Clinical trial NCT04855240
Conditions: Acute Postoperative Pain Bunionectomy
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2021-03-29; Completion date: 2022-03-14
Enrollment: 239 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of ACP-044 compared with placebo in the treatment of acute postoperative pain

Detailed description:

Arms: arm 1: ACP-044 Dose A arm 2: ACP-044 Dose B arm 3: Placebo
Interventions: intervention 1: ACP-044 Dose A intervention 2: ACP-044 Dose B intervention 3: Placebo
Intervention descriptions: intervention 1: Oral dose of ACP-044 Dose A intervention 2: Oral dose of ACP-044 Dose B intervention 3: Oral dose of placebo

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Efficacy and Safety of ACP-044 for Acute Postoperative Pain Following Orthopedic 
Surgery (Bunionectomy) 
NCT Number: NCT04855240
Document Date:  01 February 2022


Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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CLINICAL STUDY PROTOCOL 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of ACP-044 for Acute Postoperative Pain 
Following Orthopedic Surgery (Bunionectomy) 
Protocol Number: ACP-044-004 
Amendment 5 
Original Protocol Date: 14 January 2021 
Protocol Amendment 1 Date: 15 March 2021 
Protocol Amendment 2 Date: 06 May 2021 
Protocol Amendment 3 Date: 13 August 2021 
Protocol Amendment 4 Date: 2 September 2021 
Protocol Amendment 5 Date: 01 February 2022 
Confidentiality Statement 
This protocol is the confidential information of Acadia Pharmaceuticals Inc. and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not associated with the 
clinical investigation or used for any purpose without the prior written consent of Acadia Pharmaceuticals Inc. 






Study: ACP-044-004 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 5  
 
Date: 01 February 2022 
 
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DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of Good Clinical Practice, as required by International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline E6 and as 
described in the United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 
56, 312, and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or 
Consultant for review by you, your staff, and the applicable institutional review board/ethics 
committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 
Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 


Study: ACP-044-004 
Clinical Study Protocol Amendment 5 
PROTOCOL SYNOPSIS 
Final Version: 1.0 
Date: 01 Februaiy 2022 
Protocol number 
ACP-044-004 
EudraCT number 
Not applicable 
Protocol title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Efficacy and Safety of ACP-044 for 
Acute Postoperative Pain Following O1ihopedic Surge1y 
( Bunionectomy) 
Name of investigational 
product 
ACP-044 
Indication 
Management of acute postoperative pain 
Phase of development 
2 
Sponsor 
Acadia Phannaceuticals Inc. 
Study hypothesis 
ACP-044 is more effective at managing acute postoperative 
pain following orthopedic surge1y than placebo and is safe 
and well tolerated 
Primary Objective 
To evaluate the efficacy of ACP-044 
compared with placebo in the treatment 
of acute postoperative pain 
Secondary Objectives 
To evaluate the efficacy of ACP-044 
compared with placebo in the treatment 
of acute postoperative pain 
To evaluate opioid use among 
ACP-044-treated subjects compared 
with placebo in the treatment of acute 
postoperative pain 
Primary Endpoint 
•
Mean area under the curve (AUC) of the
Numeric Rating Scale (NRS) of pain intensity
scores from time 0 ( when first dose on Day 1
is administered) through 24 hours (AUCo-24)
forACP-044
Key Secondary Endpoints 
•
Time to first rescue medication use after
time 0 ( when first dose on Day 1 is
administered)
•
Propo1iion of subjects who were opioid free
through 24, 48, and 72 hours
Secondary Endpoints 
•
MeanAUC of the NRS of pain intensity
scores from time 0 through 48 and 72 hours
(AUC0-4s; AUCo-12) for ACP-044
•
MeanAUC of the NRS of pain intensity
scores from time 0 through 4, 6, and 12 hours
(AUCo-4; AUCo-6; AUCo-12), 24-48 hours
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Study: ACP-044-004 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 5  
 
Date: 01 February 2022 
 
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(AUC24-48), and 48-72 hours (AUC48-72) for 
ACP-044  
• Amount of rescue medication taken during 
0-24, 24-48, and 48-72 hours (individually), 
0-48 hours, and 0-72 hours 
• Proportion of subjects who did not use rescue 
medication through 24, 48, and 72 hours 
• Proportion of subjects who are pain free 
(NRS ≤2) at 24, 48, and 72 hours  
• Number of hours subjects are pain free 
(NRS ≤2) 
• Proportion of subjects who were opioid free 
during 24-48 hours and 48-72 hours 
• Global evaluation of study drug just before 
time of first rescue medication and at the end 
of 24, 48, and 72 hours relative to time 0 
(when first dose on Day 1 is administered) 
Exploratory Objective 
To evaluate the proportion of subjects 
with severe pain and to compare the 
impact of ACP-044 on activities of 
daily living compared with placebo in 
the treatment of acute postoperative 
pain 
Exploratory Endpoints 
• Proportion of subjects with severe pain 
(defined as an NRS pain intensity score ≥7 at 
any timepoint through 72 hours)  
• Foot and Ankle Ability Measure (FAAM) 
Safety Objective 
To evaluate the safety and tolerability 
of ACP-044 compared with placebo in 
the treatment of acute postoperative 
pain  
 
Safety Endpoints 
Safety will be evaluated by analyses of the 
following: 
• Treatment-emergent adverse events (TEAEs) 
• Opioid-related adverse events (ORAEs) 
• Vital signs  
• Electrocardiograms (ECGs) 
• Physical examination results 
• Clinical laboratory tests 
• Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
Pharmacokinetic Objective 
Pharmacokinetic Endpoints 


Study: ACP-044-004 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 5  
 
Date: 01 February 2022 
 
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To characterize the pharmacokinetic 
(PK) profile of ACP-044 in subjects 
treated for acute postoperative pain 
• Plasma concentrations of ACP-044 for a total 
of six (6) samples: Day -1 (predose), Day 1 
(one sample taken between 2-3 hours and one 
sample taken between 4-6 hours, after the first 
dose of the day), Day 2 (prior to the first dose 
of the day), and Day 3 (one sample taken 
between 2-6 hours and one sample taken 
between 8-12 hours, after the first dose of the 
day) 
• ACP-044 PK parameters determined using a 
population PK approach 
Pharmacokinetic/Pharmacodynamic 
Objective 
To characterize the exposure-response 
relationship using appropriate 
modelling and simulation methods 
 
Pharmacokinetic/Pharmacodynamic 
Endpoints 
• ACP-044 exposure-response relationship: 
o for efficacy using the primary endpoint, 
key secondary and selected secondary 
endpoints 
o for safety using selected TEAEs 
Number of study sites 
Approximately 3 sites in the United States (US) will 
participate in this study. 
Number of subjects 
planned 
Approximately 375 subjects will be screened and 
approximately 240 subjects are planned for enrollment 
(80 subjects per treatment group), assuming a screen failure 
rate of approximately 35%. 
Test product, dose, and 
administration 
The test products are ACP-044, 400 mg tablets or matching 
placebo (size- and color-matched) tablets. Study drug doses 
are to be administered orally prior to surgery through 
approximately 90 hours after the first dose of study drug on 
Day -1. 
Doses to be studied are: 
• ACP-044, 1600 mg total dose delivered once daily in 
the morning (provided as 4×400 mg ACP-044 tablets 
once daily)  
• ACP-044, 400 mg total dose delivered every 6 hours 
(provided as 1×400 mg ACP-044 tablet 4 times per 
day for a total daily dose of 1600 mg)  
• Placebo size- and color-matched to ACP-044 
An unblinded pharmacist and a verifier will prepare the study 
drug, while keeping all subjects, investigators, and other site 


Study: ACP-044-004 
 
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Date: 01 February 2022 
 
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staff blinded during the study. Neither the pharmacist nor the 
verifier will have any involvement with subjects or pain 
assessments. 
In order to maintain the double-blind design of the study, on 
each treatment day (Days -1 to Day 3) all subjects will 
receive four tablets (either active study drug and/or placebo) 
for the first dose of the day and one tablet (either active study 
drug or placebo) for the second, third, and fourth doses of the 
day. 
Study design 
This study will be conducted as a Phase 2, randomized, 
double-blind, placebo-controlled, multicenter, inpatient study 
in subjects with acute postoperative pain (following 
bunionectomy surgery). The study will compare each of the 
two active treatment groups receiving a total daily dose of 
1600 mg ACP-044, administered either once daily or 400 mg 
every 6 hours, with a placebo group. The Sponsor, subjects, 
and Investigators will be blinded to treatment assignment. 
The study periods are: 
• Screening: up to 4 weeks (prior to surgery) 
• Double-blind treatment: Day -1 (post first dose of 
study drug/day of surgery) to Day 4  
• Safety follow-up: approximately 7 days after end of 
treatment (EOT)/early termination (ET) and 
approximately 30 days (post last dose of study drug) 
Screening Period  
During the Screening period, subjects will be assessed for 
study eligibility. Only those subjects who meet all inclusion 
and no exclusion criteria will be eligible for the study.  
All prohibited medications should be discontinued during the 
Screening period and prior to surgery. Investigators must not 
withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications will be 
discontinued only if it is deemed clinically appropriate to do 
so and in consultation with the prescribing physician. 
With approval of the Medical Monitor, rescreening of a 
subject will be allowed one time if there is an extenuating 
circumstance that was not under the subject’s control or if is 
due to an identifiable cause, and it is medically appropriate to 
address that cause, and there is no medical reason that would 
prevent the subject to be rescreened and enrolled in the study.  
Treatment Period 


Study: ACP-044-004 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 5  
 
Date: 01 February 2022 
 
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On the day of surgery (Day -1), eligible subjects will be 
randomly assigned in a 1:1:1 ratio to receive 1600 mg 
ACP-044, administered either once daily or 400 mg every 
6 hours, or placebo, according to a randomization schedule. 
Randomization will be stratified by site. 
The first dose of study drug will be administered within 
60 (±15) minutes prior to the start of surgery. Subjects will 
then have a popliteal and/or ankle nerve block administered to 
anesthetize the knee, distal leg, and foot, after which they will 
enter into surgery. Following surgery, subjects will be 
administered the remaining three daily doses approximately 
every 6 hours after the initial dose.  
The popliteal and/or ankle nerve block will be discontinued 
approximately 2-4 hours prior to the first dose on Day 1 
(i.e., the fifth dose of the study) and nerve block removal; a 
discontinuation window of approximately 2 hours is 
permitted. The time at which the first dose on Day 1 is 
administered will be time 0 for all pain assessments. Study 
drug administration and study procedures are to be completed 
on Days -1 through 4 according to the schedule of 
assessments (Table S-1). Subjects will be encouraged to 
refrain from taking rescue medication until 1-2 hours 
following the first dose of study drug on Day 1 (details 
provided in Section 4.8.1). 
On Day 4, after the 72 hour pain assessments are performed, 
the EOT procedures will be completed and subjects will be 
discharged from the clinical site. 
Safety Follow-up Period 
Safety will be further assessed during a follow-up visit to 
occur in the clinic approximately 7 (±3) days after EOT/ET 
procedures and subjects will receive a follow-up telephone 
call approximately 30 (+4) days after the last dose of study 
drug. Subjects should return to standard of care after the 
follow-up visit that will occur in the clinic 7 (±3) days after 
the EOT/ET. 
The study schematic is presented in Figure S–1. 
Study duration 
The duration of participation for individual study subjects 
will be approximately 9 weeks, consisting of a screening 
period of up to 4 weeks, a 4-day treatment period, and a 
safety follow-up period of approximately 30 (+4) days. 
The study completion date is defined as the date the final 
subject, across all sites, completes their final protocol-defined 


Study: ACP-044-004 
 
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Date: 01 February 2022 
 
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assessment (note: this includes the safety follow-up visit or 
contact). 
Main criteria for inclusion 
and exclusion 
To be eligible for this study, subjects must meet all of the 
inclusion criteria and none of the exclusion criteria. 
Inclusion Criteria: 
1. Male or female ≥18 and ≤65 years of age at the time of 
Screening 
2. Has a body mass index (BMI) <40 kg/m2 
3. Able to understand and provide signed informed 
consent 
4. Able to complete subject-reported outcome measures 
5. Is in need of a primary unilateral, first metatarsal 
bunionectomy with osteotomy and internal fixation 
under regional anesthesia and sedation  
6. Is judged by the Investigator to be American Society 
of Anesthesiologists Physical Status of I or II 
(Appendix A) 
7. Willing to remain inpatient at the study center for 
4 days following surgery 
8. Must have a negative COVID-19 diagnostic 
polymerase chain reaction (PCR) test at Screening and 
a rapid antigen test on Day -1 predose and is not 
planning to receive a COVID-19 vaccine within 
30 days of the last dose of study drug. If the subject 
has received a COVID-19 vaccine, they must be fully 
vaccinated at least one week before the Screening visit. 
If subjects have received a COVID-19 booster shot, 
they will need to have received the shot at least one 
week before Screening and have no residual 
symptoms.  
Note: subjects are considered fully vaccinated 2 weeks 
after their second dose in a 2-dose series or 2 weeks 
after a single-dose vaccine. 
9. If the subject is male, the subject and his partner must 
use a highly effective form of contraception (i.e., 
double-barrier method which includes a condom plus 
diaphragm with spermicide or condom plus 
spermicide) at the time of Screening and for at least 
30 days after the last dose of study drug. If subjects 
have had a vasectomy, they must still use a condom. 


Study: ACP-044-004 
 
Final Version: 1.0 
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Date: 01 February 2022 
 
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Subjects must also agree to not donate sperm for the 
duration of the study and for at least 30 days after the 
last dose of study drug. 
10. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing 
potential (defined as either surgically sterilized or at 
least 1 year postmenopausal) OR must agree to use 
TWO clinically acceptable methods of contraception 
for at least 30 days prior to Day -1, throughout the 
entire study, and for at least 30 days following 
completion of the study. Note the exception is that a 
barrier method can be initiated following the Screening 
visit. 
Acceptable methods of contraception include the 
following: 
a. A barrier method (condom, diaphragm, or 
cervical cap) with spermicide 
b. Hormonal contraception, including oral, 
injectable, transdermal, or implantable 
methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can 
be a hormonal method. 
All female subjects of childbearing potential must have 
a negative serum human chorionic gonadotropin (hCG) 
pregnancy test at Screening and a negative urine 
pregnancy test immediately prior to surgery. 
 
Exclusion Criteria: 
Medical Conditions 
1. Has had a contralateral foot bunionectomy in the past 
3 months 
2. Has a planned concurrent surgical procedure 
(e.g. bilateral bunionectomy or collateral procedures 
like hammertoe correction on the surgical foot) 
3. Any subacute or chronic pain condition or use of a 
medication that would impair/impact the ability to rate 
the pain associated with the bunionectomy, in the 
opinion of the Investigator and Medical Monitor 
Concomitant Treatments (Appendix B) 
4. Has known or suspected regular use of opioids within 
the previous 6 months 


Study: ACP-044-004 
 
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5. Has taken opioids within 24 hours prior to the 
scheduled surgery or within five half-lives of the drug, 
whichever is longer 
6. Has a positive drug screen at Screening or Day -1, or a 
recent (i.e., within the last 5 years) history of drug or 
alcohol abuse. Subjects using marijuana are not 
allowed to participate in the study. 
7. Has taken any aspirin (ASA) or non-steroidal 
anti-inflammatory drugs (NSAIDs) within 2 days prior 
to the scheduled surgery or within five half-lives of the 
drug, whichever is longer 
8. Has initiated treatment with any medications within 
1 month prior to study drug administration that could 
impact pain control or quantitation of their pain 
response 
9. Has been administered systemic steroids within 
five half-lives or 10 days prior to administration of 
study drug, whichever is longer 
Medical History, Laboratory Studies, Vital Signs, and 
Electrocardiogram 
10. Has current evidence, or medical history of a serious 
and/or unstable psychiatric, neurologic, cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, 
hematologic, endocrinologic, or other medical 
disorder, within the previous 12 weeks prior to 
Screening and on Day -1, that in the judgment of the 
Investigator and/or Medical Monitor would jeopardize 
the safe participation of the subject in the study. Also, 
subject must not have had a malignancy in the last 
year, with the exception of nonmetastatic basal cell of 
the skin or localized carcinoma in situ of the cervix. 
11. Has an ECG QTcF result at Screening or Day -1 of 
>480 ms 
12. Has a history of myocardial infarction  
13. Has a history of uncontrolled diabetes mellitus (DM), 
Type 1 or 2 DM requiring insulin treatment, or 
glycosylated hemoglobin (HbA1c) >7% at Screening 
14. Is suicidal at Screening or Day -1 as defined below: 
a. An answer of “yes” to C-SSRS questions 4 or 
5 (current or over the last 6 months); OR 
b. Has attempted suicide within 1 year prior to 
Screening; OR 
c. Is actively suicidal in the Investigator’s 
judgment 


Study: ACP-044-004 
 
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15. Has clinically significant laboratory abnormalities at 
Screening that in the judgment of the Investigator or 
Medical Monitor would jeopardize the safe 
participation of the subject in the study 
16. Known history of infection with hepatitis B virus 
(HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV). Subjects with a history 
of hepatitis B are eligible if there is documentation of a 
negative test for hepatitis B surface antigen and a 
positive test for antibodies to the hepatitis B virus 
surface antigen. Subjects with a history of hepatitis C 
are eligible if there is documentation of a negative 
hepatitis C virus RNA test. 
Other Criteria 
17. Has received an investigational product or device in a 
clinical trial within 30 days or within five elimination 
half-lives, whichever is longer, prior to Screening  
18. Is an employee or is a family member of an employee 
of Acadia Pharmaceuticals Inc. or the clinical research 
site or the clinical research organization (CRO) 
administering this study 
19. Is judged by the Investigator or the Medical Monitor to 
be inappropriate for the study 
Pharmacokinetic 
assessments 
At each predefined timepoint, a total of six (6) PK samples 
will be obtained for measurement of concentrations of 
ACP-044. PK blood samples will be collected Day -1 
(predose, within one hour of dosing), Day 1 (one sample 
taken between 2-3 hours and one sample taken between 
4-6 hours, after the first dose of the day), Day 2 (prior to the 
first dose of the day), and Day 3 (one sample taken between 
2-6 hours and one sample taken between 8-12 hours, after the 
first dose of the day). 
When possible, an additional PK sample will be collected 
from subjects who experience a serious adverse event (SAE) 
or an adverse event (AE) leading to discontinuation, as soon 
as possible after the occurrence of that event. For samples 
collected from subjects who experience an SAE or an AE 
leading to discontinuation, the date and time of the last dose 
prior to the SAE or AE should also be recorded. 
ACP-044 plasma concentration data will remain blinded until 
the unblinding of the clinical database at the end of the study.  


Study: ACP-044-004 
 
Final Version: 1.0 
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Sample size calculations 
The planned sample size is 240 subjects randomized 
(80 subjects per treatment group). Randomization will be 
stratified by site. 
Assuming a treatment difference in the AUC from 0 to 
24 hours is 23 points between the ACP-044 groups and 
placebo group, and the common standard deviation is 
50 points, 76 subjects per treatment arm will provide 
approximately 80% power to detect the assumed treatment 
difference between each ACP-044 dose arm and placebo at a 
2-sided significance level of 0.05. Assuming no more than 
5% of randomized patients will be excluded from primary 
efficacy analysis, 80 subjects per treatment group will be 
randomized. 
Statistical methods 
Population Analysis Sets 
The Safety Analysis Set includes all randomized subjects 
who received at least one dose of study drug (ACP-044 or 
placebo). Subjects will be analyzed based on the treatment 
that they actually received. The Safety Analysis Set will be 
used for all safety analyses. 
The Full Analysis Set (FAS) includes all randomized 
subjects who received at least one dose of study drug and 
who have undergone bunionectomy with at least one 
postoperative pain assessment. The Full Analysis Set will be 
used for the analysis of all efficacy endpoints. 
The Per-protocol (PP) Analysis Set will consist of those 
subjects in the FAS who did not have any protocol deviations 
that could potentially have a substantial impact on the 
primary efficacy outcome. The precise reasons for excluding 
subjects from the PP Analysis Set will be fully defined and 
documented prior to the clinical database lock. Subjects will 
be analyzed based on their randomized treatment assignment. 
The PP Analysis Set will be used for supportive analyses of 
selected efficacy endpoints. 
For ACP-044 plasma concentration summaries, the 
Pharmacokinetics Analysis Set will consist of subjects with 
at least one measurable ACP-044 plasma concentration. 
Subgroup Analysis 
Selected analyses will be performed in subgroups and will be 
defined in the statistical analysis plan (SAP). 
Primary Analysis 
The primary efficacy variable, AUC0-24, will be analyzed by 
using analysis of variance (ANOVA) with treatment group 


Study: ACP-044-004 
 
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and site as factors in the model. Each active dose group will 
be compared to placebo using this model.  
Details of the analysis procedure will be described in the 
SAP.  
Key Secondary Analyses 
Time to first rescue medication use will be analyzed using log 
rank test stratified by site. 
Proportion of patients who are opioid free through 24, 48, and 
72 hours will be analyzed using stratified Cochran-Mantel-
Haenszel (CMH) test controlling for study site.  
Secondary Analyses 
Continuous secondary variables will be analyzed similarly as 
the primary efficacy variable. Proportion of patients who are 
pain free at each specific timepoint will be analyzed using 
stratified Cochran-Mantel-Haenszel (CMH) test controlling 
for study site. 
General Statistical Approach 
Continuous measurement results will be reported using the 
number of subjects with data values, mean, standard error of 
the mean, standard deviation, minimum, maximum, and 
median. For each categorical outcome, the number and 
percentage of subjects in each category will be reported. All 
statistical hypothesis tests will be 2-sided at the significance 
level of 0.05. 
Multiple Comparisons / Multiplicity 
A fixed sequence method at alpha=0.05 for the primary and 
key secondary efficacy endpoints will be used to control for 
multiplicity. The sequence of endpoints for testing is listed in 
Section 9.2.1. 
Safety Analyses 
Safety results will be summarized by treatment group using 
descriptive statistics. No formal statistical testing will be 
performed for any of the safety endpoints. Adverse events 
will be classified into standard terminology using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events, TEAEs leading to 
discontinuation, TEAEs related to study drug, TEAEs by 
maximum severity, fatal TEAEs, and SAEs reported after 
study drug start will all be summarized. Other TEAEs of 
special interest (e.g., ORAEs) may also be summarized.  


Study: ACP-044-004 
 
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Descriptive statistics for ECG, vital signs and weight, and 
clinical laboratory parameters, including changes from 
Day -1 (prior to first dose), will be tabulated by timepoint. 
Additionally, categorical analyses will be conducted on the 
incidence of subjects with prolonged QTc intervals and 
changes in QTc intervals in accordance with International 
Council for Harmonisation (ICH) guidelines. 
Pharmacokinetic Analyses 
Plasma concentration data for ACP-044 will be listed and 
summarized using descriptive statistics. Results will be used 
for other analyses (e.g., population PK modelling), which will 
be presented in a separate report. 
Pharmacokinetic/Pharmacodynamic (PD) Analyses 
A population PK/PD model to describe the exposure response 
relationship between ACP-044 plasma concentrations and the 
relevant efficacy and safety endpoints will be developed 
using appropriate PK/PD methods. Results will be presented 
in a separate report. 
Date 
01 February 2022 
 


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Figure S–1 
Schematic of Study Design for ACP-044-004 
 
 
Abbreviations: EOT=end of treatment 
a 
Subjects to be randomized in a 1:1:1 ratio to receive either a once-daily oral dose of 1600 mg ACP-044, four oral doses of 400 mg ACP-044, or placebo. 
Randomization will occur just prior to surgery when the first dose of study drug is given.  
b 
The time at which the first dose on Day 1 (i.e., the fifth dose of study drug) is administered will be considered time 0 for pain assessments. 
 


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Table S–1 
Schedule of Events and Assessments for ACP-044-004 
 
Screening 
Period 
Double-blind 
Treatment Period 
 
Safety 
Follow-up Period 
Visit Day 
-28 to -2 
Day -1 
Predose 
Day -1 
(Dosing 
and 
Postdose) 
Day 1 
(Time 0) Day 2 Day 3  
Day 4 
(EOT/ET) 
Unscheduled 
Visitm 
Clinic 
visit 
Telephone 
call 
7 days 
after 
EOT 
30 days 
after last 
dose 
Visit window (# days) 
 
0 
0 
0 
0 
0 
0 
 
±3 
+4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical and surgical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
Xk 
 
Xk 
 
Vital signsa 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Height, weightb 
X 
X 
 
 
 
 
 
 
 
 
12-lead ECGc 
X 
X 
 
X 
X 
X 
X 
 
 
 
Clinical laboratory tests 
X 
X 
 
 
 
 
X 
 
 
 
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
 
Urine toxicology screen 
X 
X 
 
 
 
 
 
 
 
 
COVID-19 teste 
X 
X 
 
 
 
 
 
 
 
 
Clinic check in/out 
 
X 
 
 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
X 
X 
X 
X 
 
 
 
 
Pain assessment trainingf 
X 
X 
 
 
 
 
 
 
 
 
Bunionectomy 
 
 
X 
 
 
 
 
 
 
 
Block Quality Assessmentg 
 
 
X 
 
 
 
 
 
 
 
11-point Numeric Rating Scale (NRS) of pain 
intensityh 
 
 
 
X 
X 
X 
X 
 
 
 
Foot and Ankle Ability Measure 
 
X 
 
 
 
 
 
 
X 
 
Rescue medicationi 
 
 
 
X 
X 
X 
X 
 
 
 
 


Study: ACP-044-004 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 5 
 
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Table S–1 
Schedule of Events and Assessments for ACP-044-004 (Continued) 
 
Screening 
Period 
Double-blind 
Treatment Period 
 
Safety 
Follow-up Period 
Visit Day 
-28 to -2 
Day -1 
Predose 
Day -1 
(Dosing 
and 
Postdose) 
Day 1 
(Time 0) Day 2 Day 3  
Day 4 
(EOT/ET) 
Unscheduled 
Visitm 
Clinic 
visit 
Telephone 
call 
7 days 
after 
EOT 
30 days 
after last 
dose 
Visit window (# days) 
 
0 
0 
0 
0 
0 
0 
 
±3 
+4 
Global evaluation of study drug 
 
 
 
X 
X 
X 
X 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
X 
 
 
 
PK blood sample collectionj 
 
X 
 
X 
X 
X 
 
 
 
 
Issue diary 
 
 
 
 
 
 
Xl 
 
 
 
Collect diary 
 
 
 
 
 
 
 
 
X 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; COVID-19=Coronavirus disease 2019; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
EOT=end of treatment; ET=early termination; SAE=serious adverse event 
 
a 
Vital signs will be evaluated starting at Screening; Day -1 predose and on Day 1 every 2 hours for the first 6 hours after the initial dose. Vital signs then to be 
evaluated every 6 hours thereafter until Day 4/end of treatment. A 15-minute window is permitted for vital sign measurements. 
b  
Height and BMI will only be measured and calculated at the Screening visit; weight will be measured at Screening and Day -1 predose. 
c  
A single 12-lead ECG will be performed at Screening, on Day -1 predose, on Days 1 through 3 at 1 hour postdose (the first dose of the day), and EOT/ET. 
A 1-hour window is permitted for the predose ECG and a 20-minute window is permitted for the postdose ECGs. 
d 
Applicable to women of childbearing potential. A serum pregnancy test should be performed at Screening and a urine test must be performed at clinic 
check-in, prior to surgery. 
e 
COVID-19 diagnostic polymerase chain reaction (PCR) test at Screening and a rapid antigen test on Day -1 predose. 
f  
Subjects will be trained on the process for completion of pain assessments. 
g 
Block Quality assessments are to be performed and recorded hourly (±15 minutes) on Day -1 until the block is removed, except between 2200 and 
0600 hours when the subject is asleep. Between these hours, the subject will not be awaken, except at 0300 hours (±15 minutes) when the assessment is to be 
completed. 


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h 
Subjects should not have ice administered to the surgical area within the 30 minutes prior to each pain assessment. Pain (efficacy) assessments are to be 
recorded hourly (±15 minutes) for a 12 hour interval on Day 1 beginning immediately prior to the fifth dose (time 0) administered in the study. Pain 
assessments will continue every 3 hours during the subsequent 12 hour interval, and then every 6 hours thereafter until 72 hours, then once daily in the 
morning until the follow-up clinic visit. Rescue medication use is to be recorded until the safety follow-up clinic visit. Pain intensity should also be obtained 
immediately prior to rescue medication being taken. 
i 
Record name, amount, date, and time of rescue medication ingested and current pain score until the follow-up clinic visit 7 days after EOT. 
j 
PK blood samples will be collected Day -1 (predose, within one hour of dosing), Day 1 (one sample taken between 2-3 hours and one sample taken between 
4-6 hours, after the first dose of the day), Day 2 (prior to the first dose of the day), and Day 3 (one sample taken between 2-6 hours and one sample taken 
between 8-12 hours, after the first dose of the day); and in the event of an SAE or an AE leading to discontinuation. A 15-minute window is permitted around 
each nominal timepoint on Day 1 and beyond. 
k 
The physical exam on Day 4 (EOT/ET) must include an exam of the operative site. The physical exam at the follow-up visit 7 (±3) days after the EOT 
procedures is for examination of the operative site only. Examination of the operative site must include visual inspection. 
l 
Diary will be issued to take home which will be returned at the follow-up clinic visit 7 days after EOT. 
m 
The designated study procedures are to be completed; however, the Investigator may complete any study procedure deemed necessary. 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 21 
LIST OF TABLES ................................................................................................................... 26 
LIST OF FIGURES ................................................................................................................. 26 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 27 
1 
INTRODUCTION ...................................................................................................... 28 
1.1 
Background Information ............................................................................................ 28 
1.2 
Investigational Product ............................................................................................... 28 
1.3 
Nonclinical Data ......................................................................................................... 29 
1.4 
Previous Clinical Experience ..................................................................................... 29 
1.4.1 
Clinical Pharmacology ............................................................................................... 29 
1.5 
Study Rationale .......................................................................................................... 30 
1.5.1 
Rationale for Study Design ........................................................................................ 30 
1.5.2 
Rationale for Dose Selection ...................................................................................... 31 
1.6 
Potential Risks and Benefits ....................................................................................... 31 
1.6.1 
Known Potential Risks ............................................................................................... 31 
1.6.2 
Known Potential Benefits ........................................................................................... 32 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 32 
2.1 
Primary Objective....................................................................................................... 32 
2.1.1 
Primary Endpoint ....................................................................................................... 32 
2.2 
Secondary Objectives ................................................................................................. 32 
2.2.1 
Key Secondary Endpoints .......................................................................................... 32 
2.2.2 
Secondary Endpoints .................................................................................................. 32 
2.3 
Exploratory Objectives ............................................................................................... 33 
2.3.1 
Exploratory Endpoints ................................................................................................ 33 
2.4 
Safety Objectives ........................................................................................................ 33 
2.4.1 
Safety Endpoints......................................................................................................... 33 
2.5 
Pharmacokinetic Objectives ....................................................................................... 34 
2.5.1 
Pharmacokinetic Endpoints ........................................................................................ 34 
2.6 
Pharmacokinetic/Pharmacodynamic Objective .......................................................... 34 
2.6.1 
Pharmacokinetic/Pharmacodynamic Endpoints ......................................................... 34 


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3 
STUDY DESCRIPTION ............................................................................................ 34 
3.1 
Overview of Study Design ......................................................................................... 34 
3.1.1 
Screening Period (Up to 4 Weeks) ............................................................................. 35 
3.1.2 
Treatment Period (Day -1 to Day 4) ........................................................................... 35 
3.1.3 
Safety Follow-up Period (30 Days) ............................................................................ 36 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 36 
4.1 
Inclusion Criteria ........................................................................................................ 36 
4.2 
Exclusion Criteria ....................................................................................................... 38 
4.3 
Screen Failures ........................................................................................................... 39 
4.4 
Subject Withdrawal of Consent .................................................................................. 40 
4.5 
Subject or Study Discontinuation ............................................................................... 40 
4.5.1 
Discontinuation of Study Drug for Individual Subjects ............................................. 41 
4.5.1.1 Cardiovascular-Related Stopping Criteria .................................................................. 41 
4.5.2 
Handling of Subject Discontinuation During the Treatment Period .......................... 42 
4.6 
Subject Lost to Follow-up .......................................................................................... 42 
4.7 
Prior and Concomitant Therapy ................................................................................. 42 
4.7.1 
Prior Medication ......................................................................................................... 42 
4.7.2 
Concomitant Medication ............................................................................................ 42 
4.8 
Permitted, Restricted, and Prohibited Medications .................................................... 43 
4.8.1 
Rescue Medications, Treatments, and Procedures ..................................................... 43 
4.9 
Lifestyle Considerations ............................................................................................. 44 
4.9.1 
Activity ....................................................................................................................... 44 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 44 
5.1 
Investigational Product Description ........................................................................... 44 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 44 
5.1.2 
Product Storage and Stability ..................................................................................... 44 
5.1.3 
Dosing and Administration ......................................................................................... 45 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 45 
5.1.5 
Blinding ...................................................................................................................... 45 
5.1.6 
Study Drug Compliance ............................................................................................. 46 
5.1.7 
Overdose ..................................................................................................................... 46 
5.2 
Investigational Product and Rescue Medication Accountability Procedures ............. 46 
6 
STUDY PROCEDURES ............................................................................................ 46 
6.1 
Remote Assessments or Visits .................................................................................... 47 
6.2 
Screening Assessments ............................................................................................... 47 


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6.2.1 
Medical and Medication History ................................................................................ 47 
6.3 
Block Quality Assessment .......................................................................................... 47 
6.4 
Efficacy Assessments ................................................................................................. 48 
6.4.1 
Numeric Rating Scale of Pain Intensity ..................................................................... 48 
6.4.2 
Global Evaluation of Study Drug ............................................................................... 48 
6.4.3 
Foot and Ankle Ability Measure ................................................................................ 48 
6.5 
Safety Assessments..................................................................................................... 49 
6.5.1 
Physical Examination ................................................................................................. 49 
6.5.2 
Vital Signs .................................................................................................................. 49 
6.5.3 
Electrocardiograms ..................................................................................................... 50 
6.5.4 
Columbia-Suicide Severity Rating Scale ................................................................... 50 
6.5.5 
Laboratory Evaluations .............................................................................................. 50 
6.6 
Pharmacokinetic Assessments .................................................................................... 53 
6.6.1 
Blood Sampling .......................................................................................................... 53 
6.6.2 
Specimen Preparation, Handling, Storage, and Shipment.......................................... 53 
6.7 
Safety Follow-up ........................................................................................................ 53 
6.8 
Unscheduled Visits ..................................................................................................... 54 
7 
ADVERSE EVENTS ................................................................................................. 54 
7.1 
Specification of Safety Parameters............................................................................. 54 
7.1.1 
Definition of Adverse Event ....................................................................................... 54 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 55 
7.2 
Classification of an Adverse Event ............................................................................ 56 
7.2.1 
Severity of Event ........................................................................................................ 56 
7.2.2 
Relationship to Study Drug ........................................................................................ 57 
7.2.3 
Duration ...................................................................................................................... 57 
7.2.4 
Frequency ................................................................................................................... 57 
7.2.5 
Action Taken with Study Drug ................................................................................... 57 
7.2.6 
Therapy ....................................................................................................................... 58 
7.2.7 
Outcome ..................................................................................................................... 58 
7.2.8 
Seriousness ................................................................................................................. 58 
7.2.9 
Definition of Unexpectedness .................................................................................... 58 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 58 
7.4 
Reporting Procedures ................................................................................................. 59 
7.4.1 
Adverse Event Reporting ........................................................................................... 59 
7.4.2 
Serious Adverse Event Reporting............................................................................... 59 
7.4.3 
Reporting of Pregnancy .............................................................................................. 60 


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7.4.4 
Reporting of Overdose ............................................................................................... 60 
8 
CLINICAL MONITORING ....................................................................................... 61 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 61 
9.1 
Statistical and Analytical Plans .................................................................................. 61 
9.2 
Statistical Hypotheses................................................................................................. 61 
9.2.1 
Multiple Comparisons/Multiplicity ............................................................................ 61 
9.3 
Sample Size Determination ........................................................................................ 62 
9.4 
Subject Populations for Analysis ................................................................................ 62 
9.5 
Statistical Analyses ..................................................................................................... 63 
9.5.1 
General Statistical Approach ...................................................................................... 63 
9.5.2 
Primary Analyses ........................................................................................................ 63 
9.5.3 
Key Secondary Analyses ............................................................................................ 63 
9.5.4 
Secondary Analyses .................................................................................................... 63 
9.5.5 
Exploratory Analyses ................................................................................................. 63 
9.5.6 
Safety Analyses .......................................................................................................... 63 
9.5.7 
Pharmacokinetic Analyses .......................................................................................... 64 
9.5.8 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................... 64 
9.5.9 
Subgroup Analyses ..................................................................................................... 64 
9.6 
Interim Analyses ......................................................................................................... 64 
9.7 
Measures to Minimize Bias ........................................................................................ 64 
9.8 
Breaking the Study Blind/Subject Code ..................................................................... 65 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 65 
10.1 
Data Collection and Management Responsibilities.................................................... 65 
10.2 
Source Documents ...................................................................................................... 65 
10.3 
Case Report Forms ..................................................................................................... 66 
10.4 
Confidentiality ............................................................................................................ 66 
10.5 
Study Records Retention ............................................................................................ 66 
10.6 
Protocol Exceptions and Deviations........................................................................... 66 
10.7 
Protocol Amendments ................................................................................................ 67 
11 
QUALITY MANAGEMENT .................................................................................... 67 
11.1 
Risk Management ....................................................................................................... 67 
11.2 
Quality Control and Quality Assurance...................................................................... 68 
12 
ETHICAL CONSIDERATIONS ................................................................................ 68 
12.1 
Ethical Standard ......................................................................................................... 68 


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12.2 
Institutional Review Board/Ethics Committee ........................................................... 69 
12.3 
Informed Consent Process .......................................................................................... 69 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 70 
12.3.2 Consent Procedures and Documentation .................................................................... 70 
13 
PUBLICATION PLAN .............................................................................................. 70 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 70 
14.1 
Finance, Insurance, and Indemnity............................................................................. 70 
15 
LITERATURE REFERENCES .................................................................................. 71 
16 
APPENDICES ............................................................................................................ 73 
Appendix A American Society of Anesthesiologists Physical Status Classification 
System ........................................................................................................................ 73 
Appendix B Prohibited and Restricted Medications ............................................................. 74 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-044-004 .................................. 18 
Table 5-1 
Blinded Daily Dosing Regimen ....................................................................... 45 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 52 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-044-004 ................................................. 17 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE(s) 
adverse event(s) 
AUC 
area under the curve 
AUC0-4  
area under the curve from time 0 to 4 hours 
AUC0-6 
area under the curve from time 0 to 6 hours 
AUC0-12 
area under the curve from time 0 to 12 hours 
AUC0-24 
area under the curve from time 0 to 24 hours 
AUC0-48 
area under the curve from time 0 to 48 hours 
AUC0-72 
area under the curve from time 0 to 72 hours 
BMI 
body mass index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
FAAM 
Foot and Ankle Ability Measure 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
NRS 
Numeric Rating Scale 
PD 
pharmacodynamic 
PK 
pharmacokinetics 
PP 
per-protocol 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
TEAE(s) 
treatment-emergent adverse event(s) 
US 
United States 


Study: ACP-044-004 
 
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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol, the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline, and applicable regulatory requirements. 
1.1 
Background Information 
Acute postoperative pain has limited treatment options, each with their own benefits and 
shortcomings. The mainstays of acute pain treatment are opioids. While they provide efficacy 
to the patients that take them, there are significant risks of constipation, tolerance and 
dependence, respiratory depression, abuse, diversion and potentially addiction. Postoperative 
pain following surgery is expected to be moderate to severe and often requires opioids for 
analgesia that thereby improve the quality of the recovery period. Many operative procedures 
result in pain that follows a predictable course and is typically short in duration. More than 
thirteen million ambulatory surgeries were performed in hospital-owned facilities in the 
United States in 2016 (Karaca and McDermott 2019). Following the procedure, patients are 
typically given opioids to treat their pain and promote recovery. While opioids are often 
effective in this setting, many physicians have concerns about the potential for subsequent 
opioid medication misuse, addiction, and diversion. With an ongoing opioid epidemic in the 
United States that is leading to an average of 128 overdose deaths each day (Wilson et al. 
2020), and prescription opioid misuse costing $78.5 billion per year, new nonaddictive pain 
therapies are critically needed (Florence et al. 2016). There is a growing medical need for 
non-opioid pain management options. Therefore, Acadia is developing ACP-044, a 
peripherally-acting molecule with demonstrated efficacy in a wide array of nonclinical 
models of pain to prevent and treat acute postsurgical pain. 
1.2 
Investigational Product 
ACP-044, is a non-metal based, orally bioavailable, small molecule Reactive Species 
Decomposition Accelerant (RSDAx) that works by promoting degradation of peroxynitrite 
(PN) and peroxide. Peroxynitrite and peroxide are powerful oxidants produced under 
conditions of injury (e.g., surgical incision) and disease (e.g., diabetes) that cause untoward 
effects via protein nitration and modification of sensory ion channels leading to neuronal 
sensitization and pain (McConnell et al. 2003; Lee et al. 1998a; Lee et al. 1998b; 
Chaplan et al. 1994; Hargreaves et al. 1988; Fehrenbacher et al. 2012; Sluka and Willis 1997; 
Brennan et al. 1996). By removing PN, ACP-044 prevents or disrupts the ensuing pathways 
causing hypersensitivity thereby preventing the development of hyperalgesia or reversing 
existing hyperalgesia. 


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1.3 
Nonclinical Data 
In vivo, ACP-044 is efficacious in pre-clinical models of acute post-incisional hyperalgesia, 
both prophylactically and palliatively. This suggests that ACP-044 may be of use in 
peri-operative settings as a replacement or to reduce the amount of opioid products 
(i.e., Percocet, Vicodin) often prescribed following minimally invasive surgical procedures. 
1.4 
Previous Clinical Experience 
1.4.1 
Clinical Pharmacology 
Three Phase 1 studies have been clinically completed to date in healthy subjects up to 
55 years of age. A total of 54 subjects have received ACP-044 (single oral doses up to 
2000 mg) and 14 subjects received placebo. In the single ascending dose study, 32 subjects 
were enrolled in four dose cohorts (150, 450, 1100, and 2000 mg ACP-044; subjects were 
randomized to six active and two placebo for each dose cohort). In the food effect study, 
12 subjects received two single oral doses of 600 mg ACP-044 according to fed or fasting 
conditions. In the multiple ascending dose study, 24 subjects were enrolled in three dose 
cohorts (200, 400, and 600 mg dosed orally three times each day for 7 days; subjects were 
randomized to 6 active and 2 placebo for each dose cohort). The single and multiple 
ACP-044 doses were safe and well tolerated in healthy subjects. 
ACP-044 exhibits linear kinetics with no time- or dose-dependent effect on pharmacokinetic 
(PK) parameters. Systemic exposure to ACP-044 was dose-proportional across the studied 
dose range. Minimal to no accumulation was observed following multiple-dose 
administration, and as such the single-dose PK profile is considered representative of the 
steady-state profile. The PK profile of ACP-044 following oral administration is best 
described by a one-compartment model with first-order absorption and first-order 
elimination. Following oral administration, ACP-044 is rapidly absorbed with a median time 
to maximum drug concentration (Tmax) of approximately 1-2 hours. Ingestion of a high-fat 
meal had a small effect on the rate of absorption (approximately 23% reduction in maximum 
observed drug concentration (Cmax) and 1 hour delay in Tmax) and had no effect on the extent 
(area under the curve [AUC]) of ACP-044 absorption. Since the relative extent of absorption 
was unaffected by the presence of a high fat meal, it is anticipated that the slight reduction in 
Cmax and prolongation of Tmax will be of no clinical significance. 
In vitro, ACP-044 has shown moderate protein binding in human plasma. At concentrations 
of 10 µM, binding was 88%. 
Consistent with the nonclinical data, ACP-044 volume of distribution in studied subjects was 
<30 L, which suggests that ACP-044 does not reach beyond the extracellular fluid with 
limited to no distribution into tissues (intracellularly). 


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ACP-044 is primarily metabolized and the major metabolite is sulfate conjugate and to a 
lesser extent is glucuronide conjugate. Consistent with preclinical data, following oral 
administration in healthy subjects, approximately 35% of ACP-044 was excreted unchanged 
in urine indicating that hepatic metabolism and renal excretion contribute to ACP-044 
elimination. Following oral administration in healthy subjects, decline from peak is 
mono-exponential and is characterized by a rapid elimination phase with rapid clearance 
(mean CL/F=6.04 to 11.3 L/h) and a short half-life (mean t½=1.6 to 3.2 hours).   
According to nonclinical assessments ACP-044 did not directly inhibit (IC50 values >100 
µM) the cytochrome P450 (CYP) isozymes tested (1A2, 2C8, 2C19, 2D6, and 3A4) nor 
transporters (IC50 >600 µM for P-gp, OATP1B1, OATP1B3, OAT1, OCT1, MATE1 and 
MATE2-K; IC50=174 µM for OAT3; IC50 >30 µM for breast cancer resistant protein 
(BCRP). Future studies are planned to investigate the full panel of CYPs and transporters and 
their drug-drug interaction (DDI) potential. 
Always refer to the latest version of the ACP-044 Investigator’s brochure for the overall 
benefit/risk assessment and the most accurate and current information regarding nonclinical 
data, drug metabolism, pharmacokinetics, efficacy, and safety. 
1.5 
Study Rationale 
ACP-044 has demonstrated efficacy in acute and chronic nociceptive models in rodents and 
has been shown to be safe and well tolerated in single and multiple ascending dose studies in 
healthy volunteer subjects. The present study is a proof of concept study to evaluate the 
efficacy of ACP-044 as an analgesic for the treatment of acute postoperative pain and to 
evaluate the safety, tolerability, and pharmacokinetic profile. The postoperative 
bunionectomy model is a widely used human orthopedic model in the development of 
analgesic drugs (Desjardins et al. 2002; Daniels et al. 2009; Pollak et al. 2018). 
1.5.1 
Rationale for Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled inpatient study in subjects 
with acute postoperative pain following bunionectomy. The study will assess the efficacy of 
ACP-044 by comparing the same maximum dose of ACP-044, 1600 mg administered either 
as a single dose or as 400 mg administered every six hours. Guided by nonclinical animal 
models where ACP-044 provided robust analgesic effects when given prior to incision as a 
single dose or when administered daily at 24, 48, and 72 h post-incision, dosing in the present 
study will begin prior to surgery and will continue for 3 days after surgery. 


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1.5.2 
Rationale for Dose Selection 
In a nonclinical animal model, a single oral dose of ACP-044 prevented the development of 
incisional hyperalgesia for at least 3 days, with the highest dose tested (30 mg/kg) producing 
essentially complete prevention of hyperalgesia. Similarly, daily doses of ACP-044 given 
postincision provided continuous relief from an ongoing hyperalgesic insult in a 
dose-dependent manner. It is not clear, however, whether the response is driven by Cmax or 
AUC. In the present proof of concept study, the maximum tolerated dose of ACP-044 is 
being evaluated by testing two dosing regimens (i.e., once-daily or every 6 hours) to allow 
the selection of the optimal dosing regimen and better characterization of the 
exposure-response relationship.  
1.6 
Potential Risks and Benefits 
Nonclinical studies in animal models of acute and chronic nociception have demonstrated 
efficacy (i.e., analgesia) with ACP-044 and that it is safe and well tolerated. This study will 
help identify whether ACP-044 is efficacious as an analgesic treatment in humans as it is the 
first clinical efficacy study to date. If the study shows treatment with ACP-044 is effective, 
this could lead to further clinical development of this treatment for pain. 
A detailed summary of the potential risks and benefits is available in the ACP-044 
Investigator’s brochure. 
1.6.1 
Known Potential Risks 
In the Phase 1 clinical studies in healthy volunteers, the side effects that occurred in more 
than 1 subject treated with ACP-044 were indigestion and headache.  
In the nonclinical studies, side effects seen in animals that were given ACP-044 were 
vomiting, stomach acid reflux, loose stools, and changes in some organ weights. Although 
these side effects have not been seen in human studies, they may be potential risks. 
There may be unforeseeable risks or side effects that are related to the study drug and that are 
unknown at this time. The study drug, when taken alone or in combination with other 
medications, may have risks that are unknown. Rare or unknown side effects may occur. It is 
not possible to predict the chances of such problems or how bad they could be. 
All drugs have a potential risk of an allergic reaction which, if not treated promptly, could 
become life threatening. Some symptoms of allergic reaction are: rash, difficulty breathing, 
wheezing, swelling around the mouth, throat or eyes, a fast pulse, and sweating. Each 
research center is expected to have qualified staff, equipment, and drugs to be able to manage 
an acute allergic reaction. 


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1.6.2 
Known Potential Benefits 
ACP-044 is being assessed for the treatment of postoperative acute pain. As the present study 
is a proof of concept study, there have been no clinical benefits demonstrated to date. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of ACP-044 compared with 
placebo in the treatment of acute postoperative pain. 
2.1.1 
Primary Endpoint 
The primary endpoint is AUC of the Numeric Rating Scale (NRS) of pain intensity scores 
from time 0 (when first dose on Day 1 is administered) through 24 hours (AUC0-24) for 
ACP-044. 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
• to evaluate the efficacy of ACP-044 compared with placebo in the treatment of acute 
postoperative pain 
• to evaluate opioid use among ACP-044-treated subjects compared with placebo in the 
treatment of acute postoperative pain 
2.2.1 
Key Secondary Endpoints 
• Time to first rescue medication use after time 0 (when first dose on Day 1 is 
administered) 
• Proportion of subjects who were opioid free through 24, 48, and 72 hours 
2.2.2 
Secondary Endpoints 
The secondary endpoints are: 
• Mean AUC of the NRS of pain intensity scores from time 0 through 48 and 72 hours 
(AUC0-48; AUC0-72) for ACP-044  
• Mean AUC of the NRS of pain intensity scores from time 0 through 4, 6, and 12 hours 
(AUC0-4; AUC0-6; AUC0-12), 24-48 hours (AUC24-48), and 48-72 hours (AUC48-72) for 
ACP-044  
• Amount of rescue medication taken during 0-24, 24-48, and 48-72 hours 
(individually), 0-48 hours, and 0-72 hours 


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• Proportion of subjects who did not use rescue medication through 24, 48, and 72 hours 
• Proportion of subjects who are pain free (NRS ≤2) at 24, 48, and 72 hours 
• Number of hours subjects are pain free (NRS ≤2) 
• Proportion of subjects who were opioid free during 24-48 hours and 48-72 hours 
• Global evaluation of study drug just before time of first rescue medication and at the 
end of 24, 48, and 72 hours relative to time 0 (when first dose on Day 1 is 
administered) 
2.3 
Exploratory Objectives 
The exploratory objectives are to evaluate the proportion of subjects with severe pain and to 
compare the impact of ACP-044 on activities of daily living compared with placebo in the 
treatment of acute postoperative pain. 
2.3.1 
Exploratory Endpoints 
The exploratory endpoints are: 
• Proportion of subjects with severe pain (defined as an NRS pain intensity score ≥7 at 
any timepoint through 72 hours)  
• Foot and Ankle Ability Measure (FAAM) 
2.4 
Safety Objectives 
The safety objective of the study is to evaluate the safety and tolerability of ACP-044 
compared with placebo in the treatment of acute postoperative pain. 
2.4.1 
Safety Endpoints 
Safety will be evaluated by analyses of the following: 
• Treatment-emergent adverse events (TEAEs) 
• Opioid-related adverse events (ORAEs) 
• Vital signs  
• Electrocardiograms (ECGs) 
• Physical examination results 
• Clinical laboratory tests 
• Columbia-Suicide Severity Rating Scale (C-SSRS) 


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2.5 
Pharmacokinetic Objectives 
The PK objective of the study is to characterize the PK profile of ACP-044 in subjects treated 
for acute postoperative pain. 
2.5.1 
Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• Plasma concentrations of ACP-044 for a total of six (6) samples: Day -1 (predose), 
Day 1 (one sample taken between 2-3 hours and one sample taken between 4-6 hours, 
after the first dose of the day), Day 2 (prior to the first dose of the day), and Day 3 
(one sample taken between 2-6 hours and one sample taken between 8-12 hours, after 
the first dose of the day) 
• ACP-044 PK parameters determined using a population PK approach 
2.6 
Pharmacokinetic/Pharmacodynamic Objective 
The PK/pharmacodynamic (PD) objective of the study is to characterize the 
exposure-response relationship using appropriate modelling and simulation methods. 
2.6.1 
Pharmacokinetic/Pharmacodynamic Endpoints 
The PK/PD endpoints include: 
• ACP-044 exposure-response relationship:  
o for efficacy using the primary endpoint, key secondary and selected secondary 
endpoints 
o for safety using selected TEAEs 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a Phase 2, randomized, double-blind, placebo-controlled, 
multicenter, inpatient study in subjects with acute postoperative pain (following 
bunionectomy surgery). The study will compare each of the two active treatment groups 
receiving a total daily dose of 1600 mg ACP-044, administered either once daily or 400 mg 
every 6 hours, with a placebo group. The Sponsor, subjects, and Investigators will be blinded 
to treatment assignment. 
Approximately three sites in the United States (US) will screen approximately 375 subjects 
and approximately 240 subjects are planned for enrollment (80 subjects per treatment group). 


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The duration of participation for individual study subjects will be approximately 9 weeks, 
consisting of a screening period of up to 4 weeks, a 4-day treatment period, and a safety 
follow-up period of approximately 30 (+4) days. 
The study periods are: 
• Screening: up to 4 weeks (prior to surgery) 
• Double-blind treatment: Day -1 (post first dose of study drug/day of surgery) to Day 4 
• Safety follow-up: approximately 7 days after end of treatment (EOT)/early termination 
(ET) and approximately 30 days (post last dose of study drug) 
The study start date is defined as the date the first subject signs the informed consent form. 
The study completion date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note: this includes the safety follow-up visit or 
contact). Procedures for when a subject is lost to follow-up are provided in Section 4.6. 
The study schematic is presented in Figure S–1 and the schedule of assessments is provided 
in Table S-1. 
3.1.1 
Screening Period (Up to 4 Weeks) 
During the Screening period, subjects will be assessed for study eligibility. Only those 
subjects who meet all inclusion and no exclusion criteria will be eligible for the study. 
All prohibited medications should be discontinued during the Screening period and prior to 
surgery. Investigators must not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications will be discontinued only if it is deemed clinically 
appropriate to do so and in consultation with the prescribing physician. 
With approval of the Medical Monitor, rescreening of a subject will be allowed one time if 
there is an extenuating circumstance that was not under the subject’s control or if it is due to 
an identifiable cause, and it is medically appropriate to address that cause, and there is no 
medical reason that would prevent the subject to be rescreened and enrolled in the study. 
3.1.2 
Treatment Period (Day -1 to Day 4) 
On the day of surgery (Day -1), eligible subjects will be randomly assigned in a 1:1:1 ratio to 
receive 1600 mg ACP-044, administered either once daily or 400 mg every 6 hours, or 
placebo, according to a randomization schedule. Randomization will be stratified by site. 
The first dose of study drug will be administered within 60 (±15) minutes prior to the start of 
surgery. Subjects will then have a popliteal and/or ankle nerve block administered to 
anesthetize the knee, distal leg, and foot, after which they will enter into surgery. Following 


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surgery, subjects will be administered the remaining three daily doses approximately every 
6 hours after the initial dose.  
The popliteal and/or ankle nerve block will be discontinued approximately 2-4 hours prior to 
the first dose on Day 1 (i.e., the fifth dose of the study) and nerve block removal; a 
discontinuation window of approximately 2 hours is permitted. The time at which the first 
dose on Day 1 is administered will be time 0 for all pain assessments. Study drug 
administration and study procedures are to be completed on Days -1 through 4 according to 
the schedule of assessments (Table S–1). Subjects will be encouraged to refrain from taking 
rescue medication until 1-2 hours following the first dose of study drug on Day 1 (details 
provided in Section 4.8.1). 
On Day 4, after the 72 hour pain assessments are performed, the EOT procedures will be 
completed and subjects will be discharged from the clinical site.  
See Section 4.5 for subjects who discontinue early from the study. 
3.1.3 
Safety Follow-up Period (30 Days) 
Safety will be further assessed during a follow-up visit to occur in the clinic approximately 
7 (±3) days after EOT/ET procedures and subjects will receive a follow-up telephone call 
approximately 30 (+4) days after the last dose of study drug. Subjects should return to 
standard of care after the follow-up visit that will occur in the clinic 7 (±3) days after the 
EOT/ET. 
The study schematic is presented in Figure S–1. 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Male or female ≥18 and ≤65 years of age at the time of Screening 
2. Has a body mass index (BMI) <40 kg/m2 
3. Able to understand and provide signed informed consent 
4. Able to complete subject-reported outcome measures 
5. Is in need of a primary unilateral, first metatarsal bunionectomy with osteotomy and 
internal fixation under regional anesthesia and sedation 


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6. Is judged by the Investigator to be American Society of Anesthesiologists Physical 
Status of I or II (Appendix A) 
7. Willing to remain inpatient at the study center for 4 days following surgery 
8. Must have a negative COVID-19 diagnostic polymerase chain reaction (PCR) test at 
Screening and a rapid antigen test on Day -1 predose and is not planning to receive a 
COVID-19 vaccine within 30 days of the last dose study drug. If the subject has 
received a COVID-19 vaccine, they must be fully vaccinated at least one week before 
the Screening visit. If subjects have received a COVID-19 booster shot, they will need 
to have received the shot at least one week before Screening and have no residual 
symptoms. 
Note: subjects are considered fully vaccinated 2 weeks after their second dose in a 
2-dose series or 2 weeks after a single-dose vaccine. 
9. If the subject is male, the subject and his partner must use a highly effective form of 
contraception (i.e., double-barrier method which includes a condom plus diaphragm 
with spermicide or condom plus spermicide) at the time of Screening and for at least 
30 days after the last dose of study drug. If subjects have had a vasectomy, they must 
still use a condom. 
Subjects must also agree to not donate sperm for the duration of the study and for at 
least 30 days after the last dose of study drug 
10. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically acceptable methods of 
contraception for at least 30 days prior to Day -1, throughout the entire study, and for 
at least 30 days following completion of the study. Note the exception is that a barrier 
method can be initiated following the Screening visit. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a hormonal method. 
All female subjects of childbearing potential must have a negative serum human 
chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine 
pregnancy test immediately prior to surgery. 


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4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
Medical Conditions 
1. Has had a contralateral foot bunionectomy in the past 3 months 
2. Has a planned concurrent surgical procedure (e.g. bilateral bunionectomy or collateral 
procedures like hammertoe correction on the surgical foot) 
3. Any subacute or chronic pain condition or use of a medication that would 
impair/impact the ability to rate the pain associated with the bunionectomy, in the 
opinion of the Investigator and Medical Monitor 
Concomitant Treatments (Appendix B) 
4. Has known or suspected regular use of opioids within the previous 6 months 
5. Has taken opioids within 24 hours prior to the scheduled surgery or within five 
half-lives of the drug, whichever is longer 
6. Has a positive drug screen at Screening or Day -1, or a recent (i.e., within the last 
5 years) history of drug or alcohol abuse. Subjects using marijuana are not allowed to 
participate in the study. 
7. Has taken any aspirin (ASA) or non-steroidal anti-inflammatory drugs (NSAIDs) 
within 2 days prior to the scheduled surgery or within five half-lives of the drug, 
whichever is longer 
8. Has initiated treatment with any medications within 1 month prior to study drug 
administration that could impact pain control or quantitation of their pain response 
9. Has been administered systemic steroids within five half-lives or 10 days prior to 
administration of study drug, whichever is longer 
Medical History, Laboratory Studies, Vital Signs, and Electrocardiogram 
10. Has current evidence, or medical history of a serious and/or unstable psychiatric, 
neurologic, cardiovascular, respiratory, gastrointestinal, renal, hepatic, hematologic, 
endocrinologic, or other medical disorder, within the previous 12 weeks prior to 
Screening and on Day -1, that in the judgment of the Investigator and/or Medical 
Monitor would jeopardize the safe participation of the subject in the study. Also, 
subject must not have had a malignancy in the last year, with the exception of 
nonmetastatic basal cell of the skin or localized carcinoma in situ of the cervix. 
11. Has an ECG QTcF result at Screening or Day -1 of >480 ms 
12. Has a history of myocardial infarction   


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13. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 DM requiring 
insulin treatment, or glycosylated hemoglobin (HbA1c) >7% at Screening 
14. Is suicidal at Screening or Day -1 as defined below: 
a. An answer of “yes” to C-SSRS questions 4 or 5 (current or over the last 
6 months); OR 
b. Has attempted suicide within 1 year prior to Screening; OR 
c. Is actively suicidal in the Investigator’s judgment 
15. Has clinically significant laboratory abnormalities at Screening that in the judgment of 
the Investigator or Medical Monitor would jeopardize the safe participation of the 
subject in the study 
16. Known history of infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV). Subjects with a history of hepatitis B are 
eligible if there is documentation of a negative test for hepatitis B surface antigen and 
a positive test for antibodies to the hepatitis B virus surface antigen. Subjects with a 
history of hepatitis C are eligible if there is documentation of a negative hepatitis C 
virus RNA test. 
Other Criteria 
17. Has received an investigational product or device in a clinical trial within 30 days or 
within five elimination half-lives, whichever is longer, prior to Screening  
18. Is an employee or is a family member of an employee of Acadia Pharmaceuticals Inc. 
or the clinical research site or the clinical research organization (CRO) administering 
this study 
19. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
4.3 
Screen Failures 
Rescreening of a subject will be allowed one time, with the approval of the Medical Monitor, 
if there is an extenuating circumstance that was not under the subject’s control, or if it is due 
to an identifiable cause, and it is medically appropriate to address that cause, and there is no 
medical reason that would prevent the subject to be rescreened and enrolled in the study. 
Subjects may be rescreened following a COVID-19 infection as long as they have no 
sequelae from COVID-19 infection, per Exclusion Criterion 10. 
The minimum information that will be captured includes, date informed consent is signed, 
demography, screen failure details, and any adverse event (AE)/serious adverse event (SAE). 


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4.4 
Subject Withdrawal of Consent 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 
If a subject decides to withdraw consent from all components of the study, this must be 
documented and no additional assessments will be performed. If the subject wants to 
discontinue treatment and agrees to the evaluations specified at the EOT/ET and/or safety 
follow-up visit (whichever visit is applicable), as outlined in Table S–1, the agreed 
assessments should be conducted. The subject’s reason for wanting to discontinue treatment 
and the agreement to continue with the applicable assessments for study termination must be 
documented. 
4.5 
Subject or Study Discontinuation 
Subjects may be discontinued from the study for a number of reasons, including, but not 
limited to, those listed below: 
• AE 
• Death 
• Lack of efficacy 
• Lost to follow-up (Section 4.6) 
• Non-compliance with study drug 
• Investigator decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• Use of prohibited medication 
• Withdrawal of consent by subject 
• Other 
If at any time the C-SSRS results for a given subject reveal potential suicidality, then the 
Investigator should assess the clinical significance of such results. If a clinically significant 
risk of suicidality is identified for a subject, then the Investigator should discontinue the 
subject and implement appropriate treatment (Section 6.5.4). 


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The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
• Occurrence of AEs unknown to date in respect of their nature, severity, and duration or 
the unexpected incidence of known AEs 
• Medical, ethical, or business reasons affecting the continued conduct of the study 
Regulatory authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
If the study is terminated for any reason, subjects remaining in the study will return to standard of 
care. 
4.5.1 
Discontinuation of Study Drug for Individual Subjects 
The Investigator and Medical Monitor will review all laboratory, ECG, and related safety 
data regularly throughout the study for all individual subjects in order to determine whether 
any individual subject may continue to safely participate in the study. In general, either the 
Investigator or the Medical Monitor may discontinue the subject from the study at any time 
when any specific laboratory or ECG data change from Baseline indicates that the subject is 
placed at increased risk from continued participation in the study. 
In rare instances, it may be necessary for a subject to permanently discontinue study drug. 
Study drug stopping criteria are described below. If a subject experiences any of the below 
events, it must be documented as an AE. 
4.5.1.1 
Cardiovascular-Related Stopping Criteria 
If a clinically significant finding of change in blood pressure, bradycardia, or change in 
QTcF, as defined below, is identified after enrollment, the Investigator or qualified designee 
or Medical Monitor will determine if the subject can continue in the study and if any change 
in subject management is needed. 
• Clinically significant hypotension defined as systolic blood pressure (SBP) <85 mmHg 
and changes in blood pressure with decrease in SBP ≥20 mmHg or diastolic BP (DBP) 
≥10 mmHg  
• Significant bradycardia, defined as heart rate of ≤45 beats per minute (BPM) on an 
ECG, or pulse decrease of ≥25% from Baseline with resulting heart rate <60 BPM 
• QTcF result >480 ms or QTcF increases ≥60 ms from Baseline 
 
 


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4.5.2 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent from all components of the study, every reasonable 
effort should be made to complete Day 4/EOT/ET and all safety follow-up assessments 
(as outlined in Table S–1) for all subjects who discontinue prematurely during the treatment 
period of the study. All information will be reported on the applicable pages of the electronic 
case report form (eCRF). 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow and appropriately treat (or refer for treatment) the subject until the AE 
resolves or until the Investigator deems the AE to be chronic or stable. For subjects who 
continue to be followed for safety, SAEs should continue to be reported as described in 
Section 7.4.2. All SAEs will continue to be followed and appropriately treated until such 
events have resolved or the Investigator deems them to be chronic or stable. 
4.6 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(including the safety follow-up clinic visit [7 days after EOT]) and are unable to be contacted 
by the study site.  
Every reasonable effort should be made to contact the subject and will include a minimum of 
three documented phone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods. All contact attempts are to be documented in the 
source documents. 
4.7 
Prior and Concomitant Therapy 
All medications used from study screening until completion of the safety follow-up telephone 
call contact are to be recorded. 
4.7.1 
Prior Medication 
Prior medication is defined as any medication with stop dates prior to the date of the first 
dose of study drug. 
4.7.2 
Concomitant Medication 
Concomitant medication is defined as any medications taken after the date of the first dose of 
study drug through to the follow-up telephone call.  
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 


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The Investigator may prescribe appropriate medication to treat AEs. Drugs that confound the 
potential analgesic response and are prohibited (Appendix B) include:  
• opioids, NSAIDs and, importantly, drugs that are used to treat chronic pain (e.g., 
gabapentin, pregabalin, carbamazepine, and tricyclic antidepressants, and duloxetine) 
• systemic corticosteroids 
• immune suppressant drugs 
4.8 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and the safety follow-up clinic visit that occurs 7 days after EOT/ET as 
specified in Appendix B. 
Permitted concomitant medications should remain at a stable dose throughout the study. 
Ondansetron may be used at the discretion of the Investigator to treat moderate or severe 
nausea and vomiting.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have taken a prohibited medication during the study will be withdrawn from 
the study unless: 
• the prohibited medication has been discontinued, AND 
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject who has taken a prohibited medication to continue in 
the trial will be made by the Sponsor/Medical Monitor, with medical input from the 
Investigator, and will be documented. If a subject is allowed to remain in the trial, this will be 
reported as a major protocol deviation and not a waiver. 
4.8.1 
Rescue Medications, Treatments, and Procedures 
Subjects will be encouraged to refrain from taking rescue medication until 1-2 hours after 
removal of the nerve block. The allowed rescue medication in the present study is 400 mg of 
ibuprofen every 4 to 6 hours as needed for pain. The total daily dose of ibuprofen should not 
exceed 3200 mg (8 tablets). If ibuprofen does not provide the necessary pain relief, subjects 
may take hydrocodone/acetaminophen 5 mg/325 mg every 4 to 6 hours as needed for pain. 
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4.9 
Lifestyle Considerations 
4.9.1 
Activity 
Walking should be limited until after the 72-hour pain assessment. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be ACP-044, 400 mg or matching placebo. Placebo tablets 
will be size- and color-matched to the ACP-044 tablets. 
In order to maintain the double-blind design of the study, tablet(s) will be administered orally 
four times per day. 
ACP-044 doses to be studied are: 
• ACP-044, 1600 mg total dose delivered once daily in the morning (provided as 
4×400 mg ACP-044 tablets once daily)  
• ACP-044, 400 mg total dose delivered every 6 hours (provided as 1×400 mg 
ACP-044 tablet 4 times per day for a total daily dose of 1600 mg)  
• Placebo size- and color-matched to ACP-044 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply ACP-044, 400 mg tablets and matching placebo tablets packaged in 
HDPE bottles, each containing 30 tablets. 
ACP-044 is a white to off-white powder. ACP-044, 400 mg tablets include the active 
compound (ACP-044) and the following excipients: microcrystalline cellulose, 
polyvinylpyrrolidone, croscarmellose sodium, silicon dioxide magnesium stearate, 
 
 coating. The drug product is formulated with standard pharmaceutical 
excipients at 400 mg strength (454.5 mg of ACP-044). 
Placebo tablets contain all of the same excipients as ACP-044, 400 mg tablets but do not 
contain any ACP-044. 
ACP-044 tablets and placebo tablets are manufactured under Good Manufacturing Practice. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored between 20°C to 25°C (68°F and 77°F); excursions 
permitted between 15°C to 30°C [See USP controlled conditions] in a secure area with 
restricted access and according to local and national regulations. 


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5.1.3 
Dosing and Administration 
An unblinded pharmacist and unblinded verifier will prepare the study drug to be dispensed 
by site staff, while keeping all subjects, investigators, and other site staff blinded during the 
study. The unblinded verifier will cross check the preparation of the study drug to ensure 
accuracy of the study drug to be dispensed. Neither the pharmacist nor the verifier will have 
any involvement with subjects or pain assessments. 
On Day -1, subjects will be randomized 1:1:1 to receive 1600 mg ACP-044, administered 
either once daily or 400 mg every 6 hours, or placebo (Table 5-1). In order to maintain the 
double-blind design of the study, all subjects will receive the same numbers of tablets at the 
same intervals, regardless of the treatment group to which they are randomized. The first 
daily dose of study drug (either active and/or placebo) will be administered as four tablets on 
Day -1 prior to the application of the popliteal and/or ankle nerve block (see Section 3.1.2) 
and one tablet (either active study drug or placebo) will be administered for the second, third, 
and fourth doses of the day. Subjects will receive study drug (either active or placebo) 
according to this schedule on Day 1 through Day 3. 
Study drug doses are to be administered orally prior to surgery through approximately 
90 hours after the first dose of study drug on Day -1. 
Table 5-1 
Blinded Daily Dosing Regimen 
 
First 
Daily Dose 
Second Daily 
Dose 
Third 
Daily Dose 
Fourth 
Daily Dose 
Placebo 
PPPP 
P 
P 
P 
ACP-044 
400 mg (every 6 hours) 
XPPP 
X 
X 
X 
ACP-044 
1600 mg (once-daily) 
XXXX 
P 
P 
P 
Abbreviations: P=ACP-044 placebo tablet; X=ACP-044, 400 mg tablet 
 
5.1.4 
Method of Assigning Subjects to Treatment Groups 
On Day -1 eligible subjects who meet inclusion and do not meet exclusion criteria will be 
randomized in a 1:1:1 ratio to receive 1600 mg ACP-044, administered either once daily or 
400 mg every 6 hours, or placebo, according to a randomization schedule.  
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, Investigators, site personnel, and 
Sponsor personnel. An unblinded pharmacist and unblinded verifier will prepare the study 
drug to be dispensed by site staff (see Section 5.1.3). In the event of a potential SUSAR, in 


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accordance with current health authority guidance, treatment assignments for the affected 
subject may be unblinded to a controlled group of the Sponsor’s Safety and/or Regulatory 
personnel for reporting purposes; the site personnel, Investigators, and monitors will remain 
blinded in this situation.  
Details regarding medical emergency unblinding procedures are provided in Section 9.8. 
5.1.6 
Study Drug Compliance 
Study drug dosing will be observed by the clinical site staff. If a subject misses a dose, they 
should not take an extra dose. Missed doses will be documented as protocol deviations. 
5.1.7 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported, irrespective of outcome, 
even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured as protocol deviations. 
5.2 
Investigational Product and Rescue Medication Accountability Procedures 
An unblinded pharmacist will keep current and accurate records of the study drug product 
used and returned for each subject to assure the regulatory authority and the Sponsor that the 
study drug is being handled appropriately. Any study drug supplied is for use in this study 
only and should not be used for any other purpose. An unblinded clinical research associate 
(CRA) will be responsible for monitoring product accountability procedures and tablet counts 
by the site staff. 
Site staff will keep current records of rescue medication dispensed, used, and returned for 
each subject to assure the regulatory authority and the Sponsor that the study drug is being 
handled appropriately. 
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction. Documentation of study drug destruction will 
be recorded and maintained by both the Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1. Every effort should be made to complete the required 
procedures and evaluations at the designated visits and times. 


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6.1 
Remote Assessments or Visits 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when the 
follow-up safety assessment at the clinic may not be possible. In those cases, the follow-up 
assessments may be performed at a location other than the research site either in person, or 
via video technology or telephone where possible. The Investigator must contact the Medical 
Monitor for approval with the plan. Sites must keep a log to identify details of all visits that 
are performed remotely. The location of the collected assessments should be captured in the 
source documents. 
6.2 
Screening Assessments 
All screening assessments must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
6.2.1 
Medical and Medication History 
A complete medical and surgical history will be obtained from each potential subject at the 
Screening visit. Demographic information, including date of birth, sex, race, and ethnicity 
will be recorded as well.  
Any new medical condition reported with a start date after the informed consent form (ICF) 
has been signed will be captured as an AE. Subjects may be asked to provide pharmacy or 
medical records to substantiate the medication history. 
Any medication reported as taken on or after Day -1 will be captured as concomitant 
medication. 
6.3 
Block Quality Assessment 
Postoperatively, assessments of the popliteal block depth (Block Quality Assessment) will be 
performed and recorded hourly (±15 minutes) at the top of each hour until 2200 hours. 
Between the hours of 2200 and 0600 hours, Block Quality Assessments will continue to be 
performed hourly (±15 minutes) if subject is awake, but, even if asleep, the subject will be 
awakened to perform a Block Quality Assessment at 0300 hours (±15 minutes). Block 
Quality Assessments will continue until the block is removed. 


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6.4 
Efficacy Assessments 
6.4.1 
Numeric Rating Scale of Pain Intensity 
A 0 to 10 NRS will be used to assess the subject’s pain at the time of popliteal and/or ankle 
nerve block removal, for the subsequent 72 hours, and for the 7 days after EOT. Subjects will 
be asked: 
“Please describe your foot pain at the present time from 0 to 10 where “0” 
means “no pain at all” and “10” means “the worst pain imaginable”. 
Trained study coordinators will present the NRS scale and all other questionnaires at the 
designated times. 
Pain (efficacy) assessments are to be recorded hourly (±15 minutes) for a 12-hour interval on 
Day 1 beginning immediately prior to the fifth dose (time 0) administered in the study. Pain 
assessments will continue every 3 hours during the subsequent 12 hour interval, and then 
every 6 hours thereafter until 72 hours, then once daily in the morning until the follow-up 
clinical visit. Pain assessments should also be obtained immediately prior to the 
administration of rescue medication. 
Subjects should not have ice administered to the surgical area within the 30 minutes prior to 
each pain assessment. Pain assessments should be performed before blood sample collection, 
ECG, and other procedures. 
Subjects will be provided a diary upon discharge to document their pain from EOT to the 
follow-up clinic visit that occurs 7 days after EOT.  
6.4.2 
Global Evaluation of Study Drug 
For the global evaluation of study drug subjects will be asked to provide a graded response 
(4=excellent, 3=very good, 2=good, 1=fair, or 0=poor) to the statement “How would you rate 
the study drug you received to delay or reduce your foot pain?” The time at which the 
statement is completed will be recorded. 
Evaluation of study drug will be completed just before receiving the first dose of rescue 
medication, and at the end of 24 hours, 48 hours, and 72 hours relative to time 0 (when the 
first dose on Day 1 is administered). The evaluation of study drug should be performed 
before blood sample collection, ECG, and other procedures. 
6.4.3 
Foot and Ankle Ability Measure 
The FAAM is a validated, self-reported evaluative instrument specific to those with leg, 
ankle, and foot musculoskeletal disorders (Martin et al. 2005). The questionnaire consists of 
21 movements the subject rates as “no difficulty at all”, “slight difficulty”, “moderate 


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difficulty”, “extreme difficulty”, “unable to do”, and “N/A”, and an overall grade for the level 
of function during usual activities of daily living, graded on a scale of 0 to 100 with 
100 being at the level of function prior to the foot and ankle problem and 0 being the inability 
to perform any of their usual daily activities. 
The FAAM will be completed prior to the subject receiving their first dose on Day -1 and at 
the follow-up visit conducted 7 days after the EOT procedures. 
6.5 
Safety Assessments 
6.5.1 
Physical Examination 
A complete, general physical examination will be conducted at Screening and a brief physical 
exam, including mental status exam, will be conducted on Day -1 and Day 4/EOT/ET. Height 
will only be measured and reported at Screening and weight will be measured and recorded at 
Screening and Day -1 predose. An exam of the operative site will also be performed on Day 4 
(EOT/ET) prior to discharge and at the follow-up visit 7 (±3) days after the EOT procedures 
are completed. Both exams must include visual inspection of the operative site. 
The full examination should include a review of body systems and should include a 
neurological examination (e.g., level of consciousness, speech, cranial nerves [including 
pupil equality and reactivity], motor assessment, sensory assessment, coordination, gait, 
reflexes, and Romberg test). Height and weight will be measured and reported as described 
above. 
The brief physical exam will include the following: evaluation of general appearance, 
respiratory, cardiovascular, and gastrointestinal systems. A general physical examination will 
be conducted. 
6.5.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting systolic and 
diastolic blood pressure, and pulse rate. The sitting blood pressure should be measured after 
the subject has been sitting for ≥3 minutes. 
Vital signs will be evaluated at Screening, Day -1 predose, and on Day 1 every 2 hours for 
the first 6 hours after the initial dose. Vital signs will then be evaluated every 6 hours 
thereafter until Day 4/EOT/ET. A 15-minute window is permitted for vital sign 
measurements. 
Vital signs should be measured prior to (PK and laboratory) blood draws. 


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6.5.3 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings. A single 
12-lead ECG will be performed at Screening, Day -1 predose, on Days 1 through 3 at 1 hour 
postdose (the first dose of the day), and Day 4/EOT/ET. A 1-hour window is permitted for the 
predose ECG; a 20-minute window is permitted for the postdose ECG. ECGs should be 
performed prior to blood sampling and vital signs but after pain assessments are completed. 
Electrocardiograms should be performed before blood sampling or at least 30 minutes after 
blood sampling. The subject must rest in a supine position for 5 minutes before the ECG is 
obtained. ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified 
clinician. ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF, and QTcB 
intervals) will be included in the subject's study records. 
At Screening, if the ECGs has a prolonged QTcF due to an identifiable cause, and it is 
medically appropriate to address that cause, a repeat ECG may be performed during 
Screening at the discretion of the Medical Monitor. 
On Day -1, a subject may be enrolled based on the review and interpretation of the ECG by a 
qualified physician. If the interpretation of the ECG indicates a QTcF outside of the allowable 
range, the subject will be discontinued from the study, but this will not be considered a 
protocol deviation. 
6.5.4 
Columbia-Suicide Severity Rating Scale 
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to 
determine risk (Posner et al. 2011). The following four constructs are measured: the severity 
of ideation, the intensity of ideation, behavior, and lethality.  
The Baseline/Screening version will be administered at Screening, and the Since Last Visit 
version will be administered at all subsequent visits. The C-SSRS results for each subject 
should be reviewed by the Investigator after completion. If at any time the C-SSRS results for 
a given subject reveal potential suicidality, then the Investigator should assess the clinical 
significance of such results. If a clinically significant risk of suicidality is identified for a 
subject, then the Investigator should discontinue the subject and implement appropriate 
treatment (Section 4.5). 
6.5.5 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c at Screening only) is encouraged, but 
not required to be completed under fasting conditions. The laboratory evaluations will 
include, but are not limited to, the following: 
• Clinical chemistry serum tests (CHEM) 


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o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca),carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid,  
 Mg should only be performed at Visit 1 (Screening) 
o Estimated glomerular filtration rate (eGFR) should only be performed at Visit 1 
(Screening) 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel should only be performed at Visit 1 (Screening): 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol; should only be performed at 
Visit 1 (Screening) 
o HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB) should only be performed at Visit 1 (Screening) 
o Total protein should only be performed at Visit 1 (Screening) 
• Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• Endocrinology 
o Thyroid stimulating hormone (TSH) and free T4 (Screening) 
o Vitamin B12 should only be performed at Visit 1 (Screening) 
• Pregnancy test 
o A serum pregnancy test should only be performed at screening (Table 6–1) for 
women of childbearing potential 
o A urine pregnancy test should be performed before surgery on Day -1 (Table 6–1) 
for women of child-bearing potential 
 If urine cannot be obtained in women of childbearing potential, a 
serum pregnancy test should be done in its place 


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• COVID-19 test:  
o COVID-19 diagnostic PCR test at Screening 
o COVID-19 rapid antigen test on Day-1 predose  
• Urinalysis (UA) 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, nitrates  
• Urine toxicology screen with repeat testing 
o Urine toxicology screen will test for controlled substances. The following 
controlled substances may be tested with a urine toxicology screen according to 
the schedule presented in Table 6–1: amphetamine, barbiturates, benzodiazepines, 
cocaine, methadone, morphine/opiates, methamphetamine, marijuana (THC), 
phencyclidine (PCP), ecstasy (MDMA). Negative drug screens are required for 
study eligibility. 
 If there is a positive urine drug screen (UDS) for a medication that 
is known to give a false positive on UDS panel, the subject has a 
valid prescription for such medication and that medication is not 
prohibited in this study, and the subject denies use of the positive 
prohibited medication, they can be included in the study and it will 
not be considered a protocol deviation. 
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study laboratory manual. Additional safety testing may be 
performed at the discretion of the Investigator or designee. 
Table 6–1 
Safety Laboratory Evaluations 
Visit 
Tests 
Screening 
CHEM, CBC, UA, COVID-19a, serum pregnancy, and urine 
toxicology screen 
Day -1 predose 
CHEM, CBC, UA, COVID-19a ,urine pregnancy, and urine 
toxicology screen 
Day 4 (EOT/ET) 
CHEM, CBC, UA  
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; COVID-19=Coronavirus 
Disease 2019; EOT=end of treatment; ET=early termination; UA=urinalysis 
a 
COVID-19 diagnostic PCR test at Screening and a rapid antigen test on Day -1 predose. 
 


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6.6 
Pharmacokinetic Assessments 
Pharmacokinetic blood samples will be collected for measurement of plasma concentrations 
of ACP-044. ACP-044 plasma concentration data will remain blinded until the unblinding of 
the clinical database at the end of the study. 
PK blood samples will be collected Day -1 (predose, within one hour of dosing), Day 1 
(one sample taken between 2-3 hours and one sample taken between 4-6 hours, after the first 
dose of the day), Day 2 (prior to the first dose of the day), and Day 3 (one sample taken 
between 2-6 hours and one sample taken between 8-12 hours, after the first dose of the day). 
A 15-minute window is permitted around each nominal timepoint on Day 1 and beyond. 
Pharmacokinetic samples will also be collected, if possible, at any ET visit or the visit 
immediately following any SAE or following any AE leading to discontinuation, even if it is 
an unscheduled visit. 
6.6.1 
Blood Sampling 
Six (6) approximately 4 mL venous blood samples will be collected from each subject for 
measurement of plasma ACP-044 concentrations. 
In addition, a blood sample (approximately 4 mL sample) for determination of concentrations 
of ACP-044 will be collected in the event of an SAE or an AE leading to discontinuation. 
6.6.2 
Specimen Preparation, Handling, Storage, and Shipment 
PK blood samples may be collected from a cannula port or via venipuncture. Pre-prepared 
PK sampling tubes will be provided to each site within the lab visit kits for collection and 
storage of PK samples. At each time point, blood will be collected, processed as appropriate, 
and samples will be shipped to the central laboratory for storage and to the bioanalytical 
laboratory for analysis. 
For samples collected from subjects who experience any SAE or experience an AE leading to 
discontinuation, the date and time of the last dose of study drug prior to the SAE or AE 
leading to discontinuation will also be recorded. 
A laboratory manual will be provided for sample processing, storage, and shipping 
procedures. 
6.7 
Safety Follow-up 
Safety will be further assessed during the follow-up period regardless of whether a subject 
completes the study or withdraws (or when they withdraw; see also Section 4.4 for 
limitations in case of withdrawal of consent). The assessments to be conducted are outlined 
below and in Table S–1. 


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The first evaluation is a follow-up visit that will be conducted at the clinic approximately 
7 (±3) days after EOT visit. The assessments to be conducted at this visit include: 
• Examination of the operative site, which must include visual inspection (at the 
follow-up visit 7 days after EOT) 
• FAAM (at the follow-up visit 7 days after EOT) 
• Collect diary (at the follow-up visit 7 days after EOT) 
• Concomitant medications 
• AEs  
The second evaluation is a follow-up telephone call to occur approximately 30 (+4) days after 
the last dose of study drug. The subject will be asked about the following during the 
telephone call: 
• Concomitant medications 
• AEs  
6.8 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled visit: assessment of AEs, 
concomitant medications/treatments, and measurement of vital signs. The Investigator may 
perform any additional safety evaluations deemed by the Investigator to be clinically 
indicated. 
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study drug, whether or not considered 
related to study drug”. 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug 
(e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 


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A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. 
AEs do not include the following: 
• Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to Baseline and do not worsen during the study 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if not present at the 
time of informed consent, or scheduled surgery/procedure. 
• Overdose of concomitant medication without any signs or symptoms. If subject is 
hospitalized or has other serious criteria, the overdose shall be reported on the 
Sponsor’s Overdose Reporting form 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is life threatening 
• Results in disability or permanent damage 
• Requires hospitalization (initial or prolonged) 
• Results in congenital anomaly or birth defect 
• Other serious event (medically significant/important medical event) 
Definition of Life Threatening 
A life threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE, which, had it occurred in a more severe form, might 
have caused death. 


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Definition of Hospitalization 
Hospitalization is defined by the Sponsor as a full admission to the hospital for diagnosis and 
treatment. This includes prolongation of an existing inpatient hospitalization. 
Examples of visits to a hospital facility that do not meet the serious criteria for 
hospitalization include: 
• Emergency room visits (that do not result in a full hospital admission) 
• Outpatient surgery 
• Preplanned or elective procedures 
• Protocol procedures 
• Social hospitalization, defined as admission to the hospital as a result of inadequate 
family support or care at the subject’s primary residence  
Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 
7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be assessed as described below and reported in detail as 
indicated on the eCRF: 
• Mild: awareness of sign or symptom but easily tolerated, causing minimal discomfort, 
and not interfering with normal everyday activities 
• Moderate: sufficiently discomforting to interfere with normal everyday activities 


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• Severe: incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.” An event is considered related if there is a reasonable possibility that the event 
may have been caused by the product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 
• Response to drug cessation (de-challenge) or re-challenge  
• Compatibility with known class effect 
• Known effects of concomitant medications 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
• Past medical history 
7.2.3 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start: Date of the first episode of the AE or date of worsening in severity 
• Stop: Date when AE ceased permanently, worsened in severity, or resolved with or 
without sequelae 
7.2.4 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence 
• Recurrent: More than one discrete episode with the same severity 
7.2.5 
Action Taken with Study Drug 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 


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• Not applicable 
• Unknown  
7.2.6 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.7 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 
• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death due to an AE 
• Unknown: Unknown 
7.2.8 
Seriousness 
• Not serious 
• Serious (see Section 7.1.2) 
7.2.9 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current ACP-044 Investigator’s brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be recorded from the time informed consent is obtained through the 
study safety follow-up period. If an AE is ongoing at the end of the study safety follow-up 
period, every reasonable attempt should be made to follow and appropriately treat the subject 
until the AE resolves or until the Investigator deems the AE to be chronic or stable. 
In the event that a subject discontinues and has an ongoing AE at the time of discontinuation 
(Section 4.5.2) or is withdrawn from the study because of an AE, the subject should be 
followed and appropriately treated until the AE resolves or until the Investigator deems the 
AE to be chronic or stable. 


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7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms 
(e.g., “cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; use 
the appropriate form for initial and/or follow-up reporting. 
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board/ethics committee (IRB/EC), as per applicable regulations. These 
will be provided by the Sponsor after their assessment. For European Union member states, 
the Sponsor or its designee will provide reports of suspected unexpected serious adverse 
reactions (SUSARs) directly to the ECs, as required by local legislation. In all other 
countries, it is the Investigator’s responsibility to provide these expedited reports to the 
responsible IRB/EC. It is also the Investigator’s responsibility to notify the responsible 
IRB/EC regarding any new and significant safety information. 
When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form with all required information (for initial and/or follow-up 


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information) and fax or email (within 24 hours of discovery) to the contact information 
provided on the SAE form. 
Subjects will be followed through the safety follow-up period (i.e., 30 [+4] days after last 
dose of study drug) for any SAEs and/or other reportable information until such events have 
resolved or the Investigator deems them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the safety follow-up period (i.e., 30 [+4] days after last dose of 
study drug) should be reported if in the judgment of the Investigator there is “a reasonable 
possibility” that the event may have been caused by the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
withdrawn from the study and the pregnancy must be reported on the Pregnancy form within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes 
pregnant during the study will be followed through the pregnancy outcome. 
If pregnancy occurs during the study, the pregnant subject should be unblinded so that 
counseling may be offered based on whether the fetus was exposed to the active drug or 
placebo. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 Reporting Paternal Drug Exposure 
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or 
during his partner’s pregnancy. Any paternal drug exposure cases must be reported to the 
Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal drug exposure and which meet the criteria for serious must also be 
reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 


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designee on the Sponsor Overdose Reporting form within 24 hours of discovery. In addition, 
all events of overdose are to be captured as protocol deviations (see Section 5.1.7). 
8 CLINICAL MONITORING  
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. Deviations from the approved SAP will be 
described and justified in the final clinical study report. 
9.2 
Statistical Hypotheses 
The primary endpoint is AUC0-24 based on the pain intensity scores from 0 to 24 hours 
assessed using NRS. 
Let Δauc_1 and Δauc_2 be the difference between each of the two ACP-044 dose groups and 
placebo group in the mean AUC0-24, respectively. 
The null hypotheses are: Δauc_i = 0 and the alternative hypothesis is: Δauc_i ≠ 0, i=1,2 
9.2.1 
Multiple Comparisons/Multiplicity 
A fixed-sequence method at alpha=0.05 for the primary and key secondary efficacy endpoints 
will be used to control for multiplicity. The following will be the sequence for testing: 
1. 400 mg Q6H compared to placebo on mean AUC0-24 of NRS of pain intensity scores 
2. 1600 mg QD compared to placebo on mean AUC0-24 of NRS of pain intensity scores 
3. 400 mg Q6H compared to placebo on time to first rescue medication use after time 0 
4. 400 mg Q6H compared to placebo on proportion of subjects who were opioid free 
through 24 hours 
5. 1600 mg QD compared to placebo on time to first rescue medication use after time 0 


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6. 1600 mg QD compared to placebo on proportion of subjects who were opioid free 
through 24 hours 
7. 400 mg Q6H compared to placebo on proportion of subjects who were opioid free 
through 48 hours 
8. 1600 mg QD compared to placebo on proportion of subjects who were opioid free 
through 48 hours 
9. 400 mg Q6H compared to placebo on proportion of subjects who were opioid free 
through 72 hours 
10. 1600 mg QD compared to placebo on proportion of subjects who were opioid free 
through 72 hours 
The testing procedure will stop once a p-value in the sequence is greater than 0.05. P-values that 
are less than or equal to 0.05 prior to stopping, will be declared statistically significant; p-values 
after stopping will be nominal. 
9.3 
Sample Size Determination 
The planned sample size is 240 subjects randomized (80 subjects per treatment group). 
Randomization will be stratified by site. 
Assuming a treatment difference in the AUC from 0 to 24 hours is 23 points between the 
ACP-044 groups and placebo group, and the common standard deviation is 50 points, 
76 subjects per treatment arm will provide approximately 80% power to detect the assumed 
treatment difference between each ACP-044 dose arm and placebo at a 2-sided significance 
level of 0.05. Assuming no more than 5% of randomized patients will be excluded from 
primary efficacy analysis, 80 subjects per treatment group will be randomized. 
9.4 
Subject Populations for Analysis 
The Safety Analysis Set includes all randomized subjects who received at least one dose of 
study drug (ACP-044 or placebo). Subjects will be analyzed based on the treatment that they 
actually received. The Safety Analysis Set will be used for all safety analyses. 
The Full Analysis Set includes all randomized subjects who received at least one dose of 
study drug and who have undergone bunionectomy with at least one postoperative pain 
assessment. The Full Analysis Set will be used for the analysis of all efficacy endpoints. 
The Per-protocol (PP) Analysis Set will consist of those subjects in the FAS who did not 
have any protocol deviations that could potentially have a substantial impact on the primary 
efficacy outcome. The precise reasons for excluding subjects from the PP Analysis Set will be 
fully defined and documented prior to the clinical database lock. Subjects will be analyzed 


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based on their randomized treatment assignment. The PP Analysis Set will be used for 
supportive analyses of selected efficacy endpoints. 
For ACP-044 plasma concentration summaries, the Pharmacokinetics Analysis Set will 
consist of subjects with at least one measurable ACP-044 plasma concentration. 
9.5 
Statistical Analyses 
9.5.1 
General Statistical Approach 
Continuous measurement results will be reported using the number of subjects with data 
values, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median. For each categorical outcome, the number and percentage of subjects in each 
category will be reported. All statistical hypothesis tests will be 2-sided at the significance 
level of 0.05. 
9.5.2 
Primary Analyses 
The primary efficacy variable, AUC0-24, will be analyzed by using analysis of variance 
(ANOVA) with treatment group and site as factors in the model. Each active dose group will 
be compared to placebo using this model. P-value and associated 95% confidence interval for 
treatment difference between each active dose and placebo will be presented. Missing pain 
assessment at scheduled time point will be imputed. The details of missing data imputation 
and multiplicity adjustment will be described in the SAP. 
9.5.3 
Key Secondary Analyses 
Time to first rescue medication use will be analyzed using log rank test stratified by site. 
Proportion of patients who are opioid free through 24, 48, and 72 hours will be analyzed 
using stratified Cochran-Mantel-Haenszel (CMH) test controlling for study site. 
9.5.4 
Secondary Analyses 
Continuous secondary variables will be analyzed similarly as the primary efficacy variable. 
Proportion of patients who are pain free at each specific timepoint will be analyzed using 
stratified Cochran-Mantel-Haenszel (CMH) test controlling for study site. 
9.5.5 
Exploratory Analyses 
The analysis of the exploratory variables will be described in the SAP.  
9.5.6 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive statistics. No formal 
statistical testing will be performed for any of the safety endpoints. Adverse events will be 
classified into standard terminology using the Medical Dictionary for Regulatory Activities 


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(MedDRA). Treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, 
TEAEs related to study drug, TEAEs by maximum severity, fatal TEAEs, and SAEs reported 
after study drug start will all be summarized. Other TEAEs of special interest (e.g., ORAEs) 
may also be summarized. 
Descriptive statistics for ECG, vital signs and weight, and clinical laboratory parameters, 
including changes from Day -1 (prior to first dose), will be tabulated by timepoint. 
Additionally, categorical analyses will be conducted on the incidence of subjects with 
prolonged QTc intervals and changes in QTc intervals in accordance with ICH guidelines. 
9.5.7 
Pharmacokinetic Analyses 
Plasma concentration data for ACP-044 will be listed and summarized using descriptive 
statistics. Results will be used for other analyses (e.g., population PK modelling), which will 
be presented in a separate report. 
9.5.8 
Pharmacokinetic/Pharmacodynamic Analyses 
A population PK/PD model to describe the exposure response relationship between ACP-044 
plasma concentrations and the relevant efficacy and safety endpoints will be developed using 
appropriate PK/PD methods. Results will be presented in a separate report. 
9.5.9 
Subgroup Analyses 
Selected analyses may be performed in subgroups. Details will be provided in the SAP. 
9.6 
Interim Analyses 
No interim analyses are planned for this study. 
9.7 
Measures to Minimize Bias 
On Day -1 eligible subjects who meet inclusion and do not meet exclusion criteria will be 
randomized in a 1:1:1 ratio to receive 1600 mg ACP-044, administered either once daily or 
400 mg every 6 hours, or placebo, according to a randomization schedule. Treatment 
assignments will be blinded to all study subjects, Investigators, site personnel (with the 
exception of the unblinded pharmacist and verifier), and Sponsor personnel. An unblinded 
pharmacist and a verifier will prepare the study drug and shall have no role in pain 
assessment or patient care. 
In order to maintain the double-blind design of the study, all subjects will receive the same 
numbers of tablets at the same intervals, regardless of the treatment group to which they are 
randomized. Placebo tablets will be size- and color-matched to the ACP-044 tablets. 


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9.8 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to the Sponsor after 
all subjects have completed the study and the clinical database is locked. 
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the investigator decides 
that unblinding is warranted, the investigator should make every effort to contact the Sponsor 
prior to unblinding a participant’s intervention assignment unless this could delay emergency 
treatment of the participant. If a participant’s intervention assignment is unblinded, the 
sponsor must be notified within 24 hours after breaking the blind. 
If pregnancy occurs during the study, the pregnant subject should be withdrawn and 
unblinded so that counseling may be offered based on whether the fetus was exposed to the 
active drug or placebo. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory authorities. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (including inspectors), 
and the IRB/EC direct (or remote) access to source documents (such as original medical 
records) as allowed by local regulations. Direct (or remote) access includes permission to 
examine, analyze, verify, and reproduce any records and reports that are needed for the 
evaluation of the study, either in person or through a remote video/electronic medium, if 
applicable. The Investigator must ensure the reliability and availability of source documents 
from which the information on the eCRF was derived. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation), and then entered into a validated electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 


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10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs. The 
Investigator and his or her site personnel will be responsible for completing the eCRFs. The 
Investigator is responsible for the accuracy and reliability of all the information recorded on 
the eCRFs. All information requested on the eCRFs needs to be supplied, including subject 
identification data, visit date(s), assessment values, etc., and any omission or discrepancy will 
require explanation. All information on eCRFs must be traceable to source documentation 
(unless eCRF is considered the source) at the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs, medical records, or other documents submitted to the Sponsor or designees, 
subjects must be identified by a subject identification number only. Subject identifiers 
uniquely identify subjects within the study and do not identify any person specifically. 
Documents that are not for submission to the Sponsor or designees (e.g., signed ICFs) should 
be kept in strict confidence by the Investigator in compliance with Federal regulations or 
other applicable laws or ICH guidance on GCP. Data collection and handling should comply 
with the European Union General Data Protection Regulation (EU GDPR), where applicable. 
Acadia has assigned a Data Protection Officer (DPO) as per the EU GDPR. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 
2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 
notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
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that the subject did not meet all eligibility criteria, this will be reported as a major protocol 
deviation and not a waiver. In this situation, the subject will be discontinued, unless the 
discontinuation presents an unacceptable medical risk. The justification to allow the subject 
to continue in the trial will be made by the Sponsor, with medical input from the Investigator, 
and will be documented. All follow-up safety assessments must be completed and 
documented as outlined in the protocol (Section 6.7). The Investigator must report any 
protocol deviation to the Sponsor and, if required, to the IRB/EC in accordance with local 
regulations, within reasonable time. 
10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
accordance with local requirements and, if required, to regulatory authorities, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. 
No approval is required for notifications. 
11 QUALITY MANAGEMENT 
11.1 Risk Management 
The Sponsor utilizes the ICH E6 (GCP) Revision 2 risk management approach that includes 
methods to assure and control the quality of the trial proportionate to the risks inherent in the 
trial and the importance of the information collected. The intent is that all aspects of this trial 
are operationally feasible and that any unnecessary complexity, procedures, and data 
collection are avoided. The Sponsor’s risk management approach includes the following 
documented activities: 
• Critical Process and Data Identification: during protocol development, risks of 
processes and data that are critical to ensure human subject protection and the 
reliability of trial results are identified and assessed. 
• 
Risk Identification: risks to critical trial processes, governing systems, investigational 
product, trial design, data collection, and recording are identified. 
• Risk Evaluation: identified risks are evaluated by considering the following factors: 
(a) likelihood of occurrence, (b) impact on human subject protection and data 
integrity, and (c) detectability of errors. 
• Risk Control: risks that can be avoided, reduced (i.e., mitigated), or accepted are 
differentiated. Risk mitigation activities are incorporated in protocol design and 


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implementation, study plans, training, processes, and other documents governing the 
oversight and execution of study activities. Where possible, predefined quality 
tolerance limits are defined to identify systematic issues that can impact subject safety 
or data integrity and deviations from the predefined quality tolerance limits will 
trigger an evaluation and possibly an action. Contingency plans are developed for 
issues with a high risk factor that cannot be avoided. 
• Periodic risk review, communication, and escalation of risk management activities 
during trial execution and risk outcome reporting in the clinical study report (CSR). 
11.2 Quality Control and Quality Assurance 
The Sponsor or designees and regulatory authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial (e.g., eCRFs and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor’s or designee’s monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. The monitor may review documents 
remotely, as needed, in conjunction with site policies and procedures. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH guidance on GCP and the Sponsor’s audit plans, sites participating in 
this study may be audited. These audits may include a review of site facilities (e.g., 
pharmacy, drug storage areas, and laboratories) and review of study-related records may 
occur in order to evaluate the trial conduct and compliance with the protocol, ICH guidance 
on GCP, and applicable regulatory requirements. 
The Sponsor’s or designee’s representatives, regulatory authority inspectors and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
12 ETHICAL CONSIDERATIONS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements (e.g., Serious Breach reporting, 


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urgent safety measures, and European Union General Data Protection Regulation [EU 
GDPR]). 
The study will be performed in accordance with current US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH guidance on GCP (E6) and clinical safety data management (E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, any subject information or advertising materials, and 
any other requested information. The study will not be initiated until the IRB/EC provides 
written approval of the protocol and the informed consent and until approved documents 
have been obtained by the Investigator and copies received by the Sponsor. All amendments 
will be sent to the IRB/EC for information (minor amendment) or for submission (major 
amendment) before implementation. The Investigator will supply the IRB/EC and the 
Sponsor with appropriate reports on the progress of this study, including any necessary safety 
updates, in accordance with the applicable government regulations and in agreement with 
policy established by the Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to any 
screening procedures.  
The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject’s willingness to continue participation. Any revision must be 
submitted to the appropriate IRB/EC for review and approval in advance of use. 


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12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent and the original maintained 
in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject must be given ample time to decide about study participation 
and opportunity to inquire about details of the study. The IRB/EC-approved consent form must 
be personally signed and dated by the subject and by the person who conducted the 
informed-consent discussion. The Investigator or appropriate site personnel must document the 
details of obtaining informed consent in the subject’s study documents. 
The subject must also indicate his/her understanding of the study. The subject must provide 
written agreement prior to any screening visit procedures being performed indicating his/her 
agreement to participate in the study. 
Records related to a study subject’s participation will be maintained and processed according 
to local laws, and where applicable, the European Union General Data Protection Regulation 
(EU GDPR). The consent and study information documentation will include statements 
describing local and regional requirements concerning data privacy, and who to contact for 
questions. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance, and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 
 


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15 LITERATURE REFERENCES 
American Society of Anesthesiologists. Physical Status Classification System, last amended 
on 13 December 2020. Accessed 22 December 2020. https://www.asahq.org/standards-and-
guidelines/asa-physical-status-classification-system 
Brennan TJ, Vandermeulen EP, Gebhart GF. Characterization of a rat model of incisional 
pain. Pain. 1996;64(3):493-501. 
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile 
allodynia in the rat paw. J Neurosci Methods. 1994;53(1):55-63. 
Daniels SE, Upmalis D, Okamato A, Lange C, Häeussler J. A randomized, double-blind, 
phase III study comparing multiple doses of tapentadol IR, oxycodone IR, and placebo for 
postoperative (bunionectomy) pain. Curr Med Res Opin 2009;25(3):765-776. 
Desjardins PJ, Shu VS, Recker DP, Verburg KM, Woolf CJ. A single preoperative oral dose 
of valdecoxib, a new cyclooxygenase-2 specific inhibitor, relieves post-oral surgery or 
bunionectomy pain. Anesthesiology 2002;97:563-73. 
Fehrenbacher JC, Vasko MR, Duarte DB. Models of inflammation: Carrageenan- or complete 
Freund's Adjuvant (CFA)-induced edema and hypersensitivity in the rat. Curr Protoc 
Pharmacol. 2012;56(1):5.4.1‐5.4.4 
Florence CS, Zhou C, Luo F, Xu L. The Economic burden of prescription opioid overdose, 
abuse, and dependence in the United States, 2013. Med Care. 2016;54(10):901-906. 
Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for 
measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77-88. 
Karaca Z, McDermott KW. High-volume invasive, therapeutic ambulatory surgeries 
performed in hospital-owned facilities. 2016. Statistical brief #252. September 2019. 
Lee J, Hunt JA, Groves JT. Manganese Porphyrins as Redox-Coupled Peroxynitrite 
Reductases. J Am Chem Soc. 1998a;120(24):6053-6061.  
Lee J, Hunt JA, Groves JT. Mechanisms of iron porphyrin reactions with peroxynitrite. J Am 
Chem Soc. 1998b;120(30):7493-7501. 
Martin RL, Irrgang JJ, Burdett RG, Conti SF, Van Swearingen JM. Evidence of validity for 
the foot and ankle ability measure (FAAM). Foot & Ankle International. 2005;26:968-983. 
McConnell P, Reasor MJ, Van Dyke K. Three model systems measure oxidation/nitration 
damage caused by peroxynitrite. J Biosci. 2003;28(1):71-76. 


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Pollak RA, Gottlieb IJ, Hakakian F, Zimmerman JC, McCallum SW, Mack RJ, et al. Efficacy 
and safety of intravenous meloxicam in patients with moderate-to-severe pain following 
bunionectomy. A randomized, double-blind, placebo-controlled trial. Clin J Pain 
2018;34:918.926. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011; 168(12):1266-1277. 
Sluka KA, Willis WD. The effects of G-protein and protein kinase inhibitors on the 
behavioral responses of rats to intradermal injection of capsaicin. Pain. 1997;71(2):165-178. 
Wilson N, Kariisa M, Seth P, Smith H IV, Davis NL. Drug and Opioid-Involved Overdose 
Deaths — United States, 2017–2018. MMWR/Morb Mortal Wkly Rep 2020;69:290–297. 


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16 APPENDICES 
Appendix A American Society of Anesthesiologists Physical Status Classification 
System 
Examples below include (but are not limited to) those provided. 
 
ASA I: A normal healthy patient. Example: Healthy, non-smoking, no or minimal alcohol 
use. 
ASA II: A patient with a mild systemic disease. Example: Mild diseases only without 
substantive functional limitations. Current smoker, social alcohol drinker, pregnancy, obesity 
(30<BMI<40), well-controlled diabetes mellitus/hypertension (DM/HTN), mild lung disease. 
ASA III: A patient with severe systemic disease. Example: substantive functional limitations; 
one or more moderate to severe diseases. Poorly controlled DM or HTN, chronic obstructive 
pulmonary disease (COPD), morbid obesity (BMI ≥40), active hepatitis, alcohol dependence 
or abuse, implanted pacemaker, moderate reduction of ejection fraction, end stage renal 
disease (ESRD) undergoing regularly scheduled dialysis, history (>3 months) of myocardial 
infarction (MI), cerebrovascular accident (CVA), transient ischemic attack (TIA), or coronary 
artery stent (CAD)/stents. 
ASA IV: A patient with a severe systemic disease that is a constant threat to 
life. Example: recent (<3 months) MI, CVA, TIA or CAD/stents, ongoing cardiac ischemia or 
severe valve dysfunction, severe reduction of ejection fraction, shock, sepsis, disseminated 
intravascular coagulation (DIC), acute respiratory distress (ARD) or ESRD not undergoing 
regularly scheduled dialysis. 
Source: American Society of Anesthesiologists 2020 
 


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Appendix B Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the trial, this will be reported as a major protocol deviation and not a 
waiver. 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. A restricted 
medication is allowed only under certain conditions. 
Medication Class 
Medicationa 
Prohibition/restrictions 
Analgesics 
RESTRICTED 
• 
acetaminophen 
 
• Allowed as rescue medication when used 
with hydrocodone 
(hydrocodone/acetaminophen 
5 mg/325 mg) every 4 to 6 hours 
• Total daily dose should not exceed 
3250 mg (10 tablets) 
Anticoagulant 
PROHIBITED 
• 
heparin 
• 
warfarin 
• 
rivaroxaban 
• 
dabigatran  
• 
apixaban  
• 
edoxaban  
• 
enoxaparin  
• 
fondaparinux 
• Prohibited throughout the study 
Anticonvulsants  
PROHIBITED 
• 
gabapentin 
• 
pregabalin 
• 
carbamazepine 
• Prohibited throughout the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
Antidepressants 
PROHIBITED 
• 
tricyclic antidepressants 
• 
duloxetine 
  
• Prohibited throughout the study 
Anxiolytics 
PROHIBITED 
• 
benzodiazepines 
• Benzodiazepines are prohibited, except 
for IV midazolam for sedation preceding 
placement of the popliteal catheter  
RESTRICTED 
• 
midazolam 
• IV midazolam may be used for sedation 
preceding placement of the popliteal 
catheter 
Nonsteroidal 
anti-inflammatory 
drug (NSAID) 
PROHIBITED 
• 
aspirin 
• Prohibited use within 2 days prior to 
scheduled surgery or within five 
half-lives of the drug, whichever is longer 
• Prohibited throughout the study 
RESTRICTED 
• 
ibuprofen 
 
• Allowed rescue medication is 400 mg of 
ibuprofen every 4 to 6 hours as needed 
for pain 
• Total daily should not exceed 3200 mg 
(8 tablets) 
Opioids 
PROHIBITED 
• 
methadone 
• 
oxycodone 
• 
codeine 
• Prohibited use within the previous 
6 months of Screening 
• Prohibited use within 24 hours prior to 
scheduled surgery or within five 
half-lives of the drug, whichever is longer 
• Subjects who have a history of drug 
abuse are not eligible for this study 
• Hydrocodone/acetaminophen 
5 mg/325 mg is allowed as a rescue 
medication every 4 to 6 hours as needed 
for pain.  
o 
Subjects will be encouraged to 
refrain from taking rescue 
medication until 1-2 hours after 
stopping the nerve block 
o 
Ibuprofen (400 mg) alone should 
be used prior to using  
hydrocodone/acetaminophen 
5 mg/325 mg 
• Morphine allowed during Day -1 as 
indicated in the Anesthetic and Surgical 
Guidelines 
RESTRICTED 
• 
hydrocodone 
• 
morphine 
 


Study: ACP-044-004 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 5 
 
Date: 01 February 2022 
 
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Medication Class 
Medicationa 
Prohibition/restrictions 
Steroids and 
immunosuppressant 
drugs 
PROHIBITED 
• 
hydrocortisone 
• 
prednisone 
• 
prednisolone 
 
• Prohibited throughout the study 
a  
Medications within each class include but are not limited to the examples listed in this table. 

SAP_001.pdf: 
Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ACP-044 for Acute Postoperative Pain Following Orthopedic Surgery 
(Bunionectomy) 
NCT Number: NCT04855240
Document Date:  14 March 2022




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SIGNATURE/APPROVAL PAGE 
AUTHOR 
 
See appended electronic signature page                                                       _____________ 
 
Date 
Senior Director, Biostatistics  
Acadia Pharmaceuticals Inc. 
 
 
APPROVERS 
 
See appended electronic signature page                                                       ____________ 
                                                                                     Date 
Executive Director, Clinical Science  
Acadia Pharmaceuticals Inc. 
 
See appended electronic signature page                                                       ____________ 
 
 Date 
Executive Director, Biostatistics  
Acadia Pharmaceuticals Inc. 
 
 
 
 
 




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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................... 7 
ABBREVIATIONS .................................................................................................................... 8 
1 INTRODUCTION ............................................................................................................. 10 
2 OBJECTIVES .................................................................................................................... 10 
2.1 
Primary Objective .......................................................................................................... 10 
2.2 
Secondary Objectives .................................................................................................... 10 
2.3 
Exploratory Objectives .................................................................................................. 10 
2.4 
Safety Objective ............................................................................................................ 10 
2.5 
Pharmacokinetic Objective ............................................................................................ 10 
2.6 
Pharmacokinetic/Pharmacodynamic Objective ............................................................. 10 
3 STUDY DESIGN ............................................................................................................... 11 
3.1 
General Study Design .................................................................................................... 11 
3.2 
Schedule of Assessments ............................................................................................... 13 
3.3 
Randomization ............................................................................................................... 14 
3.4 
Blinding ......................................................................................................................... 14 
3.5 
Determination of Sample Size ....................................................................................... 14 
3.6 
Coronavirus Disease 2019 ............................................................................................. 15 
4 ANALYSIS SETS .............................................................................................................. 15 
5 DATA HANDLING CONVENTIONS .............................................................................. 16 
5.1 
General Data Reporting Conventions ............................................................................ 16 
5.2 
Derived Variables........................................................................................................... 16 
5.2.1 
Numeric Rating Scale (NRS) of Pain Intensity Scores ............................................. 16 
5.2.2 
Time to First Rescue Medication Use ....................................................................... 19 
5.2.3 
Amount of Rescue Medication .................................................................................. 19 
5.2.4 
Proportion of Subject Who Did Not Use Rescue Medication ................................... 19 
5.2.5 
Proportion of Subjects Who Are Pain Free (NRS ≤2) ............................................... 19 
5.2.6 
Number of Hours Subjects are Pain Free (NRS ≤2) .................................................. 19 
5.2.7 
Proportion of Subjects Who Are Opioid Free............................................................ 20 
5.2.8 
Global Evaluation of Study Drug (GESD) ................................................................ 20 
5.2.9 
Proportion of Subjects with Severe Pain ................................................................... 20 


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5.2.10 
Foot and Ankle Ability Measure (FAAM) ................................................................. 20 
5.2.11 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 21 
5.3 
Study Analysis Day ....................................................................................................... 22 
5.4 
Baseline Definition ........................................................................................................ 22 
5.5 
Analysis Visit Windows ................................................................................................. 22 
5.5.1 
Unscheduled Assessments ......................................................................................... 23 
5.5.2 
Multiple Measurements within Visit or Timepoint Windows.................................... 23 
5.6 
Missing or Incomplete Date for Last Dose of Study Drug ............................................ 24 
5.7 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ........... 24 
5.8 
Missing or Incomplete Dates for Adverse Events ......................................................... 24 
6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 25 
6.1 
Block Quality Assessments ........................................................................................... 25 
6.2 
Missing Severity Assessment for Adverse Events ......................................................... 25 
6.3 
Missing Relationship to Study Drug for Adverse Events .............................................. 25 
6.4 
Character Values of Clinical Laboratory Variables ....................................................... 25 
7 SUBJECT DISPOSITION ................................................................................................. 25 
8 PROTOCOL DEVIATIONS .............................................................................................. 26 
9 MEDICAL HISTORY ....................................................................................................... 26 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 27 
10.1 Exposure to Study Drug ................................................................................................ 27 
10.2 Treatment Compliance ................................................................................................... 27 
11 CONCOMITANT AND POST-TREATMENT MEDICATION ....................................... 27 
12 EFFICACY ANALYSES ................................................................................................... 28 
12.1 Efficacy Variables .......................................................................................................... 28 
12.2 Adjustment for Covariates ............................................................................................. 29 
12.3 Multiple Comparisons / Multiplicity ............................................................................. 29 
12.4 Examination of Subgroups ............................................................................................ 30 
13 METHODS OF EFFICACY ANALYSES ........................................................................ 30 
13.1 Primary Efficacy Endpoints ........................................................................................... 30 
13.1.1 
Primary Analysis ........................................................................................................ 30 
13.1.2 
Sensitivity Analyses ................................................................................................... 32 
13.1.2.1 
Alternative Handling of Rescue Medication Censoring ........................................ 32 


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13.1.2.2 
Multiple Imputation Variations .............................................................................. 33 
13.1.3 
Supportive Analyses .................................................................................................. 33 
13.2 Key Secondary Efficacy Endpoints ............................................................................... 33 
13.3 Secondary Efficacy Endpoints ....................................................................................... 34 
13.4 Exploratory Efficacy Endpoints .................................................................................... 36 
14 SAFETY ANALYSES ....................................................................................................... 37 
14.1 Adverse Events .............................................................................................................. 37 
14.2 Clinical Laboratory Variables ........................................................................................ 38 
14.3 Vital Signs ...................................................................................................................... 42 
14.4 Electrocardiogram (ECG) .............................................................................................. 44 
14.5 Physical Examination .................................................................................................... 45 
14.6 Other Safety Variables ................................................................................................... 45 
14.6.1 
Suicidality Based on C-SSRS .................................................................................... 45 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 46 
15.1 Pharmacokinetic Endpoints ........................................................................................... 46 
15.2 Pharmacokinetic/Pharmacodynamic Endpoints ............................................................ 46 
16 INTERIM ANALYSIS ....................................................................................................... 46 
17 DATA MONITORING/REVIEW COMMITTEE ............................................................. 46 
18 COMPUTER METHODS ................................................................................................. 46 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 47 
20 REFERENCES .................................................................................................................. 48 
21 APPENDICES ................................................................................................................... 49 
21.1 Schedule of Events and Assessments ............................................................................ 49 
21.2 Multiple Imputation Details ........................................................................................... 51 
21.3 Summary of Version Changes ....................................................................................... 53 
 


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LIST OF TABLES 
Table 1 
Blinded Daily Dosing Regimen ....................................................................... 14 
Table 2 
Analysis Visit Windows ................................................................................... 22 
Table 3 
Analysis Timepoint Windows .......................................................................... 23 
Table 4 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 41 
Table 5 
Criteria for Potentially Clinically Important Laboratory Values – 
Urinalysis ......................................................................................................... 42 
Table 6 
Criteria for Potentially Clinically Important Vital Signs ................................. 44 
Table 7 
Criteria for Potentially Clinically Important ECG Values ............................... 45 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .............................................................................. 13 
 


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ABBREVIATIONS 
AE 
adverse event 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BMI 
body mass index 
CMH 
Cochran-Mantel Haenszel 
COVID-19 
Coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
ET 
early termination 
FAAM 
Foot and Ankle Ability Measure 
GESD 
Global Evaluation of Study Drug 
GSD 
Guidance for Site Documentation and Data Management Querying of 
Data Impacted by COVID-19 
ICE 
intercurrent event 
MAR 
Missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MME 
Morphine milligram equivalents 
MNAR 
Missing not at random 
msec 
milliseconds 
NRS 
numerical rating scale 
PCI 
potentially clinically important 
ORAE 
opioid-related adverse event 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 


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TEAE  
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 


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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety and efficacy data as described in the study protocol Version 1.0 
amendment 5 dated 01 February 2022. 
Specifications for tables, figures, and listings are contained in a separate document. Statistical 
analyses for population pharmacokinetic (PK) and PK/pharmacodynamics (PD) modeling 
will be presented in a separate report and therefore will not be included in this SAP. 
This plan should be read in conjunction with the study protocol and the electronic case report 
forms (eCRF). 
2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of ACP-044 compared with 
placebo in the treatment of acute postoperative pain. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the efficacy of ACP-044 compared 
with placebo in the treatment of acute postoperative pain and to evaluate opioid use among 
ACP-044 treated subjects compared with placebo in the treatment of acute postoperative 
pain. 
2.3 
Exploratory Objectives 
The exploratory objectives of this study are to evaluate the proportion of subjects with severe 
pain and to compare the impact of ACP-044 on activities of daily living compared with 
placebo in the treatment of acute postoperative pain. 
2.4 
Safety Objective 
The safety objective of this study is to evaluate the safety and tolerability of ACP-044 
compared with placebo in the treatment of acute postoperative pain. 
2.5 
Pharmacokinetic Objective 
The pharmacokinetic objective of this study is to characterize the pharmacokinetic (PK) 
profile of ACP-044 in subjects treated for acute postoperative pain. 
2.6 
Pharmacokinetic/Pharmacodynamic Objective 
The pharmacokinetic/pharmacodynamic objective of this study is to characterize the 
exposure-response relationship using appropriate modelling and simulation methods. 


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3 STUDY DESIGN 
3.1 
General Study Design 
This study will be conducted as a Phase 2, randomized, double-blind, placebo-controlled, 
multicenter study in subjects with acute postoperative pain (following bunionectomy 
surgery). The study will compare each of the two active treatment groups receiving a total 
daily dose of 1600 mg ACP-044, administered either once daily or 400 mg every 6 hours, 
with a placebo group. The Sponsor, subjects, and Investigators will be blinded to treatment 
assignment. 
Approximately three sites in the United States (US) will screen approximately 375 subjects 
and approximately 240 subjects are planned for enrollment (80 subjects per treatment group). 
The duration of participation for individual study subjects will be approximately 9 weeks, 
consisting of a screening period of up to 4 weeks, a 4-day treatment period, and a safety 
follow-up period of approximately 30 (+4) days. 
The study periods are: 
• Screening: up to 4 weeks (prior to surgery) 
• Double-blind treatment: Day -1 (post first dose of study drug/day of surgery) to Day 4 
• Safety follow-up: approximately 7 days after end of treatment (EOT)/early 
termination (ET) and approximately 30 days (post last dose of study drug) 
The study start date is defined as the date the first subject signs the informed consent form. 
The study completion date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note: this includes the safety follow-up visit or 
contact. 
Screening Period 
During the Screening period, subjects will be assessed for study eligibility. Only those 
subjects who meet all inclusion and no exclusion criteria will be eligible for the study. 
All prohibited medications should be discontinued during the Screening period and prior to 
surgery. Investigators must not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications will be discontinued only if it is deemed clinically 
appropriate to do so and in consultation with the prescribing physician. 
With approval of the Medical Monitor, rescreening of a subject will be allowed one time if 
there is an extenuating circumstance that was not under the subject’s control or if is due to an 


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identifiable cause, and it is medically appropriate to address that cause, and there is 
no medical reason that would prevent the subject to be rescreened and enrolled in the study. 
Treatment Period 
The first dose of study drug will be administered within 60 (±15) minutes prior to the start of 
surgery. Subjects will then have a popliteal and/or ankle nerve block administered to 
anesthetize the knee, distal leg, and foot, after which they will enter into surgery. Following 
surgery, subjects will be administered the remaining three daily doses approximately every 
6 hours after the initial dose. 
Day 1 is defined as the day after surgery. The popliteal and/or ankle nerve block will be 
discontinued approximately 2-4 hours prior to the first dose on Day 1 (i.e., the fifth dose of 
the study) and nerve block removal; a discontinuation window of approximately 2 hours is 
permitted. The time at which the first dose on Day 1 is administered will be time 0 for all 
pain assessments. Study drug administration and study procedures are to be completed on 
Days -1 through 4 according to the schedule of assessments (Section 21.1). Subjects will be 
encouraged to refrain from taking rescue medication until 1-2 hours following the first dose 
of study drug on Day 1. 
On Day 4, after the 72 hour pain assessments are performed, the EOT procedures will be 
completed and subjects will be discharged from the clinical site. 
Safety Follow-up Period 
Safety will be further assessed during a follow-up visit to occur in the clinic approximately 
7 (±3) days after EOT/ET procedures and subjects will receive a follow-up telephone call 
approximately 30 (+4) days after the last dose of study drug. Subjects should return to 
standard of care after the follow-up visit that will occur in the clinic 7 (±3) days after the 
EOT/ET. 
The study schematic is presented in Figure 1. 


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Figure 1 
Schematic of Study Design 
 
Abbreviations: EOT=end of treatment  
a Subjects to be randomized in a 1:1:1 ratio to receive either a once-daily oral dose of 1600 mg ACP-044, 
four oral doses of 400 mg ACP-044, or placebo. Randomization will occur just prior to surgery when the first 
dose of study drug is given.  
b The time at which the first dose on Day 1 (i.e., the fifth dose of study drug) is administered will be considered 
time 0 for pain assessments. 
3.2 
Schedule of Assessments 
Schedule of events and assessments can be found in Section 21.1.


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3.3 
Randomization 
On Day -1 eligible subjects who meet inclusion and do not meet exclusion criteria will be 
randomized in a 1:1:1 ratio to receive 1600 mg ACP-044, administered either once daily or 
400 mg every 6 hours, or placebo, according to a randomization schedule. Randomization 
will be stratified by site. 
Approximately three sites in the United States (US) will screen approximately 375 subjects 
and approximately 240 subjects are planned for randomization (80 subjects per treatment 
group). 
3.4 
Blinding 
Treatment assignments will be blinded to all study subjects, Investigators, site personnel 
(with the exception of the unblinded pharmacist and verifier), and Sponsor personnel. An 
unblinded pharmacist and a verifier will prepare the study drug and shall have no role in pain 
assessment or patient care. 
In order to maintain the double-blind design of the study, all subjects will receive the same 
numbers of tablets at the same intervals (four times per day), regardless of the treatment 
group to which they are randomized. Placebo tablets will be size- and color-matched to the 
ACP-044 tablets. 
Table 1 
Blinded Daily Dosing Regimen 
 
First Daily Dose 
Second Daily 
Dose 
Third Daily 
Dose  
Fourth Daily 
Dose  
Placebo  
PPPP  
P  
P  
P  
ACP-044 400 mg (every 6 
hours)  
XPPP  
X  
X  
X  
ACP-044 1600 mg (once-
daily)  
XXXX  
P  
P  
P  
Abbreviations: P=ACP-044 placebo table; X=ACP-044, 400 mg tablet 
3.5 
Determination of Sample Size 
The planned sample size is 240 randomized subjects (80 subjects per treatment group).  
Assuming a treatment difference in the AUC from 0 to 24 hours is 23 points between the 
ACP-044 groups and placebo group, and the common standard deviation is 50 points, 
76 subjects per treatment arm will provide approximately 80% power to detect the assumed 
treatment difference using a t-test between each ACP-044 dose arm and placebo at a 2-sided 
significance level of 0.05. Assuming no more than 5% of randomized subjects will be 
excluded from primary efficacy analysis, 80 subjects per treatment group will be randomized. 


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3.6 
Coronavirus Disease 2019  
Mechanisms to record information on the potential impact of the COVID-19 pandemic on 
data itself, as well as data collection and integrity, were implemented (as detailed in the 
“Guidance for Site Documentation and Data Management Querying of Data Impacted by 
COVID-19” [GSD]).  
The impact of COVID-19 on the statistical analysis is discussed in Section 6 Subject 
Disposition, Section 7 Protocol Deviations, Section 11 Concomitant and Post-Treatment 
Medication, and Section 14.1 Adverse Events. 
4 ANALYSIS SETS 
Randomized Analysis Set 
The Randomized Analysis Set includes all randomized subjects. Subjects will be analyzed 
based on their randomized treatment assignment. 
Safety Analysis Set 
The Safety Analysis Set includes all randomized subjects who received at least one dose of 
study drug (ACP-044 or placebo). Subjects will be analyzed based on the treatment that they 
actually received. The Safety Analysis Set will be used for all safety analyses. 
Full Analysis Set 
The Full Analysis Set includes all randomized subjects who received at least one dose of 
study drug post operation and who have undergone bunionectomy. Subjects will be analyzed 
based on their randomized treatment assignment. The Full Analysis Set will be used for the 
analysis of all efficacy endpoints. 
Per-protocol Analysis Set 
The Per-protocol (PP) Analysis Set includes all subjects in the Full Analysis Set who did not 
have any protocol deviations that could potentially have a substantial impact on the primary 
efficacy outcome. The precise reasons for excluding subjects from the PP Analysis Set will be 
fully defined and documented in a separate PD log file prior to the clinical database lock. 
Subjects will be analyzed based on their randomized treatment assignment. The PP Analysis 
Set will be used for supportive analyses of the primary efficacy endpoint. 
Pharmacokinetics Analysis Set 
The Pharmacokinetics Analysis Set includes all subjects with at least one measurable 
ACP-044 plasma concentration. 


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5 DATA HANDLING CONVENTIONS 
5.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: number 
of subjects, mean, median, standard deviation (SD), standard error (SE), minimum, and 
maximum. Unless specified otherwise, means, medians, and confidence intervals (CIs) will 
be presented to one more decimal place than the raw data, and the standard deviations and 
standard errors will be presented to two more decimal places than the raw data. In general, 
the maximum number of decimal places is 4 and values will be truncated to 4 decimal places 
in situations where there are more than 4 decimal places. Wherever possible data will be 
decimal aligned.  
Categorical variables will be summarized by the number of subjects and the percent of 
subjects in each category; the number of subjects and the percentage of subjects with missing 
data will be summarized for demographic and baseline characteristics (if applicable). 
Categories with zero counts will not have zero percentages displayed. For demographic 
summaries, percentages will be calculated by using the total number of subjects in the given 
treatment group as the denominator. Percentages will be presented with one decimal place.  
Unless specified otherwise, all statistical hypothesis tests will be 2-sided and performed at the 
significance level of 5% for treatment comparisons and all CIs will be 2-sided 95% CIs. 
P-values will generally be presented to 4 decimal places; values less than 0.0001 will be 
presented as <0.0001.  
Values that are collected with “<” or “>” signs will generally be analyzed as the numerical 
value without the sign in tables and figures. In listings, these data will be reported as 
collected with the sign.  
5.2 
Derived Variables 
In general, the assessment scale scores will be directly taken from the electronic case report 
form (eCRF), the variables of mean area under the curve values will be derived and used for 
all analyses. 
5.2.1 
Numeric Rating Scale (NRS) of Pain Intensity Scores 
A 0-10 NRS will be used to assess the subject’s pain intensity scores from time 0 (when first 
dose on Day 1 is administered) through the subsequent 72 hours, and for the 7 days after 
EOT, subjects will be asked: “Please describe your foot pain at the present time from 0 to 10 
where “0” means “no pain at all” and “10” means “the worst pain imaginable”. 
Pain (efficacy) assessments are to be recorded hourly (±15 minutes) for a 12-hour interval on 
Day 1 beginning immediately prior to the fifth dose (time 0) administered in the study. 


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Pain assessments will continue every 3 hours during the subsequent 12 hour interval, and 
then every 6 hours thereafter until 72 hours, and then once daily in the morning until the 
follow-up clinical visit. 
There will be a total of 25 scheduled timepoints across 3 days:  
• Day 1 (indexed 0 to 16): 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 21, 24 hours 
• Day 2 (indexed 17 to 20): 30, 36, 42, 48 hours 
• Day 3 (indexed 21 to 24): 54, 60, 66, 72 hours 
Missing NRS pain intensity scores will be multiply imputed by performing the following 
steps: 
1. Subjects with missing Time 0 assessments will be imputed by using the mean of the 
non-missing Time 0 assessments of the same treatment group. 
2. Intermediate or interval missing records, i.e. missing pain intensity scores that are 
between two timepoints with non-missing pain intensity scores, will not be imputed; 
the AUC calculation will connect the non-missing values per the trapezoidal rule 
(below), effectively using linear interpolation.  
3. For subjects who took rescue medication the following will be performed: 
o If the subject took any rescue medication (i.e. Acetaminophen-hydrocodone 
oral tablet, ibuprofen), assessments within 4 hours post taking the rescue 
medication will be replaced by the pre-rescue value if the pain score assessed 
prior to starting the rescue medication is greater than the scheduled 
assessment. However, if a pain score assessed within the window is the same 
or worse than the pre-rescue value, the scheduled assessment will be retained; 
this process will be repeated scheduled assessments occurring within the 
window. 
4. Right censored missing data (i.e. missing due to discontinuation) will be imputed 
using multiple imputation: 
o Multiple imputation will be used to impute values at the scheduled assessment 
times for subjects that discontinue.  For the purposes of imputation, 
unscheduled values and pre-rescue values will not be included, but will be 
added back into the dataset prior to calculating the AUC; however, scheduled 
values will be replaced with pre-rescue values during the censoring period 
prior to the imputation (and solely for the purpose of imputation).  First, 
subjects that discontinue for reasons other than lack of efficacy (LOE) and 


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adverse events (AEs) will have their values imputed within treatment group 
with MI assuming MAR with covariates for all observed time points.  For 
subjects who discontinue due to AEs or LOE, the MI will be based off the 
distribution of worst values through the time of discontinuation. This will 
done iteratively for each time point starting at the earliest time point with 
missing data; covariates will be included for observed data through that time 
point. Full details of the MI algorithm are given in Appendix 21.2. 
 
In general, the area under the curve (AUC) from start time of interest, tstart, to end time of 
interest, tk, for each subject will be calculated using the linear trapezoidal method. All pain 
assessments (including unscheduled) will be used in the calculation. 
𝐴𝐴𝐴𝐴𝐶𝐶𝑡𝑡𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠−𝑡𝑡𝑘𝑘= ෎1
2 ∗(𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛𝑖𝑖+ 𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛𝑖𝑖+1) ∗(𝑡𝑡𝑖𝑖+1 −𝑡𝑡𝑖𝑖)
𝑘𝑘−1
𝑖𝑖=𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
 
Where i indexes the timepoints from 0 hour to 72 hours as 0 to 24; start is the index value of 
the starting time; k is the index value of the end time; tstart is the start time of the AUC is to be 
calculated; tk is the end time of the AUC to be calculated; Paini is the NRS pain intensity 
score at index i; ti is the time at index i. Note: The index count will be adjusted on an 
individual basis to account for unscheduled assessments and pre-rescue assessments.  
Calculations will be performed at a 1-minute precision, but final values will be scale to hours, 
thus the AUC0-24 will be scaled 0-240. 
For the primary efficacy endpoint the formula would be as follows: 
𝐴𝐴𝐴𝐴𝐶𝐶0−24 = ෎1
2 ∗(𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛𝑖𝑖+ 𝑃𝑃𝑃𝑃𝑃𝑃𝑛𝑛𝑖𝑖+1) ∗(𝑡𝑡𝑖𝑖+1 −𝑡𝑡𝑖𝑖)
16−1
𝑖𝑖=0
 
Note: The index count will be adjusted to account for unscheduled assessments. 
5.2.1.1 
Time Point Capping for AUC Endpoints Only 
If the relative time (from time 0) of the last scheduled timepoint for the AUC is greater than 
or less than the nominal terminal time for the AUC endpoint being calculated, i.e. 24 hours 
for AUC0-24, then the calculated AUC will be scaled by the ratio of actual time to nominal 
time. This will ensure that the time considered for AUC will be consistent for each subject. 
For example, if time 0 is at 8:00 am and the 24 hour time point is 7:50 am the next day, then 
the AUC will be multiplied by 1440/1430 ([nominal minutes]/[actual minutes]). 


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5.2.2 
Time to First Rescue Medication Use 
The time to first rescue medication use will be derived relative to Time 0, Day 1. The units of 
hours will be used for time to event analysis.  
5.2.3 
Amount of Rescue Medication 
The average of the total amount of ibuprofen taken (400 mg per tablet), total amount of 
acetaminophen (325mg per tablet) and hydrocodone taken (5 mg per tablet), or instances of 
any rescue medication (mg) taken during 0-24, 24-48, 48-72,0-48, and 0-72 hours by 
treatment group will be derived. Missing amount of rescue medication data will not be 
imputed. Summarize out of clinic rescue tablets/usage/add mgs.  
In addition, the total amount of opioids in morphine milligram equivalents (MME) taken 
during the time periods will be summarized by treatment group. Both in clinic and out of 
clinic (Diary). In clinic, subjects should only receive hydrocodone and a 1:1 conversion of 
hydrocodone to MME will be utilized; should subjects take any other opioid, then the CDC 
conversion guide will be used for converting to MME: 
https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf 
5.2.4 
Proportion of Subject Who Did Not Use Rescue Medication 
The proportion of subjects who did not use rescue medication through 24, 48, and 72 hours 
will be derived as the number of subjects who did not use any kind of rescue medication 
through 24, 48 and 72 hours divided by the number of subjects per treatment group that were 
still in the trial through that time point. 
5.2.5 
Proportion of Subjects Who Are Pain Free (NRS ≤2) 
The proportion of subjects who are pain free at each scheduled time point will be derived as 
the number of subject who have a NRS pain intensity score ≤2  divided by the number of 
subjects per treatment group with non-missing NRS values. If a subject took rescue 
medication within 4 hours prior to the timepoint, the subject will not be considered as pain 
free even if the NRS pain intensity score is ≤2. 
5.2.6 
Number of Hours Subjects are Pain Free (NRS ≤2) 
The number of hours subjects are pain free (from 0-72 hours) will be derived as follows: 
A horizontal line will be drawn at NRS of 2 on a line plot of a subject’s NRS pain intensity 
scores. Then the time between the hours of 0 and 72, inclusive, where NRS pain intensity 
score is less or equal to 2 will be summed; linear interpolation will be used to calculate the 
amount of time for when the line plot and horizontal line intersects. If a subject took rescue 
medication, the next 4 hours after taking any rescue medication will not be considered pain 


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free even if the NRS pain intensity score is ≤2.  Subjects that drop out will not have the time 
after they drop out considered to be ≤2 following their last reported NRS. 
5.2.7 
Proportion of Subjects Who Are Opioid Free 
The proportion of subjects who are opioid free 0-<24, 0-<48 and 0-<72 hours and 
24-<48 hours and 48-72 hours will be derived as the number of subject who did not take 
opioids divided by the number of subjects per treatment group.  Likewise, the proportion of 
subjects that are opioid free starting at 0, 12, 24, 36 hours will be reported. Subjects that drop 
out of the study prior to a given time point will be assumed to have not subsequently taken 
opioids, unless concomitant medication or diary data suggest that an opioid was available to 
them at that time (whether or not the subject reported taking it in the period in question). 
5.2.8 
Global Evaluation of Study Drug (GESD) 
The global evaluation of study drug is assessed just before receiving the first dose of rescue 
medication and at the end of 24 hours, 48 hours, and 72 hours relative to time 0. This will be 
considered three ways: 
• With all values reported as recorded 
• With values following rescue censored 
• With the pre-rescue values grouped with the subsequent time point and values 
following rescue censored 
For the GESD, subjects will be asked to provide a graded response (4=excellent, 3=very 
good, 2=good, 1=fair, or 0=poor) to the statement “How would you rate the study drug you 
received to delay or reduce your foot pain?” 
5.2.9 
Proportion of Subjects with Severe Pain  
The proportion of subjects with severe pain will be derived as the number of subjects with an 
NRS pain intensity score of ≥7 at any timepoint through 72 hours divided by the number of 
subjects per treatment group. 
5.2.10 Foot and Ankle Ability Measure (FAAM) 
The foot and ankle ability measure (FAAM) is assessed at Baseline and in the Safety 
Follow-up Period, 7 days after EOT/ET. 
There are two subscales: activities of daily living (ADL) and Sports. For ADL subscale, there 
are 21 movements the subject rates as “4=no difficulty at all”, “3=slight difficulty”, 
“2=moderate difficulty”, “1=extreme difficulty”, “0=unable to do”, and “N/A”, and an 
overall grade for the level of function during usual activities of daily living, graded on a scale 


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of 0 to 100 with 100 being at the level of function prior to the foot and ankle problem and 
0 being the inability to perform any of their usual daily activities. 
For Sports subscale, there are 8 movements and an overall grade for the level of function 
during sports related activities, graded in the same manner as ADL (0-4 for items, 0-100 for 
overall grade). 
Missing FAAM data will not be imputed. 
Within subscale, the item score total will be derived as the sum of items with a response 
(NA responses are not counted). The total number of items with a response is multiplied by 
4 to get the highest potential score (For ADL, if all 21 items have a response that has a score 
of 0-4, the highest potential score is 84, if there is one item with a NA or missing response, 
then the highest potential score is 80; the highest potential score for Sports subscale is 
derived similarly; however, the Sports subscale only has 8 items). The item score total will be 
divided by the highest potential score; this value will be multiplied by 100 to get a 
percentage. A higher percentage represents a higher level of physical function. 
If there are less than 90% completed items (NA responses are considered as not completed), 
i.e., less than 19 items completed for ADL or less than 7 items for Sports subscales, then the 
corresponding item percentage score will be considered missing. 
Total score will be derived as the sum of the ADL and Sports subscales. If either subscale is 
missing, total score will also be missing. 
5.2.11 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Screening, Day -1 and Day 4 (EOT/ET). 
The C-SSRS baseline/screening version will be administered at screening. 
The C-SSRS version assessing information since the last visit will be completed at Day -1 
and Day 4 (EOT/ET) visits.  
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish 
to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods 
(not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent. If a subject answers “yes” 
to any of these 5 questions, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If 
a subject answers “yes” to any of these 5 questions, this subject will be counted as having 
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Suicidality is defined as a subject who reported at least 1 occurrence of suicidal ideation or at 
least 1 occurrence of suicidal behavior at any post-Baseline visit including unscheduled and 
out of window visits. 
Missing C-SSRS item scores will not be imputed. 
5.3 
Study Analysis Day 
If the date of assessment occurs on or after the first dose date, then the study analysis day will 
be calculated as (date of assessment – first dose date) + 1. If the date of assessment occurs 
prior to the first dose date, then study analysis day will be calculated as (date of assessment – 
first dose post operation). There is no study analysis day 0. 
5.4 
Baseline Definition 
In general, baseline for safety data and FAAM are defined as data collected which are prior to 
the administration of the first dose. If there is more than one value on or prior to first dose, 
the value closest to and prior to the receipt of the first dose, whether scheduled or 
unscheduled, will be used as the Baseline value.  
NRS pain severity score does not have a baseline.  
5.5 
Analysis Visit Windows  
Efficacy, safety, and PK assessments will be summarized by analysis visit and timepoint as 
presented in Table 2 and Table 3 below. 
Study analysis visit window will be used to map visits using study day intervals. In Table 2, 
the first day of double-blind dosing is defined as “Study Analysis Day 1”. 
Table 2 
Analysis Visit Windows 
Analysis Visit Name 
Target Study Analysis Day 
Study Analysis Day 
Interval 
Baseline[1] (Day -1) 
1 
≤ 1 and pre-dose 
Day 1 
2 
2 
Day 2 
3 
3 
Day 3 
4 
4 
Day 4 
5 
5 
[1] The Baseline is not applicable to NRS assessment. 
 


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Table 3 
Analysis Timepoint Windows 
Parameter 
Target Study Timepoints 
Timepoint Window 
Vital Signs 
Day -1 predose, Day 1: 2h, 4h, 6h postdose and 
then every 6 hours thereafter up to Day 
4/EOT(12h, 18h, 24h, 30h, 36h, 42h, 48h, 54h, 
60h, 66h, 72h…) 
Predose assessment must be prior to 
dose on Day -1. For postdose records, 
the scheduled time will be used for 
analysis; the midpoint between each 
timepoint will be used to map the 
assessments such that there is no gap 
in windowing. 
ECG 
Day -1 predose, Days 1-3 at 1h postdose, and 
EOT/ET. 
Predose assessments must be prior to 
dose on Day -1. For post-dose 
assessments, the midpoint between 
each timepoint will be used to map the 
assessments such that there is no gap 
in windowing. 
PK Blood 
Samples 
Day -1 predose within one hour of dosing, Day 1 
between 2-3h postdose, Day 1 between 4-6h 
postdose, Day 2 predose, Day 3 between 2-6h 
postdose, Day 3 between 8-12h postdose, and in 
the event of an SAE or AE leading to 
discontinuation (if possible). 
For time points prior to Day 2 predose, 
the window will be ±15 min on top of 
the collection window range. For 
timepoints on Day 2 and beyond will 
be ±1 hour on top of the collection 
window range. 
Block Quality 
Assessments 
Postoperatively, assessments will be performed 
and recorded hourly (±15 minutes) at the top of 
each hour until 2200 hours. Between the hours of 
2200 and 0600 hours, assessments will continue to 
be performed hourly (±15 minutes) if subject is 
awake, but, even if asleep, the subject will be 
awakened to perform a Block Quality Assessment 
at 0300 hours (±15 minutes). Block Quality 
Assessments will continue until the block is 
removed. 
For each hour 0-24 post surgery 
completion, the time of the surgery 
completion defines analysis timepoint 
0, a +/- 30 min window will be used. 
For time 0 the window will start at the 
time of surgery completion. 
 
NRS 
Day 1: 0h (Time 0), 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 
9h, 10h, 11h, 12, 15h, 18h, 21h, 24h, 30h, 36h, 
42h, 48h, 54h, 60h, 66h, 72h, and then once daily 
in starting the morning of Day 4 until the follow-
up clinic visit. 
For each timepoint up to 72h the 
window will be ±30 min. For AUC 
calculation, all NRS timepoints will be 
considered. Only windowed 
assessments will be summarized in the 
by timepoint summary and for specific 
steps outlined for the multiple 
imputation of missing data in the 
sensitivity analysis. 
5.5.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including the assessments at early termination 
visits, will be considered for planned timepoint summaries based on the above analysis visit 
windowing rules. All assessments will be presented in data listings. 
5.5.2 
Multiple Measurements within Visit or Timepoint Windows 
In general, in the event that more than one assessment falls within a given visit or timepoint 
window, the assessment closest to the target study day and time will be selected for the 


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by-visit or by-timepoint analysis. If two assessments are equidistant from the target study day 
or nominal time, then the chronologically last assessment will be used. Details are provided 
in a separate programming conventions document. 
All NRS timepoints will be used regardless if the assessment is scheduled or unscheduled. 
For safety analyses where the most extreme values should be selected, e.g. overall 
post-baseline minimum, overall post-baseline maximum, and potentially clinically important 
values for overall post-Baseline summaries, all non-missing post-Baseline values should be 
considered, regardless of whether the value is selected for the by-visit summaries. All results 
will be presented in data listings. 
5.6 
Missing or Incomplete Date for Last Dose of Study Drug 
For subjects with completely missing last dose date, the last dose date will be imputed by the 
last expected dosing date, defined as the earliest of the following dates: last dose administer 
date + scheduled dosing interval per protocol, EOT/ET date. For subjects with partial missing 
last dose date, the imputation will be compared against the last expected dosing date as 
defined above. Detailed algorithms will be documented in a separate programming 
specifications document. The missing or incomplete dates will be displayed in the data 
listings as reported on the eCRF rather than the imputed dates.  
5.7 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 11 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as 
concomitant. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported 
on the eCRF rather than the imputed dates. 
5.8 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When 
the chronological order of an AE onset relative to the study drug treatment period is unclear 
due to missing or incomplete date(s), the AE will be considered as treatment-emergent. The 
imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF 
rather than the imputed dates. 


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6 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and Baseline characteristics will be summarized for the Safety Analysis Set 
using descriptive statistics. Variables include age, sex, primary race, ethnicity, height, weight, 
and body mass index (BMI). 
Race will also be categorized by an additional binary category of White vs. Non-White. The 
eCRF reported age will reflect a subject’s age at the Screening visit date; age at screening 
will be used for all analysis. 
6.1 
Block Quality Assessments 
Assessments of the popliteal block depth (Block Quality Assessment) will be summarized by 
timepoint (For each hour 0-24 post surgery completion) and treatment group. The assessment 
consists of three categories, motor, sensory and pain. The categories of motor and sensory 
will be categorically summarized as None, Some, Normal. The pain category will consist of 
the intervals based off of a categorical NRS pain intensity score: (0= NRS 0-2), (1=NRS 3-6) 
and (2=NRS 7-10). Each component of the block quality assessment collected will be listed. 
6.2 
Missing Severity Assessment for Adverse Events 
If will be used for incidence summaries, and the actual values will be presented in data 
listings. 
6.3 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for a treatment-emergent AE, a causality of 
“Related” will be assigned. The imputed values for relationship to study drug will be used for 
incidence summaries, and the actual values will be presented in data listings. 
6.4 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a summary due to, for 
example, a character string reported for a numeric variable, an appropriately determined 
coded value will be used in the summary. The coding algorithms will be detailed in the 
analysis dataset specification document. The actual values as reported in the database will be 
presented in data listings. 
7 SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not randomized (screen failures), 
their demographics information (including age, sex, and primary race), screen failure reasons 
(the specific inclusion/exclusion criterion (or criteria) not met or other reasons including the 
reason due to the COVID-19 public health emergency (PHE) and protocol version will be 
listed. If a subject is re-screened, then the re-screening subject ID and the final enrollment 


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status (whether eventually enrolled) will also be displayed in this listing. In addition, the 
frequency that the screen failure reasons are reported will be summarized. Note that one 
subject may be deemed ineligible for multiple inclusion/exclusion criteria and may be 
allowed to rescreen with the permission of the Medical Monitor, provided the screen failure 
was due to a temporary condition that subsequently resolved. 
The number of sites that screened at least 1 subject, number of sites that randomized at least 
1 subject, number of subjects screened, and number of unique subjects screened will be 
tabulated. In addition, the number of subjects enrolled at each site will also be tabulated by 
Analysis Set and by treatment group and overall. 
The number and percentage of subjects who completed the study, discontinued early (all 
discontinued and by discontinuation reasons including reason due to the COVID-19 PHE), 
and the reason for discontinuation will be summarized by treatment group using the 
Randomized Analysis Set. All subjects excluded from the Safety, Full or Per-protocol 
Analysis Sets, and the reason(s) for exclusion will be listed. The number and percentage of 
subjects who are excluded from the Per-protocol Analysis Set will be presented in a summary 
table by reason, and by treatment group and overall. 
8 PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major 
or minor are detailed in the Protocol Deviation Management Plan. Protocol deviations will 
also be assessed with respect to relationship to the COVID-19 PHE. A summary of the 
number and percentage of subjects with major protocol deviations for each deviation 
category may be presented by treatment group for the Randomized Analysis Set in three 
ways: all major protocol deviations, COVID-19-PHE related major protocol deviations 
(if applicable), and non-COVID-19-PHE related major protocol deviations (if applicable). 
Three data listings of all protocol deviations, COVID-19-PHE related protocol deviations 
(if applicable), and non-COVID-19-PHE related protocol deviations (if applicable) may be 
provided.  
9 MEDICAL HISTORY 
Medical history data will be coded using Medical Dictionary for Regulatory activities 
(MedDRA) version 24.0. The subject incidence will be summarized for each system organ 
class (SOC) and preferred term for the Safety Analysis Set. A subject will be counted only 
once per SOC or per preferred term for the summary. 


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A listing of the SOC, preferred term, verbatim term for the medical history condition/event, 
start and stop dates (when available), and an indicator for whether or not the condition is 
ongoing will be provided. 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety 
Analysis Set. 
10.1 Exposure to Study Drug 
Exposure in days, the number of doses administered, the number of missed doses and the 
number of total tablets dosed will be summarized. 
10.2 Treatment Compliance 
Study drug compliance will be calculated as the number of tablets taken, divided by the 
expected number of tablets taken*100. 
Treatment compliance will be summarized as a categorical variable. The number and 
percentage of subjects within each of the following compliance levels will be tabulated: 
<80%, 80 to 120% and >120%. 
The number of missed doses will be summarized as a categorical variable: none, at least 1, 
2-4, 5-8, 8-12, and >13. 
11 CONCOMITANT AND POST-TREATMENT MEDICATION 
Prior medication is defined as any medication with stop dates prior to the date of the first 
dose of study drug. Concomitant medication is defined as any medications that are ongoing at 
the first dose of study drug or with a start date between the dates of the first and last doses of 
study drug, inclusive. Post-treatment medication is defined as any medication with a start 
date after the date of the last dose of study drug. Medications will be coded using WHO Drug 
Global Dictionary March 2021 or newer version. 
The number and percentage of subjects taking prior, concomitant and post-treatment 
medications will be tabulated separately by each drug class (ATC Level 3) and medication 
preferred term, treatment group and overall for Safety Analysis Set. Multiple medication 
usage by a subject in the same category will be counted only once. 
Summary of pharmacokinetic concomitant medications will be summarized. Pharmacokinetic 
concomitant medication is defined as any medications that are ongoing at first dose of study 
drug or with a start date between the dates of the first and last doses of study drug, inclusive; 
and taken within two days prior to a pharmacokinetic sample collection. The details of this 
summary will be discussed in a separate PK analysis plan. 


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Listings of the prior, concomitant and post-treatment medications will also be provided. 
COVID-19 Public Health Emergency (PHE) Related Medications 
Concomitant medication analyses described above may also be tabulated and listed by 
relationship to the COVID-19 PHE (Not related to the COVID-19-PHE vs. Related to the 
COVID-19-PHE), if applicable. 
12 EFFICACY ANALYSES 
Unless otherwise specified, all efficacy analyses will be performed using the planned 
treatment assignments based on the randomization schedule for the Full Analysis Set. 
12.1 Efficacy Variables 
Primary Efficacy Endpoint 
• The mean AUC0-24 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
Key Secondary Efficacy Endpoints 
• Time to first rescue medication use after time 0 (when the first dose on Day 1 is 
administered) 
• Proportion of subjects who were opioid free through 24 hours 
• Proportion of subjects who were opioid free through 48 hours 
• Proportion of subjects who were opioid free through 72 hours 
Secondary Efficacy Endpoints 
• The mean AUC0-48 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
• The mean AUC0-72 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
• The mean AUC0-4 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
• The mean AUC0-6 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
• The mean AUC0-12 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
• The mean AUC24-48 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 


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• The mean AUC48-72 of NRS of pain intensity scores (using 4 hour window for rescue 
medications) 
• Amount of rescue medication taken during 0-24, 24-48, and 48-72 hours 
(individually), 0-48 hours, and 0-72 hours 
• Proportion of subjects who did not use rescue medication through 24, 48, and 
72 hours 
• Proportion of subjects who are pain free (NRS ≤2) at 24, 48, and 72 hours 
• Number of hours subjects are pain free (NRS ≤2) 
• Proportion of subjects who were opioid free during 24-48 hours and 48-72 hours 
• Global evaluation of study drug just before time of first rescue and at the end of 24, 
48, and 72 hours relative to the time 0 (when the first dose on Day 1 is administered) 
Exploratory Efficacy Endpoints 
• Proportion of subjects with severe pain (defined as an NRS pain intensity score ≥7 at 
any timepoint through 72 hours) 
• Foot and Ankle Ability Measure (FAAM) 
12.2 Adjustment for Covariates 
Unless otherwise specified, there will be no adjustment for covariates. 
12.3 Multiple Comparisons / Multiplicity 
A fixed sequence method at alpha=0.05 for the primary and key secondary efficacy endpoints 
will be used to control for multiplicity. The following will be the sequence for testing: 
1. 400 mg Q6H compared to placebo on mean AUC0-24 of NRS of pain intensity scores 
2. 1600 mg QD compared to placebo on mean AUC0-24 of NRS of pain intensity scores 
3. 400 mg Q6H compared to placebo on time to first rescue medication use after time 0 
4. 400 mg Q6H compared to placebo on proportion of subjects who were opioid free 
through 24 hours 
5. 1600 mg QD compared to placebo on time to first rescue medication use after time 0 
6. 1600 mg QD compared to placebo on proportion of subjects who were opioid free 
through 24 hours 
7. 400 mg Q6H compared to placebo on proportion of subjects who were opioid free 
through 48 hours 


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8. 1600 mg QD compared to placebo on proportion of subjects who were opioid free 
through 48 hours 
9. 400 mg Q6H compared to placebo on proportion of subjects who were opioid free 
through 72 hours 
10. 1600 mg QD compared to placebo on proportion of subjects who were opioid free 
through 72 hours 
The testing procedure will stop once a p-value in the sequence is greater than 0.05. P-values 
that are less than or equal to 0.05 prior to stopping, will be declared statistically significant; 
p-values after stopping will be nominal. P-values obtained from the stratified log-rank test 
stratified by site will be used to for the endpoints that compare the time to first rescue 
medication use after time 0 by treatment group. 
12.4 Examination of Subgroups 
Treatment effect will be examined with respect to the primary endpoint using ANOVA 
described in Section 13.1.1 for the following subgroups: 
• Age (<median or ≥median) 
• Sex (male or female; reporting on the male subgroup may be omitted if there are 
insufficient counts)  
• Primary race (white or non-white) 
13 METHODS OF EFFICACY ANALYSES 
In general, comparisons will be pairwise between ACP-044 400 mg Q6H, ACP-044 1600 mg 
QD and placebo. 
13.1 Primary Efficacy Endpoints 
13.1.1 Primary Analysis 
The primary clinical question of interest for the primary objective is: what is the difference in 
the mean AUC0-24 of the NRS of pain intensity scores comparing ACP-044 400 mg Q6H vs. 
placebo and ACP-044 1600 mg QD vs. placebo, in subjects with acute postoperative pain 
following orthopedic surgery? 
The estimand is described by the following attributes: 
Population: Adult subjects that have acute postoperative pain following orthopedic surgery, 
as defined by the inclusion/exclusion criteria of the study. 
Variables (Primary Endpoint): mean AUC0-24 of NRS pain intensity scores 


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Treatment Condition: ACP-044 400 mg Q6H, ACP-044 1600 mg QD and placebo, with use 
of rescue medications. 
Intercurrent Events and Strategies: 
• Treatment Discontinuation will be addressed by the hypothetical strategy, i.e., 
assuming that subjects with these intercurrent events (ICEs) continue to experience 
the following the distribution of worst observed pain prior to the ICE occurrence if 
they discontinue for lack of efficacy or an adverse event; subjects discontinuing for 
other reasons will be assumed to follow the distribution of values within their 
treatment group.  
• Taking Rescue Medication will be addressed by the composite strategy of estimating 
pain scores in the presence of taking rescue medication by replacing assessments 
taken within a 4-hour window with the pre-rescue value. Should the NRS pain 
assessment taken immediately prior to rescue be less than a scheduled pain 
assessment, that scheduled pain assessment will be retained. 
Alternative approaches to handling ICEs will be addressed in sensitivity analyses. 
Population-level Summary Measure: 
The treatment difference (ACP-044 400 mg Q6H vs placebo, ACP-044 1600 mg QD vs 
placebo) in the mean NRS pain intensity score AUC0-24. 
Hypotheses 
The primary endpoint is AUC0-24 based on the pain intensity scores from 0 to 24 hours 
assessed using NRS. 
Let Δauc_1 and Δauc_2 be the difference between each of the two ACP-044 dose groups and 
placebo group in the mean AUC0-24, respectively. 
The null hypotheses are: Δauc_i = 0 and the alternative hypothesis is: Δauc_i ≠ 0, i=1,2. 
Primary Estimator 
The hypothesis testing will be performed for the Full Analysis Set using analysis of variance 
(ANOVA) with treatment group and site as factors in the model. Prior to analysis, missing 
pain assessments will be imputed before calculating AUC per Section 5.2.1. In addition, the 
AUC will have the last time point adjusted by as described in Section 5.2.1.1. 
The ANOVA results will be processed using the SAS MIANALYZE procedure to yield a 
combined estimate for treatment effect, standard error, and associated 95% confidence 
interval (CI) and p-value (Rubin 1976). 


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The treatment effect size, Cohen’s d, will be presented for both ACP-044 comparisons to 
placebo using the following formula: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆= 𝐿𝐿𝐿𝐿 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 
Where Standard Deviation is approximated: 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑜𝑜𝑜𝑜 𝐿𝐿𝐿𝐿 𝑚𝑚𝑚𝑚𝑚𝑚𝑛𝑛 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷
ට1
𝑛𝑛1 + 1
𝑛𝑛2
 
And n1 and n2 are the sample sizes in each group. The sign (+ or -) of the effect size will be 
chosen so that a positive value favors ACP-044. 
Summary statistics for the mean NRS pain intensity assessments (before and after single 
imputation) and the mean of AUC of pain intensity scores, the LS means, the between-group 
difference in LS mean with the corresponding confidence interval, p-value, and the effect size 
(Cohen’s d) will be presented. 
All pairwise treatment group comparisons will be presented. 
A line plot of the mean (+/- the SE) NRS pain intensity assessments over time will be 
presented by treatment group. 
13.1.2 Sensitivity Analyses 
The following sensitivity analyses of the primary efficacy endpoint are planned to describe 
different strategies for intercurrent events. 
13.1.2.1 
Alternative Handling of Rescue Medication Censoring 
As an alternative strategy to the intercurrent event of taking rescue medication, the impact of 
the censoring described in Section 5.2.1 will be investigated a few different ways: 
1. A 2 hour censoring window will be used.  
2. A 6 hour censoring window will be used. 
3. No values will be censored for use of rescue medication. 
For each of the above scenarios, the other components of the imputation and data handling 
will be identical to the primary and the NRS pain intensity score AUC0-24 values will then be 
calculated, and analyzed similarly as in the primary analysis.  


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13.1.2.2 
Multiple Imputation Variations 
As a sensitivity to the primary endpoint analysis, the multiple imputation approach will be 
adjusted to better understand the impacts of its assumptions.  Four approaches will be 
investigated: 
1. All subjects, regardless of reason for withdrawal, will have missing data imputed 
under a missing-at-random assumption within treatment groups. 
2. All subjects, regardless of reason for withdrawal, will have missing data imputed 
using the distribution of the worst values through that point. 
3. Subjects that withdraw due to “other” and “unknown” reasons will be grouped with 
those that withdraw for LOE and AEs; all other imputation rules from the primary 
analysis will be unchanged. 
4. In addition, the placebo-based imputation will be applied to the missing data due to 
AE or LOE. Like “standard” multiple imputations, except parameters for imputation 
model will be obtained from only the placebo (control) group. Both placebo and drug 
groups will be imputed based on the imputation model derived from placebo data. If 
drug improves outcomes prior to dropout, this benefit is carried into subsequent 
imputed values, but will diminish over time in accordance with the correlation 
structure. Subjects that discontinue for reasons other than LOE or AE will have their 
values imputed within treatment group with MI assuming MAR with covariates for all 
observed time points.   
13.1.3 Supportive Analyses 
Supportive analysis of the primary efficacy endpoint may be analyzed in a similar fashion as 
the primary analysis, using the Per-Protocol analysis set.  
13.2 Key Secondary Efficacy Endpoints 
Analysis of the key secondary efficacy endpoints will be performed using the Full Analysis 
Set. 
Time to first rescue medication use after time 0 (hours) 
A stratified log-rank test stratified by site will be used to compare the time to first rescue 
medication use after time 0 by treatment group. The follow-up time will end at 72 hours. The 
time at which subjects discontinue due to the lack of efficacy will be considered as an event. 
Subjects who do not take rescue medication and who do not discontinue for lack of efficacy 
will be censored at 72 hours or their last follow-up time, whichever is earlier. The estimate 
and 95% CI’s for the median time to event will be summarized by treatment group, where 


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event is the time to first rescue medication use after time 0. The p-value of the stratified test 
of equality over treatment group for each pairwise comparison will be summarized. 
Sample SAS code: 
proc lifetest data=indata; 
time time*cnsr(1); 
strata site /group=trt; 
run; 
where time is the time to first rescue or censor, cnsr is the censor status, site is the site 
variable, and trt is the treatment group variable. 
In addition, a stratified by site Cox proportional hazards model treatment group as a factor 
will be used to analyze the time to rescue medication or censoring. The follow-up time will 
end at 72 hours. The time at which subjects discontinue due to the lack of efficacy will be 
considered as an event. Subjects who do not take rescue medication and who do not 
discontinue for lack of efficacy will be censored at 72 hours or their last follow-up time, 
whichever is earlier.  
The hazard ratio and 95% confidence interval will be summarized for each pairwise 
comparison as defined previously. 
Kaplan-Meier curves of time to first rescue will be presented. 
Sample SAS code: 
proc phreg data=indata covsandwich; 
class trt(ref=”Placebo”); 
model time*cnsr(1)= trt/ ties=exact; 
strata site; 
run; 
In addition, the number and percentage of subjects taking rescue medication or discontinuing 
due to lack of efficacy and the number and percentage of subjects censored will be 
summarized. 
Proportion of subjects who were opioid free through 24, 48, and 72 hours 
The proportion of subjects who are opioid free (did not take acetaminophen-hydrocodone 
oral tablet as rescue medication or any other opioid) through 24, 48, and 72 hours and during 
0-<24 hours, 24-<48 hours, and 48-72 hours will be analyzed using a stratified CMH test 
controlling for site.  
The risk difference, 95% confidence interval and p-values will be provided by treatment 
group pairwise. 
13.3 Secondary Efficacy Endpoints 
Analyses of the secondary efficacy endpoints will be performed using the Full Analysis Set. 
The following secondary efficacy endpoints will be analyzed similarly as the primary 
analysis for the primary efficacy endpoint. 
• The mean AUC0-48 of NRS of pain intensity scores 


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• The mean AUC0-72 of NRS of pain intensity scores 
• The mean AUC0-4 of NRS of pain intensity scores 
• The mean AUC0-6 of NRS of pain intensity scores 
• The mean AUC0-12 of NRS of pain intensity scores 
• The mean AUC24-48 of NRS of pain intensity scores 
• The mean AUC48-72 of NRS of pain intensity scores 
Amount of rescue medication taken during 0-24, 24-48, 48-72, 0-48, and 0-72 hours 
The following will be summarized: 
• The number of tablets of ibuprofen taken during 0-24, 24-48, 48-72, 0-48, and 0-72 
hours. 
• The number of tablets acetaminophen-hydrocodone taken during 0-24, 24-48, 48-72, 
0-48, and 0-72 hours. 
• The number of instances of any rescue medication taken during 0-24, 24-48, 48-72, 
0-48, and 0-72 hours. 
• The amount of opioids in Morphine Milligram Equivalents (MME) taken during 0-24, 
24-48, 48-72, 0-48, and 0-72 hours  
Each of the above items will be analyzed using ANOVA with treatment group and site as 
factors in the model by rescue medication type.  
The LS mean (SE), 95% confidence intervals, and p-values will be presented by treatment 
group. The LS mean difference (SE), associated 95% confidence intervals, p-values, and 
Cohen’s d will be presented by treatment group pairwise. 
Proportion of subjects who did not use rescue medication through 24, 48, and 72 hours 
Given the in-clinic setting of this study, subjects with no records of rescue medication 
dispensation will be assumed to not have used any rescue medication. 
The proportion of subjects who did not use rescue medication (neither acetaminophen-
hydrocodone oral tablets nor ibuprofen nor any other) through 24, 48, and 72 hours will be 
summarized and will be analyzed using a stratified Cochran-Mantel-Haenszel (CMH) test 
controlling for site.  
The risk difference, 95% confidence interval and p-values will be provided by treatment 
group pairwise. 
Proportion of subjects who were opioid free during 24-48 hours and 48-72 hours 
The proportion of subjects who are opioid free (did not take acetaminophen-hydrocodone 
oral tablet as rescue medication or any other opioid) through 24, 48, and 72 hours and during 
0-<24 hours, 24-<48 hours, and 48-72 hours will be analyzed using a stratified CMH test 
controlling for site.  


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The risk difference, 95% confidence interval and p-values will be provided by treatment 
group pairwise. 
Proportion of subjects who are pain free (NRS ≤2) at 24, 48, and 72 hours 
The proportion of subjects who are pain free at 24, 48, and 72 hours will be analyzed using a 
stratified CMH test controlling for site. 
The risk difference, 95% confidence interval and p-values will be provided by treatment 
group pairwise. 
Number of hours subjects are pain free (NRS ≤2) 
The number of hours subjects are pain free will be analyzed using ANOVA with treatment 
group and site as factors in the model. Each active dose group will be compared to placebo 
using this model. 
The LS mean (SE), 95% confidence intervals, and p-values will be presented by treatment 
group. The LS mean difference (SE), associated 95% confidence intervals, p-values, and 
Cohen’s d will be presented by treatment group pairwise. 
Global evaluation of study drug just before time of first rescue and at the end of 24, 48, 
and 72 hours 
The global evaluation of study drug (GESD) will be summarized as a categorical and as a 
continuous variable for each visit and for each censoring approach: 
• With all values reported as recorded 
• With values following rescue censored 
• With the pre-rescue values grouped with the subsequent time point and values 
following rescue censored 
The GESD will be analyzed by visit using ANOVA with treatment group and site as factors 
in the model.  
The LS mean (SE), 95% confidence intervals, and p-values will be presented by treatment 
group. The LS mean difference (SE), associated 95% confidence intervals, p-values, and 
Cohen’s d will be presented by treatment group pairwise. 
13.4 Exploratory Efficacy Endpoints 
Proportion of subjects with severe pain (defined as an NRS pain intensity score ≥7 at 
any timepoint through 72 hours) 
The proportion of subjects with severe pain will be analyzed using a stratified CMH test 
controlling for site. 


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The odds ratio, 95% confidence interval and p-values from the CMH test will be provided by 
treatment group pairwise. 
Foot and Ankle Ability Measure (FAAM) 
The summary of each movement category will be summarized descriptively as a categorical 
variable. The overall grades (ADL item score percentage, patient reported ADL overall score, 
Sports item score percentage, patient reported Sports overall score, and derived total score) 
will be summarized as a continuous variable. The change from baseline in overall grade will 
be analyzed using analysis of covariance (ANCOVA) with treatment group and site as factors 
and baseline (Day -1) FAAM as a covariate in the model.  
The LS mean (SE), 95% confidence intervals, and p-values will be presented by treatment 
group. The LS mean difference (SE), associated 95% confidence intervals, p-values, and 
Cohen’s d will be presented by treatment group pairwise. 
14 SAFETY ANALYSES 
All safety analyses will be performed using the actual treatment received for the Safety 
Analysis Set. 
14.1 Adverse Events  
Adverse events will be coded using MedDRA dictionary, Version 24.0 or newer. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if 
started after first dose administration and no later than last dose date + 30 days. AEs reported 
on Day -1 based on Baseline (pre-dose) findings (e.g., clinically significantly abnormal vital 
signs, laboratory test results, or electrocardiogram parameters) will not be considered as 
TEAEs. 
The event counts, the number, and percentage of subjects reporting TEAEs in each treatment 
group will be tabulated by system organ class (SOC) and preferred term; by SOC, preferred 
term, and maximum severity; and by SOC, preferred term, and relationship to study drug. If 
more than one TEAE occurs with the same preferred term for the same subject, then the 
subject will be counted only once for that preferred term using the most severe and most 
related occurrence for the summarization by severity and by relationship to study drug. The 
display in these tables will be sorted alphabetically by SOC and then by descending subject 
frequency for the preferred terms (counts from ACP-044 treated group) within each SOC. 
The event counts, the number and percentage of subjects with any TEAEs will also be 
tabulated by preferred term without SOCs. This table will be sorted by descending subject 
frequency within ACP-044 treated group. 


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The incidence of most frequently reported (preferred terms reported by ≥ 5% of subjects in 
any treatment group) TEAEs, SAEs reported after treatment start, TEAEs leading to 
discontinuation of study drug, and TEAEs related to study drug will be summarized by SOC, 
preferred term, and treatment group. The tables will be sorted alphabetically by SOC and 
then by descending frequency within each SOC in ACP-044 treated group. In addition, the 
incidence of fatal treatment-emergent AEs (i.e., events that cause death) will be summarized 
separately by SOC and preferred term. 
The incidence of adverse events of special interest, such as opioid-related adverse events 
(ORAEs) will be summarized separately by SOC and preferred term. ORAEs evaluation will 
be based on the following prespecified preferred terms of nausea, vomiting, constipation, 
pruritus, pruritus generalized, somnolence, sedation, respiratory depression, urinary retention 
hypotension, pre-syncope, syncope, and bradycardia, regardless of whether a subject actually 
received an opioid medication. 
These summary tables except for the most frequently reported TEAEs tables may also be 
presented for COVID-19 and non-COVID-19 related events, if applicable. 
An AE listing by subject will display all events, including those which occur during 
screening, and will include the verbatim term in addition to the MedDRA SOC and preferred 
term. This listing will also include all relevant eCRF data associated with the event: date of 
onset, date resolved, date of last dose, severity, frequency, outcome, relationship to study 
drug, and action taken with study drug. A listing by subject will display all TEAE, excluding 
AE that are not treatment-emergent. Separate listings will be presented for subjects with 
treatment-emergent SAEs, related TEAEs, TEAEs leading to discontinuation, fatal TEAEs 
(if any), and COVID-19 related TEAEs (if applicable).  
14.2 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Day -1 predose and Day 4 (EOT/ET). 
The laboratory evaluations will include, but are not limited to, the following: 
• Clinical chemistry serum tests (CHEM) 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium 
(Ca),carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric 
acid, 
 Mg should only be performed at Visit 1 (Screening) 
o Estimated glomerular filtration rate (eGFR) should only be performed at 
Visit 1 (Screening) 


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o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel should only be performed at Visit 1 (Screening): 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol; should only be 
performed at Visit 1 (Screening) 
o HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB) should only be performed at Visit 1 (Screening) 
o Total protein should only be performed at Visit 1 (Screening) 
• Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• Endocrinology 
o Thyroid stimulating hormone (TSH) and free T4 (Screening) 
o Vitamin B12 should only be performed at Visit 1 (Screening) 
• Pregnancy test 
o A serum pregnancy test should only be performed at screening for women of 
childbearing potential 
o A urine pregnancy test should be performed before surgery on Day -1 for 
women of child-bearing potential 
• COVID-19 test: 
o COVID-19 diagnostic PCR test at Screening 
o COVID-19 rapid antigen test on Day-1 predose 


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• Urinalysis (UA) 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, nitrates 
• Urine toxicology screen 
o Urine toxicology screen will test for controlled substances. The following 
controlled substances may be tested with a urine toxicology screen at 
Screening and Day -1: amphetamine, barbiturates, benzodiazepines, cocaine, 
methadone, morphine/opiates, methamphetamine, marijuana (THC), 
phencyclidine (PCP), ecstasy (MDMA). 
Clinical laboratory values (in Système International [SI] units) and the change from Baseline 
values will be summarized by treatment group at each post-Baseline visit using descriptive 
statistics. The overall minimum, maximum as well as the last post-Baseline observed and 
change from Baseline values will also be summarized. For urinalysis with categorical results, 
the number and percentage of subjects will be tabulated by category at Baseline and each 
post-Baseline visit, and the denominator is the number of subjects with non-missing values 
for the given parameter, visit and treatment group. 
Laboratory values will also be summarized in shift tables by treatment group, to determine 
the number and percentage of subjects with values classified as below, within, and above 
normal ranges at each post-Baseline visit relative to the same classification at the Baseline 
visit. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing values at Baseline and the given visit for the given parameter and treatment 
group. For the shift to the overall post-Baseline minimum or maximum, all post-Baseline 
values will be considered, including unscheduled and out of window values and the 
denominator is the number of subjects with non-missing Baseline value and at least 1 
post-Baseline value for the given parameter and treatment group. 
Clinical laboratory values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Tables 4 and 5. The number and percentage of subjects with 
post-Baseline PCI values for each of the categories in Table 4 and 5 will be summarized by 
treatment group for selected parameters. For the overall post-Baseline summaries of PCI 
values, all post-Baseline values will be considered, including unscheduled and out of window 
values. Subjects with multiple PCI values for a given parameter will be counted only once for 
that parameter. For the overall post-Baseline summary, the numerator of the percentage is the 
number of subjects with at least 1 post-Baseline PCI laboratory value for the given parameter 
and treatment group, and the denominator is the number of subjects with at least 
1 post-Baseline laboratory value for the given parameter and treatment group. 


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Table 4 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry 
 
Analyte 
Conventi
onal Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin (female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55 
L/L 
<0.3 
>0.55 
Hematocrit (female) 
% 
<30 
>50 
L/L 
<0.3 
>0.5 
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase (CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase (LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
T4, free 
ng/dL 
below 
normal range 
above normal 
range  
pmol/L 
below normal 
range 
above normal 
range  
TSH 
uU/L 
below 
normal range 
above normal 
range  
mIU/L 
below normal 
range 
above normal 
range  
 


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Table 5 
Criteria for Potentially Clinically Important Laboratory Values – Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥ +2 
Protein 
Not Applicable 
≥ +2 
Glucose 
Not Applicable 
≥ +2 
Clinical laboratory data will be displayed in data listings with date and study day of 
collection. All units will be displayed according to SI conventions for units. Out of range 
values will be flagged in the data listings (i.e., ‘L’ or ‘H’). A separate listing will be provided 
for a subset of the chemistry, hematology, and urinalysis analytes with values classified as 
PCI.  
The pregnancy results (positive or negative) for female subjects will be presented in a listing. 
In addition, the following additional PCI criteria for liver function tests will be flagged, 
listed, and summarized: 
• ALT (SGPT)>=2x ULN U/L 
• AST (SGOT)>=2x ULN U/L 
• Gamma Glutamyl Transferase>=2x ULN U/L 
• Alkaline Phosphatase>=2x ULN IU/L 
14.3 Vital Signs 
Vital signs are assessed at Screening, Day -1 predose, and on Day 1 every 2 hours for the first 
6 hours after the initial dose; vital signs then to be evaluated every 6 hours thereafter until 
Day 4 (EOT).  
Vital signs will be summarized using descriptive statistics at Baseline and all scheduled 
post-Baseline visits/timepoints. The change from Baseline values will also be summarized at 
the scheduled post-Baseline visits/timepoints.  
Vital sign values will be considered PCI if they meet the criteria listed in Table 6. The 
number and percentage of subjects with post-Baseline vital signs that are PCI will be 
summarized by treatment group at each post-Baseline visit and for overall post-Baseline. For 
the overall post-Baseline summaries, all post-Baseline values will be considered, including 
unscheduled and out of window values. Subjects with multiple PCI values for a given 
parameter will be counted only once for that parameter. For the by-visit summary, the 
numerator for the percentage is the number of subjects with a post-Baseline PCI vital sign for 
the given parameter, visit and treatment group, and the denominator is the number of subjects 
with non-missing values for the given parameter, visit and treatment group. For the overall 


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post-Baseline summary, the numerator for the percentage is the number of subjects with at 
least 1 post-Baseline PCI vital sign for the given parameter and treatment group, and the 
denominator is the number of subjects with at least 1 post-Baseline vital sign for the given 
parameter and treatment group. A listing of overall and of subjects with any PCI vital sign 
values will be provided. 


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Table 6 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change 
from baseline. 
 
14.4 Electrocardiogram (ECG) 
12-lead ECGs are collected at Screening, Day -1 predose, Days 1 through 3 (at 1 hour 
postdose), and EOT/ET. Observed values of ECG variables (e.g., heart rate, PR interval, QRS 
interval, QT interval, and QTc interval) and the changes from Day -1 (predose) at each 
assessment time point will be summarized by treatment group. 
QTcB and QTcF will also be categorized into the following categories (msec) and the number 
and percentage of subjects in each category will be summarized by treatment group at each 
visit and for the overall post Day -1 dose maximum: 
• Observed: ≤450, 451 - ≤480, 481 - ≤500, and >500; >450; >480. 
• Change from Baseline: ≤10, 11 – 30, 31 – 60, and >60; >30. 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results 
that are determined as normal or abnormal will be summarized at scheduled visits. The 
overall post-baseline worst interpretation will also be summarized (i.e. if a subject has one or 
more post-baseline ECG results that is/are considered as abnormal, this subject will be 
counted in the abnormal category). Cardiologist’s interpretations will also be summarized in 
a shift table. The shifts from Baseline to overall post-Baseline worst interpretation will also 
be presented. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing cardiologist’s interpretation at Baseline and the given visit for the given 
treatment group. For the summaries of shift from Baseline to the overall post-Baseline worst 
interpretation, the denominator is the number of subjects with non-missing Baseline and at 
least 1 post-Baseline cardiologist’s interpretation for the given treatment group. 
Electrocardiogram variable values will be considered PCI if they meet the criteria listed in 


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Table 7. The number and percentage of subjects with post-baseline PCI values will be 
summarized by treatment group at each post-Baseline visit and for overall post-Baseline. For 
the by-visit summary, the numerator for the percentage is the number of subjects with a 
post-Baseline PCI ECG for the given parameter, visit and treatment group, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit 
and treatment group. For the overall post-Baseline summary, the numerator for the 
percentage is the number of subjects with at least 1 post-Baseline PCI ECG for the given 
parameter and treatment group, and the denominator is the number of subjects with at least 
1 post-Baseline ECG value for the given parameter and treatment group. A listing of overall 
and of all subjects with any PCI ECG values will be provided. 
Table 7 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline 
msec 
>60 
 
14.5 Physical Examination 
Physical examinations are performed at Day -1 predose, Day 4, and at Follow-Up (surgical 
site only). Physical examination results (normal, abnormal, and not done) will be summarized 
in a frequency table by treatment group, body system and visit. A listing of overall physical 
examination data will be listed. 
A listing related to surgical site inspection will be generated (Day 4 General Appearance, 
Day 7 Musculoskeletal). A shift table for surgical site inspection will be presented 
summarizing Day 4 and Day 7 and the shifts between the two visits (Abnormal Not 
Clinically Significant, Abnormal Clinically Significant). 
14.6 Other Safety Variables 
14.6.1 Suicidality Based on C-SSRS 
The event counts and the number and percentage of subjects reporting any post Baseline 
suicidal ideation, suicidal behavior, or suicidality will be tabulated by treatment group. The 
event counts and the number and percentage of subjects reporting any post-Baseline 
non-suicidal self-injurious behavior will also be tabulated. For calculating the percentages, 
the denominator will be the number of subjects in the Safety Analysis Set. 


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15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
All summary and analyses of PK or PD of ACP-044 will be performed for the PK Analysis 
Set based on the actual treatment group. The treatment groups will be ACP-044 400 mg Q6H 
and ACP-044 1600 mg QD. 
15.1 Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• Plasma concentrations of ACP-044 for a total of six (6) samples: Day -1 (predose), 
Day 1 (one sample taken between 2-3 hours and one sample taken between 4-6 hours, 
after the first dose of the day), Day 2 (prior to the first dose of the day), and Day 3 
(one sample taken between 2-6 hours and one sample taken between 8-12 hours, after 
the first dose of the day) 
• ACP-044 PK parameters determined using a population PK approach 
Plasma concentration of ACP-044 will be summarized by treatment group using the 
Pharmacokinetic Analysis Set. 
PK parameter summary and analysis will be discussed in a separate plan. 
15.2 Pharmacokinetic/Pharmacodynamic Endpoints 
The PK/PD endpoints include: 
• ACP-044 exposure-response relationship: 
o for efficacy using the primary endpoint and selected secondary endpoints 
o for safety using selected TEAEs 
PK/PD endpoint summary and analysis will be discussed in a separate plan. 
16 INTERIM ANALYSIS 
No interim analyses are planned for this study. 
17 DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring/review committee in this study. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS® Institute, 
Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 


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19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
None. 


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20 REFERENCES 
ICH E9(R1): Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the 
Guideline on Statistical Principles for Clinical Trials, Adopted on November 2019 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic Guidance for Industry, Investigators, and Institutional Review Boards (March 
2020) 
Points to consider on implications of Coronavirus disease 4 (COVID-19) on methodological 
aspects of ongoing clinical 5 trials, March 25 2020. 
Rubin, D. B. Inference and Missing Data. Biometrika. 1976; 63:581-92. 
Centers for Disease Control and Prevention. 2018 Annual Surveillance Report of Drug-
Related Risks and Outcomes — United States. Surveillance Special Report 2. Centers for 
Disease Control and Prevention, U.S. Department of Health and Human Services. Published 
August 31, 2018.


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21  APPENDICES 
21.1 Schedule of Events and Assessments 
 
Screening 
Period 
Double-blind 
Treatment Period 
 
Safety Follow-up 
Period 
Visit Day 
-28 to -2 
Day -1 
Predose 
Day -1 
(Dosing 
and 
Postdose) 
Day 1 
(Time 
0) 
Day 
2 
Day 
3 
Day 4 
(EOT/ET) 
Unscheduled 
Visitm 
Clinic 
visit 
Telephone 
call 
7 
days 
after 
EOT 
30 days 
after last 
dose 
Visit window (# 
days) 
 
0 
0 
0 
0 
0 
0 
 
±3 
+4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical and 
surgical history 
and demographics 
X 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
X 
 
 
 
 
Xk 
 
Xk 
 
Vital signsa 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Height, weightb 
X 
X 
 
 
 
 
 
 
 
 
12-lead ECGc 
X 
X 
 
X 
X 
X 
X 
 
 
 
Clinical laboratory 
tests 
X 
X 
 
 
 
 
X 
 
 
 
Pregnancy testd 
X 
X 
 
 
 
 
 
 
 
 
Urine toxicology 
screen 
X 
X 
 
 
 
 
 
 
 
 
COVID-19 teste 
X 
X 
 
 
 
 
 
 
 
 
Clinic check in/out 
 
X 
 
 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study drug 
administration 
 
 
X 
X 
X 
X 
 
 
 
 
Pain assessment 
trainingf 
X 
X 
 
 
 
 
 
 
 
 
Bunionectomy 
 
 
X 
 
 
 
 
 
 
 
Block Quality 
Assessmentg 
 
 
X 
 
 
 
 
 
 
 
11-point Numeric 
Rating Scale 
(NRS) of pain 
intensityh 
 
 
 
X 
X 
X 
X 
 
 
 
Foot and Ankle 
Ability Measure 
 
X 
 
 
 
 
 
 
X 
 
Rescue medicationi 
 
 
 
X 
X 
X 
X 
 
 
 


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21.1 Schedule of Events and Assessments (Continued) 
 
Screening 
Period 
Double-blind 
Treatment Period 
 
Safety Follow-up 
Period 
Visit Day 
-28 to -2 
Day -1 
Predose 
Day -1 
(Dosing 
and 
Postdose) 
Day 1 
(Time 
0) 
Day 
2 
Day 
3 
Day 4 
(EOT/ET) 
Unscheduled 
Visitm 
Clinic 
visit 
Telephone 
call 
7 
days 
after 
EOT 
30 days 
after last 
dose 
Visit window (# 
days) 
 
0 
0 
0 
0 
0 
0 
 
±3 
+4 
Global evaluation 
of study drug 
 
 
 
X 
X 
X 
X 
 
 
 
C-SSRS 
X 
X 
 
 
 
 
X 
 
 
 
PK blood sample 
collectionj 
 
X 
 
X 
X 
X 
 
 
 
 
Issue diary 
 
 
 
 
 
 
Xl 
 
 
 
Collect diary 
 
 
 
 
 
 
 
 
X 
 
Prior and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE=adverse event; COVID-19=Coronavirus disease 2019; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EOT=end of treatment; ET=early termination; SAE=serious adverse event 
a Vital signs will be evaluated starting at Screening; Day -1 predose and on Day 1 every 2 hours for the first 6 hours after the 
initial dose. Vital signs then to be evaluated every 6 hours thereafter until Day 4/end of treatment. A 15-minute window is 
permitted for vital sign measurements. 
b Height and BMI will only be measured and calculated at the Screening visit; weight will be measured at Screening and Day -1 
predose. 
c A single 12-lead ECG will be performed at Screening, on Day -1 predose, on Days 1 through 3 at 1 hour postdose (the first 
dose of the day), and EOT/ET. A 1-hour window is permitted for the predose ECG and a 20-minute window is permitted for the 
postdose ECGs. 
d Applicable to women of childbearing potential. A serum pregnancy test should be performed at Screening and a urine test must 
be performed at clinic check-in, prior to surgery. 
e COVID-19 diagnostic polymerase chain reaction (PCR) test at Screening and a rapid antigen test on Day -1 predose. 
f Subjects will be trained on the process for completion of pain assessments. 
g Block Quality assessments are to be performed and recorded hourly (±15 minutes) on Day -1 until the block is removed, except 
between 2200 and 0600 hours when the subject is asleep. Between these hours, the subject will not be awaken, except at 0300 
hours (±15 minutes) when the assessment is to be completed. 
h Subjects should not have ice administered to the surgical area within the 30 minutes prior to each pain assessment. Pain 
(efficacy) assessments are to be recorded hourly (±15 minutes) for a 12 hour interval on Day 1 beginning immediately prior to 
the fifth dose (time 0) administered in the study. Pain assessments will continue every 3 hours during the subsequent 12 hour 
interval, and then every 6 hours thereafter until 72 hours, then once daily in the morning until the follow-up clinic visit. Rescue 
medication use is to be recorded until the safety follow-up clinic visit. Pain intensity should also be obtained immediately prior to 
rescue medication being taken. 
i Record name, amount, date, and time of rescue medication ingested and current pain score until the follow-up clinic visit 7 days 
after EOT. 


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j PK blood samples will be collected Day -1 (predose, within one hour of dosing), Day 1 (one sample taken between 2-3 hours 
and one sample taken between 4-6 hours, after the first dose of the day), Day 2 (prior to the first dose of the day), and Day 3 (one 
sample taken between 2-6 hours and one sample taken between 8-12 hours, after the first dose of the day); and in the event of an 
SAE or an AE leading to discontinuation. A 15-minute window is permitted around each nominal timepoint on Day 1 and 
beyond. 
k The physical exam on Day 4 (EOT/ET) must include an exam of the operative site. The physical exam at the follow-up visit 7 
(±3) days after the EOT procedures is for examination of the operative site only. Examination of the operative site must include 
visual inspection. 
l Diary will be issued to take home which will be returned at the follow-up clinic visit 7 days after EOT. 
m The designated study procedures are to be completed; however, the Investigator may complete any study procedure deemed 
necessary. 
21.2 Multiple Imputation Details 
The multiple imputation will be performed in a multi-step process: 
1. Subjects with missing Time 0 assessments will be imputed by using the mean of the 
non-missing Time 0 assessments of the same treatment group. 
2. Subjects that take rescue medications within 4 hours prior to a scheduled assessment will 
have the scheduled value replaced with the pre-rescue value for the purposes of 
imputation.  If the scheduled value is higher than the pre-rescue value, it will not be 
replaced. 
3. The dataset will be transposed to create a one-observation-per-patient dataset with 
variables representing the values at each scheduled time point (T_0  T_1  T_2  T_3  T_4  
T_5  T_6  T_7  T_8  T_9  T_10 T_11 T_12 T_15 T_18 T_21 T_24 T_30  T_36 T_42 
T_48 T_54  T_60 T_66 T_72).   Site indicator variables (with values 0/1) will be created 
for the sites (with one less variable than number of sites).  For the purposes of illustration, 
the follow text assumes 4 sites and three variables (S_1 S_2 S_3). 
4. Values will be imputed assuming missing at random to create 50 complete datasets with 
values for all time points. 
5. Subjects that drop out for adverse events or lack of efficacy will have their post-dropout 
missing values reset to missing. 
6. Subjects with nonmissing values at 1 hour (aka T_1 variable) will have the T_1 variable 
replaced with max(T_0, T_1);  this will include ALL subjects that do not drop out due to 
AE or lack of efficacy (LOE) (thus, may include values imputed in prior steps) and 
subjects that drop out due to AE or LOE prior to them dropping out.   Proc MI will then 
be run including the site variables (S_1 S_2 S_3) and the two NRS variables through 
1 hour: (T_0, T_1). 
7. Subjects that had non-missing T_1 will have their values returned to their prior state 
(NOT the max of T_0, T_1), and the process will be repeated for T_2: Patients with 


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nonmissing values at 2 hours (aka T_2 variable) will have the T_2 variable replaced with 
max(T_0, T_1, T_2);  this will include ALL subjects that do not drop out due to AE or 
LOE (thus, may include values imputed in prior steps) and subjects that drop out due to 
AE or LOE prior to them dropping out.   Proc MI will then be run including the site 
variables (S_1 S_2 S_3) and the three NRS variables through 2 hours: (T_0, T_1, T_2). 
8. This will be repeated iteratively up to the 72-h time point, building up to a complete 
dataset.   This exercise yields values that are based on the distribution of the worse values 
through the time point being imputed for dropouts due to AE/LOE. 
9. This complete dataset will be used ONLY to fill in monotone missing values starting at 
subject dropout.  No observed values from the original dataset will be replaced and 
intermittent missing values and values following rescue med administration will be 
handled as described in above in the Section 5.2.1 when calculating AUCs.  This will 
result in 50 records for each patient for each AUC0-time. 
The following sample code represents the imputation in step 4 above:  
proc mi data=nrs seed=7238364 nimpute=50 out=nrs0 minimum=xx maximum=xx; 
mcmc impute=full chain=multiple; 
by TRT01P; 
var S 1 S 2 S 3 T 0  T 1  T 2  T 3  T 4  T 5  T 6  T 7  T 8  T_9  T_10 T_11 T_12 T_15 
T_18 T_21 T_24 T_30  T_36 T_42 T_48 T_54  T_60 T_66 T_72; 
run; 
The following sample code represents the imputation in step 6 above:  
proc mi data=nrs0 seed=7238364 + seq# nimpute=1 out=nrs1 minimum=xx maximum=xx; 
mcmc impute=full chain=multiple; 
by imputation  TRT01P; 
var S_1 S_2 S_3 T_0  T_1; 
run; 
The following sample code represents the imputation in step 7 above:  
proc mi data=nrs1 seed=7238364 + seq#  nimpute=1 out=nrs2 minimum=xx maximum=xx; 
mcmc impute=full chain=multiple; 
by imputation  TRT01P; 
var S_1 S_2 S_3 T_0  T_1 T_2; 
run; 
The following list of seeds will be used when needed for MI procedures or other analyses call for 
a random number seed.  Each will only be used once, but if additional seeds are required, they 
will be chosen by adding one to a digit from the below list in an organized manner.  For 
example, the primary analysis may use the list in order as it appears; a sensitivity may add one to 
the final digit of each; a second sensitivity may add one to the first digit of each.  The actual 
seeds used will be captured in the analysis dataset programing specifications. 


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Seed 7238364 will be used for the multiple imputation other than placebo-based approach. 
Seed 1592743 will be used for the placebo based multiple imputation. 
Replace Steps 6-8 with the following sample code to achieve control-based copy-placebo 
imputation for missing data due to AE and LOE:  
 PROC MI DATA=MONO SEED=xxxxx NIMPUTE=1 OUT=OUTM1 minimum=xx maximum=xx; 
 CLASS TRT01PN; 
 By _IMPUTATION_; 
 VAR S_1 S_2 S_3 AVAL1 AVAL2 AVAL3……; 
 MONOTONE REG (AVAL2 AVAL3……); 
 MNAR MODEL (AVAL1 AVAL2 AVAL3…../ MODELOBS = (TRT01PN = ‘1’)); 
RUN; 
21.3 Summary of Version Changes 
Version No: Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original Version 
 
14 March 2022