Clinical trial NCT04479852
Conditions: Major Depressive Disorder
Sponsor: Sirtsei Pharmaceuticals, Inc.
Start date: 2020-09-30; Completion date: 2022-08-09
Enrollment: 319 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2 clinical study evaluating the safety and effectiveness of SP-624 as compared to placebo in the treatment of adults with Major Depressive Disorder.

Detailed description:

Arms: arm 1: Daily oral capsule, 20 mg/day arm 2: Daily oral capsule
Interventions: intervention 1: SP-624 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule intervention 2: Oral capsule

Protocol documents:
Prot_000.pdf: 
 
 CLINICAL STUDY PROTOCOL: SP-624-201 
Study Title:  
A Multicenter, Double-Blind, Randomized, 
Placebo-Controlled Study of the Safety and 
Efficacy of SP-624 in the Treatment of Adults 
with Major Depressive Disorder  
Sponsor:  
Sirtsei Pharmaceuticals, Inc.  
Phase of Development:  
Phase 2  
NCT Number 
NCT04479852 
Protocol Number:  
SP-624-201  
Protocol Version:  
Amendment 3  
Protocol Version Number:  
4.0  
Protocol Version Date:  
26 May 2021  
 


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1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL: 
SP-624-201 
Study Title: 
A Multicenter, Double-Blind, Randomized, Placebo-Controlled 
Study of the Safety and Efficacy of SP-624 in the Treatment of 
Adults with Major Depressive Disorder 
Study Drug: 
SP-624 
IND Number: 
 
Sponsor: 
Sirtsei Pharmaceuticals, Inc. 
 
 
 
Phase of Development: 
Phase 2 
Protocol Number: 
SP-624-201 
Protocol Version: 
Amendment 3 
Protocol Version Number: 
4.0  
Protocol Version Date: 
26 May 2021 
 
 
Version History 
Version 
Number 
Version Date 
Comment 
1.0 
2.0 
3.0 
4.0 
09 July 2020 
17 September 2020 
27 January 2021 
26 May 2021 
Original 
Amendment 1 
Amendment 2 
Amendment 3 
 
CONFIDENTIALITY STATEMENT 
This protocol is the property of Sirtsei Pharmaceuticals, Inc. and is a confidential 
communication.  Acceptance implies an agreement not to disclose information contained herein 
that is not otherwise publicly available, except for use by an institutional review board (IRB) for 
the purpose of obtaining approval to conduct the study.  The IRB is requested and expected to 
maintain confidentiality.  This document may not be used or published in whole or in part 
without the consent of Sirtsei Pharmaceuticals, Inc. 


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INVESTIGATOR’S PROTOCOL AGREEMENT PAGE 
Note:  A signed copy of this page will be collected and filed in both the Sponsor and Investigator 
trial master files prior to the commencement of this study. 
• I have read the SP-624-201 protocol and agree to conduct the study as outlined. 
• I have received and read the Investigator’s Brochure for SP-624. 
• I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
• I will personally oversee the conduct of this study as outlined herein and will make all 
reasonable efforts to complete the study within the time designated. 
• I will provide all key study personnel under my supervision with copies of the 
protocol and access to all information provided by Sirtsei Pharmaceuticals, Inc..  I 
will discuss this material with them to ensure that they are fully informed about SP-
624, the safety parameters, and the conduct of the study in general. 
• I am aware that, before commencement of this study, the institutional review board 
responsible for such matters must approve this protocol in the clinical facility where it 
will be conducted. 
• I agree to make all reasonable efforts to adhere to the attached protocol. 
• I, or my designee, agree to be present at the site initiation visit.  In addition, I will 
ensure the presence of all key study personnel under my supervision at this meeting. 
• I agree to provide all subjects with informed consent forms, as required by 
government and International Council for Harmonisation regulations. 
• I further agree to report to Sirtsei Pharmaceuticals, Inc. any adverse experiences in 
accordance with the terms of this protocol and Food and Drug Administration (FDA) 
regulation 21 Code of Federal Regulations (CFR) 312.64. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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SPONSOR EMERGENCY CONTACT INFORMATION 
Reporting of Serious Adverse Events (SAEs) 
Any SAE occurring in a study subject must be reported to the Sponsor within 24 hours.   
See Section 8.1.2  (Serious Adverse Events) for definition and reporting procedure for SAEs. 
All relevant information must be captured, preferably on an SAE Report Form, and submitted via 
email within 24 hours to each of the individuals listed in Table 1. 
Request email confirmation of receipt, and if not confirmed, follow-up by phone to confirm 
receipt. 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Email Address 
Telephone Number 
Sponsor Clinical Study 
Leader 
 
 
 
Sponsor Medical Monitor  
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Sirtsei Pharmaceuticals, Inc. 
Name of Investigational Product: 
SP-624 (oral capsules) 
Name of Active Ingredient: 
Code Name: SP-624 
 
Title of Study:  
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of the Safety and Efficacy of 
SP-624 in the Treatment of Adults with Major Depressive Disorder 
Phase of development:  
Phase 2 
Study center(s):  
Approxmiately 40 sites in the United States 
Planned Study Duration: 
The planned study duration encompasses the estimated time from the Screening of the first subject to 
the estimated time the last subject completes the Week 6 Follow-Up Visit. 
• 
Estimated date first subject Screened: September 2020  
• 
Estimated date of last subject first visit:  October 2021 
• 
Estimated date of last subject last visit: November 2021 
Objectives:  
Primary: 
• 
Evaluate the efficacy of SP-624 administered once-daily for up to 4 weeks compared to 
placebo in the treatment of adults with major depressive disorder (MDD)  
Secondary: 
• 
Evaluate the safety and tolerability of SP-624 administered once-daily for up to 4 weeks 
compared to placebo in the treatment of adults with MDD  
• 
Characterize the population pharmacokinetics (PK) of SP-624 in plasma when 
administered orally to subjects with MDD 


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Study Design:  
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study of the safety and 
efficacy of SP-624 in the treatment of adult subjects with MDD as defined by the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).  Following the successful completion 
of a Screening Phase, subjects will be randomized to one of two treatment groups in a 1:1 ratio and 
will receive SP-624 or placebo over a treatment period of four weeks (Treatment Group #1: SP-624 
20 mg/day; Treatment Group #2: Placebo).  
Approximately 300 subjects (150 per treatment group) will be enrolled into the study.  Each subject 
will complete Screening, Baseline, Treatment, and Follow-up Visits.  
Prior to initiating the 4-week treatment period, subjects will complete a Screening/Baseline period of 
up to 28 days, during which time all Screening assessments will be performed, and any current 
depression medications discontinued.  All Screening assessments should be completed before 
discontinuing any current depression medications.  Subjects will return for a Baseline Visit to 
complete efficacy and safety assessments.  During the treatment period, subjects will return to the 
investigative site to complete efficacy and safety assessments at the end of Weeks 1, 2, 3, and 4.  
After the final dose of study drug, subjects will complete a follow-up period of two weeks and will 
return at the end of Weeks 5 and 6.  Subjects may be treated with anti-depressant medications 
according to physician recommendations after completion of the Week 5 Visit.   
Unless there are any outstanding safety issues that require follow-up, subjects will be discharged from 
the study at the Week 6 Visit. 
Number of subjects (planned):  
Approximately 300 adult subjects with MDD as defined by DSM-5; 150 subjects per treatment group 
at approximately 40 centers. 
Duration of Subject Participation: 
Subjects will receive double-blind treatment for up to 4 weeks, following a Screening/Baseline period 
of up to 28 days.  After the treatment period, subjects will complete a 2-week follow-up period.  The 
planned study duration for each subject will be approximately 70 days. 


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Investigational Product, Dosage, and Mode of Administration:  
Each dose of SP-624 will be supplied as two capsules, each containing 10 mg of active 
pharmaceutical ingredient (API).  Matching placebo capsules identical in shape and color to the active 
capsules will also be used.   
• 
Treatment Group #1: Two 10 mg capsules SP-624 each morning for 4 weeks 
• 
Treatment Group #2: Two capsules placebo each morning for 4 weeks 
If the two capsule dose is not well tolerated, the dose can be decreased to one capsule per dose after 
Week 1.    
Study drug will be packaged in weekly blister cards (Weeks 1-4 of dosing), with each blister card 
containing 20 capsules of study drug (two capsules per dose for seven days of dosing, plus three extra 
days of dosing as a provision for study visit scheduling).  Weekly blister cards will be assembled in 
subject kits containing four blister cards for use during the treatment period.  Each kit will be labeled 
with a 3-part label that specifies the randomization number, cautionary statement, and storage 
conditions.  Each blister card will have a one-part label that specifies the randomization number, 
week, number of capsules, cautionary statement, and storage conditions.   
Each study drug dose should be taken orally, once daily at approximately the same time each 
morning.  Study drug doses should be taken on an empty stomach before breakfast, and no food 
should be consumed for at least 1 hour after dosing.  High fat foods at breakfast (e.g., bacon, cheese, 
eggs, etc.) should be avoided.  Morning liquids such as coffee or tea are allowed without any 
additives (eg, cream, sugar, etc).  
If dosing on an empty stomach is not practical or not well tolerated, then a low fat, low calorie 
breakfast 2 hours before dosing, or 30-60 minutes after dosing, is acceptable.  If dosing remains not 
well tolerated, then subjects should dose 30 minutes after a low fat, low calorie meal. 
Inclusion Criteria:  
To be eligible for this study, a subject must meet all of the following inclusion criteria: 
1. Willing and able to provide written informed consent to participate in the study.  
2. Males and females, aged 18 to 65 years, inclusive. 
3. In generally good physical health, in the opinion of the Investigator. 
4. Body mass index (BMI) must be ≥ 18 and ≤ 40 kg/m2   
5. Females of reproductive potential and males with partners of reproductive potential must 
agree to remain abstinent or use adequate and reliable contraception throughout the study and 
for at least 30 days after the last dose of study drug. 
a. Adequate contraception is defined as continuous use of double-barrier method (e.g., 
condom and spermicide or diaphragm and spermicide), oral contraceptive, implant, 
dermal contraception, long-term injectable contraceptive, or intrauterine device. 
b. Non-reproductive potential is defined as surgically sterile, undergone tubal ligation or 
vasectomy, or postmenopausal (defined as at least 12 months of spontaneous 
amenorrhea).   
c. Subjects of reproductive potential but whose sole partner is of non-reproductive potential, 
or whose sole partner is of the same sex, are not required to maintain abstinence or 
contraception.  


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d. Subjects must agree to refrain from sperm and oocyte donation for at least 90 days after 
the last dose of study drug. 
6. Meets DSM-5 criteria for moderate to severe MDD, as confirmed by the Mini International 
Neuropsychiatric Interview (MINI).  Subjects with a diagnosis of co-morbid generalized 
anxiety disorder (GAD) may be included if MDD is the primary diagnosis. 
7. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 27 at both Screening 
and Baseline.   
8. History of inadequate or non-response to at least one adequate treatment, but no more than 
three of the same class of antidepressant, (i.e., an adequate dose for at least six weeks) for the 
current episode, in the opinion of the Investigator. NOTE: If immediately prior to this episode 
starting, treatment was working to the point of remission, but then the depression worsened, 
subject should not be enrolled. For example, subject should not have been on an 
antidepressant and in remission prior to the start of the current episode. 
9. Willing and able to comply with the study design schedule and other requirements. 
Exclusion Criteria:  
A subject who meets any of the following exclusion criteria will not be enrolled in the study: 
1. Female who is pregnant, breastfeeding, or less than six months postpartum at Screening. 
2. History or presence of major bowel resection, total gastrectomy, or diabetes, and/or history or 
presence of any clinically significant medical condition, disease, or surgical history that 
could, in the opinion of the Investigator, jeopardize the safety of the subject or validity of the 
study data, or interfere with the absorption, distribution, metabolism, or excretion of the study 
drug.  
3. A current DSM-5 diagnosis of depression with peripartum onset, panic disorder, obsessive 
compulsive disorder, post-traumatic stress disorder, anorexia nervosa, or bulimia nervosa. 
4. A history of or current DSM-5 diagnosis of MDD with psychotic features, any schizophrenia 
spectrum and other psychotic disorders, bipolar disorder, or personality disorder.   
5. History of treatment with electroconvulsive therapy (ECT), vagus nerve stimulation, deep 
brain stimulation, or transcranial magnetic stimulation within six months of Screening.  
6. Current episode of depression exceeds 2 years or is less than six weeks from Screening. 
7. History of inadequate or non-response, in the opinion of the Investigator, to an adequate 
treatment regimen of two or more classes of antidepressants during the current episode.   
8. Subjects treated with an antipsychotic during the current episode should be excluded.  
9. Subjects who meet DSM-5 criteria for moderate or severe substance use disorder for any 
substance except nicotine or caffeine, within 12 months of Screening.  Subjects with a urine 
drug screen positive for suspected substance of abuse will be excluded. Urine drug screen 
positive for cannabinoids is not exclusionary if the subject does not meet criteria for moderate 
or severe substance use disorder.  
10. Will require initiation of psychotherapy during the study period, in the Investigator’s opinion.  
If a subject has been in ongoing psychotherapy for a minimum of three months, the therapy 
may continue if it remains unchanged. Cognitive behavioral therapy is excluded. 


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11. Poses a current or future suicidal risk, in the Investigator’s opinion, or has a history of 
suicidal behavior within the past 12 months, and/or subject answers “yes” to “Suicidal 
Ideation” Item 4 (active suicidal ideation with some intent to act, without specific plan) or 
Item 5 (active suicidal ideation with specific plan and intent) on the Columbia-Suicide 
Severity Rating Scale (C-SSRS) assessment during the six months prior to the Screening 
period and/or at Baseline. 
12. Failure to discontinue all psychoactive medications or psychoactive supplements including 
antidepressants and mood stabilizers, within a time period prior to Baseline corresponding to 
at least five half-lives of the medication in question.   
13. Presence of a clinically significant abnormality on physical examination or electrocardiogram 
(ECG), including a corrected QT interval using Fridericia’s formula (QTcF) >450 msec for 
males and >470 msec for females.  Note: ECG may be repeated once at both Screening and 
Baseline for confirmatory purposes. 
14. Presence or history of any known clinically significant cardiovascular disorders including, but 
not limited to: coronary artery disease, heart failure, valvular heart disease, cardiomyopathies, 
myocardial infarction, chamber enlargement or hypertrophy, or orthostatic hypotension. 
15. Presence of uncontrolled hypertension, defined as consistent systolic blood pressure (SBP) 
>160 mmHg or consistent diastolic blood pressure (DBP) >95 mmHg despite present therapy. 
Note: Blood pressure measurements may be repeated twice at both Screening and Baseline 
for confirmatory purposes. 
16. Screening laboratory value(s) outside the laboratory reference range that are considered to be 
clinically significant by the Investigator (clinical chemistry, hematology, coagulation, and 
urinalysis). Note: Screening labs may be repeated once for confirmatory purposes. 
17. Screening liver function tests (ALT, AST, Alkaline phosphatase) > 2x the upper limit of 
normal. 
18. Known history of current or chronic Hepatitis B or Hepatitis C infection, or a known history 
of human immunodeficiency virus (HIV) infection.  Subjects with a history of treated 
Hepatitis C infection where liver function tests are within normal limits may participate. 
19. Subjects with a history of seizures or seizure disorder. 
Note:  Subjects with a history of only febrile seizures, limited to up to two episodes, are 
permitted. 
20. Clinically significant acute infection, other than mild viral or bacterial infections from which 
the subject has fully recovered (e.g., common cold, localized skin infection, etc.), within the 
two weeks prior to Baseline. 
21. Major trauma or surgery in the 12 weeks prior to Screening or at any time between Screening 
and randomization. 
22. Presence or history of malignancy within the last five years.  Note: History of adequately 
treated basal cell or squamous cell carcinoma of the skin or in situ cervical cancer is allowed. 
23. History of an anaphylactic allergic reaction to previous medication.  
24. Blood or plasma donation within 30 days of randomization, or planned donations or elective 
surgery during the study or during the 60 days following the study. 
25. Subjects who, in the opinion of the Investigator, are not suitable candidates for the study. 


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26. Individuals who are currently enrolled in or have participated in a clinical trial (i.e., received 
study drug) involving an investigational product within 60 days or within five half-lives of 
the investigational product (whichever is longer) prior to Baseline. 
Study Endpoints: 
Primary Efficacy Endpoint: 
• 
Change from Baseline to Week 4 in MADRS total score 
Secondary Efficacy Endpoints:  
• 
Change from Baseline to Weeks 1, 2, and 3 in MADRS total score 
• 
Change from Baseline to Weeks 1, 2, 3, and 4 in Clinical Global Impression – Severity 
(CGI-S) total score 
• 
Change from Baseline to Week 5 and change from Week 4 to Week 5 in MADRS total 
score and CGI-S total score 
• 
Change from Baseline to Week 2 and Week 4 in the 17-item Hamilton Depression Rating 
Scale (HAM-D-17) total score 
• 
Change from Baseline to Week 2 and Week 4 in the Sheehan Disability Scale (SDS) 
• 
Change from Baseline to Week 2 and Week 4 in the Quick Inventory of Depressive 
Symptomology – Self Report (QIDS-SR)  
• 
Change from Baseline to Week 2 and Week 4 in the Quality of Life Enjoyment and 
Satisfaction Questionnaire – Short Form (Q-LES-Q-SF) 
Safety Endpoints: 
• 
Adverse Events (AEs) 
• 
Clinical safety laboratory tests (serum chemistry [including thyroid function], 
hematology, coagulation, and urinalysis tests) 
• 
Vital signs (blood pressure, pulse rate, and oral body temperature) 
• 
Body weight 
• 
12-lead ECGs  
• 
Physical examinations 
• 
C-SSRS 
PK Endpoints: 
A total of four blood samples will be collected from each subject for the measurement of plasma 
concentrations of SP-624 at the following visits: 
• 
Visit 2 (Day -1) 
• 
Visit 3 (Week 1): Pre-Dose 
• 
Visit 4 (Week 2): Pre-Dose or approximately 2 to 10 hours post-dose (whichever is more 
convenient for the subject) 


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• 
Visit 6 (Week 4): approximately 2 to 10 hours post-dose 
If a subject missed the dose the day before a scheduled “pre-dose” sample collection, study personnel 
should instead collect a post-dose sample at that visit.  Should a subject inadvertently dose prior to a 
scheduled “pre-dose” sample collection at Week 1 or Week 2, study personnel should collect a post-
dose sample.   
In the event that samples cannot be conveniently collected for a given subject according to the 
scheduled sampling times specified above, study personnel should attempt to collect at least one pre-
dose sample and at least one post-dose sample during the course of the study. 
Date and time of most recent dose prior to PK sample collection, date and time of PK sample 
collection, and meal information relative to most recent dose, will be recorded on days of PK sample 
collection. 
Plasma samples will be analyzed for SP-624 concentration using a validated bioanalytical method. 
An aliquot of each subject’s post-dose samples may be used by the bioanalytical laboratory for 
metabolite profiling.  Potential metabolites will be identified using mass spectrometry techniques; and 
if conducted, these data will be summarized in a separate bioanalytical report.  
 
 
 
 
 
 
 
 
 
 
 
 
  
Statistical Methods and Sample Size Justification: 
Analysis Populations: 
Within each population, analyses will be performed comparing subjects and by-treatment assignment 
(SP-624 vs placebo). 
• 
All Subjects Population – all subjects who sign informed consent and are assigned a 
unique subject identification number.  This population will be used to summarize 
disposition. 
• 
Modified Intent-to-Treat (mITT) Population – all subjects who are randomized to receive 
treatment, receive at least one dose of study drug, and have a Baseline and at least one 
post-dose efficacy assessment. This population will be the primary population used to 
summarize demographics, baseline characteristics, medical history, treatment history, and 
all efficacy outcomes.  Subjects will be analyzed according to randomized treatment 
group. 
• 
Per Protocol (PP) Population – All subjects in the mITT population who received 
assigned study drug as randomized, completed the Week 4 assessments without any 
major protocol violations, and have 75-125% compliance.  The PP population will be 
used as an additional population for summaries of efficacy outcomes. 


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• 
Safety Population — all subjects in the mITT population who receive at least one dose of 
study drug. Safety subjects will be summarized according to the treatment they actually 
received. This population will be used to summarize all safety assessments.  
• 
PK Population — all subjects who receive active study drug and have evaluable PK data 
based on actual treatment received, protocol compliance, adequate numbers of samples, 
and successful sample assays.  
Sample Size Justification: 
Recent studies of MDD using change from Baseline in MADRS total scores suggest that placebo will 
yield an approximately nine unit decrease over four weeks with a standard deviation (SD) of around 
9.2.  SP-624 is expected to yield at least a 12 unit decrease in MADRS total score over four weeks 
with a similar SD of around 9.2.  A minimum of 150 subjects per treatment arm (300 total) would be 
needed to detect a treatment difference of three units with 80% statistical power. The sample size was 
estimated using NQuery 8 (V8.5.2.0) two group test of equal means (MTT0-1: www.statsols.com). 
Efficacy: 
The primary efficacy variable is change from Baseline in MADRS total score at Week 4, for testing 
superiority of SP-624 vs. placebo.  This variable will be analyzed using a Mixed Model for Repeated 
Measures (MMRM), with change from Baseline in MADRS total score at each visit as the response 
variable.  The MMRM model will include age, weight, and baseline MADRS total score as 
covariates, with factors for treatment, visit (Weeks 1, 2, 3, and 4; as a categorical variable), treatment 
by visit interaction term, gender, and site as a fixed effect.  An unstructured covariance matrix will be 
used for the within-subject correlation.  Kenward-Rogers approximation will be used to calculate the 
denominator degrees of freedom. The primary efficacy endpoint will be calculated using an estimate 
statement.  Subjects from low enrolling sites may be pooled in order to help with model convergence. 
In the event of a model which fails to converge, analysis strategies will be detailed in the statistical 
analysis plan (SAP) which will be used to complete the analysis of the primary endpoint.  This will 
include different model assumptions (e.g., restricted maximum likelihood vs maximum likelihood, 
covariance structure, and removing variables from the model [especially if they are associated with a 
high degree of missing values]). 
Safety: 
Laboratory parameters, vital sign data, and ECG results will be summarized by treatment group and 
presented in tabular and graphic formats where appropriate.  Appropriate change from Baseline 
calculations will be provided to detect any significant changes in laboratory parameters, vital sign 
values, ECG results, and C-SSRS results, but no formal statistical tests are planned.  
Pharmacokinetic Assessments: 
Plasma concentration data for SP-624 will be listed and summarized using descriptive statistics. 
If data allow, results will be used for other analyses (e.g., PopPK) which will be presented in a 
separate report.   
The population PK analysis of SP-624 will be performed using a nonlinear mixed effects model 
(NONMEM). This analysis will provide estimates of population PK parameters such as CL/F, Vz/F, 
etc. and a measure of their variability. Pharmacokinetic parameters of individual subjects (e.g., 
AUC[0-tau], Cavg, Cmax) may be estimated and their correlation with relevant covariates (e.g., body 
weight, gender, concomitant medications) will be explored. The population PK analysis plan will be 
prepared separately. 
Plasma concentration data will remain blinded until the unblinding of the clinical database at the end 
of the study. 


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SCHEDULE OF EVENTS 
Table 2: 
Schedule of Events  
Study Period 
Screening / 
Washout 
Baseline 
Treatment Period 
Follow-up Period 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Study Day / Week 
 
 
Day  
-28 to -2 
Day -1 
 
Week 1 
(Day 7 ± 3 
days) 
Week 2 
(Day 14 ± 3 
days) 
Week 3 
(Day 21 ± 3 
days) 
Week 4 / 
Prema-
ture D/C 
(Day 28 ± 3 
days) 
Week 5 
(7 days ±3 
days post 
Week 4 
Visit) 
Week 6 
(14 days 
±3 days 
post 
Week 4 
Visit) 
Event/Assessment 
 
 
 
 
 
 
 
 
Clinic Visit1  
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent  
X 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
Diagnosis Confirmation and 
Treatment History 
X 
 
 
 
 
 
 
 
Demographics, Medical History  
X 
X 
 
 
 
 
 
 
Height and Weight2 
X 
X 
 
 
 
X 
 
 
Physical Exam3 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS4 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test5 
X 
X 
 
 
 
X 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
Clinical Safety Labs6 
X 
X 
 
X 
 
X 
X 
 
Vital Signs7 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG8 
X 
X 
X 
X 
X 
X 
X 
 
MADRS 
X 
X 
X 
X 
X 
X 
X 
 
CGI – S 
X 
X 
X 
X 
X 
X 
X 
 
HAM-D, SDS, QIDS-SR; Q-
LES-Q-SF 
 
X 
 
X 
 
X 
 
 
Randomization  
 
X 
 
 
 
 
 
 
Dispensation / Collection / 
Accountability of Study Drug 
 
X 
X 
X 
X 
X 
 
 
Plasma PK Blood Sampling 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Con Med Record 
X 
X 
X 
X 
X 
X 
X 
X 
AE Monitoring  
X 
X 
X 
X 
X 
X 
X 
X 


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Abbreviations:  AE=adverse event; con med=concomitant medication; CGI-S=clinical global impression-severity; C-SSRS=Columbia-Suicide 
Severity Rating Scale; ECG=electrocardiogram; MADRS=Montgomery-Asberg Depression Rating Scale; PK=pharmacokinetics; Premature 
D/C=Premature Discontinuation from treatment; QIDS-SR=Quick Inventory of Depressive Symptomology – Self Report; Q-LES-Q-SF=Quality of 
Life Enjoyment and Satisfaction Questionnaire – Short Form; SDS=Sheehan Disability Scale  
 
1 If a clinic visit is not possible (e.g., due to illness), a remote visit may be conducted to complete all assessments that can 
be done remotely and assess for adverse events and concomitant medications. The Screening, Baseline, and Week 
4/Premature Discontinuation Visits cannot be done remotely. The sponsor should be contacted prior to conducting any 
remote visits whenever possible. 
2 Height and body weight at Visit 1.  Body weight only at Visit 2 and Visit 6/Premature Discontinuation. 
3 Physical examinations will include a review of the following body systems:  general appearance, skin and extremities, 
ear/eyes/nose/throat, head/neck, heart/chest, abdomen, musculoskeletal, and neurological. 
4 Baseline/Screening Version at Visit 1; Since Last Visit Version at Visits 2-8. 
5 All females; Serum pregnancy test at Visit 1 and Visit 6 (or Premature Discontinuation); Urine pregnancy test at Visit 2 – 
if urine pregnancy test at Visit 2 is positive, a confirmatory serum pregnancy test will be conducted. 
6 Clinical safety labs include clinical chemistry, hematology, coagulation, and urinalysis. Labs should be collected in a 
fasting state.  Urinalysis not required at Visit 4 (Week 2 visit). 
7 Vital signs include blood pressure, pulse rate, and oral body temperature. Vital signs to be assessed in a sitting position 
after three mins or more of quiet sitting.  
8 Two ECGs to be collected at the Baseline Visit separated by approximately 10 minutes. One ECG collected at all other 
visits. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR’S PROTOCOL AGREEMENT PAGE .............................................................2 
SPONSOR EMERGENCY CONTACT INFORMATION .............................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
SCHEDULE OF EVENTS ............................................................................................................12 
TABLE OF CONTENTS ...............................................................................................................14 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................21 
2. 
INTRODUCTION ......................................................................................................25 
2.1. 
Major Depressive Disorder .........................................................................................25 
2.2. 
Investigational Product ...............................................................................................25 
 
 
2.2.2. 
Non-clinical Studies ....................................................................................................26 
2.2.3. 
Clinical Studies ...........................................................................................................27 
2.2.3.1. 
SP-624-101 .................................................................................................................27 
2.2.3.2. 
SP-624-102 .................................................................................................................28 
2.3. 
SP-624 Development Plan ..........................................................................................29 
2.3.1. 
Rationale for Dose ......................................................................................................29 
2.3.2. 
Benefit and Risk Assessment ......................................................................................29 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................31 
3.1. 
Objectives ...................................................................................................................31 
3.1.1. 
Primary Objective .......................................................................................................31 
3.1.2. 
Secondary Objectives .................................................................................................31 
3.2. 
Endpoints ....................................................................................................................31 
3.2.1. 
Efficacy Endpoints ......................................................................................................31 
3.2.1.1. 
Primary Endpoint ........................................................................................................31 
3.2.1.2. 
Secondary Endpoints ..................................................................................................31 
3.2.2. 
Safety Endpoints .........................................................................................................31 
3.2.3. 
Pharmacokinetic Endpoints ........................................................................................32 
3.2.4. 
 
4. 
INVESTIGATIONAL PLAN .....................................................................................33 


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4.1. 
Overall Study Design ..................................................................................................33 
4.1.1. 
Screening Period and Baseline Visit ...........................................................................33 
4.1.2. 
Treatment and Follow-up Periods ..............................................................................33 
4.2. 
Randomization and Blinding ......................................................................................35 
4.2.1. 
Subject Identification and Randomization to Treatment ............................................35 
4.2.2. 
Blinding ......................................................................................................................35 
4.2.3. 
Emergency Unblinding ...............................................................................................35 
4.3. 
Study Centers and Personnel ......................................................................................35 
4.4. 
Number of Subjects ....................................................................................................36 
4.5. 
Study Duration ............................................................................................................36 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................37 
5.1. 
Subject Recruitment, Enrollment, and Identification .................................................37 
5.2. 
Subject Inclusion Criteria ...........................................................................................37 
5.3. 
Subject Exclusion Criteria ..........................................................................................38 
5.4. 
Subject Withdrawal from the Study ...........................................................................40 
5.5. 
Premature Termination of the Study ...........................................................................40 
6. 
STUDY TREATMENTS, MATERIALS, AND MANAGEMENT ..........................41 
6.1. 
Description of Study Drug ..........................................................................................41 
6.2. 
Acquisition of Study Drug Supplies ...........................................................................41 
6.3. 
Subject Treatment Assignment ...................................................................................41 
6.4. 
Study Drug Administration.........................................................................................41 
6.5. 
Treatment Compliance ................................................................................................42 
6.6. 
Study Drug Accountability .........................................................................................42 
6.7. 
Study Drug Storage and Stability ...............................................................................43 
6.8. 
Prior and Concomitant Medications ...........................................................................43 
7. 
STUDY PROCEDURES AND ASSESSMENTS......................................................46 
7.1. 
Schedule of Events .....................................................................................................46 
7.2. 
Study-Specific Procedures ..........................................................................................46 
7.2.1. 
Informed Consent .......................................................................................................46 
7.2.2. 
Demographic Information, Medical History/Current Medical Conditions, 
and Treatment History ................................................................................................46 
7.2.3. 
Mini International Neuropsychiatric Interview ..........................................................47 


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7.2.4. 
Assessment of Efficacy ...............................................................................................47 
7.2.4.1. 
Montgomery-Asberg Depression Rating Scale ..........................................................47 
7.2.4.2. 
Clinical Global Impression – Severity ........................................................................47 
7.2.4.3. 
Hamilton-Depression Rating Scale (17-item) ............................................................47 
7.2.4.4. 
Sheehan Disability Scale ............................................................................................48 
7.2.4.5. 
Quick Inventory of Depressive Symptomology – Self Report ...................................48 
7.2.4.6. 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form .................48 
7.2.5. 
Assessment of Safety ..................................................................................................48 
7.2.5.1. 
Physical Examination .................................................................................................48 
7.2.5.2. 
Vital Signs, Height, and Weight Measurements .........................................................49 
7.2.5.3. 
12-lead Electrocardiograms ........................................................................................49 
7.2.5.4. 
Pregnancy Test ............................................................................................................49 
7.2.5.5. 
Clinical Safety Laboratory Assessments ....................................................................50 
7.2.5.6. 
Blood Volume Collection Summary ..........................................................................50 
7.2.5.7. 
Columbia-Suicide Severity Rating Scale ....................................................................53 
7.2.6. 
Assessment of Pharmacokinetics 
..53 
7.2.6.1. 
Pharmacokinetics ........................................................................................................53 
7.2.6.2. 
54 
7.2.7. 
Biological Sample Retention and Destruction ............................................................54 
8. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
REPORTABLE EVENTS ..........................................................................................55 
8.1. 
Adverse Events ...........................................................................................................55 
8.1.1. 
Clinical Safety Assessment Abnormalities .................................................................55 
8.1.2. 
Serious Adverse Event (SAE) ....................................................................................55 
8.1.3. 
Suspected and Unexpected Serious Adverse Reactions .............................................56 
8.1.4. 
Evaluation of Adverse Events ....................................................................................56 
8.1.4.1. 
Adverse Event Term/Diagnosis ..................................................................................56 
8.1.4.2. 
Date and Time of Adverse Event Onset and Resolution ............................................57 
8.1.4.3. 
Relationship to Study Drug ........................................................................................57 
8.1.4.4. 
Intensity Categorization ..............................................................................................57 
8.1.4.5. 
Action Taken for Adverse Event ................................................................................58 
8.1.4.6. 
Outcome of Adverse Event .........................................................................................58 


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8.1.5. 
Reporting of Serious Adverse Events .........................................................................59 
8.1.6. 
Other Reportable Events .............................................................................................60 
9. 
STATISTICS ..............................................................................................................61 
9.1. 
Determination of Sample Size ....................................................................................61 
9.2. 
Analysis Populations ..................................................................................................61 
9.3. 
Description of Statistical Methods ..............................................................................62 
9.3.1. 
General Approach .......................................................................................................62 
9.3.2. 
Interim Analysis ..........................................................................................................62 
9.3.3. 
Summary of Demographics, Baseline Characteristics, Medical History, and 
Treatment History .......................................................................................................62 
9.3.4. 
Summary of Efficacy ..................................................................................................62 
9.3.4.1. 
Primary Efficacy Endpoint Analysis ..........................................................................62 
9.3.4.2. 
Secondary Efficacy Endpoint Analysis ......................................................................63 
9.3.5. 
Sensitivity Analyses ....................................................................................................64 
9.3.6. 
Summary of Pharmacokinetics ...................................................................................64 
9.3.7. 
65 
9.3.8. 
Concomitant Medications ...........................................................................................65 
9.3.9. 
Summary of Safety and Tolerability ...........................................................................65 
9.3.9.1. 
Adverse events ............................................................................................................65 
9.3.9.2. 
Vital Signs and ECGs .................................................................................................66 
9.3.9.3. 
Clinical Laboratory Assessments ...............................................................................66 
9.3.9.4. 
Physical Exams ...........................................................................................................66 
9.3.9.5. 
C-SSRS .......................................................................................................................66 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...............................67 
10.1. 
Sponsor’s Responsibilities ..........................................................................................67 
10.2. 
Investigator’s Responsibilities ....................................................................................67 
11. 
ETHICS ......................................................................................................................68 
11.1. 
Ethical Conduct of the Study ......................................................................................68 
11.2. 
Ethics Review .............................................................................................................68 
11.3. 
Written Informed Consent ..........................................................................................68 
12. 
DATA HANDLING AND RECORD KEEPING ......................................................69 
12.1. 
Data Collection and Recording ...................................................................................69 


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12.2. 
Retention of Records ..................................................................................................69 
12.3. 
Protocol Deviations ....................................................................................................69 
12.4. 
Publication Policy .......................................................................................................69 
12.5. 
Data Quality Assurance ..............................................................................................70 
12.6. 
Data Management .......................................................................................................70 
13. 
LIST OF REFERENCES ............................................................................................71 
13.1. 
Publications Referenced .............................................................................................71 
13.2. 
Sponsor Documents and Study Reports Referenced ..................................................71 
13.2.1. 
Investigator’s Brochure ..............................................................................................71 
13.2.2. 
Pharmacology Studies ................................................................................................71 
14. 
APPENDICES ............................................................................................................72 
APPENDIX A. MONTGOMERY-ASBERG DEPRESSION RATING SCALE ......................73 
APPENDIX B. CLINICAL GLOBAL IMPRESSION – SEVERITY .......................................77 
APPENDIX C. 17-ITEM HAMILTON DEPRESSION RATING SCALE ...............................78 
APPENDIX D. SHEEHAN DISABILITY SCALE ...................................................................83 
APPENDIX E. THE QUICK INVENTORY OF DEPRESSIVE SYMPTOMOLOGY – 
SELF REPORT ...........................................................................................................85 
APPENDIX F. QUALITY OF LIFE ENJOYMENT AND SATISFACTION 
QUESTIONNAIRE – SHORT FORM .......................................................................87 
APPENDIX G. COLUMBIA – SUICIDE SEVERITY RATING SCALE – 
BASELINE/SCREENING VERSION .......................................................................89 
APPENDIX H. COLUMBIA – SUICIDE SEVERITY RATING SCALE – SINCE 
LAST VISIT VERSION .............................................................................................92 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Events .....................................................................................................12 
Table 3: 
Abbreviations ..............................................................................................................21 
Table 4: 
Restricted and Prohibited Medications .......................................................................44 
Table 5: 
Clinical Safety Laboratory Analytes ..........................................................................51 
Table 6: 
Estimation of Blood Volumes Required from Screening through the End of 
the Follow-up Period ..................................................................................................52 
 


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LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................34 
 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and terms are used in this study protocol. 
Table 3: 
Abbreviations  
Abbreviation 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
API 
Active pharmaceutical ingredient 
AST 
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
AUC[0-tau] 
Area under the plasma concentration-time curve during the 24-
hour dosing interval 
BMI 
Body mass index 
BOCF 
Baseline observation carried forward 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
C 
Celsius 
Cavg 
Average plasma concentration 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression – Severity 
CL/F 
Apparent systemic clearance 
CLss/F 
Apparent systemic clearance after oral dosing at steady state 
cm 
Centimeter(s) 
Cmax 
Observed maximum serum concentration 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DBP 
Diastolic blood pressure 
DMP 
Data management plan 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG 
Electrocardiogram 


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Abbreviation 
Explanation 
ECT 
Electroconvulsive therapy 
eGFR 
Estimated glomerular filtration rate 
FCS 
Fully conditional specification 
FDA 
Food and Drug Administration 
g 
Gram(s) 
GAD 
Generalized anxiety disorder 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
h 
Hour(s) 
HAM-D-17 
17-item-Hamilton Depression Rating Scale 
hCG 
Human chorionic gonadotropin 
HED 
Human equivalent dose 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
LTFU 
Lost to follow up 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MAR 
Missing at random 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean cell volume 
MDD 
Major depressive disorder 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Explanation 
mg 
Milligram(s) 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
min 
Minutes 
MINI 
Mini International Neuropsychiatric Interview 
mITT 
Modified intent-to-treat 
MMRM 
Mixed model for repeated measures 
MNAR 
Missing not at random 
MPV 
Mean platelet volume 
MVN 
Multivariate normal distribution 
NAD+ 
Nicotinamide-adenine dinucleotide coenzyme 
ng 
Nanogram(s) 
NONMEM 
Nonlinear mixed effects model 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QA 
Quality assurance 
QIDS-SR  
Quick Inventory of Depressive Symptomology – Self-Report 
Q-LES-Q-SF 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short 
Form 
QTcF 
Corrected QT interval using Fridericia’s formula 
RBC 
Red blood cells 
RDW 
Red cell distribution width 
REML 
Restricted maximum likelihood 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 


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Abbreviation 
Explanation 
SIGH-D 
HAM-D-17 – Structured Interview Guide Version 
SIGMA 
MADRS – Structured Interview Guide Version 
 
 
SOE 
Schedule of Events 
SOPs 
Standard operating procedures 
SUSAR 
Suspected and unexpected serious adverse reaction 
t½  
Terminal phase half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach maximum concentration 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
Vz/F 
Apparent volume of distribution during the terminal phase 
WBC 
White blood cell 
WHO 
World Health Organization 


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2. 
INTRODUCTION 
2.1. 
Major Depressive Disorder 
Major depressive disorder, also known as unipolar or major depression, is characterized by a 
persistent feeling of sadness or a lack of interest in outside stimuli. The unipolar connotes a 
difference between MDD and bipolar depression, which refers to an oscillating state between 
depression and mania. Major depressive disorder is solely focused on the “lows,” or the negative 
emotions and symptoms that are experienced (adapted from Lieber 2020).  Depression is among 
the top public health concerns worldwide, causing significant disability and disease burden. In 
2012, it was estimated that 16 million people were living with depression in the United States. 
The aim of antidepressant therapy is symptom remission or the reinstatement of euthymia—often 
defined as a score ≤7 on the total Hamilton Depression Rating Scale. Response, traditionally 
defined as a ≥50% decrease in the score from Baseline on a depression rating scale (commonly, 
the Hamilton Depression Rating Scale), has proven to be an inadequate goal, as many patients 
meeting the criteria for response will continue to have residual symptoms and functional 
impairments. Moreover, unremitted patients report poorer quality of life and are at a higher risk 
for relapse and recurrence of depression. Specifically, in the Sequenced Treatment Alternatives 
to Relieve Depression (STAR*D) trial—the largest randomized depression study to date—68% 
of responders relapsed within the first year following treatment, compared with 47% of remitters 
who relapsed. In addition, when more treatment steps are needed, lower acute remission rates 
and higher relapse rates are to be expected. Indeed, one third of the STAR*D cohort never 
remitted, even after four consecutive treatment trials. The remission rate was a mere 27.5% in 
Phase 1 treatment with citalopram, based on HAM-D scores, and 32.9% based on the Quick 
Inventory of Depressive Symptomology – Self-Report (QIDS-SR) scores (adapted from Ionescu 
et al., 2015). New antidepressant treatments with new mechanisms of action are needed to treat 
MDD. 
2.2. 
Investigational Product 
 
 
2.2.1. 
 
 
 
 
 
 


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2.2.2. 
Non-clinical Studies 
 
 
 
 
2.2.2.1. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
ere 


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2.2.2.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
2.2.3. 
Clinical Studies 
2.2.3.1. 
SP-624-101 
SP-624 was assessed in a single, oral dose study, SP-624-101.  The doses assessed following an 
overnight fast were 3 mg, 10 mg, and 30 mg.  Additionally, 10 mg was assessed in a food effect 
cohort following an overnight fast and 30 minutes after a high fat meal.  Each cohort in the first 
part of the study (non-food effect) comprised of eight subjects each, of whom six subjects per 


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cohort received single oral doses of SP-624 and two subjects received placebo.  In the food effect 
part of the study, a separate cohort of eight subjects received SP-624 once under fasting 
conditions and once under fed conditions.  
Orally administered SP-624 was well-tolerated after each dose.  
There were no severe AEs, SAEs, deaths, or AEs leading to withdrawal in this study. 
No placebo subjects reported an AE, and three SP-624 subjects reported at least one AE.  One 
subject in the 3 mg dose group reported headache and insomnia, one subject in the 10 mg food 
effect fasted dose group reported headache, and one subject in the 10 mg food effect fed dose 
group reported vessel puncture site pain.  All AEs were assessed as mild in intensity and not 
related to study drug. 
Shifts in laboratory values appeared to be transient, and no patterns of clinical significance were 
observed.  There were no laboratory values in the study that were deemed clinically significant 
by the Principal Investigator (PI).   
There were no apparent patterns of mean change from Baseline in vital signs to suggest any 
effect from SP-624.  There were no clinically relevant changes from Baseline in ECG 
parameters. 
SP-624 displayed linear, dose-proportional PK when dosed following an overnight fast. At all 
dose levels SP-624 appeared to have a distinct absorption profile with some absorption occurring 
over the first two hours followed by a spike to the Cmax.  Geometric mean plasma half-lives 
were similar across dose levels at 7.1, 6.8 and 6.8 hours for the 3, 10 and 30 mg cohorts, 
respectively. Volumes of distribution (Vz/F) were similar between cohorts (175, 230, and 209 
liters) and displayed low inter-subject variability.  Apparent systemic clearance (CL/F) values 
were consistent between cohorts (17.1, 23.6, and 21.4 L/h) with low variability.  
When administered 30 minutes after a high fat meal (10 mg oral dose), plasma exposure to 
SP-624 was unchanged as assessed by area under the curve (AUC), but mean Cmax was 
decreased by approximately 30% and mean tmax was delayed from 2.25 hours to 5.13 hours. 
2.2.3.2. 
SP-624-102 
SP-624 was assessed in a multiple dose study, SP-624-102.  The doses assessed were 3 mg, 
10 mg, and 20 mg.  The 3 and 10 mg doses were orally administered, once daily, for five days.  
The 20 mg dose was orally administered, once daily, for 10 days. Cohorts 1 and 2 (3 mg and 10 
mg) comprised eight subjects each, of whom six received SP-624 and two received 
placebo.  Cohort 3 comprised seven subjects, of whom five received SP-624 and two received 
placebo.   
Orally administered SP-624 was well-tolerated after each dose. No safety concerns were 
identified for electrocardiography, vital signs, safety laboratories or adverse events for any 
cohort of subjects.   
There were no severe AEs, SAEs, deaths, or AEs leading to withdrawal in this study. 
No placebo subjects reported an AE, and five SP-624 subjects reported a total of 12 AEs.  All 
AEs were reported by single subjects.  All AEs were assessed as mild in intensity with the 
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once at mild intensity and once at moderate intensity.  No AEs were assessed as probably related 
to study drug; eight AEs were assessed as possibly related:  pallor (3 mg QD), procedural 
dizziness (3 mg QD), defecation urgency (20 mg QD), diarrhea (20 mg QD), melanocytic nevus 
(20 mg QD), oropharyngeal discomfort (20 mg QD), tongue blistering (20 mg QD), and tongue 
discomfort (20 mg QD). 
AUC and Cmax values increased in proportion to dose during multiple dosing of SP-624 at dose 
levels of 3, 10, and 20 mg per day.  Cmax exceeded predicted efficacious plasma concentrations 
of 3.28 ng/mL at all doses. t½ and CLss/F remained constant as the dose was increased. There 
was little or no accumulation during 5 days of dosing at 3, 10, and 20 mg SP-624 or 10 days of 
dosing at 20 mg SP-624. 
2.3. 
SP-624 Development Plan 
Sirtsei Pharmaceuticals, Inc. plans to investigate the safety and efficacy of SP-624 in this pilot, 
double-blind, placebo controlled, multicenter study in adults with moderate to severe MDD.  The 
study will evaluate the safety and efficacy of a 4-week, multidose regimen of SP-624 versus 
placebo in approximately 300 subjects. 
Pending the efficacy and safety profile observed from this study, additional nonclinical and 
clinical studies will be conducted. 
2.3.1. 
Rationale for Dose 
 
  
 
 
 
 
 
 
 
 
 
 
 
2.3.2. 
Benefit and Risk Assessment 
SP-624 was well tolerated at a dose of 20 mg per day for 10 days in study SP-624-102. There 
were no SAEs, AEs leading to discontinuation, or severe AEs.  There were no changes of 


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concern in clinical laboratory findings, physical exams, vital signs, ECGs, or mental status. 
Steady state Cmax values were well in excess of predicted efficacious concentrations. 
It is concluded that the dose of SP-624 planned in this study, together with the safety monitoring 
procedures, has a low foreseeable risk of inflicting harm or injury to study participants. This is 
the first study of SP-624 in subjects with MDD and the study may provide initial evidence of 
efficacy.  The Sponsor believes that the potential benefit of SP-624 for MDD and good 
tolerability profile supports conduct of this clinical study. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective 
• Evaluate the efficacy of SP-624 administered once-daily for up to 4 weeks 
compared to placebo in the treatment of adults with MDD. 
3.1.2. 
Secondary Objectives 
• Evaluate the safety and tolerability of SP-624 administered once-daily for up to 4 
weeks compared to placebo in the treatment of adults with MDD; and  
• Characterize the population PK of SP-624 in plasma when administered orally to 
subjects with MDD. 
3.2. 
Endpoints 
3.2.1. 
Efficacy Endpoints 
3.2.1.1. 
Primary Endpoint 
• Change from Baseline to Week 4 in MADRS total score 
3.2.1.2. 
Secondary Endpoints  
• Change from Baseline to Weeks 1, 2, and 3 in MADRS total score 
• Change from Baseline to Weeks 1, 2, 3, and 4 in CGI – S total score 
• Change from Baseline to Week 5 and change from Week 4 to Week 5 in MADRS 
total score and CGI-S total score 
• Change from Baseline to Week 2 and Week 4 in the HAM-D-17 total score 
• Change from Baseline to Week 2 and Week 4 in the SDS 
• Change from Baseline to Week 2 and Week 4 in the QIDS-SR  
• Change from Baseline to Week 2 and Week 4 in the Q-LES-Q-SF 
3.2.2. 
Safety Endpoints 
• AEs 
• Clinical safety laboratory tests (serum chemistry [including thyroid function], 
hematology, coagulation, and urinalysis tests) 
• Vital signs (blood pressure, pulse rate, and oral body temperature) 
• Body weight 
• 12-lead ECGs  


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• Physical examinations 
• C-SSRS 
3.2.3. 
Pharmacokinetic Endpoints 
A total of four blood samples will be collected from each subject for the measurement of plasma 
concentrations of SP-624 at the following visits: 
• Visit 2 (Day -1) 
• Visit 3 (Week 1): Pre-Dose 
• Visit 4 (Week 2): Pre-Dose or approximately 2 to 10 hours post-dose (whichever 
is more convenient for the subject) 
• Visit 6 (Week 4): approximately 2 to 10 hours post-dose 
3.2.4. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled study of the safety 
and efficacy of SP-624 in the treatment of adult subjects with MDD as defined by the DSM-5.  
Following the successful completion of a Screening Phase, subjects will be randomized to one of 
two treatment groups in a 1:1 ratio and will receive SP-624 or placebo over a treatment period of 
four weeks (Treatment Group #1: SP-624 20 mg/day; Treatment Group #2: Placebo).  
Approximately 300 subjects (150 per treatment group) will be enrolled into the study.  Each 
subject will complete Screening, Baseline, Treatment, and Follow-up Visits.  
The Schedule of Events (SOE) to be completed for subjects in the study is provided in Table 2. 
An overview of the study schematics is displayed in Figure 1.  Study periods are detailed below. 
4.1.1. 
Screening Period and Baseline Visit  
A Screening period of up to 28 days (Day -28 to Day -2) and a Baseline Visit (Day -1) will 
precede initiation of the Treatment Period.  During the Screening Period, all Screening 
assessments will be completed and any current depression medications will be discontinued.  All 
Screening assessments should be completed before discontinuing any current depression 
medications.  An adequate number of subjects will be screened to ensure the planned number of 
subjects is enrolled (approximately 300 subjects). 
The Screening Period may be extended for extenuating circumstances, such as when additional 
time is needed for medication taper/washout or to repeat laboratory testing, with the approval of 
the medical monitor. 
Subjects who continue to satisfy all entry criteria at the Baseline Visit will be randomized in a 
1:1 ratio to one of two treatment groups (Treatment Group #1: SP-624 20 mg/day; Treatment 
Group #2: placebo).  At the completion of the Baseline Visit, randomized subjects will be 
dispensed study drug and will be instructed to begin dosing the next morning (Day 1). 
4.1.2. 
Treatment and Follow-up Periods 
Subjects will be scheduled to return to the clinic for safety and efficacy assessments at the end of 
Weeks 1, 2, 3, 4, and 5 as specified in the SOE (Table 2).  After the final dose of study drug, 
subjects will complete a Follow-up Period of two weeks and will return at the end of Weeks 5 
and 6.  Subjects may be treated with anti-depressant medications according to physician 
recommendations after completion of the Week 5 Visit unless a clinically significant lab value is 
identified at the Week 4 Visit.  If a clinically significant lab value is identified at the Week 4 
Visit, consult with the Medical Monitor to determine if the lab value needs to be followed prior 
to initiating new therapy.   
Unless there are any outstanding safety issues that require follow-up, subjects will be discharged 
from the study at the Week 6 Visit. 
 


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Figure 1: 
Study Schematic  
 
 


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4.2. 
Randomization and Blinding 
4.2.1. 
Subject Identification and Randomization to Treatment 
A unique subject identification number (sometimes referred to as the Screening number and 
different from the randomization number) should be assigned to each subject who signs an 
informed consent form (ICF). The subject identification number should be used on all case report 
forms (CRFs) and in all correspondence between sites, the Sponsor, Institutional Review Boards 
(IRBs), and the Food and Drug Administration (FDA).    
Sirtsei Pharmaceuticals or designee will generate a randomization scheme with appropriate 
blocking.  Randomization numbers will be 3 digits starting with 101.  When the decision is made 
to randomize a subject to treatment, the Investigator should pick the next available 
randomization number from the study drug kits assigned to the site.  The subject randomization 
number will be recorded in the CRF, linking the subject’s unique subject identification number 
to the subject’s assigned randomization number. 
4.2.2. 
Blinding 
The study will be conducted under double-blind conditions, meaning the Investigator, study 
center personnel, study subjects, and Sponsor will be unaware of the treatment assignment for 
the subjects.   
4.2.3. 
Emergency Unblinding 
If an emergency situation occurs that, in the Investigator's opinion, cannot be adequately treated 
without knowing the identity of the study medication, the study treatment assignment can be 
unblinded via the tamper-evident covered disclosure panel attached to the study drug kit.   
Every effort will be made to contact the Sponsor Medical Monitor prior to breaking the blind.  If 
this is not possible and the situation is an emergency, the Investigator may break the blind for 
only the subject(s) involved in the emergency situation and must contact the Sponsor Medical 
Monitor as soon as possible (see Table 1 for Medical Monitor contact information).   
In any case of emergency unblinding, pertinent information including the date and reasons for 
breaking the blind must be documented in the subject CRF and in the site and Sponsor study 
files. 
4.3. 
Study Centers and Personnel 
The study will be conducted at approximately 40 investigative sites located in the United States. 
The PI at each site will be a licensed physician or clinical psychologist experienced in 
conducting studies in MDD.  For those sites where a clinical psychologist is the PI, one of the 
sub-Investigators must be a licensed physician. The PI will be responsible for delegating study 
responsibilities to only those key site personnel who have the appropriate level of education, 
training and experience, including medical expertise and good clinical practice (GCP) training, 
as applicable for their assigned role in the study. 
The clinical research facility at each investigative site will have adequate facilities and 
equipment to conduct the study procedures, and to allow for close supervision of study subjects, 


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including immediate access to equipment and appropriately qualified staff to respond in the case 
of an acute medical emergency. 
4.4. 
Number of Subjects 
Approximately 300 adult subjects with MDD as defined by DSM-5 will be enrolled with 
approximately 150 subjects per treatment group. 
4.5. 
Study Duration 
Subjects will receive double-blind treatment for up to 4 weeks, following a Screening/washout 
period of up to 28 days.  After the treatment period, subjects will complete a 2-week follow-up 
period.  The planned study duration for each subject will be approximately 70 days. 


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5. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. 
Subject Recruitment, Enrollment, and Identification 
Subject recruitment and enrollment will be organized and overseen by the Investigator at the site 
following approval of the study protocol, ICF, and any study specific advertisements/recruitment 
materials by the respective IRB. 
Subjects will be recruited via advertisements, physician referral, and from databases kept by the 
research center. 
A sufficient number of subjects will be screened in order to ensure that a total of approximately 
300 subjects who satisfy the entry criteria are randomized to treatment. 
Each subject’s signed and dated ICF to participate in the study must be obtained before 
conducting any study-related procedures.   All subjects who sign an ICF will be given a unique 
Screening identification number and their study status will be tracked on a study Screening and 
Enrollment log maintained in the Investigator study files. 
5.2. 
Subject Inclusion Criteria 
To be eligible for this study, subjects must meet all of the following inclusion criteria. 
1. Willing and able to provide written informed consent to participate in the study.  
2. Males and females, aged 18 to 65 years, inclusive. 
3. In generally good physical health, in the opinion of the Investigator. 
4. Body mass index must be ≥ 18 and ≤ 40 kg/m2   
5. Females of reproductive potential and males with partners of reproductive potential must 
agree to remain abstinent or use adequate and reliable contraception throughout the study 
and for at least 30 days after the last dose of study drug. 
a. Adequate contraception is defined as continuous use of double-barrier method (e.g., 
condom and spermicide or diaphragm and spermicide), oral contraceptive, implant, 
dermal contraception, long-term injectable contraceptive, or intrauterine device. 
b. Non-reproductive potential is defined as surgically sterile, undergone tubal ligation or 
vasectomy, or postmenopausal (defined as at least 12 months of spontaneous 
amenorrhea).   
c. Subjects of reproductive potential but whose sole partner is of non-reproductive 
potential, or whose sole partner is of the same sex, are not required to maintain 
abstinence or contraception.  
d. Subjects must agree to refrain from sperm and oocyte donation for at least 90 days 
after the last dose of study drug.  
6. Meets DSM-5 criteria for moderate to severe MDD, as confirmed by the MINI.  Subjects 
with a diagnosis of co-morbid GAD may be included if MDD is the primary diagnosis. 
7. Montgomery-Asberg Depression Rating Scale total score ≥ 27 at both Screening and 
Baseline.   


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8. History of inadequate or non-response to at least one adequate treatment, but no more 
than three of the same class of antidepressant, (i.e., an adequate dose for at least six 
weeks) for the current episode, in the opinion of the Investigator. NOTE: If immediately 
prior to this episode starting, treatment was working to the point of remission, but then 
the depression worsened, subject should not be enrolled. For example, subject should not 
have been on an antidepressant and in remission prior to the start of the current episode.  
9. Willing and able to comply with the study design schedule and other requirements. 
5.3. 
Subject Exclusion Criteria 
A subject who meets any of the following exclusion criteria will not be enrolled in the study: 
1. Female who is pregnant, breastfeeding, or less than six months postpartum at Screening. 
2. History or presence of major bowel resection, total gastrectomy, or diabetes, and/or 
history or presence of any clinically significant medical condition, disease, or surgical 
history that could, in the opinion of the Investigator, jeopardize the safety of the subject 
or validity of the study data, or interfere with the absorption, distribution, metabolism, or 
excretion of the study drug.  
3. A current DSM-5 diagnosis of depression with peripartum onset, panic disorder, 
obsessive compulsive disorder, post-traumatic stress disorder, anorexia nervosa, or 
bulimia nervosa. 
4. A history of or current DSM-5 diagnosis of MDD with psychotic features, any 
schizophrenia spectrum and other psychotic disorders, bipolar disorder, or personality 
disorder.   
5. History of treatment with ECT, vagus nerve stimulation, deep brain stimulation, or 
transcranial magnetic stimulation within six months of Screening.  
6. Current episode of depression exceeds 2 years or is less than six weeks from Screening. 
7. History of inadequate or non-response, in the opinion of the Investigator, to an adequate 
treatment regimen of two or more classes of antidepressants during the current episode.   
8. Subjects treated with an antipsychotic during the current episode should be excluded.  
9. Subjects who meet DSM-5 criteria for moderate or severe substance use disorder for any 
substance except nicotine or caffeine, within 12 months of Screening.  Subjects with a 
urine drug screen positive for suspected substance of abuse will be excluded. Urine drug 
screen positive for cannabinoids is not exclusionary if the subject does not meet criteria 
for moderate or severe substance use disorder.  
10. Will require initiation of psychotherapy during the study period, in the Investigator’s 
opinion.  If a subject has been in ongoing psychotherapy for a minimum of three months, 
the therapy may continue if it remains unchanged. Cognitive behavioral therapy is 
excluded. 
11. Poses a current or future suicidal risk, in the Investigator’s opinion, or has a history of 
suicidal behavior within the past 12 months, and/or subject answers “yes” to “Suicidal 
Ideation” Item 4 (active suicidal ideation with some intent to act, without specific plan) 


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or Item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS 
assessment during the six months prior to the Screening period and/or at Baseline. 
12. Failure to discontinue all psychoactive medications or psychoactive supplements 
including antidepressants and mood stabilizers, within a time period prior to Baseline 
corresponding to at least five half-lives of the medication in question.   
13. Presence of a clinically significant abnormality on physical examination or ECG, 
including a QTcF >450 msec for males and >470 msec for females.  Note: ECG may be 
repeated once at both Screening and Baseline for confirmatory purposes. 
14. Presence or history of any known clinically significant cardiovascular disorders 
including, but not limited to: coronary artery disease, heart failure, valvular heart disease, 
cardiomyopathies, myocardial infarction, chamber enlargement or hypertrophy, or 
orthostatic hypotension. 
15. Presence of uncontrolled hypertension, defined as consistent SBP >160 mmHg or 
consistent DBP >95 mmHg despite present therapy.  Note: Blood pressure measurements 
may be repeated twice at both Screening and Baseline for confirmatory purposes. 
16. Screening laboratory value(s) outside the laboratory reference range that are considered 
to be clinically significant by the Investigator (clinical chemistry, hematology, 
coagulation, and urinalysis). Note: Screening labs may be repeated once for confirmatory 
purposes. 
17. Screening liver function tests (ALT, AST, Alkaline phosphatase) > 2x the upper limit of 
normal. 
18. Known history of current or chronic Hepatitis B or Hepatitis C infection, or a known 
history of HIV infection.  Subjects with a history of treated Hepatitis C infection where 
liver function tests are within normal limits may participate. 
19. Subjects with a history of seizures or seizure disorder. 
Note:  Subjects with a history of only febrile seizures, limited to up to two episodes, are 
permitted. 
20. Clinically significant acute infection, other than mild viral or bacterial infections from 
which the subject has fully recovered (e.g., common cold, localized skin infection, etc.), 
within the two weeks prior to Baseline. 
21. Major trauma or surgery in the 12 weeks prior to Screening or at any time between 
Screening and randomization. 
22. Presence or history of malignancy within the last five years.  Note: History of adequately 
treated basal cell or squamous cell carcinoma of the skin or in situ cervical cancer is 
allowed. 
23. History of an anaphylactic allergic reaction to previous medication.  
24. Blood or plasma donation within 30 days of randomization, or planned donations or 
elective surgery during the study or during the 60 days following the study. 
25. Subjects who, in the opinion of the Investigator, are not suitable candidates for the study. 


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26. Individuals who are currently enrolled in or have participated in a clinical trial (i.e., 
received study drug) involving an investigational product within 60 days or within five 
half-lives of the investigational product (whichever is longer) prior to Baseline. 
5.4. 
Subject Withdrawal from the Study 
A subject may be withdrawn from the study at any time at the discretion of the Investigator. 
Justifiable reasons to discontinue a subject from the study may include, but are not limited to, 
safety, ability or willingness to comply with conditions of the protocol, withdrawal of consent, 
lost to follow-up, Investigator discretion, Sponsor decision, or premature termination of the 
study. 
The reason(s) for premature discontinuation will be documented on the subject’s CRF. 
Any AEs or SAEs that lead to study discontinuation should be followed as appropriate until the 
AE has resolved or stabilized (in the opinion of the Investigator and Sponsor Medical Monitor). 
Subjects who prematurely discontinue after receiving a dose of study drug, should continue to be 
followed for scheduled safety assessments according to the SOE (Table 2), if possible.  At a 
minimum, every attempt should be made to complete the Week 4 / Premature Discontinuation 
procedures; however, subjects are free to withdraw consent from participation in the study at any 
time, without prejudice to their medical care. 
If a subject is lost to follow-up (i.e., fails to return for study visits), all reasonable efforts should 
be made to contact the subject and complete the Week 4 / Premature Discontinuation procedures. 
Should it be discovered after a subject has begun study treatment that the subject did not meet all 
inclusion and exclusion criteria, or if during the study a subject ceases to meet all inclusion and 
exclusion criteria, the subject’s continued participation in the study will be discussed with the 
Medical Monitor.   
5.5. 
Premature Termination of the Study 
If the study is prematurely terminated, written notification, documenting the reason for study 
termination, will be promptly provided by the Sponsor to the regulatory authorities.  The 
Investigator will be responsible for informing the IRB. 
The Sponsor reserves the right to terminate the study for any reason at any time. 


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6. 
STUDY TREATMENTS, MATERIALS, AND MANAGEMENT 
6.1. 
Description of Study Drug 
The study drug code name is SP-624.  SP-624 is 
 
intended for the treatment of MDD.  
The clinical trial material for this study will consist of capsules, each containing 10 mg of 
SP-624 API.  Matching placebo capsules identical in shape and color to the active capsules will 
also be used.   
6.2. 
Acquisition of Study Drug Supplies 
After the research site has submitted all approved regulatory and study start-up documents, the 
Sponsor will initiate a requisition for an initial shipment of study kits to be delivered to the site 
via the Sponsor’s distribution facility. 
All manufacturing, packaging, and labeling operations for the supplied study drug materials will 
be performed according to Good Manufacturing Practice (GMP) and GCP guidelines, as well as 
local regulations. 
Storage and retest information will be provided for all supplied materials. 
Upon receipt of the materials, the Investigator or designee will examine the package container, 
labeling, and appearance of the packaged materials to confirm the packaged materials were 
received in good condition. 
All study materials will be stored at the study site in a restricted-access, securely locked area, 
under controlled temperature and humidity conditions in accordance with the manufacturer’s 
instructions (see Section 6.7). 
6.3. 
Subject Treatment Assignment 
When the decision is made to randomize a subject, the Investigator should pick the next 
randomization number from the study drug kits assigned to the site.  The subject randomization 
number will be recorded in the CRF. 
6.4. 
Study Drug Administration 
Each dose of SP-624 will be supplied as two capsules, each containing 10 mg of API.  Matching 
placebo capsules identical in shape and color to the active capsules will also be used.  Following 
successful completion of the Baseline Visit, subjects will be randomized in a 1:1 ratio to one of 
two treatment groups:   
• Treatment Group #1: Two 10 mg capsules SP-624 each morning for 4 weeks 
• Treatment Group #2: Two capsules placebo each morning for 4 weeks 
Each study drug dose should be taken orally, once daily at approximately the same time each 
morning.  Study drug doses should be taken on an empty stomach before breakfast, and no food 
should be consumed for at least 1 hour after dosing.  High fat foods at breakfast (e.g., bacon, 


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cheese, eggs, etc.) should be avoided.  Morning liquids such as coffee or tea are allowed without 
any additives (eg, cream, sugar, etc).  
If dosing on an empty stomach is not practical or not well tolerated, then a low fat, low calorie 
breakfast 2 hours before dosing, or 30-60 minutes after dosing, is acceptable.  If dosing remains 
not well tolerated, then subjects should dose 30 minutes after a low fat, low calorie meal. 
Study drug will be packaged in subject kits and each kit will contain four weekly blister cards 
with each card containing 20 capsules of study drug (two capsules per dose for seven days of 
dosing, plus three extra days of dosing as a provision for study visit scheduling).  Each subject 
kit will be labeled with a 3-part label that specifies the randomization number, cautionary 
statement, and storage conditions.  Each blister card will have a one-part label that specifies the 
randomization number, week, number of capsules, cautionary statement, and storage conditions.   
Study drug will be dispensed as follows: 
• Baseline Visit – one blister card for Week 1 
• Week 1 Visit – one blister card for Week 2 
• Week 2 Visit – one blister card for Week 3 
• Week 3 Visit – one blister card for Week 4 
Subjects will be instructed to return study drug at the Week 1, Week, 2, Week 3, and Week 4 (or 
Premature Discontinuation) Visits.   
If the two capsule dose, is not well tolerated, the dose can be decreased to one capsule per dose 
after Week 1.    
6.5. 
Treatment Compliance 
Study drug accountability will be recorded by study site staff, and any deviations from the 
administration instructions or dosing schedule will be entered into the subject's CRF. 
6.6. 
Study Drug Accountability 
The Investigator (or designee) is responsible for the accountability, reconciliation, and record 
maintenance of all study drug receipt, use, and disposition.  In accordance with all applicable 
regulatory requirements, the Investigator or designated study personnel must maintain study drug 
accountability and storage records throughout the study.  Unused drug will be returned to the 
investigative site and to the Sponsor or designee at the end of the study for destruction.  No study 
drug usage outside the protocol will be allowed. 
When a kit is assigned to a subject, the Investigator will tear off a 2 part segment of the label that 
contains a tamper-evident covered disclosure panel to be used for unblinding in case of 
emergency and affix the 2-part segment to the drug dispensing record.  The drug dispensing 
record will be collected for the sponsor’s files at the end of the study.  This will serve to connect 
the unique randomization number to the unique subject identification number assigned at 
Screening. 


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6.7. 
Study Drug Storage and Stability 
All study materials will be stored at the study site in a restricted-access, securely locked area, 
under controlled temperature and humidity conditions in accordance with the manufacturer’s 
instructions. 
The storage conditions for the study drug will be indicated on the label.   
All supplied study drug materials will be stored at the study site in a restricted-access, securely 
locked area at the long-term refrigerated storage condition, 2-8oC.  After a study drug kit has 
been assigned to a subject, the study drug kit and weekly blister cards dispensed to study subjects 
may be stored under room temperature conditions, 25°C (77°F), with excursions permitted 
between 15°C and 30°C (59°F-86°F). 
In the solid state, the SP-624 drug substance is stable for at least 18 months when stored at 5oC 
and for at least 6 months when stored at 25oC/60% relative humidity.   
SP-624 drug product stability is expected to directly correlate with that of the drug substance, 
since the drug product is neat drug substance filled into capsules.  A 24-month stability program 
will be initiated for these capsules once manufacturing is completed, with storage conditions at 
2-8oC and 25oC/60% relative humidity.  Retest date information for the study drug will be 
provided. 
At the Week 1, Week 2, Week 3, and Week 4 Visits, subjects will return the previously used 
blister cards, including any unused study drug.  The used study drug kits will be maintained at 
the site under room temperature storage conditions until returned to the Sponsor or designee. 
6.8. 
Prior and Concomitant Medications 
Medications taken within 28 days before Day 1 will be documented as prior medications.  
Medications taken any time on or after Day 1 and until completion of the Week 4 / Premature 
Discontinuation Visit will be documented as concomitant medications.  Medications that started 
after the date of the last dose of study drug will not be considered concomitant but will be 
considered post-treatment. 
The use of all prior, concomitant, and post-treatment medications will be recorded in the 
subject’s CRF, including the drug name, dose, route of administration, dates of administration, 
and indication. 
Once all Screening assessments have been completed, any current psychoactive medications and 
supplements must be discontinued.  Subjects should consult with the Investigator before taking 
any medications, including over-the-counter products.  
Subjects may be treated with anti-depressant medications according to physician 
recommendations after completion of the Week 5 Visit unless a clinically significant lab value is 
identified at the Week 4 Visit.  If a clinically significant lab value is identified at the Week 4 
Visit, consult with the Medical Monitor to determine if the lab value needs to be followed prior 
to initiating new therapy.   
Previous medications for medical, non-psychiatric illnesses, as well as oral contraceptives and 
contraceptive devices, are permitted. 


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Medications such as non-steroidal anti-inflammatories, antacids, and non-psychoactive allergy 
medications, may be given at the discretion of the Investigator. 
A list of restricted and prohibited medications is included in Table 4: 
Table 4: 
Restricted and Prohibited Medications 
Medication Class 
Examples1 
Comment 
Antidepressants 
Trazodone  
TCAs 
SSRIs 
SNRIs 
MAOIs 
All prohibited 
Any anti-depressants being taken at the time of Screen 
must be discontinued within a time period prior to 
Baseline corresponding to at least five half-lives of the 
medication in question. 
Antipsychotics  
Aripiprazole 
Brexpiprazole 
Haloperidol 
Olanzapine 
Risperidone 
All prohibited  
If an antipsychotic was used to treat the current episode of 
depression, the subject should be excluded. 
Anxiolytics 
Benzodiazepines 
Restricted 
Subjects on a stable dose of lorazepam (2 mg/day), or 
equivalent dose of another benzodiazepine (e.g., diazepam 
15 mg), for anxiety at the time of Screening may continue 
with the current treatment regimen.  The dose should 
remain consistent throughout the study.  
 
Should a benzodiazepine be required for increased anxiety 
during the study in a subject who had not been taking a 
consistent dose prior to Screening, lorazepam 2 mg/day, or 
an equivalent dose of another benzodiazepine (e.g., 
diazepam 15 mg), is limited to two days or less per week. 
Use the night before or the day of a study visit (prior to 
the visit) is prohibited.  Any need to exceed this amount 
must be discussed with the Medical Monitor. 
Hypnotics 
Zolpidem 
Temazepam 
Sedating 
antihistamines 
 
Restricted 
Zolpidem being taken daily for sleep at the time of the 
Screening visit is permitted for severe insomnia.  The dose 
should remain consistent throughout the study.  
 
If zolpidem is being taken as needed at the time of 
Screening, use is limited to three nights or less per week 
and use the night before a study visit is prohibited.  
 
Prohibited 
All other hypnotics 


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Medication Class 
Examples1 
Comment 
Mood stabilizers 
and anticonvulsants 
Lithium 
Valproate 
Lamotrigine 
Gabapentin 
All prohibited 
Any mood stabilizers or anticonvulsants being taken at the 
time of Screening must be discontinued within a time 
period prior to Baseline corresponding to at least five half-
lives of the medication in question. 
Muscle relaxers 
Carisoprodol 
Cyclobenzaprine 
Metaxalone 
Baclofen 
Restricted 
Use of muscle relaxants during the study is limited to 
episodic use for an acute situation (e.g., back injury during 
the study) and must be discussed with the Medical 
Monitor. 
Opioid analgesics 
Oxycodone 
Morphine 
Tramadol 
Codeine 
Restricted 
Use of opioids during the study is limited to episodic use 
for an acute situation (e.g., back injury during the study) 
and must be discussed with the Medical Monitor. 
Stimulants 
Amphetamine 
Dextroamphetami
ne 
Pemoline 
Methylphenidate 
All prohibited 
Any stimulants being taken at the time of Screening must 
be discontinued within a time period prior to Baseline 
corresponding to at least five half-lives of the medication 
in question. 
Herbal and 
nutritional 
supplements 
St. John’s Wort 
Ginkgo Biloba 
S-Adenosyl 
methionine 
(SAM-e) 
Omega-3 
supplements 
Cannabidiol 
products 
Melatonin 
Restricted 
Only multivitamins that do not contain any of the example 
ingredients are allowed during the study.  
1 Medications including, but not limited to, examples provided. 
 
 


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7. 
STUDY PROCEDURES AND ASSESSMENTS 
7.1. 
Schedule of Events 
The SOE for participants in the study is provided in Table 2. 
The actual dates of study drug administration and all study visits and assessments will be 
recorded in the subject’s CRF.  If a study visit or assessment occurs outside the specified time 
point and allowed time window (if applicable), then the reason for the deviation will be noted.  
Every attempt should be made to ensure that subsequent visits and assessments are performed 
on-time. 
The Screening Period may be extended for extenuating circumstances, such as when additional 
time is needed for medication taper/washout or to repeat laboratory testing, with the approval of 
the medical monitor. 
Study visits during the Treatment Period can be scheduled within a ± 3 day window relative to 
the Baseline Visit (i.e., the Week 1 Visit can be scheduled 7 ± 3 days relative to the completion 
of the Baseline Visit, the Week 2 Visit can be scheduled 14 ± 3 days relative to the completion of 
the Baseline Visit, the Week 3 Visit can be scheduled 21 ± 3 days relative to the completion of 
the Baseline Visit, etc.).   
The Week 5 Visit can be scheduled 7 ± 3 days relative to the Week 4 / Premature 
Discontinuation Visit and the Week 6 Visit can be scheduled 14 ± 3 days relative to the Week 4 / 
Premature Discontinuation Visit. 
Whenever ECGs, vital signs, and a blood draw for PK and/or safety labs are scheduled on a 
given day, the ECG and vital signs should be completed in the sequence of procedures either 
prior to the blood draw (preferred) or after the blood draw, such that the blood draw does not 
interfere with the ECG and vital sign recordings.   
In addition to the study visits and assessments described in the SOE, unscheduled 
visits/assessments may be performed or repeated at the discretion of the Investigator if required 
to further evaluate laboratory parameters or the subject’s clinical safety. 
7.2. 
Study-Specific Procedures 
7.2.1. 
Informed Consent 
The Investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject prior to performing any 
study-related Screening procedures.  Once written informed consent is obtained, prospective 
subjects will be screened for eligibility into the study based on the inclusion and exclusion 
criteria detailed in Section 5. 
7.2.2. 
Demographic Information, Medical History/Current Medical Conditions, and 
Treatment History 
Demographic information (e.g., date of birth, sex, race, ethnicity) will be collected and a detailed 
medical history, including review of past and ongoing medical conditions or procedures will be 


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obtained during the Screening Period as specified in the SOE (Table 2).  Additionally, treatment 
history for the current depressive episode will also be collected. 
7.2.3. 
Mini International Neuropsychiatric Interview 
Subjects must meet DSM-5 criteria for moderate to severe MDD, as confirmed by the MINI 
(Sheehan et. al, 1998). Subjects with a diagnosis of co-morbid GAD may be included if MDD is 
the primary diagnosis.  The MINI should only be completed by Sponsor approved raters.  Raters 
will be approved by the Sponsor based on education and experience conducting the MINI in 
subjects with MDD.   
Current DSM-5 diagnoses of depression with peripartum onset, panic disorder, obsessive 
compulsive disorder, post-traumatic stress disorder, anorexia nervosa, or bulimia nervosa are 
exclusionary. 
A history of or current DSM-5 diagnosis of MDD with psychotic features, any schizophrenia 
spectrum and other psychotic disorders, bipolar disorder, or personality disorder are 
exclusionary.   
7.2.4. 
Assessment of Efficacy 
Efficacy assessments will be conducted by individuals with sufficient experience conducting the 
below rating scales who have received centralized rater training and have been approved by the 
PI and Sponsor.  Whenever possible, the same rater should assess the same subject throughout 
the study. 
The schedule of these safety assessments is provided in the SOE (Table 2), and the study-specific 
procedures for completion of these assessments are detailed below. 
Assessments should not be performed on subjects who have missed two or more consecutive 
study drug doses immediately before the Week 1, Week 2, Week 3, or Week 4 / Premature 
Discontinuation visits. 
7.2.4.1. 
Montgomery-Asberg Depression Rating Scale 
Efficacy will be assessed using the MADRS – Structured Interview Guide Version (SIGMA) 
(Appendix A).  The MADRS is a 10-item depression rating scale.  The MADRS will be 
completed at study visits as specified in the SOE (Table 2).  In order to qualify for the study, 
subjects must have a MADRS total score ≥ 27 at both Screening and Baseline.   
7.2.4.2. 
Clinical Global Impression – Severity  
The CGI-S is completed by the Investigator and measures the severity of illness (Appendix B).  
The CGI-S is used to rate subjects on a 7-point scale ranging from “Normal” to “Among the 
most extremely ill patients.”. 
7.2.4.3. 
Hamilton-Depression Rating Scale (17-item) 
The Hamilton-Depression Rating Scale is a 17-item depression rating scale (Appendix C).  The 
HAM-D-17 – Structured Interview Guide Version (SIGH-D) will be completed at study visits as 
specified in the SOE (Table 2). 


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7.2.4.4. 
Sheehan Disability Scale 
The SDS is a brief, subject-completed questionnaire that assesses functional impairment in 
work/school, social life, and family life/home responsibilities (Appendix D).     
7.2.4.5. 
Quick Inventory of Depressive Symptomology – Self Report  
The QIDS-SR is a subject-completed 16-item depression rating scale (Appendix E).     
7.2.4.6. 
Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form  
The Q-LES-Q-SF is a subject-completed 16-item questionnaire that assesses life satisfaction 
over the past week (Appendix F).  Each question is rated on a 5-point scale from 1 (Very Poor) 
to 5 (Very Good).   
7.2.5. 
Assessment of Safety  
Each subject will be closely monitored for safety throughout their study participation.  Study-
specific safety assessments will include the following: 
• Physical examinations 
• Vital signs (blood pressure, pulse rate, and oral body temperature) 
• Body weight 
• 12-lead ECGs  
• Clinical safety laboratory tests (serum chemistry [including thyroid function], 
hematology, coagulation, and urinalysis tests) 
• C-SSRS 
• AEs 
The schedule of these safety assessments is provided in the SOE (Table 2), and the study-specific 
procedures for completion of these assessments are detailed below. 
7.2.5.1. 
Physical Examination 
Physical examinations will be performed as specified in the SOE (Table 2). 
Physical examinations will include a review of the following body systems:  general appearance, 
skin and extremities, ears/eyes/nose/throat, head/neck, heart/chest, abdomen, musculoskeletal, 
and neurological.  
Clinically significant findings on the Screening and Baseline physical examination will be 
evaluated to confirm the subject remains eligible for study participation.  New clinically 
significant abnormalities or exacerbations that occur after the Screening visit will be captured as 
AEs. 


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7.2.5.2. 
Vital Signs, Height, and Weight Measurements 
Vital sign measurements will be taken at the time points specified in the SOE (Table 2).  Height 
will be measured (in centimeters) at Screen only; weight (in kilograms) will be measured at 
Screen and all other scheduled time points indicated in the SOE (Table 2). 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, and oral 
body temperature. 
At each timepoint, vital signs will be assessed with the subject in the sitting position after 
approximately three minutes or more of quiet sitting.   
Abnormal vital signs may be repeated twice for confirmatory purposes.  Confirmed abnormal 
vital signs will be further categorized as clinically significant or not clinically significant by the 
Investigator based on his/her clinical judgement. 
Subjects with confirmed clinically significant abnormal vital signs at the Screening or Baseline 
Visits should be excluded from the study.  New clinically significant abnormalities or 
exacerbations that occur after the Screening Visit will be captured as AEs. 
7.2.5.3. 
12-lead Electrocardiograms 
A 12-lead ECG will be obtained at the study site during the time points specified in the SOE 
(Table 2) using an ECG machine provided by the central ECG monitoring vendor.  The central 
ECG vendor will supply the ECG quantitative and qualitative data. The ECG will be reviewed by 
medically qualified site personnel.  The Investigator will review the ECG report for 
abnormalities and/or clinically significant changes from previous readings.   
ECGs will be performed only after the subject is positioned supine, resting, and quiet for a 
minimum of three minutes.  
Subjects with clinically significant abnormal ECG findings at the Screening or Baseline Visits 
should be excluded from the study as specified in the study inclusion/exclusion criteria 
(Section 5.2 and Section 5.3). Criteria for reporting abnormal ECG findings as AEs are provided 
in Section 8.1.1. 
 ECGs may be repeated once at both Screening and Baseline for confirmatory purposes. 
The following quantitative ECG data will be recorded:  heart rate (bpm), PR interval (msec), 
QRS duration (msec), QT interval (msec), and QTcF interval (msec).  
The following qualitative ECG data will be documented:  Overall interpretation (normal or 
abnormal) and if abnormal, comment describing the abnormality.  Abnormal ECG results will be 
further categorized as clinically significant or not clinically significant by the Investigator.   
7.2.5.4. 
Pregnancy Test 
A serum pregnancy test for all females will be performed as indicated in the SOE (Table 2).  A 
serum pregnancy test is required at the Screening and Week 4 / Premature Discontinuation Visit. 
A urine pregnancy test is to be performed at Day -1 as indicated in the SOE.  If the urine 
pregnancy test at Day -1 is positive, a confirmatory serum pregnancy test will be conducted.  If 
pregnancy is confirmed, the subject will be excluded from the study. If the urine pregnancy test 
is positive, randomization should be postponed until serum pregnancy test results can be 


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obtained and pregnancy definitively ruled-out.  Any occurrence of pregnancy exposure 
(i.e., pregnancy in a female subject or the female partner of a male subject who has received 
study drug) must be reported to the Sponsor as summarized in Section 8.1.6. 
7.2.5.5. 
Clinical Safety Laboratory Assessments 
Blood samples for clinical safety laboratory tests will be collected as indicated in the SOE 
(Table 2) and analyzed at an accredited central laboratory approved by the Sponsor.  The Clinical 
Laboratory Manual should be referenced for specific procedures with regards to sample 
collection, handling, labeling, storage, and shipping. 
Clinical safety laboratory tests will include the following laboratory test panels:  serum 
chemistry (including thyroid function), hematology, coagulation, and urinalysis. 
A summary of the analytes included in each test panel is provided in Table 5. 
Any value outside of the current reference ranges for the laboratory performing the test will be 
flagged on the laboratory results report.  
Laboratory tests showing abnormal or exclusionary values at Screening may be repeated no more 
than once.  After dose administration, abnormal laboratory test results may be repeated as often 
as deemed clinically necessary by the Investigator until the test values return to clinically 
acceptable limits or until an explanation other than drug effect is given. 
Laboratory test results will be assessed in accordance with the reference ranges provided by the 
clinical laboratory.  Abnormal laboratory results will be further categorized as clinically 
significant or not clinically significant by the Investigator.  Subjects with clinically significant 
abnormal lab results at the Screening Visit should be excluded from the study.  If subjects 
present with clinically significant lab results collected at the Baseline Visit, continued subject 
participation should be discussed with the Medical Monitor.  New clinically significant 
abnormalities or exacerbations that occur after the Screening Visit will be captured as AEs. 
An estimation of the total blood collection volume per subject is provided in Section 7.2.5.6 and 
Table 6. 
7.2.5.6. 
Blood Volume Collection Summary 
An estimation of the total blood collection volume per subject required for the Screening, 
Baseline, Treatment Period, and Follow-up Period, is provided in Table 6. 
• A total of approximately 139.0 mL (about ½ of a cup) of blood is estimated to be 
drawn from subjects in the study over a period of about 70 days (depending on the 
length of the Screening period). 
 


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Table 5: 
Clinical Safety Laboratory Analytes 
Thyroid Function 
Fasting Serum Chemistry1 
Hematology 
Urinalysis2 
Urine Drug Test 
TSH 
T3 – Screen only 
T4 – Screen only 
Albumin 
Alkaline Phosphatase 
ALT 
AST 
BUN 
Calcium 
Chloride 
CO2  
Creatinine 
eGFR3 
GGT 
Glucose 
LDH 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total Bilirubin; if 
elevated obtain Direct 
Bilirubin 
Total Protein 
Uric Acid 
Total Cholesterol 
HDL Cholesterol 
LDL Cholesterol 
Triglycerides  
Creatine Phosphokinase 
Serum βhCG (all 
females)4 
RBC (Erythrocyte) 
Count 
Hemoglobin 
Hematocrit 
Platelet Count 
WBC Count with 
differential (Absolute 
and %: Basophils, 
Eosinophils, 
Lymphocytes, 
Monocytes, and 
Neutrophils) 
MCV 
MCH 
MCHC 
RDW 
MPV 
Reticulocyte Count 
(Absolute and %) 
pH 
Blood/ RBCs 
Protein 
Glucose 
Ketones 
Bilirubin 
Color 
Leukocytes or WBCs 
Nitrite 
Specific Gravity 
Urobilinogen 
Microscopic Exam 
Urine βhCG (all 
females)5 
Amphetamines  
Barbiturates  
Cannabinoids 
Benzodiazepines 
Methadone 
Opiates 
Cocaine 
Phencyclidine 
 
 
Coagulation 
PT 
PTT 
INR 
 
1 All protocol scheduled Serum Chemistry samples should be collected with the subject in a fasting state (i.e., no food for a minimum of eight hours prior to sample 
collection).  
2 If urine is positive for blood, leukocyte esterase, nitrite, or protein, then will default to reflex microtesting. 
3 Cockcroft-Gault Method of calculation – subject weight is required for calculation 
4 Serum pregnancy test at Screen and Week 4/Premature D/C 
5 Urine pregnancy test at the Baseline Visit 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CBC=complete blood count; CO2=carbon dioxide or bicarbonate; 
eGFR=estimated glomerular filtration rate; GGT=gamma glutamyl transferase; hCG= human chorionic gonadotropin; HDL=high density lipoprotein; LDH=lactate 
dehydrogenase; LDL=low density lipoprotein; MCH=mean corpuscular hemoglobin; MCHC=MCH Concentration; MCV=mean cell volume; MPV=mean platelet 
volume; Premature D/C=Premature Discontinuation from treatment; PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood cell; RDW=RBC 
distribution width; TSH=thyroid stimulating hormone; WBC=white blood cell 
 


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Table 6: 
Estimation of Blood Volumes Required from Screening through the End of 
the Follow-up Period 
Tests 
Estimated 
Blood 
Draw 
Volume/ 
Sample 
(mL) 
Study Day 
Estimated 
Total  
Blood 
Draw 
Volume 
(mL) 
Screen 
(Day -2
8 to -2) 
Day -
1 
(Pre-
Dose) 
Week 
1 
Week 
2 
Week 
3 
Week 
4/ 
Prema
ture 
D/C 
Week 
5 
Week 
6 
Serum 
Chemistry  
Serum 
Pregnancy  
(females 
only) 
7.5 
7.5 
7.5 
 
7.5 
 
7.5 
7.5 
 
37.5 
TSH/T3/T4 
5.0 
5.0 
5.0 
 
5.0 
 
5.0 
5.0 
 
25.0 
Hematology  
3.0 
3.0 
3.0 
 
3.0 
 
3.0 
3.0 
 
15.0 
Coagulation 
2.7 
2.7 
2.7 
 
2.7 
 
2.7 
2.7 
 
13.5 
PK 
6.0 
 
6.0 
6.0 
6.0 
 
6.0 
 
 
24.0 
 
 
 
 
 
 
 
 
 
 
 
 
Estimated Total mL of 
Blood Drawn: 
18.2 
30.2 
6.0 
30.2 
0.0 
30.2 
24.2 
0.0 
139.0 mL 
Abbreviations: PK=Pharmacokinetics; Premature D/C=Premature Discontinuation from treatment 
 
 


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7.2.5.7. 
Columbia-Suicide Severity Rating Scale 
The C-SSRS (Appendix G and Appendix H) will be administered by a trained site staff member 
during the Screening Period (Baseline/Screening Version) and the Treatment and Follow-up 
Periods (Since Last Visit Version) as specified in the SOE (Table 2).  Subjects who pose a 
current or future suicidal risk in the Investigator’s opinion, or have a history of suicidal behavior 
within the past 12 months, and/or answers “yes” to “Suicidal Ideation” Item 4 (active suicidal 
ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with 
specific plan and intent) on the C-SSRS assessment during the six months prior to the Screening 
period and/or at Baseline will not be eligible for study enrollment. 
Subjects who at any time during this study spontaneously report AEs of suicidal ideation or 
suicidal behavior, either as an outpatient or during visit interviews, must be assessed by the PI or 
designee and referred for further mental health evaluation as clinically indicated. 
7.2.6. 
Assessment of Pharmacokinetics 
 
7.2.6.1. 
Pharmacokinetics 
The population PK of SP-624 will be assessed. 
A total of four blood samples (6 mL) will be collected from each subject for the measurement of 
plasma concentrations of SP-624 at the following visits:  
• Visit 2 (Day -1) 
• Visit 3 (Week 1): Pre-Dose 
• Visit 4 (Week 2): Pre-Dose or approximately 2 to 10 hours post-dose (whichever is 
more convenient for the subject) 
• Visit 6 (Week 4): approximately 2 to 10 hours post-dose 
If a subject missed the dose the day before a scheduled “pre-dose” sample collection, study 
personnel should instead collect a post-dose sample at that visit.  Should a subject inadvertently 
dose prior to a scheduled “pre-dose” sample collection at Week 1 or Week 2, study personnel 
should collect a post-dose sample.   
In the event that samples cannot be conveniently collected for a given subject according to the 
scheduled sampling times specified above, study personnel should attempt to collect at least one 
pre-dose sample and at least one post-dose sample during the course of the study. 
Plasma samples will be analyzed for SP-624 concentration using a validated bioanalytical 
method. 
An aliquot of each subject’s post-dose samples may be pooled by the bioanalytical laboratory for 
metabolite profiling.  Potential metabolites will be identified using mass spectrometry 
techniques; and if conducted, these data will be summarized in a separate bioanalytical report.  
Labels on blood sample collection tubes and vials will include the protocol code number, subject 
identification code number, and visit number. 


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Samples will be stored at the study center until shipment under appropriate conditions to the 
Sponsor-designated bioanalytical laboratory for analysis.  The bioanalytical lab will analyze the 
samples for plasma concentrations of SP-624 using a validated LC-MS method. 
Detailed instructions for all blood sampling, processing, storage, and shipment procedures will 
be provided in a separate study guidance document. 
An estimation of the total blood collection volume per subject is provided in Section 7.2.5.6 and 
Table 6. 
7.2.6.2. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
7.2.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND 
OTHER REPORTABLE EVENTS 
8.1. 
Adverse Events 
An AE is any untoward medical occurrence in a clinical study subject, whether or not the event 
is considered causally related to the study drug.  An AE can be a new occurrence or an existing 
process that increases significantly in intensity or frequency. 
All AEs must be recorded in the appropriate section of the CRF. 
Adverse event monitoring for each subject begins upon Screening and continues until study 
completion.  Abnormalities present at Screening are considered AEs only if they reoccur after 
resolution or worsen in intensity or frequency during the study. 
Each AE is to be classified as serious or non-serious, and categorized with regard to relationship 
to study drug, and intensity. 
8.1.1. 
Clinical Safety Assessment Abnormalities 
Abnormal findings on clinical safety assessments, including clinical safety laboratory test results, 
vital sign measurements, ECGs, and physical examinations, will be assessed by the Investigator 
as clinically significant or not clinically significant.  Clinically significant abnormalities that are 
new or exacerbate after the Screening Visit will be reported as AEs.  Classification of 
seriousness, relationship to study drug, and intensity should use the guidelines provided in 
Section 8.1.2, Section 8.1.4.3 and Section 8.1.4.4, respectively. 
8.1.2. 
Serious Adverse Event (SAE) 
An AE is serious, regardless of whether or not it is considered related to the study drug, if the 
event meets one or more of the following criteria: 
• Results in death. 
• Is life threatening; per the Investigator, the subject was at immediate risk of death 
from the event at the time that the event occurred.  It does not include an event that 
hypothetically might have caused death if it had occurred in a more severe form. 
• Requires in-patient hospitalization; initial or prolonged, meaning that a hospital 
admission and/or prolongation of a hospital stay was required for the treatment of the 
AE, or occurred as a consequence of the event.  It does not include a pre-planned 
elective hospital admission for treatment or diagnostic procedures. 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions. 
• Congenital anomaly or birth defect that occurs in the offspring of a subject exposed to 
the study drug. 
• Important medical event that, although does not result in one of the other serious 
outcomes, requires medical or surgical intervention in order to prevent one of the 
other serious outcomes listed above.  Examples of such medical events include 


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allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias, or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
All SAEs that occur after any subject has been enrolled, before treatment, during treatment, or 
within 28 days following the Week 4 Visit, whether or not they are related to the study, must be 
recorded on forms provided by Sirtsei Pharmaceuticals. 
8.1.3. 
Suspected and Unexpected Serious Adverse Reactions 
A suspected and unexpected serious adverse reaction (SUSAR) is defined as an SAE that meets 
both of the following criteria with respect to study drug: 
• Suspected:  is assessed as probably or possibly related to study drug (see 
Section 8.1.4.3) 
• Unexpected:  in comparison to drug-related AEs described in the Investigator’s 
Brochure, the event meets any of the following criteria: 
− The event was not previously described; or is now characterized more specifically 
(e.g., an event of “interstitial nephritis” in a subject receiving an agent previously 
described as associated with “acute renal failure”); and/or 
− The event is now characterized as more severe (see Section 8.1.4.4). 
8.1.4. 
Evaluation of Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel (i.e., how are you feeling?) or revealed by observation will be recorded 
during the study at the investigational site. 
All AEs/SAEs will be recorded in the CRF and will include a concise AE term/diagnosis, date 
and time of event onset and resolution, relationship to study drug, intensity, action taken, and 
outcome as described in Section 8.1.4.1 through Section 8.1.4.6. 
Abnormalities in vital signs, laboratory results, and other safety assessments will be recorded as 
an AE if they meet the definition of an AE (Section 8.1.1). 
Events that are considered symptoms of MDD should not be recorded as medical history or AEs. 
Lack of efficacy should not be considered an AE.      
8.1.4.1. 
Adverse Event Term/Diagnosis 
The diagnosis or description of the AE will be as specific and complete as possible (i.e., “lower 
extremity edema,” rather than just “edema”). 
Whenever possible, signs, symptoms, and laboratory abnormalities due to a common etiology 
will be reported as an integrated diagnosis; for example, cough, runny nose, sneezing, sore 
throat, and head congestion would be reported as “upper respiratory infection.”  The AE term 
should be reported in standard medical terminology when possible. 
A medical or surgical procedure is not an AE; rather the condition leading to the procedure 
should be recorded as the AE.  If the condition is not known, the procedure may be reported as 


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an AE instead.  Similarly, death is not an AE, but is rather the outcome of the AE(s) that resulted 
in death.  If the AE(s) leading to death are not known, then death will be reported as an AE. 
8.1.4.2. 
Date and Time of Adverse Event Onset and Resolution 
The time, if available, and date at which the AE was first apparent will be recorded as the event 
onset.  The date and time of onset of symptoms may be appreciably earlier than the date and time 
the Investigator becomes aware of the event.  Some events may be apparent to the subject and 
Investigator independently, and information from each may contribute to the final report.  The 
date and time of resolution of the event will be recorded when they are available. 
8.1.4.3. 
Relationship to Study Drug 
A causality assessment (i.e., assessment of relationship to study drug) must be provided for all 
AEs.  This assessment must be made by a physician Investigator and recorded on the CRF.  The 
definitions for the causality assessment are provided below. 
• Probably Related:  an event that (1) follows a reasonable temporal sequence from 
administration of the drug, (2) follows a known or expected response pattern to the 
drug, (3) is improved/resolved by stopping or reducing the dosage of the drug, and/or 
(4) could not be reasonably explained by the known characteristics of the subject’s 
clinical state. 
• Possibly Related: an event that follows a reasonable temporal sequence from 
administration of the drug and where a causal relationship between drug 
administration and event is a reasonable possibility, even if the event could readily 
have been produced by a number of other factors.  The expression “reasonable 
possibility” is meant to convey in general that there are facts (evidence) or arguments 
to suggest a causal relationship. 
• Not Related: an event that is unlikely to have any relationship to the study drug even 
if such relationship cannot be definitely ruled out. 
If the relationship between the AE/SAE and the study drug is determined to be “possible” or 
“probable” the event will be classified as “related” to the study drug for the purposes of 
expedited regulatory reporting. 
8.1.4.4. 
Intensity Categorization 
The intensity of all AEs will be assessed by the Investigator using the following criteria: 
• Mild: An AE that is transient, requires minimal or no treatment, and does not 
interfere with the subject’s daily activities. 
• Moderate: An AE that is usually alleviated with specific therapeutic intervention. 
The event causes some interference with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the research 
participant. 
• Severe: An AE that is incapacitating, prevents usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 


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It is important to distinguish between serious and severe AEs.  Intensity is a measure of severity 
whereas seriousness is defined by the criteria under Section 8.1.2.  An AE of severe intensity 
may not be considered serious (e.g., a headache can be severe but not serious – e.g., is not life 
threatening, or does not result in hospitalization). 
8.1.4.5. 
Action Taken for Adverse Event 
Adverse events will be followed and managed by the Investigator, including obtaining any 
supplemental tests or assessments needed to define the nature and/or cause of the event (e.g., 
laboratory tests, diagnostic procedures, consultation with other health care professionals, etc.). 
For each AE, the Investigator will categorize one or more actions taken to manage the AE as 
follows: 
• Discontinuation:  Scheduled study procedures and/or study drug dosing (if 
applicable) were stopped due to the AE.   
• Study drug dose reduction: The study drug dose is decreased from two capsules per 
day to one capsule per day. 
• Concomitant medication: One or more medications (prescription or over the 
counter) were started or increased in dosage. 
• Study drug dose taken with food: The study drug dose is taken ≤ 2 hours following 
a meal or a meal is eaten < 1 hour after taking a dose.   
• Other action: Non-medication action(s) were ordered as management of the AE 
(e.g., bed placed in Trendelenburg position, warm compresses applied to intravenous 
access site, etc.). 
• No action: No actions were ordered for management of the AE. 
8.1.4.6. 
Outcome of Adverse Event 
If possible, AEs will be followed until resolved (i.e., recovered, recuperated, or ended) either 
with or without sequelae, or the Investigator and Sponsor Medical Monitor assess them as 
chronic or stable, and no longer requiring follow-up. 
The outcome of each event (including time if available, and date) will be described using the 
following categories: 
• Recovered: The event resolved, and subject returned to Baseline. 
• Recovered with Sequelae: The event resolved but the subject is left with residual 
problems (e.g., functional deficits, pain). 
• Not Recovered: At the last observation, the event was ongoing. 
• Death (Fatal): To be used for the one AE which, in the judgment of the Investigator, 
was the primary cause of death. 
• Unknown: There were no observations after the onset (initial observation or report) 
of the event, or subject is lost-to-follow-up and outcome of AE is unknown. 
A subject who is discontinued from study drug because of an AE must be followed by the 
Investigator until clinical recovery is complete and laboratory results have returned to normal, or 


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until progression has been stabilized.  Follow-up may need to continue after the subject has 
discontinued from the study, and additional investigations may be requested by the Investigator. 
8.1.5. 
Reporting of Serious Adverse Events 
The Investigator will review each SAE and evaluate the severity and the causal relationship of 
the event to study drug.  Serious AEs that occur after the last study visit and come to the 
attention of the Investigator must be reported only if there is (in the opinion of the Investigator) 
reasonable causal relationship with the study drug.  Serious AE reporting contact information is 
provided in Table 1. 
The Investigator is responsible for providing notification to the Sponsor (Table 1) of any SAE, 
within 24 hours of when he or she became aware of the event, whether deemed study drug 
related or not. 
An SAE report form template will be provided to the Investigator by the Sponsor (or designee) 
prior to study initiation, with the preferred format for reporting SAEs. 
As a minimum requirement, the initial notification should include the following information: 
• Study number 
• Subject number 
• Name of Investigator  
• AE term 
• Criterion for classification as ‘serious’ 
• Study drug name 
• Causality assessment (if sufficient information is available to make this classification) 
• Identifiable reporter of event 
If clarification is requested by the Sponsor for omitted or discrepant information in the initial 
notification, the Investigator or an authorized delegate is responsible for sending the requested 
information within 24 hours. 
Initial reports of SAEs must be followed later with detailed descriptions, including clear copies 
of other documents as necessary (e.g., hospital reports, consultant reports, autopsy reports), with 
the study subject’s personal identifiers removed.  Additional information on the SAE may be 
requested, which the Investigator or an authorized delegate must send to the SAE reporting 
contact (Table 1). 
The Sponsor is responsible for expedited reporting of qualifying events to relevant regulatory 
authorities.  It is the Investigator’s responsibility to notify the IRB of all SAEs that occur at his 
or her site.  Investigators will also be notified by the Sponsor of all unexpected, serious, drug-
related events [Investigational New Drug (IND) safety reports; also known as SUSARs] that 
occur during the clinical trial from any other studies or study sites.  The Investigator is 
responsible for notifying its IRB of these events. 


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8.1.6. 
Other Reportable Events 
Certain events that occur in the absence of an AE should be reported to the Sponsor.  These 
include the following events: 
• Pregnancy Exposure (subject or subject’s partner becomes pregnant at any time 
during study participation and through 30 days post-dose). 
− Should a female subject or partner of a male subject become pregnant during the 
study, the subject will inform the Investigator. 
− The subject will be asked to follow up with the study site to report the eventual 
outcome of the pregnancy.  The information will be tracked by the Sponsor. 
− The outcome of all pregnancies (spontaneous miscarriage, elective termination, 
normal birth or congenital abnormality) must be followed up and documented 
even if the subject was discontinued from the study. 
− Pregnancy in itself is not regarded as an AE. 
− All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous 
miscarriages should also be reported and handled as SAEs.  Elective abortions 
without complications should not be handled as AEs. 
• Lactation Exposure (subject was taking study drug while nursing an infant). 
• Accidental Exposure (someone other than the study subject was exposed to study 
drug). 
• Overdose of Study Drug (defined as dosing > 4 capsules in a 24-hour period) as a 
result of a dosing amount error should be reported.  Any adverse outcomes of the 
overdose should be recorded as AEs/SAEs according to the procedures described in 
Section 8.1 through Section 8.1.5 .  Intentional overdose of study drug should be 
evaluated as a potential AE/SAE and reported accordingly. 
• Other medication errors that potentially place subjects at greater risk of harm than 
was previously known or recognized (i.e., study drug was administered via an 
incorrect route). 


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9. 
STATISTICS 
Following are proposed statistical analyses.  A separate Statistical Analysis Plan (SAP) will be 
generated and finalized prior to analysis.  The SAP will specify the details of all statistical 
analyses, including all efficacy and safety analyses to be performed. 
9.1. 
Determination of Sample Size 
Recent studies of MDD using change from Baseline in MADRS total scores suggest that placebo 
will yield an approximately nine unit decrease over four weeks with a SD of around 9.2.  SP-624 
is expected to yield at least a 12 unit decrease in MADRS total score over four weeks with a 
similar SD of around 9.2.  A minimum of 150 subjects per treatment arm (300 total) would be 
needed to detect a treatment difference of three units with 80% statistical power. The sample size 
was estimated using NQuery 8 (V8.5.2.0) two group test of equal means (MTT0-1: 
www.statsols.com). 
9.2. 
Analysis Populations 
Within each population, analyses will be performed comparing subjects and by-treatment 
assignment (SP-624 vs placebo). 
• All Subjects Population – all subjects who sign informed consent and are assigned a 
unique subject identification number.  This population will be used to summarize 
disposition. 
• Modified Intent-to-Treat (mITT) Population – all subjects who are randomized to 
receive treatment, receive at least one dose of study drug, and have a Baseline and at 
least one post-dose efficacy assessment. This population will be the primary 
population used to summarize demographics, baseline characteristics, medical 
history, treatment history, and all efficacy outcomes.  Subjects will be analyzed 
according to randomized treatment group. 
• Per Protocol (PP) Population – All subjects in the mITT population who received 
assigned study drug as randomized, completed the Week 4 assessments without any 
major protocol violations, and have 75-125% compliance.  The PP population will be 
used as an additional population for summaries of efficacy outcomes. 
• Safety Population — all subjects in the mITT population who receive at least one 
dose of study drug. Safety subjects will be summarized according to the treatment 
they actually received, in case they received a different treatment than assigned at 
randomization. This population will be used to summarize all safety assessments.  
• PK Population — all subjects who receive active study drug and have evaluable PK 
data based on actual treatment received, protocol compliance, adequate numbers of 
samples, and successful sample assays.  


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9.3. 
Description of Statistical Methods 
9.3.1. 
General Approach 
All data will be provided in listing files.  Study results and information will be displayed in 
descriptive summary tables.  Inferential tests are identified below.  For measurements that have 
multiple intermediate visits, results for observed data will be summarized for each time. 
When comparisons between groups are performed, two-sided tests at a 0.05 level of significance 
(α=0.05) will be used.  The null hypothesis for all analyses is that there is no difference between 
the SP-624 and placebo treatment groups.  There is only one primary outcome for analysis, and 
there will be no adjustment for multiplicity for secondary endpoints.     
All summaries, statistical analyses, and individual subject data listings described below will be 
completed using Version 9.4 or later of the SAS Statistical Analysis System (SAS Institute, Inc. 
Cary, NC). 
Subjects who are randomized but not treated and those who are treated but have no post-
treatment follow-up assessments or data will be listed, but not analyzed. 
9.3.2. 
Interim Analysis 
No formal interim analyses are planned for this study. 
9.3.3. 
Summary of Demographics, Baseline Characteristics, Medical History, and 
Treatment History 
Listings and summaries of demographics, baseline characteristics, medical history, and treatment 
history will be provided for the mITT and safety populations.  Categorical variables will be 
assessed for homogeneity across the treatment arms using a Fisher’s exact test and numeric 
variables will be compared using a Wilcoxon rank-sum test.  If there are any ordered categorical 
variables, the homogeneity of the treatment arms will be evaluated using a CMH row-mean score 
test calculated with modified ridit ranks. This summary will be provided for the mITT 
population. 
9.3.4. 
Summary of Efficacy 
Efficacy analyses will be conducted using the mITT population.  
9.3.4.1. 
Primary Efficacy Endpoint Analysis 
The MADRS is a 10-item scale whose total score can range from 0 to 60. The primary efficacy 
variable is change from Baseline in MADRS total score at Week 4, for testing superiority of SP-
624 vs. placebo in adults with major depressive disorder.  The analysis will be completed using 
observed data without imputation.  Scores will be taken at 4 weeks regardless of subject 
discontinuation from treatment.  Subjects will not be treated with any other antidepressant 
medication until at least the completion of the Week 5 visit.   
The change from Baseline in MADRS total score at Week 4 will be analyzed from the difference 
in least square mean change using MMRM, with change from Baseline in MADRS total score at 
each visit as the response variable. The MMRM model will include age, weight, and baseline 


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MADRS total score as covariates, with factors for treatment, visit (Weeks 1, 2, 3, and 4; as a 
categorical variable), treatment by visit interaction term, gender, and site as a fixed effect. An 
unstructured covariance matrix will be used for the within-subject correlation. Kenward-Rogers 
approximation will be used to calculate the denominator degrees of freedom. The primary 
efficacy endpoint will be calculated using an estimate statement. Subjects from low enrolling 
sites may be pooled in order to help with model convergence. 
In the event of a model which fails to converge, additional strategies to address convergence may 
be required such as alternative covariance structures, using a maximum likelihood versus 
restricted maximum likelihood (REML) estimation, or dropping variables.  
The protocol may include approximately 40 sites and sites with less than 10 subjects will be 
pooled to obtain at least 10 subjects.  Sites would be pooled in order of the site number and, if 
necessary, the last un-pooled site will be pooled with the last set of sites pooled. 
Additional variables of interest that may be evaluated as covariates will be identified in the SAP, 
such as age of onset of depression and number of lifetime episodes. 
Additionally, results from the primary outcome will be summarized for the PP population. 
9.3.4.2. 
Secondary Efficacy Endpoint Analysis 
Seven secondary efficacy endpoints will be analyzed using both the mITT and PP populations.   
These include: 
• Change from Baseline to Weeks 1, 2, and 3 in MADRS total score for SP-624 vs. 
placebo. The outcome will be analyzed using the same methods as the primary outcome.   
• CGI-S is measured on a 7-point scale where 1 represents “normal” and 7 represents 
“most extremely ill”.   A summary of percentage of subjects with each score at Baseline 
and at Weeks 1, 2, 3, and 4 will be presented.  The change from Baseline in CGI-S can 
take on interval values between -6 (improvement from 7 to 1) and 6 (worsening from 1 to 
7).  Treatment comparison of change from Baseline to Weeks 1, 2, 3, and 4 in CGI-S 
scores will be performed using an MMRM model similar to that of the primary efficacy 
variable.   
• Change from Baseline to Week 5 and change from Week 4 to Week 5 will be assessed 
using descriptive statistics for the MADRS and CGI-S.   
• The HAM-D-17 is a 17-item scale whose total score can range from 0 to 52.  Change 
from Baseline to Week 2 and Week 4 in the 17-item Hamilton Depression Rating Scale 
(HAM-D-17) total score will be assessed for treatment differences using an MMRM 
model similar to that of the primary efficacy variable.  
• The Sheehan Disability Scale (SDS) is a 3-part scale that measures the degree of 
disruption on work, social and family life using an 11-point scale where 0 represents “no 
disruption” and 10 represents “extreme disruption”.  In addition to the 11-point scale, 
subjects are asked to indicate the number of days in the past week that were “lost” and 
numbers of days that were “unproductive”.  The results of these questions have a range 
from 0 to 7.  A total global functioning impairment score can be utilized by summing the 
scores from work, social and family life scales for a value range from 0 to 30.  Treatment 


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difference in change from Baseline to Week 2 and Week 4 for both global functioning 
impairment and days lost/unproductive will be assessed using an MMRM model similar 
to that of the primary efficacy variable.  Change in days lost will be analyzed separately 
from change in unproductive days.   
• The Quick Inventory of Depressive Symptomology – Self Report (QIDS-SR), is a 
16-item self-reported scale where each item has a 4-point scale where 0 represents least 
impact scores while 3 represents greatest impact scores.  Scale 6 and 7 are linked such 
that only one of these will be scored.  Likewise, scales 8 and 9 are linked such that only 
one of them will be scored.  Nine domains are scored based on the highest score of items 
within that domain. The total score from all domains can take a value ranging from 0 to 
27.  Treatment difference in change from Baseline to Week 2 and Week 4 in the 
QIDS-SR will be assessed using an MMRM model similar to that of the primary efficacy 
variable.  
• The Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-
SF) is a 16-item satisfaction scale where each item has a 5-point scale. A score of 1 
represents “very poor satisfaction”, while a score of 5 represents “very good satisfaction”. 
Only the first 14 items are summed for a total score that ranges from 14 to 70 and is 
expressed as a percentage based on the maximum total score of the items completed (0–
100).  Treatment difference in the change from Baseline to Week 2 and Week 4 in total 
scores will be assessed using an MMRM model similar to that of the primary efficacy 
variable.  The last two items pertaining to satisfaction with medications and overall 
contentment will be summarized separately by treatment group.  
9.3.5. 
Sensitivity Analyses 
A dropout rate of 20-30% is typically seen in MDD studies.  The mechanisms that cause missing 
data may be missing at random (MAR) or may be missing not at random (MNAR).  The MMRM 
model (especially as implemented within the PROC MIXED procedure in SAS) used in the 
primary analysis of the primary efficacy endpoint relies on the assumption of MAR.  Hence, a 
sensitivity analysis for the primary endpoint and secondary endpoints will be performed using a 
pattern-mixture modeling approach (Kenward, et al 2003).   
Additionally, subjects will be grouped by the visit at which they had their last MADRS total 
score measured.  This will result in five categories of discontinuation: Week 1 dropouts, Week 2 
dropouts, Week 3 dropouts, Week 4 dropouts, and completers. Mean change from Baseline in 
MADRS total score will be plotted by the dropout category and by reason for discontinuation, in 
order to assess whether this efficacy measure appears to be correlated with study dropout. 
If missing data are greater than 25% or the pattern-mixture model provides a different 
interpretation of the treatment comparison for the primary endpoint, a multiple imputation 
analysis may also be performed using a fully conditional specification (FCS) approach using 
variables identified in the SAP.   
9.3.6. 
Summary of Pharmacokinetics 
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If data allow, results will be used for other analyses (e.g., PopPK) which will be presented in a 
separate report.   
The population PK analysis of SP-624 will be performed using a nonlinear mixed effects model 
(NONMEM). This analysis will provide estimates of population PK parameters such as CL/F, 
Vz/F, etc. and a measure of their variability. Pharmacokinetic parameters of individual subjects 
(e.g., AUC[0-tau], Cavg, Cmax) may be estimated and their correlation with relevant covariates 
(e.g., body weight, gender, concomitant medications) will be explored. The population PK 
analysis plan will be prepared separately. 
Plasma concentration data will remain blinded until the unblinding of the clinical database at the 
end of the study. 
9.3.7. 
 
 
 
9.3.8. 
Concomitant Medications 
Concomitant medications will be coded using the most current version of the World Health 
Organization (WHO) drug dictionary available.   
Any medications taken during the course of the study with a start date on or after the date of the 
first dose of study drug and on or before the date of the last dose of study drug, or with a start 
date prior to, and an end date on or after, the date of the first dose of study drug, or marked as 
ongoing, will be considered concomitant medications.  Medications that ended prior to the date 
of the first dose of study drug will be considered prior medications.  Medications that started 
after the date of the last dose of study drug will not be considered concomitant but will be 
considered post-treatment.  Prior and concomitant medications will be summarized for the 
number and percentage of subjects using each medication by treatment and by the drug class and 
preferred name for the safety population. 
9.3.9. 
Summary of Safety and Tolerability 
All summaries of safety and tolerability will be performed on the safety population. 
Laboratory parameters, vital sign data, and ECG results will be summarized by treatment group 
and presented in tabular and graphic formats where appropriate.  Appropriate change from 
Baseline calculations will be provided to detect any significant changes in laboratory parameters, 
vital sign values, ECG results, and C-SSRS results, but no formal statistical tests are planned.  
9.3.9.1. 
Adverse events 
Summaries of the number and percentage of subjects in the safety population with at least one 
treatment-emergent AE (TEAE), classified according to preferred term and/or body system using 
the MedDRA dictionary, will be provided overall and by treatment group for: 
• Overall summary 
• All TEAEs 
• TEAEs by relationship (not related, possibly related, probably related) 


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• TEAEs by severity (mild, moderate, severe) 
• SAEs 
• TEAEs leading to withdrawal from the study 
• TEAEs leading to study drug dose reduction 
• TEAEs leading to study drug dose taken with food 
• Analyses of AEs with time of onset beginning 24 hours after the final dose through up to 
28 days after the final dose.  
No formal statistical tests are planned for AE data. 
9.3.9.2. 
Vital Signs and ECGs  
Vital signs and ECG results will be summarized by treatment group and presented in tabular and 
graphic formats where appropriate.  Appropriate change from Baseline calculations will be 
provided to detect any significant changes in vital sign values or ECG results, but no formal 
statistical tests are planned. Any abnormal finding or clinically significant changes will be 
captured as AEs. 
9.3.9.3. 
Clinical Laboratory Assessments 
Clinical laboratory test results for chemistry (including thyroid function), hematology, 
coagulation, and urinalysis will be summarized by treatment group and presented in tabular and 
graphic formats where appropriate.  Appropriate change from Baseline calculations will be 
provided to detect any significant changes in laboratory parameters, but no formal statistical tests 
are planned.  Any abnormal finding or clinically significant changes will be captured as AEs. 
9.3.9.4. 
Physical Exams 
Physical examination findings will be listed for each subject at each assessment period.  
Clinically significant new findings and adverse changes in physical examination findings will be 
captured as AEs, therefore eliminating the need to summarize over time.   
9.3.9.5. 
C-SSRS 
Frequency and severity of suicidal ideation and suicidal behavior as measured by the C-SSRS 
will be summarized by treatment for each visit. 
 


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10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
10.1. 
Sponsor’s Responsibilities 
• The Sponsor and its representatives will undertake the management of the study in 
compliance with all applicable national and local regulations, as well as the global 
standard International Council for Harmonisation (ICH) GCP E6 Guideline. 
• The Sponsor will ensure that all local regulatory authority requirements of the 
Sponsor are met before the start of the study including receipt of regulatory authority 
approvals and/or compliance with the appropriate wait-time required prior to release 
of the study drug for shipment to the site 
• Sponsor ensures that suitable clinical study insurance coverage is in place prior to the 
start of the study.  An insurance certificate will be supplied as needed. 
• When required by national law, Sponsor will post appropriate study information on 
government websites which may include Investigator name and contact information 
for participating sites. 
• Sponsor representatives will make periodic visits to participating sites to review 
subjects’ medical records/source documents, study drug accountability records, and 
site regulatory documents. 
10.2. 
Investigator’s Responsibilities 
• The Investigator will conduct the study in compliance with all applicable national and 
local regulations, as well as the global standard ICH GCP E6 Guideline. 
• The Investigator agrees to personally oversee the study, delegate study-related tasks 
to qualified personnel, and meet with Sponsor representatives during on-site visits. 
• The Investigator must permit representatives of Sponsor, the IRB and national, local, 
and foreign regulatory authorities to have direct access to original source 
documents/medical records, regardless of media, relevant to the study. 
• The Investigator is required to maintain all study records according to the ICH GCP 
E6 Guideline and may not destroy any records until the mandated record retention 
period is over.  Note:  Investigators are encouraged to consult with the Sponsor before 
record destruction to ensure that all retention requirements have been satisfied. 


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11. 
ETHICS 
11.1. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH GCP and applicable regulatory 
requirements. 
11.2. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved in writing by 
an IRB as appropriate.  The Investigator must submit written approval to the Sponsor before he 
or she can enroll any subject into the study. 
The Investigator is responsible for informing the IRB of any amendment to the protocol in 
accordance with local requirements.  In addition, the IRB must approve all advertising used to 
recruit subjects for the study.  The protocol must be re-approved by the IRB upon receipt of 
amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB with reports of any reportable serious 
adverse drug reactions from any other study conducted with the study drug.  The Sponsor will 
provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
according to local regulations and guidelines. 
11.3. 
Written Informed Consent 
The Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk, and benefit of the study.  The subject must 
also be notified that they are free to discontinue from the study at any time.  The subject should 
be given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated ICF must be obtained before conducting any study procedures. 
The Investigator must maintain the original, signed ICF.  A copy of the signed ICF must be 
given to the subject. 


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12. 
DATA HANDLING AND RECORD KEEPING 
12.1. 
Data Collection and Recording 
The Investigator or personnel designated by the Investigator will perform primary data collection 
based on original hospital or clinic records or other source documentation.  All required study 
information must be reported on the appropriate CRF.  The study monitor will review CRFs for 
accuracy and completeness to ensure maximum data integrity.  In addition, as the person 
ultimately responsible for the accuracy of all CRF data, the Investigator will provide 
endorsement that the data on the CRFs are accurate and complete. 
Data processed outside the study site at a central laboratory (e.g., safety lab, ECG, bioanalytical 
data, etc.) may be transferred electronically. 
12.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the study for a period of two years 
after the last marketing application approval, or if not approved, two years following the 
discontinuance of the study drug for investigation.  The Investigator agrees that any study 
documentation will be promptly disclosed to the Sponsor or the regulatory authority upon 
request for review. 
12.3. 
Protocol Deviations 
A protocol deviation is any non-compliance with the clinical study protocol, including 
compliance requirements and agreements.  Examples include an Investigator’s decision to 
deviate from the protocol, a subject’s lack of adherence to the protocol, or 
external/environmental factors (e.g., severe weather or holidays) that change the conduct of a 
protocol from that which was planned. 
The Sponsor will review the protocol deviations that occur during the study.  A determination 
will be made as to which deviations are major – e.g., deviations that impact the study results, 
data integrity, subject safety, subject consent, or admission criteria. 
Further details about the handling of protocol deviations will be included in the Sponsor Study 
Monitoring and Data Management Plans.  The Investigator is responsible for complying with 
IRB protocol deviation/violation reporting requirements, as applicable. 
12.4. 
Publication Policy 
The publication policy is provided in a separate agreement between the Sponsor and those parties 
contracted to perform services for this study.  In summary, all information received and 
developed in connection with this protocol is considered confidential by the Sponsor.  Such 
information may only be disclosed as deemed appropriate and necessary by the Sponsor.  The 
publication or presentation of data from this study is not allowed without prior agreement with 
the Sponsor. 


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12.5. 
Data Quality Assurance 
Standard operating procedures (SOPs) are available for all activities performed by the 
investigational site relevant to the quality of this study.  Designated personnel of the 
investigational site will be responsible for implementing and maintaining quality assurance (QA) 
and quality control systems to ensure that the study is conducted, and that data are generated, 
documented and reported in compliance with the study protocol, GCP and Good Laboratory 
Practice (GLP) requirements, as applicable, as well as applicable regulatory requirements and 
local laws, rules and regulations relating to the conduct of the clinical study. 
CRFs will be 100% source data verified by a Sponsor study monitor against the source notes for 
identification and clarification of any discrepancies. 
The Investigator must make study data accessible to the study monitor, to other authorized 
representatives of the Sponsor, and to the appropriate regulatory authority inspectors.  Audits for 
QA of the database may be performed according to relevant SOPs from the contract research 
organization (if applicable) or at the request of the Sponsor. 
12.6. 
Data Management 
Following are proposed data management activities.  A separate Data Management Plan (DMP) 
will be generated and finalized prior to initiating data management activities.  The DMP will 
specify the details of all data management activities. 
Sirtsei Pharmaceuticals, or their designee, will generate the CRFs.  An electronic CRF will be 
used.  Sirtsei Pharmaceuticals clinical and safety monitors will review entered data and ensure 
that they correspond to data kept by the site in source documents.  Data management activities 
such as query management and coding of AE terms will be performed by Sirtsei Pharmaceuticals 
or their designee.   
Each CRF will be reviewed and signed by the PI at each site, as applicable.  A detailed DMP will 
be prepared by the assigned data manager and approved by the Sponsor. 
All clinical data will undergo a quality control check prior to clinical database lock.  Edit checks 
are performed for appropriate databases as a validation routine using SAS® or comparable 
program to check for missing data, data inconsistencies, data ranges, etc.  Corrections will be 
made prior to database lock. 


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13. 
LIST OF REFERENCES 
13.1. 
Publications Referenced 
American Psychiatric Association. Depressive Disorders. In: Diagnostic and Statistical Manual 
of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013. 
https://dsm-psychiatryonline-
org.ahecproxy.ncahec.net/doi/full/10.1176/appi.books.9780890425596.dsm04 
Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological Approaches to the Challenge of 
Treatment-Resistant Depression. Dialogues Clin Neurosci. 2015 Jun;17(2):111-26.  
Kenward MG, Molenberghs G, Thijs H. Pattern-Mixture Models with Proper Time Dependence. 
Biometrika, 2003;90(1):53-71. 
Lieber A. Major Depression. https://www.psycom.net/depression.central.major.html.  Updated 
January 7, 2020.  Accessed July 7, 2020. 
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Amorim P, Janavs J, Weiller E, Hergueta T, 
Baker R, Dunbar G. The Mini International Neuropsychiatric Interview (M.I.N.I.): The 
Development and Validation of a Structured Diagnostic Psychiatric Interview. J. Clin Psychiatry, 
1998;59(suppl 20): 22-33. 
http://www.psychiatrist.com/JCP/article/Pages/1998/v59s20/v59s2005.aspx 
 
 
13.2. 
Sponsor Documents and Study Reports Referenced 
13.2.1. 
Investigator’s Brochure 
[SP-624 Investigator’s Brochure 2020] Investigator’s Brochure for SP-624. 2nd ed. Sirtsei 
Pharmaceuticals, Inc.; Release date 11 June 2020. 
13.2.2. 
 
 
 
 


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14. 
APPENDICES 


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APPENDIX A. MONTGOMERY-ASBERG DEPRESSION RATING 
SCALE 
 
 


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APPENDIX B. CLINICAL GLOBAL IMPRESSION – SEVERITY   
 
 
Clinical Global Impression - Severity (CGI-S) 
 
Considering your total clinical experience with this particular population, how mentally ill is the 
patient at this time?  
0 = Not assessed  
1 = Normal, not at all ill  
2 = Borderline mentally ill  
3 = Mildly ill  
4 = Moderately ill  
5 = Markedly ill  
6 = Severely ill  
7 = Among the most extremely ill patients 
 


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APPENDIX C. 17-ITEM HAMILTON DEPRESSION RATING SCALE 
 
 


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APPENDIX D. SHEEHAN DISABILITY SCALE 


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APPENDIX E. THE QUICK INVENTORY OF DEPRESSIVE 
SYMPTOMOLOGY – SELF REPORT 
 
 
 


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APPENDIX F. QUALITY OF LIFE ENJOYMENT AND SATISFACTION 
QUESTIONNAIRE – SHORT FORM 
 
 
 


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APPENDIX G. COLUMBIA – SUICIDE SEVERITY RATING SCALE – 
BASELINE/SCREENING VERSION 
 
 


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APPENDIX H. COLUMBIA – SUICIDE SEVERITY RATING SCALE – 
SINCE LAST VISIT VERSION 
 
 


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SAP_001.pdf: 
 
 CLINICAL STUDY PROTOCOL: SP-624-201 
Study Title:  
A Multicenter, Double-Blind, Randomized, 
Placebo-Controlled Study of the Safety and 
Efficacy of SP-624 in the Treatment of Adults 
with Major Depressive Disorder  
Sponsor:  
Sirtsei Pharmaceuticals, Inc.  
Phase of Development:  
Phase 2  
NCT Number 
NCT04479852 
Protocol Number:  
SP-624-201  
Statistical Analysis Plan:  
Original  
Statistical Analysis Plan Version Number:  
1.0  
Statistical Analysis Plan Version Date:  
26 August 2022  
 






















8.3.3.1
Concomitant Medications


8.3.5.1
Primary Efficacy Endpoint
8.3.5.2
Intercurrent Events of Interest and Strategy for Addressing


8.3.5.3
Primary Efficacy Hypothesis
8.3.5.4
Primary Efficacy Analysis
8.3.5.5
Sensitivity and Supporting Analyses


8.3.5.6
Covariate and Other Supporting Analyses


8.3.6.1
Handling of Missing Items Within a Clinical Assessment
8.3.7.1
Safety Analyses


8.3.7.2
Adverse Events
8.3.7.3
Vital Signs and ECGs
o


o
8.3.7.4
Clinical Laboratory Assessments
8.3.7.5
Physical Exams
8.3.7.6
C-SSRS