Phase 2b Study of ALTO-100 in MDD

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine efficacy differences between ALTO-100 and placebo, used either as monotherapy or adjunctively to an antidepressant, related to patient characteristics.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Study of ALTO-100 With an Open-Label Extension in Adults With Major Depressive Disorder

Conditions
-----------------
Major Depressive Disorder

Intervention / Treatment
-----------------
* Drug: ALTO-100
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Have a diagnosis of moderate to severe major depressive disorder (MDD) At baseline, either not taking an antidepressant medication, or currently taking a single SSRI, SNRI, mirtazapine, or bupropion for at least 6 weeks with no dose modifications in the past 2 weeks Willing to comply with all study assessments and procedures Must not be pregnant or breastfeeding at time of enrollment or throughout study Exclusion Criteria: Evidence of unstable medical condition Diagnosed bipolar disorder, psychotic disorder, or dementia Current moderate or severe substance use disorder Has a history of hypersensitivity or allergic reaction to ALTO-100 or any of its components/excipients Concurrent or recent participation in another clinical trial for mental illness involving an investigational product or device

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALTO-100<br>Participants will receive ALTO-100 tablet twice daily, from Day 1 to Day 42 in double blind (DB) treatment period. Eligible participants who will enter the open label (OL) treatment period will receive ALTO-100 tablet twice daily from OL baseline until the end of OL period/early termination visit (Up to 7 weeks). | Drug: ALTO-100<br>* ALTO-100 tablet BID<br>|
| Placebo Comparator: Placebo DB<br>Participants will receive matching placebo tablet twice daily, from Day 1 to Day 42 in double blind (DB) treatment period. | Drug: Placebo<br>* Placebo tablet BID<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess efficacy of ALTO-100 versus placebo on symptoms of MDD in a pre-defined subgroup of participants as measured by the change from Day 1 to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Change assessed from Day 1 to Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess efficacy of ALTO-100 versus placebo for symptoms of MDD in a pre-defined subgroup of participants who are taking ALTO-100 as monotherapy for MDD as measured by the change from Day 1 to Week 6 on the MADRS total score. | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Change assessed from Day 1 to Week 6 | 
| To assess efficacy of ALTO-100 versus placebo on symptoms of MDD in all randomized participants as measured by the change from Day 1 to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Assessed 4 times over a 6 week interval, from Day 1 to Week 6 | 
| To assess efficacy of ALTO-100 versus placebo for MDD as measured by the change from Day 1 to Week 6 in Clinician Global Impression Scale-severity (CGI-S). | The CGI-S is a 7-point global assessment scale that measures the clinician's impression of the severity of illness exhibited by a participant, rating according to: 1=normal (not at all ill); 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; and 7=among the most extremely ill participants. Higher scores represent a more severe condition. | Assessed 4 times over a 6 week interval, from Day 1 to Week 6 | 
| To assess efficacy of ALTO-100 vs placebo for MDD as measured by the change from Day 1 to Week 6 in response (>50% improvement from baseline) and remission (total MADRS score of <10) rates based on the Montgomery-Åsberg Depression Rating Scale (MADRS) | MADRS is a clinician-administered scale designed to measure depression severity and detects changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Assessed 4 times over a 6- week interval, from Day 1 to Week 6 | 
| To assess efficacy of ALTO-100 versus placebo for MDD as measured by the change from Day 1 to Week 6 in Patient Health Questionnaire, 9 item (PHQ-9). | The PHQ-9 is a 9-item, participant reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the diagnostic and statistical manual of mental disorders-5th edition (DSM-5) major depressive disorder (MDD) criteria. Each item is rated on a 4- point scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The participant's item responses are summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. | Assessed 4 times over a 6- week interval, from Day 1 to Week 6 | 
| To evaluate the safety of ALTO-100 during both the OL and DB periods of the study as measured by the assessment of the incidence, severity, and relatedness of Adverse Events. | Incidence, severity, and relatedness of Adverse Events. | Assessed from Day 1 to Week 13 | 
| To evaluate the safety of ALTO-100 during both the OL and DB periods of the study as measured by the assessment of Heart Rate. | Assessment of Heart Rate. | Assessed from Day 1 to Week 13 | 
| To evaluate the safety of ALTO-100 during both the OL and DB periods of the study as measured by the assessment of Blood Pressure. | Assessment of Blood Pressure. | Assessed from Day 1 to Week 13 | 
| To evaluate the safety of ALTO-100 during both the OL and DB periods of the study as measured by the assessment of Weight. | Assessment of Weight. | Assessed from Day 1 to Week 13 | 
| To evaluate the safety of ALTO-100 during both the OL and DB periods of the study as measured by the assessment of suicidality with the Concise Health Risk Tracking Self-Report,12 item scale (CHRT-SR12). | The CHRT is a brief, self-report measure that systematically assesses both suicidal thinking and associated thoughts that may indicate the propensity for suicidal acts. The CHRT-SR12 is a 12 item scale. The patient assigns a score of 0-4 for each item of the scale, allowing for a total score of 0 to 48, with the higher score signifying more severe symptoms. | Assessed from Day 1 to Week 13 |