteers (EudraCT no. trial supportedalso by its reversal of scopolamine-induced no. 2009–011624-62).Apotential procognitive was effect safetyhad agood and tolerability profile (EudraCT trial cognitive symptoms. glutamate transmission, thus reducing depressive and with MDD,diagnosed decoglurant may restore normal METHODS It isIt illegal to post this copyrighted PDF on any website. ■ ■ Diagnostic and Statistical Manual of Statistical and Patients with aDiagnostic This randomized, placebo-controlled, double-blind, was current to trial the objectiveThe of primary In safety initial studies inhealthy volunteers, decoglurant ■ ■

or serotonin-norepinephrine reuptake inhibitors. combination serotonin withselective reuptake inhibitors not have anantidepressant orprocognitive effectsin antagonist decoglurant was well tolerated butdid metabotropic glutamate receptor 2/3(mGlu type treatment-resistant patients withpartially In MDD, the deficits. treatments donotimprove theassociated cognitive not respond to first- orsecond-line therapies, andcurrent Many patients withmajordepressive disorder (MDD) do ), diagnosis of MDD without psychotic features, 20 25 on Montgomery-Åsberg the Depression were eligible. The index depressive episode Clinical PointsClinical 19 The protocol was approved by the 2/3 ) DSM- Impressions–Severity (CGI-S), of Illness scale Rating Scale (MADRS) Rating Scale and Satisfaction Questionnaire–Short Form (Q-LES-Q-SF), Automated (CANTAB). Battery Cambridge Neuropsychologicalthe tests of [SOC]) Test [PAL]),Learning and executive (Stockings of Cambridge Visual Processing [RVP]), (Paired memory Associates attentional mean combinedthe the score (Rapid of mean of as ascoredefined of 1standard deviation below normative the andsex, geographic region. Cognitive impairment was initially system. Randomization was stratified by cognitive impairment, administered by an interactive voice or response web-based administration of study medication). medications Supplementary (see Table 2for details on the or 30mg or placebo, inaddition all to existing permitted groups: decoglurant at aonce-daily of dose 5mg, 15mg, Randomization exclusion criteria). stable Supplementary (see Table 1 for inclusion full and other than depression were allowed, providing were doses Medications trial. the to treat used stable conditions medical were not enrolled. Only 1SSRI/SNRI was continued during respective antidepressantthe of were undetectable, patients SSRI/SNRIlevels treatment tests; with blood if was assessed by blinded centralized fully raters. Compliance with current MADRS-SIGMA revision. score, by assessed centralized, blinded raters fully using the Endpoints categorized as “cognitively impaired.” cognitively impaired”; subsequently, would they have been Before change, this 13patients were categorized as “not normative mean few patients as too criterion. met original the participants, threshold the was lowered to 0.5SD below the two key factors: one measures loading on of accuracy all cognitive test battery, clinician-ratedthe CGI-S. and Patient-Rated Improvement Global (PGI),adapted from Sheehan (SDS), Disability Scale Cognitive and Physical Functioning Questionnaire (CPFQ), andCGI-S CGI-Improvement (CGI-I) scale Symptomatology–Self-Report 30-item version (IDS-SR rated measures comprising Inventory the of Depressive basimglurant intreatment-refractory MDD, currentthe study, and asimultaneously conducted study of (excluding data obtainedthe at ERT)—of the in baseline using CANTAB 2key parametersthe for each test of battery 42); and Attention Shifting Test (AST). A factor analysis— Touch Stockings of Cambridge at (OTS, and baseline day Recognition Task (ERT); PAL; at SOC screening, or One- (MOT); RVP; Delayed Matched to Sample (DMS); Emotional Randomization generated codes by sponsor the were After screening, participants were randomized into 4 The primary efficacy endpoint efficacy was MADRS the The primary total Cognitive impairment with CANTAB the was assessed and functioning mood endpointsSecondary included the © 2020Copyright Physicians Postgraduate Press, Inc. 23 J ClinPsychiatry 81:4,July/August 2020 which included Motor Screening 21 22 24 and ≥ 27 23 Quality of Quality Life Enjoyment 4 on the Clinical 4 Globalon Clinical the After recruitment of 79 22 and participant- 13 demonstrated 22 as assessed assessed as 30 ), 25 28 26

You are prohibited from making this PDF publicly available. excluded of because protocol violation criteria) with no MADRS total scores [centralized rating] were who not randomized(ie, all patients and baseline with valid 6-week analysis was conducted for per-protocol the (PP) population and remission as MADRS total score ≤ as ≥ treatment. from Response was defined to baseline week 6of decoglurant each between and dose inmean placebo change interactiontime contrast to was estimate used difference the applied to within-patient the model errors. Atreatment-by- score. An unstructured variance-covariance matrix was MADRSalong total with continuous the baseline of effect medication (ie, and time), treatment-by-time interaction, region, assessment weeks relative of to first dose the study treatment, stratification of variables,effects geographical (MMRM) that fixed includedthe independent variables of using model for amixed-effects repeated measures scoretreatment—was from baseline analyzed to end of Statistical Analysis only MOT, the RVP, and PAL was administered at day 7. baseline, and week 6.Alimited CANTAB battery including 1). The CANTAB battery was administered at screening, and 14during follow-up the (Supplementary period Figure during 6-week the treatment and at period, weeks 8,10, outcome assessments were conducted at baseline, weekly indicated to follow up on only] AEs Abbreviated, J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ Rating Scale, administered rating (Columbia–Suicide scales Severity examinations; recording of adverse events clinician- (AEs); CANTAB). Supplementary(see Table tasks tested forthe 4for details of composite scores cognitive as primary the outcome variables completion and cognitive to calculated speed use accuracy analysis). Thus, an apriori decision was made before study Supplementary testsall (see Table 3for exploratory factor tests and one loading on measures of reaction time across SR administered MADRS and patient-rated the CGI-S, IDS- design). Supplementaryweek trial 6(see the Figure 1for details of MADRS and at CGI-S and baseline week 6and at CGI-I the standardized rating administered inMDD) also scales the psychiatric practice and ≥ psychologist,clinical worker or social with certified language. Site raters physician, trial-site (alocal nurse, and follow-up telephone via periods patient’s inthe native and at CGI-S and baseline at visits all during treatment using MADRS, the and administered they MADRS the Assessments signs,vital electrocardiograms, and laboratory parameters. It isIt illegal to post this copyrighted PDF on any website. 30 The primary efficacy variable—change efficacy The in primary MADRS total Safety data were through collected and clinical neurologic At screening, assessments included centrally the ratersCentralized at illness severity assessed screening 50% improvement from in MADRS baseline total score , and CANTAB the battery. and Primary secondary 30 29 and Young Mania [item Rating 1 when Scale Extrapyramidal Symptom Rating Scale– 2 years’ administering experience 31 ), and measurement of 10. The primary imputation. A“MADRS interest-activity” score treatment) MMRMor forward via carried last observation populationtreat patients (ITT) (all randomly assigned to variable analyzed using was also intention-to- the efficacy ofdose decoglurant. As asensitivity analysis, primary the adjustment for multiple comparisons) are reported for each treatment(CIs) difference and of nominal P imputation for missing values. The 95%confidence intervals mg, 15mg, and 30mg, respectively. The decoglurant 30-mg study werethe 6.5%, 3.7%, andof 6.6% for decoglurant 5 probabilities of sizeof reaching ≥ effect afinal Interim Analysis matched across arms (Table 1). characteristics and antidepressant treatment were well than 120% (> were instances less inwhich than 80%(< treatment arm. The majority of protocol violations (82%) in20patients, withobserved similar proportions ineach violations (Figure 1).Major protocol violations were completedtreatment without 6 weeks of major protocol screening and were randomized, and 310 participants total of 357 patients (48% of screened patients) all passed for absence of detectable levels of antidepressant A drug. screening failures (n Patient Characteristics andBaseline Disposition (safety population). ofdose study medication safety with assessment a post-dose at αlevel of a1-sided sizeof 5%,with an 0.38. effect dropped treatment arm provided approximately 80% power criterion.this probabilityboth of success and tolerability if2or 3arms met study completion wasthe < the of measure at arm efficacy anda dose primary inthe placebo probability of reaching size of an effect at least 0.25 between the study to stopthe arm if before1dose decided of start the treatment arm had completed 6weeks’ treatment. It was futility analysis was conducted after 30participants ineach and aprespecified Bayesian associated sideeffects, interim databinary using Fisher the test. exact data were analyzed using Wilcoxon the rank test signed and endpoints. Ordered efficacy secondary categoricalselected onanalyses categorical based variables were on performed endpoints using populations. PP the and ITT Subgroup investigate of decoglurant effect the efficacy on secondary the Lassitude, andDifficulties, Inability to Feel items. Concentration bycalculated the summing scores the of ineligible owing to MADRS scores below 25and 15%(n RESULTS The interim analysis showed that Bayesian the predictive A total of 744individuals were screened;among the Safety patients inall was assessed received who at least 1 A sample sizeof 85evaluable participants non- per To minimizeexposure to potentially ineffective treatment, ofAnalyses variance and covariance were to used © 2020Copyright Physicians Postgraduate Press, Inc. Adjunctive Decoglurant in Partially Refractory MDD Adjunctive Decoglurant inPartially Refractory 58) of were doses received. Demographic = 387), 24%of patients (n 20%, taking into20%, taking account 0.25 at end the 34) or more value (no = 92) were 32

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You are prohibited from making this PDF publicly available. Umbricht etal subjective cognitive complaints (CPFQ total score ≥ a family of history MDD, cognitive baseline impairment, by age, sex, of history at least 4 previous depressive episodes, (dataplacebo not shown). activity scores in treatment the groups compared with population findings (Table these confirmed 2). and remission rates). The supporting analysis using ITT the groups Supplementary (see Figure 2 for MADRS response did not significantly differ treatment between and placebo week 6(35%–47%and 29%–38%of patients, respectively) groups (Figure 2,Table 2).Response and remission rates at significantly decoglurant between treatment and placebo MADRSthe total score but were didnot they observed, differ treatment groups was 31(6).At 6weeks, large in decreases Endpoint Primary discontinued. arm, was which associated with highest the rate of was AEs, Abbreviations: ITT e4 For [email protected]. reprints orpermissions, contact ♦ b a Figure 1.CONSORT Trial Flow Diagram It isIt illegal to post this copyrighted PDF on any website. Other reasons forOther screening failure were asfollows: comorbid diagnoses exclusionary (n Patients were initiallyrandomized 1:1:1:1. The low numberofpatients resulted inthe30-mgarm from stopping recruitment thefutility to after thisarm analysis was conducted. treatment history (n treatment history SSRI Perrotocol oulation n8 violations n cluded for ajorrotocol Coleted treatent n2 ithdre consent n2 treatentRefused n1 ailure to return n1 Adinistrative/other n Discontinued n trial Missed ostaseline efficacy n1 ostaseline efficacy Missed oulation n1 otal ecluded fro oulation n8 afety oulation n Allocated to laceo n Additional analyses in subgroups of participants stratified No significant reductions ininterest- were observed At baseline, mean the (SD) MADRS total score across all

selective serotoninselective reuptake inhibitor. = intention-to-treat, MADRS = 17), current episode>

Perrotocol oulation n8 violations n4 cluded for ajorrotocol Coleted treatent n ithdre consent n ailure to return n1 Adinistrative/other n1 Adverse event n1 Discontinued n8 trial Missed ostaseline efficacy n2 ostaseline efficacy Missed oulation n2 otal ecluded fro oulation n afety oulation n101 n101 Allocated to decoglurant g 1 year induration (n =

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You are prohibited from making this PDF publicly available. J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ Abbreviation: MADRS Population) Treatment With Placebo orDecoglurant 5,15,or30mg(Per-Protocol Figure Change From 2.Mean inMADRS Baseline Total Score During c b a At least1SNRItreatment Table Characteristics 1.Baseline the centralizedthe raters by assessed than tended smaller those to be Centralized Versus Site Raters compared with (data placebo not shown). of cognitive impairment), showed no significant treatment effects Abbreviations: MDD Characteristic Years ofeducation, mean(SD) Cognitive impairment Sex Age group Age, mean(SD), y At least1SSRItreatment Previous depressive episodes Family ofMDD history Region It isIt illegal to post this copyrighted PDF on any website. Safety analysis population: total n Values noted. shown asn(%)unlessotherwise Defined asfollows:Defined for < reuptake inhibitor. serotonin SSRI =selective inhibitor, reuptake SNRI =serotonin-norepinephrine 3 =nonimpaired. 3 3 (> 2 (≥ 1 (< Female Male > ≤ Unknown > ≤ Missing Yes No ofworldRest America North = Mean changes from baseline in MADRS score as by assessed 45 y 45 y 4 4 mean) mean) normal mean) nonimpaired; for <

Change ro aseline in 0.5 SDbelow normal 1 SDto < 1 SDbelow normal MADR otal core, Mean M 14 12 10 1 8 4 2 0 aseline 0.5 SDbelow = = major depressive disorder, SD b Montgomery-Åsberg Depression Rating Scale.Montgomery-Åsberg Depression Rating 0.5 SDbelow normative mean:1and2 c c 1 SDbelow normative mean:1 14.15 (2.67) Placebo 14 (n = 24 (24.2) 75 (75.8) 66 (76.7) 13 (15.1) 59 (68.6) 27 (31.4) 40 (46.5) 46 (53.5) 46 (11.2) 41 (47.7) 43 (50.0) 37 (43.0) 47 (54.7) 35 (40.7) 51 (59.3) 99, 101,102,and55,respectively. Day ofreatent = 7 (8.1) 2 (2.3) 2 (2.3) 86) a 21 13.76 (2.44) 46.9 (10.7) (n 32 (31.7) 69 (68.3) 71 (79.8) 11 (12.4) 62 (69.7) 27 (30.3) 54 (60.7) 35 (39.3) 37 (41.6) 52 (58.4) 41 (46.1) 48 (53.9) 34 (38.2) 55 (61.8) 5 mg 28 = … … 7 (7.9) = 89) standard deviation, Decoglurant 0g Decoglurant 1g Decoglurant g Placeo = impaired, 2and Decoglurant 46.9 (10.9) (n 15 mg 14 (13.7) 87 (85.3) 14 (2.31) 62 (70.5) 17 (19.3) 63 (71.6) 25 (28.4) 53 (60.2) 35 (39.8) 33 (37.5) 55 (62.5) 37 (42.0) 51 (58.0) 34 (38.6) 54 (61.4) = 9 (10.2) = … … impaired, 88) 42 14.36 (2.95) 44.5 (13.1) (n 30 mg 13 (23.6) 41 (74.5) 36 (76.6) 30 (63.8) 17 (36.2) 25 (53.2) 22 (46.8) 20 (42.6) 26 (55.3) 20 (42.6) 27 (57.4) 27 (57.4) 18 (38.3) 29 (61.7) 5 (10.6) 6 (12.8) 1 (2.1) = 47) © 2020Copyright Physicians Postgraduate Press, Inc. exceeded the IC the exceeded tolerated overall. procognitive versus effects and placebo was well did not demonstrate significant antidepressant or As an adjunct to SRRI/SNRI therapy, decoglurant individuals treatment-resistant with partially MDD. antagonist decoglurant compared with in placebo treatment: < weeks of concentrations measured weekly during last the 3 were grouped by their mean pre-dose plasma drug exposure of arms. 90–100ng/mL inall Participants thus putative the exceeded minimum therapeutic mg, and 835(8–2,960)ng/mL with 30mg; exposure decoglurant 5mg, 532(1–2,090)ng/mL with 15 concentration was 143 (1–697) ng/mL with and Exposure to Treatment Pharmacokinetics comparable (Supplementary Table 5). byas assessed centralized and site raters were However, remission rates group placebo inthe site assessments, group. placebo inthe particularly Responsebaseline). rates were on based higher Supplementary Table 5for mean changes from site raters, group placebo inthe particularly (see in preclinical studies and central the system nervous However, given brain high the penetrance observed central exposure was suboptimal. to drug the in humans,occupancy it out cannot ruled that be of data confirming target engagement/receptor and any main endpoint In absence the was observed. mean plasmabetween decoglurant concentration arms were treated with decoglurant for > Most participants 3treatment (85.5%–87.1%)inthe endpointssecondary (data not were shown). observed exposure between groupeffects and and primary the ≥ antidepressant mGlu the and procognitive of effects reported (Table seriousAEs 3). No deaths and during trial, few patients occurred the included headache, nausea, and dizziness (Table 3). (77.5%) treatment arms. The most frequent AEs (85.5%) compared with 5-mg the (75.2%)and 15-mg decoglurant inthe higher 30-mg treatment arm due to (Figure AEs 1).The incidence of any was AEs Safety 1,260 (30–1,320)mg 30-mg inthe arm. 5-mg arm, 630(60–660)mg 15-mg inthe arm, and median (range) was total 210(30–220)mg dose inthe DISCUSSION 200–< Drug exposure wasDrug adequate arms inall and At 6weeks, mean the (range) maximum plasma This phase 2 clinical trial investigatedThis phase trial 2 clinical putative discontinuationTheretrial was a low incidence of Adjunctive Decoglurant in Partially Refractory MDD Adjunctive Decoglurant inPartially Refractory 300 ng/mL; and ≥ 80 (90–100ng/mL). No relationship 100 ng/mL; ≥ 300 ng/mL. No significant 100–<

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You are prohibited from making this PDF publicly available. Umbricht etal Adverse Event e6 For [email protected]. reprints orpermissions, contact ♦ However, study to atreatmentthe detect power the effect of CANTAB with decoglurant. cognitive battery was observed healthy volunteers, suboptimal exposure unlikely. is highly nature in safetythe of studies adverse observed in effects a Table 3.Adverse Events Related Serious Severe At weeks 0to 1 Total Nervous system Nervous Gastrointestinal It isIt illegal to post this copyrighted PDF on any website. All values are shown as n (%). Multiple occurrences of the sameadverse the All values are shown occurrences asn(%).Multiple of event inanindividual are counted onlyonce. Probable Possible Somnolence Dizziness Headache Vomiting Diarrhea Nausea No significant improvement in performance on the

CPFQ CANTAB cognitive speed CANTAB cognitive accuracy Abbreviations: CANTAB Measure (Per-Protocol Population Except Where Noted) Table Endpoints From andSecondary 2.Change inPrimary to Baseline 6 Weeks b a MADRS MADRS (ITT population) MADRS (ITT IDS-SR Effect size was calculated astheestimated difference dividedby thestandard deviation. Signs have beeninverted sothat a See Supplementary Supplementary See Table CANTABthe 4for calculation cognitive of andspeedscores. accuracy Questionnaire, IDS-SR positive treatment effect isreflected by apositive effectsize. MADRS Decoglurant 5mg Placebo Placebo Placebo Decoglurant 15mg Decoglurant 5mg Decoglurant 30mg Decoglurant 15mg Decoglurant 5mg Decoglurant 15mg Decoglurant 30mg Placebo Decoglurant 30mg Decoglurant 5mg Decoglurant 15mg Decoglurant 30mg Placebo Decoglurant 5mg Decoglurant 15mg Decoglurant 30mg Placebo Decoglurant 5mg Decoglurant 30mg Decoglurant 15mg 30 (30.3) 74 (74.7) 11 (11.1) 37 (37.4) 12 (12.1) 28 (28.3) 10 (10.1) 15 (15.2) Placebo (n =99) 30 1 (1) 7 (7.1) 1 (1.0) 5 (5.1) = Montgomery-Åsberg Depression Rating Scale,Montgomery-Åsberg Depression SD Rating a (n =101) 39 (38.6) 76 (75.2) 20 (19.8) 28 (27.7) 12 (11.9) 24 (23.8) 11 (10.9) 10 (9.9) 3 (3) 7 (6.9) 7 (6.9) 6 (5.9) 5 mg = 30 b Cambridge Neuropsychological Test Automated Battery, CPFQ

= ofDepressiveInventory Symptomatology version, ITT Report–30-item Self b Total n Decoglurant 100 74 75 75 86 72 89 35 72 74 88 35 86 47 89 87 46 86 89 88 47 95 95 52 (n =102) 46 (45.1) 79 (77.5) 22 (21.6) 41 (40.2) 22 (21.6) 32 (31.4) 10 (9.8) 25 (24.5) 15 mg 2 (2.0) 6 (5.9) 4 (3.9) 6 (5.9) Baseline Score, Mean (SD)Mean 42.7 (10.7) 41.8 (10.3) 42.6 (9.8) 29.4 (5.8) 40.9 (9.6) 29.1 (6.2) 28.1 (5.9) 30.9 (5.9) 30.5 (5.8) 30.9 (5.7) 31.2 (7.4) 31.1 (5.9) 30.4 (6.3) 30.7 (5.7) 31.4 (7.3) −0.04 −0.04 −0.05 30 (5) 0.14 0.01 0.25 0.05 0.09 33 (60.0) 47 (85.5) 14 (25.5) 23 (41.8) 22 (40.0) 18 (32.7) 10 (18.2) 16 (29.1) (n =55) 0 6 (10.9) 1 (1.8) 7 (12.1) 30 mg

From Baseline Mean Change Mean = standard deviation (centralized ratings). −18.39 −18.80 −17.96 −17.62 −11.77 −12.82 −11.79 −13.20 −11.43 −10.92 −12.04 −12.12 −6.00 −6.29 −6.89 −5.93 optimal to procognitive detect of our effects compound—a patients were more impaired. each country. Compared healthy with these volunteers, our and education-matched controls at study selected centers in during we obtained trial, this cognitive data inage-, sex-, population,a restricted namely UKresidents. Indeed, and resulting from of use the normative data obtained in absence of cognitive impairment may have spurious been than commercially oriented research centers. However, the maythey have recruited from different patient populations MDD were primarily performed at centers; academic hence, studies reporting relevant clinically cognitive impairment in significant cognitive impairment may have because arisen meeting initial threshold. this absence of The unexpected low numberreducedthe of to 0.5 SD patients because of as 1SD below CANTAB normative means, was which criterion for cognitive impairment was initially defined with andthose without those cognitive impairment. The an inclusion criterion. Rather, patients were into stratified no cognitiveeffects, impairment threshold as was defined study wasthis to demonstrate goal of antidepressant of clinically relevant cognitive impairment. As primary the lower-than-expectedthe prevalence was limited of because 0.12 0.15 0.07 0.15 0.08 0.03 0.14 0.04 Lastly, cognitive the may battery used not have been © 2020Copyright Physicians Postgraduate Press, Inc. Estimated Difference for Decoglurant −0.03 (−0.16to 0.11) −0.41 (−4.40to 3.58) −0.12 (−0.29to 0.05) −0.03 (−0.16to 0.11) −0.29 (−0.13to 1.55) −0.89 (−2.75to 0.97) −0.60 (−3.70to 2.49) −0.69 (−4.31to 2.94) −1.05 (−4.38to 2.27) −0.02 (−3.34to 3.30) −1.44 (−5.42to 2.55) 0.07 (−0.04to 0.18) 0.43 (−3.58to 4.43) 0.77 (−4.02to 5.57) 0.07 (−2.17to 2.30) 0.51 (−2.54to 3.55) Mean (95%CI) Mean 0 (−0.13to 0.14) 0 (−0.11to 0.11) … … … … … … = Cognitive andPhysical Functioning – Placebo, J ClinPsychiatry 81:4,July/August 2020

= Effect Size intention-to-treat, −0.06 −0.03 −0.3 −0.06 −0.09 −0.01 −0.05 0 0.01 0.03 0.21 0.05 0.14 0.09 0 0.13 0.05 0.06 … … … … … … a P Value .70 .98 .95 .84 .21 .83 .16 .75 .67 .76 .35 .95 .53 .99 .48 .74 .70 .71 … … … … … …

You are prohibited from making this PDF publicly available. treatment effects. groundsthe of inadequate treatment resistance, distorting and resistant may ineligible, disease be actually mainly on sites. Around 15%of patients of recruited to MDD trials original diagnosis of MDD was made at individual the ofseverity MDD centrally was assessed the inour trial, protocolthe and study visit. We recognize that the while than outcome assessments byperformed raters blinded to afactorbe determining response placebo more strongly resultsThese suggest that patient initial may selection 29% met MADRS the criteria for remission full of MDD. group met MADRS the criteria for treatment response, and relative to previous placebo antidepressantthe 35% of trials: response placebo the and remission were rates high observed tests forblood SSRIs/SNRIs. Despite safeguards, initial these MADRSlow scores or screening negative criteria of because individualsthe screened, 39%(150patients) these failed J ClinPsychiatry 81:4,July/August 2020 For [email protected]. reprints orpermissions, contact ♦ analysis, collection, the and study this of design the sponsor:the Role of Ltd. Roche Hoffman-La Funding/support: Inc. Checkpoint Immunobrain to aconsultant as acting currently Dr Deptula study. this of time the at Ltd Roche F. in, shares Hoffmann-La owned of, and employees were authors All interest: of conflicts Potential in the results. interpreting role important an played and study the designing in involved was Fontoura Dr and results; the interpreting in role important an played and data of acquisition the in involved were Grünbauer Dr and Moore, Ms Deptula, Dr manuscript; the of versions drafted and results, the interpreting in role important an played data, of acquisition the in involved were implementation, its led and study the designed Sanwald-Ducray Dr and Niggli, Dr Boak, Dr Umbricht, Dr addition, In version. final the approved and manuscript the revised Author contributions: Published online: Submitted: scoring based SNRI) and also—given fortendency the inflated site- scores and of evidence compliance with relevant the SSRI/ implemented inclusion criteria (at least moderate MADRS To response, placebo minimizethe current the trial confounded by response placebo high rates, impairment endpoint. as aprimary than one cognitive battery, along with analyzing cognitive utilize an explicit cognitive impairment criterion and more To treatment detect future effects, may trials clinical to need hypothesis that cannot evaluated be withstudy this alone. assess baseline severity andassess severity baseline outcome. maysuggest less effect the than be originally reported. data from large USFood and Administration Drug trials treatment-resistant patients; reasoning indeed,the behind arguedcan be that criterion selection this excluded truly current episode did notdurationthe 1 exceed year, of it to centers. academic, As patients we selected inwhom the pronounced with recruitment at non-academic, as opposed It isIt illegal to post this copyrighted PDF on any website. Clinical trials of antidepressants trials Clinical inMDD have been July 17, July 13, 2018; May 2020. accepted July 14, July 2020. This study was funded by F. by funded was study This 39 The sponsor was involved in in involved was sponsor The —used fully blinded, fully centralized raters—used to All authors reviewed and and reviewed authors All 40 This finding appears more to be is is 37 Notably, among conflicts of interest to declare. declare. to interest of conflicts no have Hunt Dr and Townshend Ms company. Ashfield an (UK), Medical Watermeadow PhD, of Hunt, Charlie and MSc, Townshend, Grace by provided was Ltd, Roche F. by Hoffman-La funded Acknowledgments: Florida. 6–10, 2015;December Hollywood, American College of Neuropsychopharmacology; the of Meeting Annual 54th ▪the Netherlands 01, 2015; The 29–September Amsterdam, August Congress; ECNP 28th the at presentations 2017; 1–6, poster as and Italy, Taormina, October Receptors; Glutamate Metabotropic on Meeting 21–25, International 9th ▪the 2015; Florida Miami, June Psychopharmacology; Clinical of Society American the of Meeting Annual Canada ▪the 14–16, May 2015; Psychiatry; Toronto, Ontario, Biological of Society the of Meeting Annual 70th the at presentations oral as part in presented were Previous presentation: authors. the of responsibility the was publication for manuscript this submit, to decision final of, and development The study. the of time the at sponsor the of employees were authors All data. study of interpretation and 33–37 although 38 Medical writing assistance, assistance, writing Medical

Results from this study study this from Results patients may help to address issues these infuture trials. and procognitive An evenmore effects. of careful selection reduced possibility the of demonstrating antidepressant cognitive impairment majority inthe of patients may have responseplacebo and absence of aseeming relevant clinically resistant MDD compared with placebo. Arelatively high inindividualswere treatment- with partially observed investigated,doses no antidepressant or procognitive effects notdoes any exert antidepressant effects. subgroup analyses supports our conclusion that decoglurant treatment inour study effect across multiple endpoints inthe implemented for future absence the of trials, any of signal a it is clear that aforementioned the improvements should be of study drug. nonresponse to background therapy before administration SSRI/SNRI therapy as welltreatment as prospective testing of appropriatenessthe assessment of of adjunctive treatment to treatment-resistantindependent diagnosis of MDD and suggests that improvements might achieved by be blinded, studies with additional safeguards for patient selection thatwith adesign may increase response. placebo one active arm is risky, and researcher the is therefore left engagement, of as case inthe decoglurant, with only adesign optimal Without dose. the of selection the any data on target The challengewith effect. this infirst-in-patient studies is ofboth have which shown been positively to be associated run-in period may beneficial. be also period run-in placebo) probability of only 25%for apatient randomized to be to include number the of study treatment arms (leading to a possible reasons for response placebo high the inour trial if anything, response high to any avery intervention. Other results suggest that patients the entering our study showed, of any low. response very to be was expected However, our criterionthis was to exclude patients inwhom likelihood the To conclude, decoglurant was well tolerated, and, at the Comparison of the placebo response placebo ratethe to ratesComparison of in © 2020Copyright Physicians Postgraduate Press, Inc. 37,41 Adjunctive Decoglurant in Partially Refractory MDD Adjunctive Decoglurant inPartially Refractory and extended interaction with patients, 40,43–45 PSYCHIATRIST. Supplementary material: corresponding author. the to directed be should and possible whenever facilitated be will data study to access for Additional information: 3. 2. 1. REFERENCES Adouble- or single-blind placebo

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Article Title: Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder

Author(s): Daniel Umbricht, MDa,*; Markus Niggli, PhDb; Patricia Sanwald-Ducray, PhDa; Dennis Deptula, PhDc; Rema Moore, MSc; Waltraud Grünbauer, PhDa; Lauren Boak, PhDd; and Paulo Fontoura, MD, PhDd

DOI Number: https://doi.org/10.4088/JCP.18m12470

List of Supplementary Material for the article

1. Table 1 Inclusion and exclusion criteria

2. Table 2 Administration of study medication

3. Table 3 Exploratory factor analysis

4. Table 4 Cambridge Neuropsychological Test Automated Battery (CANTAB) tasks and composite score computation

5. Table 5 Mean changes from baseline to day 42 in MADRS score, and response and remission rates, as assessed by the centralized and site raters

6. Figure 1 Trial design and schedule of endpoint assessments

7. Figure 2 MADRS response and remission rates. (a) Response rates, defined as MADRS reduction of ≥50%; (b) Remission rates, defined as total MADRS score ≤10. P-values are from Fisher exact test results at day 42

Disclaimer This Supplementary Material has been provided by the author(s) as an enhancement to the published article. It has been approved by peer review; however, it has undergone neither editing nor formatting by in-house editorial staff. The material is presented in the manner supplied by the author. © Copyright 2020 Physicians Postgraduate Press, Inc.

Supplementary Table 1. Inclusion and exclusion criteria

Inclusion criteria

1. An outpatient with a primary diagnosis of MDD without psychotic features as defined by DSM-IV-TR, on the basis of a structured interview (Structured Clinical Interview for DSM-IV-TR clinical trial version [SCID-CT]).

2. Having inadequate response to current, ongoing antidepressant treatment including an SSRI/SNRI. Inadequate response is defined as having a CGI-S score ≥4 (moderately ill or worse) and an MADRS score ≥25 (generated at screening) while being treated for at least 6 weeks at a dose equal to or greater than the minimum acceptable dose indicated in the MGH ATRQ.

3. Having at least one but no more than two antidepressant treatment trial failures within the index depressive episode, with the current, ongoing antidepressant trial counted as one treatment failure. A single antidepressant treatment regimen including more than one pharmacological agent (eg, combination or augmentation) will only be considered as a single antidepressant trial.

4. Dose and duration of antidepressant treatment in the index episode can be verified by written documentation from at least one of the following: medical records; pharmacy records; treating and/or referring physician (indicating medication, dose, and dates of treatment).

5. Documentation of clinical and treatment history must be available.

6. The index depressive episode should have started within 1 year of screening.

7. Confirmed compliance with current SSRI/SNRI treatment based on blood screen.

8. Existing medication regimens should be stable for 6 weeks, with the intent to remain stable throughout the study.

9. Legally adult (minimum of 18 up to 65 years of age at time of informed consent).

10. BMI 18.0–35.0 kg/m2 inclusive.

11. Patients with reproductive potential must agree to use contraceptive protection from screening until 90 days after the last dose of study medication as follows:

- Males with partners of childbearing potential or partners must use a barrier method of contraception or remain sexually abstinent.

- Females who are not either surgically sterile (tubal ligation, removal of ovaries or uterus) or post-menopausal (no spontaneous menstrual periods for at least 1 year confirmed by a hormone panel [FSH and 17βestradiol]) must agree to use two adequate methods of contraception, including at least one method with a failure rate of <1% per year (eg, hormonal implants, combined oral contraceptives, vasectomized partner, abstinence).

12. In the investigator’s opinion, the patient is deemed appropriate for participation in the study, capable of following the study schedule of assessments and complying with the

study restrictions and participation in the study, or discontinuation of prohibited medication will not pose undue risks to the patient.

13. Able to participate and willing to give written informed consent.

Exclusion criteria

1. Currently receiving treatment with a combination of three or more antidepressants.

2. Currently receiving treatment with prohibited medications (see list at end of table) and not willing to cease treatment at least 2 weeks before randomization (or 5 half-lives, whichever is longer).

3. Significant ongoing use of high doses of barbiturates, benzodiazepines or other anxiolytic drugs, withdrawal from which is judged by the investigator to be clinically inadvisable.

4. Previously received decoglurant.

5. Participated in an investigational drug or device study within 6 months of screening or in the index depressive episode.

6. History of non-response to, or current use of, a non-pharmacological treatment including electroconvulsive therapy (ECT), vagus nerve stimulation (VNS), or repetitive transcranial magnetic stimulation (RTMS).

7. Planning to begin or change current regimen of individual psychotherapy, including cognitive behavioral therapy, during the 6-week treatment period of the study and the first 2 weeks of follow-up. Patients undergoing regular psychotherapy (ie, at least 3 months’ duration at the time of screening) are eligible to participate in the study.

8. Present DSM-IV-TR axis I diagnosis, except for anxiety comorbidity (obsessive compulsive disorder or post-traumatic stress disorder specifically not allowed).

9. Past or present psychotic symptoms.

10. Mood disorder owing to a medical condition or substance use/abuse/dependence.

11. Established personality disorder that might interfere with compliance or increase suicidal risk.

12. Alcohol and/or substance abuse/dependence during the last 6 months.

13. A current (at screening) significant risk for suicidal behavior as judged by the investigator following a thorough clinical evaluation and supported by information collected on the C-SSRS.

14. Past or present neurological disorder (for example, but not restricted to, seizure disorder, stroke, head trauma, disorders associated with ataxia or vertigo, dementia or neurodegenerative disorders).

15. Present eating disorder (anorexia nervosa and bulimia nervosa).

16. Abnormal thyroid function. Note that patients undergoing treatment may be allowed to participate in the study if currently euthyroid and not having had a change in treatment regimen within the last 8 weeks.

17. Active upper gastrointestinal tract disease (stomach ulcer/peptic ulcer, gastritis/gastroenteritis or GERD).

18. Other significant or unstable medical condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the patient in this study.

19. Positive result on hepatitis B (HBV), hepatitis C (HCV), or HIV 1 and 2.

20. Positive test for abuse of drugs.

21. Clinically significant abnormality on 12-lead electrocardiogram (ECG), including a QTcF of ≥450 milliseconds.

22. Clinically significant lab abnormality (note that re-testing is allowed to rule out potential laboratory errors).

23. For females of child-bearing potential, positive pregnancy test, breast-feeding, or intention to become pregnant during the course of the trial.

24. Hypersensitivity to the excipients of the study drug.

25. Individuals whose occupation is to drive or operate mass transportation (ie, buses, trains), large vehicles (ie, trucks), or heavy machinery.

Prohibited medications

The following medications were prohibited at least 2 weeks or up to 5 half-lives (whichever was longer) before randomization until the end of the 8-week follow-up period:

– Strong CYP1A inhibitors (eg, fluvoxamine, ciprofloxacin) – Strong CYP450 enzyme inducers (eg, rifampicin, EIAEDs [eg, carbamazepine, phenytoin], St John’s Wort) – Substrates for PgP with a narrow therapeutic window (eg, digoxin) – Other drugs with a narrow therapeutic window (eg, theophylline, warfarin)

The following medications were prohibited at least 2 weeks or up to 5 half-lives (whichever was longer) before randomization until after at least 2 weeks of follow-up. (Note that use of these agents before the end of the 8-week follow-up period was only permitted following consultation with the Sponsor/Medical Monitor).

– Non-SSRI or non-SNRI antidepressants (eg, moclobemide, clomipramine, trazodone) – Second antidepressant if patient was on two antidepressants at screening – Alternative therapies/herbal supplements used as antidepressants (eg, omega-3 fatty acids) – Adjunctive or potentiating antidepressant treatments (eg, antipsychotics [typical or atypical], mood stabilizers, lithium, triiodothyronine or stimulants) – Opioid analgesics (eg, tramadol) – GABA agonists (eg, tiagabine, vigabatrin, baclofen) – Glutamatergic drugs (eg, riluzole, topiramate, memantine, lamotrigine) – MAO inhibitors – 5-hydroxytryptophan L-tryptophan – All other psychotropic drugs (with the exception of allowed medications listed above) BMI, body mass index; CGI-S, Clinical Global Impression – Severity; C-SSRS, Columbia Suicide Severity Rating Scale; CYP, cytochrome P; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision; EIAEDs, enzyme-inducing antiepileptic drugs; FSH, follicle-stimulating hormone; GABA, gamma-aminobutyric acid; GERD, gastroesophageal reflux disease; HIV, human immunodeficiency virus; MADRS, Montgomery–Åsberg Depression Rating Scale; MAO, monoamine oxidase; MDD, major depressive disorder; MGH ATRQ, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; QTcF, QT interval corrected for heart rate via Fridericia's method; SNRI, serotonin- norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Supplementary Table 2. Administration of study medication

The first dose of study medication (decoglurant 5 mg, 15 mg, or 30 mg or placebo) was administered in the clinic on day 1 within 15 minutes of completing a meal. Patients remained at the clinic for at least 4 hours after the first dose for safety monitoring and other assessments.

On clinic visit days involving pharmacokinetic (PK) sampling, patients arrived at the clinic in the morning without having taken their daily dose of study medication. Following collection of the pre- dose PK blood sample and within 15 minutes of completing a meal, patients took their dose of study medication.

On clinic visit days not involving PK sampling, patients took their daily dose of study medication in the morning, either before or after arrival at the clinic and within 15 minutes of completing a meal.

On days when a study visit was not scheduled, patients took their dose once daily in the morning within 15 minutes of completing a meal.

The last dose of study medication was administered on day 42 (+/− 2 days).

Patients were required to complete a daily diary to record the actual time of dosing. The actual time of the first meal consumed on each day of the treatment period and the meal consumed on the evening before clinic visits were also recorded in the patient diary, as well as information regarding skipped doses and vomiting.

Supplementary Table 3. Exploratory factor analysis

Rotated factor pattern

Study NP25620 (N = 181) Study BP25712 (N = 115)

Factor 1 Factor 2 Factor 1 Factor 2

OTS – Problems 73 12 62 –14 solved on first choice

RVP – A prime 72 –40 78 –14

DMS – Percent 52 –32 49 –20 correct

PAL – Total errors –69 8 –65 15 (adjusted)

AST – Incongruent –75 –1 –81 –22 errors

AST – Reaction –23 73 –19 76 latency (median, congruent)

DMS – Correct 3 72 15 73 latency, mean

RVP – Median –38 69 –56 50 response latency

OTS – Median 7 52 –26 49 correct latency

Printed values are multiplied by 100. AST, attentional set shifting; DMS, delayed matching to sample; N, number of patients; OTS, One-Touch Stockings of Cambridge; PAL, paired associates learning; RVP, rapid visual processing.

Supplementary Table 4. Cambridge Neuropsychological Test Automated Battery (CANTAB) tasks and composite score computation

Task Abbreviation for Domain Key parameter Abbreviation for test scores

Attentional set AST Attention; Incongruent ASTICE shifting executive errors function Reaction latency ASTLCMD (median, congruent)

Delayed DMS Working memory Percent correct DMSPC matching to overall sample Correct latency DMSML (mean)

One-Touch OTS Executive Problems solved OTSPSFC Stockings of Function on first choice Cambridge Correct latency OTSMDCL (median)

Paired PAL Episodic memory Total errors PALTEA associates (adjusted) learning

Rapid visual RVP Attention A prime RVPA processing Median response RVPMDL latency

Accuracy = (DMSPC*+OTSPSFC*−PALTEA*+RVPA*−ASTICE*)/5, composite score where DMSPC*, OTSPSFC*, PALTEA*, RVPA*, ASTICE* are the standardized values of the original variables Speed composite = −1*(DMSML*+RVPMDL*+ASTLCMD*+OTSMDCL*)/4, score where DMSML*, RVPMDL*, ASTLCMD*, OTSMDCL* are the standardized values of the original variables

Supplementary Table 5. Mean changes from baseline to day 42 in MADRS score, and response and remission rates, as assessed by the centralized and site raters

Decoglurant Decoglurant Decoglurant Placebo 5 mg 15 mg 30 mg n = 86 n = 89 n = 88 n = 47

Centralized Site Centralized Site Centralized Site Centralized Site

Change in MADRS total scorea

Mean (SD) −11.8 (11.2) −14.5 (10.1) −12.8 (11.2) −15.0 (10.1) −11.8 (11.2) −13.7 (10.1) −13.2 (11.2) −13.2 (10.1)

95% CI [−14.2, −9.4] [−16.7, −12.3] [−15.2, −10.5] [−17.2, −12.8] [−14.2, −9.4] [−15.9, −11.5] [−16.4, −10.0] [−16.1, −10.2]

Response at day 42, %b 34.9 47.7 39.3 47.2 43.2 51.1 46.8 46.8

Remission at day 42, %b 29.1 30.2 37.1 38.2 29.5 37.5 31.9 29.8

aChange from baseline, least-squares means from mixed-model repeated measures. bResponse defined as MADRS reduction of ≥50%, remission defined as total MADRS score ≤10.

CI, confidence interval; MADRS, Montgomery–Åsberg Depression Rating Scale; SD, standard deviation.

Supplementary Figure 1. Trial design and schedule of endpoint assessments

Schedule of endpoint assessments

Scale Screening Baseline W1 W2 W3 W4 W5 W6 W8 W10 W14

MADRS CR Site CR CR CR CR CR CR Site CR CR CR CR

CGI-S CR Site CR CR CR CR CR CR Site CR CR CR CR

CANTAB Pt Pt Pt Pt

CGI-I Site

IDS-SR30 Pt Pt Pt Pt Pt Pt Pt Pt Pt Pt Pt

PGI Pt Pt Pt Pt Pt Pt Pt

CPFQ Pt Pt Pt

SDS Pt Pt Pt Pt Pt Pt Pt Pt Pt Pt

Q-LES-Q-SF Pt Pt Pt

CANTAB, Cambridge Neuropsychological Test Automated Battery; CGI-I, Clinical Global Impression of Improvement; CGI-S, Clinical Global Impression – Severity of Illness scale; CPFQ, Cognitive and Physical Functioning Questionnaire; CR, centralized rater; IDS-SR30, Inventory of Depressive Symptomatology Self Report-30 item version; MADRS, Montgomery–Åsberg Depression Rating Scale; PGI, Patient-Rated Global Improvement; Pt, patient; Q-LES-Q-SF, Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form; SDS, Sheehan Disability Scale; W, week.

Supplementary Figure 2. MADRS response and remission rates. (a) Response rates, defined as MADRS reduction of ≥50%; (b) Remission rates, defined as total MADRS score ≤10. P-values are from Fisher exact test results at day 42

Decog, decoglurant.