Clinical trial NCT05008835
Conditions: Osteoarthritis Pain
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2021-07-20; Completion date: 2022-11-16
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of ACP-044 compared with placebo in the treatment of pain associated with osteoarthritis of the knee

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: 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 in Subjects With Pain Associated With 
Osteoarthritis of the Knee 
NCT Number: NCT05008835 
Document Date: 16 February 2022 


 
  
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 90 
 
 
CLINICAL STUDY PROTOCOL 
 
UNMASKED PROTOCOL 
 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of ACP-044 in Subjects With Pain 
Associated With Osteoarthritis of the Knee 
 
Protocol Number: ACP-044-005 
Amendment 4 
 
Original Protocol Date: 04 March 2021 
Protocol Amendment 1 Date: 10 May 2021 
Protocol Amendment 2 Date: 21 May 2021 
Protocol Amendment 3 Date: 03 August 2021 
Protocol Amendment 4 Date: 16 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-044-005 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 UNMASKED VERSION 
Date: 16 February 2022 
 
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SPONSOR SIGNATURE PAGE 
Title: A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of ACP-044 in Subjects With Pain Associated With Osteoarthritis of the 
Knee 
 
Acadia Head of Clinical Development: 
 
 
 
 
 
 
 
 
 
 
See appended electronic signature page 
 
Signature 
Date 
 
 
 
Acadia Study Lead: 
 
 
 
 
 
 
 
See appended electronic signature page 
 
Signature 
Date 
 
 
 
 
 
 


Signature Page for ACP-044-005 Protocol Amendment 4 UNMASKED Version NOT FOR DIS
Signature Page for ACP-044-005 Protocol Amendment 4 UNMASKED Version NOT FOR DIS
Approve
17-Feb-2022 19:13:35 GMT+0000
Approve
18-Feb-2022 14:31:04 GMT+0000


Study: ACP-044-005 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 UNMASKED VERSION 
Date: 16 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-044-005 
 
Final Version: 1.0 
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Date: 16 February 2022 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-044-005 
EudraCT Number 
Not applicable 
Protocol Title 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of ACP-044 in Subjects With Pain 
Associated With Osteoarthritis of the Knee 
Name of 
Investigational 
Product 
ACP-044 
Indication 
Treatment of osteoarthritis pain 
Phase of 
Development 
2 
Sponsor 
Acadia Pharmaceuticals Inc. 
 
 
Study Hypothesis 
ACP-044 is more effective at treating osteoarthritis pain than 
placebo and is safe and well tolerated  
Primary Objective 
To evaluate the efficacy of ACP-044 
compared with placebo in the treatment of 
pain associated with osteoarthritis (OA) 
of the knee 
Primary Endpoint 
Change from Baseline to Week 4 in the weekly 
average of the daily average Numeric Rating 
Scale (NRS) pain intensity scores 
Secondary Objective 
To evaluate the efficacy of ACP-044 
compared with placebo in the treatment 
of pain associated with OA of the knee  
 
Key Secondary Endpoints 
• Patient Global Impression of Change 
(PGIC) at Week 4 with reference to 
baseline status 
• Change from Baseline to Week 4 in 
Western Ontario and McMaster 
Universities Osteoarthritis Index 
(WOMAC) total score and individual 
subscale scores for pain, stiffness, and 
physical function  
• Proportion of subjects who are responders 
as defined by 30% and 50% reduction from 
Baseline to Week 4 in the weekly average 
of the daily average NRS pain intensity 
scores 


Study: ACP-044-005 
 
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Additional Secondary Endpoints  
Change from Baseline to Week 4 in: 
• Weekly average of the daily worst NRS 
pain intensity scores 
• Brief Pain Inventory–Short Form (BPI-sf)  
• 12-item Short Form Survey (SF-12) 
Exploratory Objective 
To evaluate the use of rescue medication 
in subjects with pain associated with 
OA of the knee treated with ACP-044 
compared with placebo 
Exploratory Endpoints 
• Comparison of average daily rescue 
medication use 
• Hospital Anxiety and Depression Scale 
(HADS) 
Safety Objective 
To evaluate the safety and tolerability of 
ACP-044 compared with placebo in the 
treatment of pain associated with OA of 
the knee 
Safety Endpoints 
• Treatment-emergent adverse events 
(TEAEs) 
• Vital signs 
• Electrocardiograms (ECGs) 
• Physical examination results 
• Clinical laboratory tests 
• Columbia–Suicide Severity Rating Scale 
(C-SSRS) 
Pharmacokinetic Objective 
To characterize the pharmacokinetic (PK) 
profile of ACP-044 in subjects with pain 
associated with OA of the knee  
Pharmacokinetic Endpoints 
• Plasma concentrations of ACP-044 using 
sparse sampling on the following study 
days: Baseline (Week 0), Week 1, Week 2, 
and Week 4 (EOT)/ET 
• 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 
• Guided by exploratory analyses, appropriate 
ACP-044 exposure-response relationship: 
o for efficacy using the primary endpoint 
o for safety using the most frequent and 
other relevant TEAEs 
Number of Study 
Sites 
Up to approximately 50 US sites will participate in this study. 


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Number of Subjects 
Planned 
Approximately 480 subjects will be screened and approximately 
240 subjects are planned for randomization. Each treatment arm 
(ACP-044 800 mg BID dose, ACP-044 400 mg QID dose, and 
placebo) will randomize approximately 80 subjects, assuming a 
screen failure rate of 50%. 
Test Product, Dose, 
and Administration 
The investigational products are ACP-044 400 mg tablets, or 
matching placebo (size- and color-matched) tablets. Study drug 
doses are to be administered orally for 4 weeks. 
Doses to be studied are: 
• ACP-044 800 mg dose delivered two times a day (provided 
as 2×400 mg ACP-044 tablets) 
• ACP-044 400 mg dose delivered four times a day (provided 
as 1×400 mg ACP-044 tablet) 
• Placebo, size- and color-matched to ACP-044 tablets  
Blinded drug will be provided in blister cards. All subjects will take 
the same number of tablets per day in order to maintain the blinded 
study design.  
Dosing is to occur in the morning (2 tablets), noon (1 tablet), 
evening (2 tablets), and night (1 tablet) and should occur at the same 
time each day over the duration of the study. 
Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the efficacy and safety of ACP-044 
in subjects with pain associated with radiographically confirmed 
OA of the knee. The study will compare active treatment groups, 
receiving either 800 mg ACP-044 BID or 400 mg ACP-044 QID, 
with a placebo group. The Sponsor, subjects, and Investigators will 
be blinded to treatment assignment. 
This unmasked protocol version provides details of certain study 
design elements, procedures, and statistical methods that are 
intended for use only by the unmasked Sponsor and restricted 
clinical service providers and their designated agents. 
The study periods are: 
• Screening: up to 4 weeks  
• Baseline Pain Assessment: a 7-day period during which 
baseline pain assessments will be recorded for 7 days. 
Additional 3-day window may be added, if needed. 
• Double-blind treatment: 4 weeks 


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• Safety follow-up: approximately 7 days after end of 
treatment (EOT)/early termination (ET) and approximately 
30 days after the last dose of study drug 
Screening Period (Up to 4 weeks) 
During the Screening period, subjects will be assessed for study 
eligibility. All subjects must have radiographically confirmed OA of 
the knee, including review of imaging and confirmation of a 
Kellgren-Lawrence (K-L) score of 2 or 3. Subjects who have had an 
X-ray of the index knee within 12 weeks of Screening may provide 
a historical image for central reading to confirm eligibility, or 
imaging can be done during Screening at protocol-trained 
radiological sites. Randomization visits cannot occur until there is 
confirmation from the central reader that there are no exclusionary 
findings on the knee joint images. The index knee is defined as the 
most painful knee at Screening. 
Prohibited analgesic medications must be discontinued during the 
Screening period. Investigators must not withdraw a subject’s 
prohibited medication other than analgesics solely 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. 
All pain medication, except for the rescue medication 
(acetaminophen), will be discontinued 7 days or 5 half-lives, 
whichever is longer, prior to the Baseline Pain Assessment Period. 
In the event of inadequate pain relief, acetaminophen may be taken 
with a maximum daily dose of 2500 mg. 
Rescreening of a subject will be allowed, with the approval of the 
Medical Monitor. 
Baseline Pain Assessment Period (1 Week) 
Following eligibility at screening, subjects will complete a Baseline 
Pain Assessment Period that will occur approximately 7 days before 
randomization; an additional 3-day window may be added, if 
needed. During the Baseline Pain Assessment Period, subjects will 
be instructed in the use of a handheld device (electronic diary 
[eDiary]) to record their daily pain scores and rescue medication 
use. Compliance with recording of pain score and use of rescue 
medication will be assessed for continued subject eligibility. 
Subjects must discontinue taking study-provided rescue medication 
during the Baseline Pain Assessment Period and for at least 24 hours 
prior to the start of study visits. Rescue medication use during the 
Baseline Pain Assessment Period through Visit 3 and within 


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24 hours of the study visits (Visits 5, 6, and 8) will be documented 
in the electronic data capture (EDC). 
Subjects who enter the Baseline Pain Assessment Period will not be 
allowed to rescreen. Subjects who experience technical issues with 
the device and their pain scores were not assessed may be 
rescreened and the Baseline Pain Assessment Period may be 
extended, if needed and with permission of the Sponsor. 
Treatment Period (4 Weeks)  
At Baseline (Week 0), eligible subjects will be randomly assigned in 
a 1:1:1 ratio to receive ACP-044 800 mg BID, ACP-044 400 mg 
QID, or placebo, according to a randomization schedule. 
Randomization will be stratified by sex and baseline K-L score 
(2 or 3). 
All efficacy assessments will be completed and a PK blood sample 
will be taken at the Baseline visit prior to administration of the first 
dose of study drug (Table S–1). Subjects will continue daily entry 
into the eDiary of pain scores, compliance with ingestion of study 
medication, and rescue medication use from Week 0 through to 
Week 4/EOT/ET. 
Subjects will receive their first dose at the study site after all 
Baseline assessments have been completed and a PK blood sample 
will be taken approximately 1 hour after dosing. Dosing is four 
times a day. 
During the treatment period (Week 0 through Week 4), subjects will 
be permitted to use only acetaminophen as rescue medication. 
Subjects will record their use of acetaminophen in their eDiary. 
Subjects must discontinue acetaminophen use for at least 24 hours 
prior to the start of study visits in order to minimize the confounding 
effects of the rescue medication on efficacy measurements. 
A PK sample will be taken at each study visit according to the 
schedule described in the Pharmacokinetic Assessments section. 
At the Week 4 visit, end of treatment (EOT) procedures will be 
completed. 
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. 
During this in-clinic visit, pain intensity, adverse events (AEs), and 
concomitant medications will be assessed, since the EOT/ET. Then, 
a follow-up telephone call will occur approximately 30 (+4) days 
after the last dose of study drug to assess AEs and concomitant 
medications. 


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The study design schematic is presented in Figure S–1. The schedule 
of assessments is provided in Table S–1. 
Study Duration 
The duration of participation for individual study subjects will be 
approximately 13 weeks, consisting of a screening period of up to 
4 weeks, a 7-day baseline pain assessment period, a 4-week 
double-blind treatment period, and a safety follow-up period of 
approximately 30 (+4) days (Figure S–1). 
The study start date is defined as the date the first subject is 
enrolled, which is the date the first subject is randomized. 
The primary completion date is the last date that subject data was 
collected for the primary outcome measure. 
The study completion date is defined as the last date that subject 
data was collected for the primary outcome measure, secondary 
outcome measure(s), and adverse events, which includes the safety 
follow-up telephone call visit. 
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 subjects ≥18 and <65 years of age at the time 
of Screening  
2. Able to understand and provide signed informed consent 
3. Has a body mass index (BMI) ≤39 kg/m2 at Screening 
4. Confirmed history of pain associated with OA in the index 
knee  
5. Clinical diagnosis of OA in at least one knee joint (i.e., the 
index knee) based on the American College of 
Rheumatology Criteria with radiographic evidence of 
OA (K-L score of 2 or 3) at Screening 
Note: K-L scores of 1 or 4 are exclusionary  
6. Willing to maintain current activity and exercise levels 
throughout the study 
7. Willing and able to comply with clinic visits and 
study-related procedures 
8. Consent to allow all radiographs and 
medical/surgical/hospitalization records of care received 
elsewhere to be shared with the Investigator and third parties 
who will examine the images (i.e., central x-ray reader) 
9. Negative urine drug screen result at Screening, Baseline Pain 
Assessment Period, and Baseline. A positive urine drug test 


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for a prescribed medication that is permitted at Screening, 
but not in the study, is acceptable if it has been prescribed. 
The subject will need to washout from this medication, if 
appropriate, and have a negative screen for this medication 
prior to randomization. Investigators must not withdraw a 
subject’s prohibited medication other than analgesics solely 
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. 
10. Must have a negative COVID-19 diagnostic polymerase 
chain reaction (PCR) test at Screening. Not planning to 
receive a COVID-19 vaccine during Screening through 
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 1 week before the Screening visit and be symptom 
free. If subjects have received a COVID-19 booster shot, 
they will need to have completed 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. 
11. 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 
12. 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. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical 
cap) with spermicide 


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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 at Baseline. 
Inclusion Criteria Specific to Baseline Pain Assessment Period 
13. Baseline Pain Assessment Period weekly average daily pain 
score ≥4 
14. Has no more than 1 day with a pain score of 10 during the 
Baseline Pain Assessment Period 
15. Has a standard deviation of <1.6 for average daily pain score 
diary entries during the Baseline Pain Assessment Period 
16. Able to complete logging of pain scores for at least 6 of the 
last 7 days of the Baseline Pain Assessment Period 
 
Exclusion Criteria: 
Medical Conditions 
1. Pain anywhere else in the body which is greater than or equal 
to OA pain in the index knee, or likely to interfere with 
subject’s assessment of pain throughout the study, as judged 
by the Investigator 
2. History or presence on imaging of knee arthropathy 
(osteonecrosis, subchondral insufficiency fracture, rapidly 
progressive OA type 1 or type 2), recent fall, injury, or 
trauma affecting the index knee, ligament tear, neuropathic 
joint arthropathy, knee dislocation (patella dislocation is 
eligible), extensive subchondral cysts, Baker’s cyst, evidence 
of bone fragmentation or collapse, or primary metastatic 
tumor with the exception of chondromas, or pathological 
fractures during the Screening Period 
3. History or presence at Screening of non-OA inflammatory 
joint disease (e.g., rheumatoid arthritis, lupus erythematosus, 
psoriatic arthritis, pseudo-gout, gout, spondyloarthropathy, 
joint infections within the past 5 years, Paget’s disease of the 
spine, pelvis, or femur, neuropathic disorders, multiple 
sclerosis, fibromyalgia, tumors or infections of the spinal 


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cord, or renal osteodystrophy) or any condition that would 
interfere with the rating of OA pain 
4. Recent arthroscopic surgery within 1 month of Screening; or 
has any planned surgery or procedure during the study 
Concomitant Treatments 
5. Use of monoamine reuptake inhibitors, tricyclic 
antidepressants, anticonvulsants, and/or serotonin 
norepinephrine reuptake inhibitors within 4 weeks prior to 
Screening. 
6. Unwilling to discontinue current use of analgesic medication 
following Screening and to adhere to study requirements for 
rescue treatments (acetaminophen to be taken as needed with 
a maximum daily dose of 2500 mg), including, but not 
limited to, nonsteroidal anti-inflammatory drugs (NSAIDs), 
opioids, selective cyclooxygenase 2 inhibitors, or 
combinations thereof, within 7 days or five half-lives of the 
drug prior to the Baseline Pain Assessment Period, 
whichever is longer  
Note: only the rescue medication, i.e., acetaminophen, is 
allowed for OA pain in the knee; aspirin, at a dose of up to 
81 mg per day, is allowed for prophylaxis of coronary and 
cerebrovascular events if stable for 30 days prior to 
Screening and the dose is expected to remain the same 
throughout the duration of the study. 
7. Use of immediate- or extended-release or controlled-release 
opioids (e.g., oxycontin), transdermal fentanyl, or methadone 
within 3 months prior to Screening 
8. Use of opioids, for the treatment of pain other than OA of the 
knee, with a morphine equivalent dose of ≥30 mg per day for 
more than 2 days per week within 1 month prior to Screening 
9. Use of systemic (i.e., oral) corticosteroids or intra-articular 
corticosteroids in any joint within 30 days prior to the 
screening visit (topical, intranasal, and inhaled 
corticosteroids are permitted) 
10. Intra-articular injection of any approved (i.e., hyaluronic acid 
and corticosteroids) or unapproved treatments (e.g., platelet-
rich plasma, capsaicin) into the index knee within 3 months 
of Screening 
11. Physical/occupational/chiropractic therapy for the lower 
extremities or acupuncture for the lower extremities within 


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30 days of Screening, or the need for such therapy during the 
study 
Medical History, Laboratory Studies, Vital Signs, and 
Electrocardiograms 
12. Has current evidence, or history within the previous 
12 weeks prior to Screening, of a serious and/or unstable 
psychiatric, neurologic, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, endocrinologic, 
or other medical disorder, that in the judgment of the 
Investigator and/or Medical Monitor would jeopardize the 
safe participation of the subject in the study 
13. 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 
14. Has any 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. Has one or more clinical laboratory test 
values outside the range specified below at Screening or 
Baseline:  
a. aspartate aminotransferase (AST) ≥1.5 × the upper 
limit of normal range (ULN) 
b. alanine aminotransferase (ALT) ≥1.5 × ULN 
c. total bilirubin (TBL) >ULN range or has a known 
condition that is associated with hyperbilirubinemia 
(e.g. Gilbert’s syndrome) 
15. Has moderate or severe renal impairment (estimated 
glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 from 
screening clinical laboratory tests) 
16. Has an ECG QTcF result >480 ms at Screening or Baseline  
17. Has a history of uncontrolled hypertension, as defined by: 
a. Systolic blood pressure ≥180 mmHg or diastolic 
blood pressure ≥100 mmHg at Screening or Baseline  
b. Systolic blood pressure of 160-179 mmHg or 
diastolic blood pressure of 100-109 mmHg at 
Screening or Baseline, AND a history of end-organ 
damage (including history of left ventricular 
hypertrophy, heart failure, angina, myocardial 
infraction, stroke, transient ischemic attack, renal 
failure, peripheral arterial disease and moderate to 
advanced retinopathy [hemorrhages or exudates, 
papilledema]) 


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c. Known clinical diagnosis of orthostatic hypotension 
d. Evidence of orthostatic hypotension at Baseline, 
defined as a decrease in systolic blood pressure 
≥20 mmHg or diastolic blood pressure ≥10 mmHg 
after transitioning from the supine position (after 
resting for 5 minutes) to standing at 1 or 3 minutes. 
Subjects unable to stand may be assessed while 
sitting upright. 
18. Congestive heart failure with New York Heart Classification 
of stage III or IV (Appendix A) 
19. Transient ischemic attack or cerebrovascular accident within 
the past 12 months prior to Screening, or myocardial 
infarction, or acute coronary syndromes within the past 
6 months prior to Screening  
20. 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  
21. Beck Depression Inventory–II (BDI-II) score ≥29 at 
Screening  
22. Has a history of uncontrolled diabetes mellitus (DM), Type 1 
or Type 2 DM, or glycosylated hemoglobin (HbA1c) >8.0% 
at Screening  
23. Known history of human immunodeficiency virus (HIV) 
infection 
24. Known history of infection with hepatitis B virus. 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 
25. Known history of infection with the hepatitis C virus. 
Subjects with a history of hepatitis C are eligible if there is 
documentation of a negative hepatitis C virus RNA test 
26. Has a known or suspected history of drug abuse or a recent 
(within the last 5 years) history of alcohol abuse. 
27. Use of medicinal or recreational marijuana or cannabidiol 
(CBD) within 1 month prior to Screening. The use of these 
substances are not allowed throughout the study. 


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Other Criteria 
28. Subject is unlikely to be able to swallow double-blind study 
drug (i.e., swallowing tablets 4 times per day, including 
two tablets at the first and third dosing) 
29. Subject is unwilling or unable to comply with the use of the 
handheld devices 
30. Has a significant sensitivity or allergic reaction to ACP-044 
or its excipients, or rescue medication 
31. Has participated in or is participating in a clinical research 
study evaluating ACP-044 or has received another 
investigational product within 30 days or 5 half-lives, 
whichever is longer, prior to Screening 
32. Is an employee or is a family member of an employee of 
Acadia Pharmaceuticals Inc. or the clinical research site or 
the CRO administering this study 
Pharmacokinetic 
Assessments 
At each predefined timepoint, PK samples will be obtained for 
measurement of concentrations of ACP-044 at the following visits: 
• Baseline (Week 0) visit (Visit 3; both before dosing and 
approximately 1 hour after dosing) 
• Visit 5 
• Visit 6 
• Visit 8/or upon early termination (ET) 
PK blood samples taken at Visits 5, 6, and 8 should be collected at 
one of the following time intervals: 
• 2-5 hours after morning dosing  
• 6-9 hours after morning dosing  
• 10-12 hours after morning dosing  
Every effort should be made to collect PK samples at distinct time 
intervals during Visits 5, 6, and 8. However, if the interval is the 
same across these visits, then the collection time should vary within 
that interval. The following scenario is only for illustrative purposes, 
a number of other scenarios are possible. 
• For example, if the time interval of 6-9 hours after morning 
dosing is used for Visits 5, 6, and 8, then every effort should 
be made to collect PK samples at 6, 7, and 8 hours after 
morning dosing at each of these visits, respectively. 
When possible, an additional PK sample (approximately 4 mL) will 
be collected from subjects who experience a serious adverse event 


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(SAE) or an adverse event (AE) leading to discontinuation, as soon 
as possible after the occurrence of that event. 
For all PK samples (scheduled and unscheduled), with the exception 
of those taken following an AE or SAE, the dates and times of 
administration of the last three doses of the study drug should be 
recorded. 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. 
Sample Size 
Calculations 
Approximately 240 subjects will be randomized in a 1:1:1 ratio to 
ACP-044 800 mg BID dose, ACP-044 400 mg QID dose, or 
placebo. Assuming a treatment difference of 0.85 and a common 
standard deviation of 1.7 between an ACP-044 dose arm and 
placebo, 64 subjects per arm is needed to provide approximately 
80% power to detect this treatment difference using a 2 sample t-test 
at 2-sided alpha level of 0.05. Assuming a discontinuation rate of 
20%, 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 with baseline pain 
assessments and at least one post-baseline pain assessment. Subjects 
will be analyzed based on the treatment to which they are assigned. 
The Full Analysis Set will be used for the analysis of all 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. 
General Statistical Approach 
For continuous variables, descriptive statistics will include the 
following information: the number of subjects with data values (n), 
mean, standard error of the mean, median, standard deviation, 
minimum, and maximum. For categorical or ordinal data, 
frequencies and percentages will be displayed for each category. All 
statistical hypotheses will be tested at the 0.05 significance level. 


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Demographic and baseline characteristics, including medical history 
and exposure to study drug will be summarized descriptively by 
treatment group and by all subjects combined. 
Primary Analysis 
The primary efficacy variable will be analyzed using an analysis of 
covariance model (ANCOVA) based on the FAS with treatment, 
sex, and baseline K-L score (randomization strata) as factors and 
baseline weekly average of daily average pain score as a covariate in 
the model. The primary comparison will be between each ACP-044 
dose group versus the placebo group. The comparison between the 
average of the means of the two ACP-044 dose groups versus the 
mean of the placebo group will also be conducted. Missing data will 
be imputed using multiple imputation based on missing at random 
assumption (MAR) with an exception of missing data from subjects 
who are treated with ACP-044 and discontinue the study due to lack 
of efficacy or adverse events. Their missing data will be imputed 
using the data from placebo group. 
Sensitivity analysis using pattern mixture model and tipping point 
approach with multiple imputation to impute missing data will be 
performed to assess the robustness of the results due to treatment 
discontinuation and other intercurrent events. 
Secondary Analyses 
For analysis of continuous secondary endpoints, the analysis method 
will be the same as that used for the primary variables except for 
PGIC which will be analyzed using analysis of variance (ANOVA) 
with treatment, sex, and baseline K-L score as factors. For analysis 
of categorical variables in secondary endpoints, e.g., proportions of 
subjects with ≥30% reduction from baseline to Week 4 in the 
weekly average of the daily average NRS score; the Cochran Mantel 
Haenszel approach stratified by the randomization strata will be 
used for subjects with missing data considered as non-responders. 
Safety Analyses 
Safety data 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), TEAEs 
leading to discontinuation, TEAEs related to study drug, TEAEs by 
maximum severity, fatal TEAEs, SAEs, SAEs related to study drug, 
and TEAEs of special interest (AESI) will all be summarized. 
Descriptive statistics for ECGs, vital signs and weight, and clinical 
laboratory parameters, including changes from Baseline (prior to 
first dose), will be tabulated by timepoint and by treatment group. 


Study: ACP-044-005 
 
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The incidence of subjects with prolonged QTc intervals and changes 
in QTc intervals in accordance with International Council for 
Harmonisation (ICH) guidelines will also be summarized by 
treatment group. 
Additional safety analysis details will be specified in the SAP. 
Pharmacokinetic (PK) 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 (PK/PD) Analyses 
Guided by exploratory analyses, PK/PD models to describe the 
exposure-response relationship between ACP-044 exposure 
parameters and the relevant efficacy and safety endpoints will be 
developed using appropriate PK/PD methods. Results will be 
presented in a separate report per a prespecified data analysis plan. 
Date 
16 February 2022 


Study: ACP-044-005 
 
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Figure S–1 
Schematic of Study Design for ACP-044-005 
 
 
 
 
Abbreviations: BID=twice daily; EOT=end of treatment; QID=four times daily; R=randomization 
 


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Table S–1 
Schedule of Events and Assessments for ACP-044-005 
 
Screening 
Period 
Baseline Pain 
Assessment 
Period 
Double-Blind Treatment Period 
 
Safety 
Follow-up Period 
Visit Day/Week 
Days -35 
to -8 
Days -7 to -1 
Baseline 
Week 0  
Day 3 Week 1  Week 2  Week 3 
Week 4  
Unscheduled 
Visitr 
Clinic 
visit 
Telephone 
call 
7 days 
after 
EOT 
30 days 
after last 
dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 (EOT/ET) 
 
 
 
Visit window (# days) 
 
+3 
0 
±1 
±3 
±3 
±3 
±3 
 
±3 
+4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Medical, medication, and surgical 
history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
X 
 
 
 
Vital signs (including orthostatic 
changes)a 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Height, weight, and BMI calculationb 
X 
 
X 
 
 
 
 
X 
 
 
 
12-lead ECGc 
X 
 
Xc 
 
X 
X 
 
X 
 
 
 
Clinical laboratory tests 
X 
 
X 
Xd 
X 
X 
Xd 
X 
 
 
 
Pregnancy teste 
X 
 
X 
 
 
 
 
X 
 
 
 
Urine drug screen 
X 
X 
Xf 
 
 
 
 
X 
 
 
 
COVID-19 testg 
X 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Beck Depression Inventory–II 
X 
 
 
 
 
 
 
 
 
 
 
Verified Clinical Trials Subject Registry 
X 
 
 
 
 
 
 
 
 
 
 
Central Imagingh 
X 
 
 
 
 
 
 
 
 
 
 
Issue eDiary and train on usei 
 
X 
 
 
 
 
 
 
 
 
 
Collect eDiary 
 
 
 
 
 
 
 
X 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 


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Table S-1 
Schedule of Events and Assessments for ACP-044-005 (Continued) 
 
Screening 
Period 
Baseline Pain 
Assessment 
Period 
Double-Blind Treatment Period 
 
Safety 
Follow-up Period 
Visit Day/Week 
Days -35 
to -8 
Days -7 to -1 
Baseline 
Week 0  Day 3 
Week 1  Week 2  Week 3 
Week 4  
Unscheduled 
Visitr 
Clinic 
visit 
Telephone 
call 
7 days 
after 
EOT 
30 days after 
last dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
 
 
 
Visit window (# days) 
 
+3 
0 
±1 
±3 
±3 
±3 
±3 
 
±3 
+4 
PK blood sample collectionj 
 
 
Xk 
 
Xl 
Xl 
 
Xl 
 
 
 
eDiary completion: Numeric Rating 
Scale Daily Pain Score (Average and 
Worst)m 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
PGICn 
 
 
 
 
X 
X 
 
X 
 
 
 
WOMACn 
 
 
X 
 
X 
X 
 
X 
 
 
 
BPI-sfn 
 
 
X 
 
X 
X 
 
X 
 
 
 
SF-12 
 
 
X 
 
 
 
 
X 
 
 
 
HADS 
X 
 
X 
 
 
 
 
X 
 
 
 
Participant Scorecardo 
 
 
 
 
X 
X 
 
X 
 
 
 
Accurate Symptom Reporting (ASR) 
Training – subject facing 
X 
 
X 
 
Xp 
Xp 
 
Xp 
 
 
 
Placebo Response Reduction (PRR) 
Training – subject facing 
X 
 
X 
 
Xp 
Xp 
 
Xp 
 
 
 
Study drug dispensing/accountability 
 
 
X 
 
X 
X 
 
X 
 
 
 
eDiary completion: Rescue 
medication 
dispensing/accountabilityq 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Abbreviations: ASR=accurate symptom reporting; BMI=body mass index; BPI-sf=Brief Pain Inventory–Short Form; COVID-19=coronavirus disease 2019; 
C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; eDiary=electronic diary; EOT=end of treatment; ET=early termination; 
HADS=Hospital Anxiety and Depression Scale; PGIC=Patient Global Impression of Change; PK=pharmacokinetic; PRR=placebo response reduction; 
SF-12=12-item Short Form Survey; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index 
a 
Vital signs will include body temperature, resting respiration rate, supine and standing systolic and diastolic blood pressure, and pulse rate. Blood pressure 
and pulse rate will be measured after the subject rests for 5 minutes in the supine position. The subject will then be asked to stand and blood pressure and 
pulse rate will be taken after standing for 1 minute and then again after 3 minutes. Subjects unable to stand may be assessed while sitting upright. The same 
position and arm should be used each time vital signs are measured for a given subject. 
b 
Height will only be measured at the Screening visit, and BMI will be calculated based on height and weight measurements at Screening. Weight will also be 
measured at any unscheduled visit. 
c 
A single 12-lead ECG will be performed at Screening, at Baseline (Week 0) both predose and at 1 hour postdose (the first dose of the day), Week 1, Week 2, 
and EOT/ET. A 1-hour window is permitted for the predose ECG and a 20-minute window is permitted for the postdose ECGs. Electrocardiograms should 
be performed before blood sampling or at least 30 minutes after blood sampling.  
d 
A full chemistry (CHEM) panel of clinical laboratory tests will be completed, excluding glucose and the CHEM tests noted in Section 6.5.5 to only be 
performed at Screening. 
e 
Applicable to women of childbearing potential. A serum pregnancy test should be performed at Screening and a urine test must be performed at all other 
designated visits. 
f 
At Baseline, urine drug screen will be performed using a dipstick test which must be negative for any non-permitted medications or drugs in order for the 
subject to continue in the study.  
g 
COVID-19 diagnostic PCR test at Screening. 
 
h 
Randomization visit cannot occur until there is confirmation from the central reader that there are no exclusionary findings. 
i 
Subjects will be instructed on the use of and will complete electronic clinical outcome assessments using handheld devices during the study. An eDiary, will 
be used to record pain scores, compliance with ingestion of study medication, and use of rescue medication.  
j 
A PK sample (approximately 4 mL) should also be taken from subjects who experience SAEs or AEs leading to discontinuation, as soon as possible after the 
occurrence of the event. 
k 
A predose PK blood sample must be collected before administration of study drug. A postdose PK blood sample will be collected at the end of ECG 
assessment approximately 1 hour after study drug administration. 
l 
PK samples at Visits 5, 6, and 8 will be collected at one of the following time intervals: 1) 2-5 hours after morning dosing OR 2) 6-9 hours after morning 
dosing OR 3) 10-12 hours after morning dosing. Every effort should be made to collect the PK samples at distinct time intervals during Visits 5, 6, and 8. 
However, if the interval is the same across these visits, then the collection time should vary within that interval.  


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m 
Pain intensity assessments are to be recorded in the evening during the Baseline Assessment Period and prior to their 4th dose of the day during the 
Double-blind period. Subjects will be rating both the average daily pain as well as their worst daily pain. At the Safety Follow-up Clinic Visit (7 days after 
EOT), subjects will rate both the average daily pain as well as their worst daily pain over the past week and the data will be entered into EDC. 
n 
At study visits, PGIC, WOMAC, and BPI-sf should be performed before blood sample collection, ECG, and other procedures. 
o 
Participant Scorecard is viewed by the subject and reviewed by the Investigator at the designated study visits. The Investigator or designee, will 
acknowledge the scorecard review on the training platform, aLearn. 
p 
ASR and PPR training at Visits 5, 6, and/or 8 is on an as needed basis and the need for training will be determined by Participant Scorecard intervention 
recommendations. 
q 
Record rescue medication use in eDiary. 
r 
The Investigator may perform any additional evaluations deemed to be clinically indicated. If an unscheduled visit is required for safety reasons, a 12-lead 
ECG and all appropriate clinical laboratory tests are to be performed. 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 25 
LIST OF TABLES ................................................................................................................... 30 
LIST OF FIGURES ................................................................................................................. 30 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 31 
1 
INTRODUCTION ...................................................................................................... 33 
1.1 
Background Information ............................................................................................ 33 
1.2 
Investigational Product ............................................................................................... 33 
1.3 
Nonclinical Data ......................................................................................................... 34 
1.4 
Previous Clinical Experience ..................................................................................... 34 
1.4.1 
Clinical Pharmacology ............................................................................................... 34 
1.5 
Study Rationale .......................................................................................................... 35 
1.5.1 
Rationale for Study Design ........................................................................................ 35 
1.5.2 
Rationale for Dose Selection ...................................................................................... 36 
1.6 
Potential Risks and Benefits ....................................................................................... 36 
1.6.1 
Known Potential Risks ............................................................................................... 36 
1.6.2 
Known Potential Benefits ........................................................................................... 37 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 37 
2.1 
Primary Objective ....................................................................................................... 37 
2.1.1 
Primary Endpoint ....................................................................................................... 37 
2.2 
Secondary Objective ................................................................................................... 37 
2.2.1 
Secondary Endpoints .................................................................................................. 37 
2.3 
Exploratory Objective ................................................................................................ 38 
2.3.1 
Exploratory Endpoints ................................................................................................ 38 
2.4 
Safety Objective ......................................................................................................... 38 
2.4.1 
Safety Endpoints......................................................................................................... 38 
2.5 
Pharmacokinetic Objectives ....................................................................................... 38 
2.5.1 
Pharmacokinetic Endpoints ........................................................................................ 38 
2.6 
Pharmacokinetic/Pharmacodynamic Objective .......................................................... 38 
2.6.1 
Pharmacokinetic/Pharmacodynamic Endpoints ......................................................... 39 
3 
STUDY DESCRIPTION ............................................................................................ 39 


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3.1 
Overview of Study Design ......................................................................................... 39 
3.1.1 
Screening Period (Up to 4 Weeks) ............................................................................. 40 
3.1.2 
Baseline Pain Assessment Period (1 Week) ............................................................... 40 
3.1.3 
Treatment Period (4 Weeks) ....................................................................................... 41 
3.1.4 
Safety Follow-up Period (30 Days) ............................................................................ 41 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 42 
4.1 
Inclusion Criteria ........................................................................................................ 42 
4.2 
Exclusion Criteria ....................................................................................................... 44 
4.3 
Screen Failures ........................................................................................................... 47 
4.4 
Subject Withdrawal of Consent .................................................................................. 47 
4.5 
Subject or Study Discontinuation ............................................................................... 48 
4.5.1 
Discontinuation of Study Drug for Individual Subjects ............................................. 49 
4.5.1.1 Liver Chemistry Stopping Criteria ............................................................................. 49 
4.5.1.2 Cardiovascular-Related Stopping Criteria .................................................................. 50 
4.5.1.3 Adverse Event Stopping Criteria ................................................................................ 50 
4.5.2 
Handling of Subject Discontinuation During the Treatment Period .......................... 51 
4.6 
Subject Lost to Follow-up .......................................................................................... 51 
4.7 
Prior and Concomitant Therapy ................................................................................. 51 
4.7.1 
Prior Medication ......................................................................................................... 51 
4.7.2 
Concomitant Medication ............................................................................................ 51 
4.8 
Permitted, Restricted, and Prohibited Medications .................................................... 52 
4.8.1 
Rescue Medications, Treatments, and Procedures ..................................................... 53 
4.9 
Lifestyle Considerations ............................................................................................. 53 
4.9.1 
Activity ....................................................................................................................... 53 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 53 
5.1 
Investigational Product Description ........................................................................... 53 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 53 
5.1.2 
Product Storage and Stability ..................................................................................... 54 
5.1.3 
Rescue Medication ..................................................................................................... 54 
5.1.4 
Dosing and Administration ......................................................................................... 54 
5.1.5 
Method of Assigning Subjects to Treatment Groups.................................................. 55 
5.1.6 
Blinding ...................................................................................................................... 55 
5.1.7 
Study Drug Compliance ............................................................................................. 55 
5.1.8 
Overdose ..................................................................................................................... 55 
5.2 
Investigational Product and Rescue Medication Accountability Procedures ............. 55 
6 
STUDY PROCEDURES ............................................................................................ 56 


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6.1 
Remote Assessments or Visits .................................................................................... 56 
6.2 
Screening Assessments ............................................................................................... 56 
6.2.1 
Medical and Medication History ................................................................................ 56 
6.2.2 
Beck Depression Inventory–II .................................................................................... 57 
6.2.3 
Verified Clinical Trials Registry ................................................................................. 57 
6.3 
Baseline Pain Assessment Period ............................................................................... 57 
6.3.1 
Accurate Symptom Reporting Training ..................................................................... 58 
6.3.2 
Placebo Response Reduction Training ....................................................................... 58 
6.4 
Efficacy Assessments ................................................................................................. 58 
6.4.1 
Numeric Rating Scale of Pain Intensity ..................................................................... 58 
6.4.2 
Patient Global Impression of Change ......................................................................... 58 
6.4.3 
Western Ontario and McMaster Universities Osteoarthritis Index ............................ 59 
6.4.4 
Brief Pain Inventory–Short Form ............................................................................... 59 
6.4.5 
12-Item Short Form Survey ........................................................................................ 60 
6.4.6 
Hospital Anxiety and Depression Scale ..................................................................... 60 
6.4.7 
Participant Scorecard .................................................................................................. 60 
6.5 
Safety Assessments .................................................................................................... 61 
6.5.1 
Physical Examination ................................................................................................. 61 
6.5.2 
Vital Signs .................................................................................................................. 61 
6.5.3 
Electrocardiograms ..................................................................................................... 62 
6.5.4 
Columbia-Suicide Severity Rating Scale ................................................................... 62 
6.5.5 
Laboratory Evaluations .............................................................................................. 63 
6.6 
Electronic Clinical Outcome Assessments ................................................................. 65 
6.7 
Pharmacokinetic Assessments .................................................................................... 66 
6.7.1 
Blood Sampling .......................................................................................................... 67 
6.7.2 
Specimen Preparation, Handling, Storage, and Shipment .......................................... 67 
6.8 
Safety Follow-up ........................................................................................................ 67 
6.9 
Unscheduled Visits ..................................................................................................... 67 
7 
ADVERSE EVENTS ................................................................................................. 68 
7.1 
Specification of Safety Parameters ............................................................................. 68 
7.1.1 
Definition of Adverse Event ....................................................................................... 68 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 69 
7.2 
Classification of an Adverse Event ............................................................................ 70 
7.2.1 
Severity of Event ........................................................................................................ 70 
7.2.2 
Relationship to Study Drug ........................................................................................ 70 
7.2.3 
Duration ...................................................................................................................... 71 


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7.2.4 
Frequency ................................................................................................................... 71 
7.2.5 
Action Taken with Study Drug ................................................................................... 71 
7.2.6 
Therapy ....................................................................................................................... 71 
7.2.7 
Outcome ..................................................................................................................... 71 
7.2.8 
Seriousness ................................................................................................................. 72 
7.2.9 
Definition of Unexpectedness .................................................................................... 72 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 72 
7.4 
Reporting Procedures ................................................................................................. 72 
7.4.1 
Adverse Event Reporting ........................................................................................... 72 
7.4.2 
Serious Adverse Event Reporting ............................................................................... 73 
7.4.3 
Reporting of Pregnancy .............................................................................................. 73 
7.4.4 
Reporting of Overdose ............................................................................................... 74 
8 
CLINICAL MONITORING ....................................................................................... 74 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 74 
9.1 
Statistical and Analytical Plans .................................................................................. 74 
9.2 
Statistical Hypotheses................................................................................................. 75 
9.3 
Sample Size Determination ........................................................................................ 75 
9.4 
Subject Populations for Analysis ................................................................................ 75 
9.5 
Statistical Analyses ..................................................................................................... 75 
9.5.1 
General Statistical Approach ...................................................................................... 75 
9.5.2 
Primary Analyses ........................................................................................................ 76 
9.5.3 
Secondary Analyses .................................................................................................... 76 
9.5.4 
Exploratory Analyses ................................................................................................. 76 
9.5.5 
Safety Analyses .......................................................................................................... 76 
9.5.6 
Pharmacokinetic Analyses .......................................................................................... 77 
9.5.7 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................... 77 
9.5.8 
Subgroup Analyses ..................................................................................................... 77 
9.6 
Interim Analyses ......................................................................................................... 77 
9.7 
Measures to Minimize Bias ........................................................................................ 77 
9.7.1 
Masking Procedures ................................................................................................... 77 
9.8 
Breaking the Study Blind/Subject Code ..................................................................... 78 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 78 
10.1 
Data Collection and Management Responsibilities.................................................... 78 
10.2 
Source Documents ...................................................................................................... 79 
10.3 
Case Report Forms ..................................................................................................... 79 


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10.4 
Confidentiality ............................................................................................................ 79 
10.5 
Study Records Retention ............................................................................................ 79 
10.6 
Protocol Exceptions and Deviations ........................................................................... 80 
10.7 
Protocol Amendments ................................................................................................ 80 
11 
QUALITY MANAGEMENT .................................................................................... 80 
11.1 
Risk Management ....................................................................................................... 80 
11.2 
Quality Control and Quality Assurance...................................................................... 81 
12 
ETHICAL CONSIDERATIONS ................................................................................ 82 
12.1 
Ethical Standard ......................................................................................................... 82 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 82 
12.3 
Informed Consent Process .......................................................................................... 82 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 83 
12.3.2 Consent Procedures and Documentation .................................................................... 83 
13 
PUBLICATION PLAN .............................................................................................. 83 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 84 
14.1 
Finance, Insurance, and Indemnity............................................................................. 84 
15 
LITERATURE REFERENCES .................................................................................. 85 
16 
APPENDICES ............................................................................................................ 87 
Appendix A New York Heart Association Class Guidelines ................................................ 87 
Appendix B Prohibited and Restricted Medications ............................................................. 88 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-044-005 .................................. 21 
Table 5-1 
Blinded Daily Dosing Regimen ....................................................................... 54 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 65 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-044-005 ................................................. 20 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE 
adverse event 
BID 
twice daily 
BMI 
body mass index 
BPI-sf 
Brief Pain Inventory–Short Form 
CL/F 
apparent systemic clearance following nonintravenous (e.g., oral) 
administration 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
EOT 
end of treatment 
ET 
early termination 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HbA1c 
glycosylated hemoglobin 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
K-L 
Kellgren-Lawrence score 
NRS 
Numeric Rating Scale 
OA 
osteoarthritis 
PGIC 
Patient Global Impression of Change 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PP 
Per-protocol 
PR 
PR interval of ECG 
QID 
four times daily 
QRS interval 
QRS interval of ECG 
QT interval 
QT interval for heart rate of ECG 
QTc 
corrected QT interval of ECG for heart rate 


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Term 
Definition 
QTcB 
corrected QT interval using Bazett’s correction method 
QTcF 
corrected QT interval using Fridericia’s correction method 
RNA 
riboxynucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF-12 
12-item Short Form Survey 
t½ 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
UDS 
urine drug screen 
US 
United States 
VCT 
Verified Clinical Trials 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 


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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 
Chronic musculoskeletal pain affects a large proportion of the global population. A 
significant cause of chronic musculoskeletal pain is due to osteoarthritis (OA). Osteoarthritis 
is a progressive, chronic disease caused by the breakdown and loss of cartilage of the joints, 
which leads to pain in the hips, knees, hands, feet, and spine. Symptoms and disability 
increase with increasing age. The prevalence of OA in patients aged 65 and older is 60% in 
men and 70% in women, and is continually rising (Sarzi-Puttini et al. 2005). 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment in patients 
with mild-to-moderate OA. The efficacy of NSAIDs is well documented, albeit modest, 
while their use is associated with a number of well recognized risks (Bjordal et al. 2004). The 
risks associated with long-term therapy with NSAIDs have been well characterized and 
include gastrointestinal bleeding and increased risk of cardiovascular events (Lanas 2011; 
Trelle et al. 2011). Those with advanced OA pain typically try several NSAIDs and must 
often escalate to other therapies including opioids as well as a variety of transiently effective 
intra-articular therapies. 
As a chronically progressive disease, many patients progress until their last option is a joint 
replacement. However, even with surgery, the complete relief of pain or disability is not 
guaranteed. For the majority of patients worldwide the inadequate pain relief and disability 
due to OA has a profound impact on the quality of life with an associated loss of productivity, 
(Dibonaventura et al. 2011), and substantial cost to society, including healthcare cost 
(Salmon et al. 2016). 
1.2 
Investigational Product 
ACP-044 is a non-metal based, orally bioavailable, small molecule reactive species 
decomposition accelerant (RSDAx) with minimal brain distribution that works by 
accelerating the 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 and osteoarthritis pain) that cause untoward effects via protein 
nitration, release of pro-inflammatory mediators, and modification of sensory ion channels 
leading to neuronal sensitization and pain (Aubdool et al. 2016; Muscoli et al. 2007; 
Pacher et al. 2007; Salvemini and Neumann 2009; Stavniichuk et al. 2014; 


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Sugiyama et al. 2017; Trevisan et al. 2014; Virag et al. 2002). By removing PN, ACP-044 
may prevent or reverse neuronal sensitization that underlies acute and persistent pain. 
1.3 
Nonclinical Data 
In vivo, ACP-044 is efficacious in acute animal models of hyperalgesia and allodynia 
including the chronic pain condition such as OA pain. In a rat OA pain model 
(mono-iodoacetate [MIA]-induced), ACP-044 significantly reduced mechanical hyperalgesia 
for at least 24 hours postdose. 
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 (maximum of 2000 mg 
administered as a single oral dose) 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 6 active and 2 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. Decline from peak is characterized by a relatively quick elimination phase with a 
mean half-life of 1.6 to 3.2 hours.  
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 [peak] drug concentration 
(Cmax) and 1 hour delay in Tmax) and had no effect on the extent (area under the plasma 
concentration-time 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. 


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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). 
ACP-044 is primarily metabolized in the liver and the major metabolite is a sulfate 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 (CYP) isozymes tested (1A2, 2C8, 2C19, 2D6, and 3A4) or 
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 subjects. The present study is a proof-of-concept study to evaluate the efficacy of 
ACP-044 as an analgesic for the management of pain associated with OA of the knee and to 
evaluate the safety, tolerability, and PK profile of ACP-044. 
1.5.1 
Rationale for Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled study in subjects with pain 
who have radiographically confirmed OA of the knee. The study will assess the efficacy of 
ACP-044 by comparing active treatment groups receiving either 800 mg ACP-044 BID or 
400 mg ACP-044 QID, with a placebo group. In a rat model of OA pain (mono-iodoacetate 
[MIA] model), a significant reduction in mechanical hyperalgesia was observed for at least 
24 hours postdose in ACP-044 treated animals. Guided by the nonclinical MIA animal model, 


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the present study is designed to ascertain the efficacy of ACP-044 in treating pain in a clinical 
setting. 
1.5.2 
Rationale for Dose Selection 
In a nonclinical MIA rodent model of OA pain, ACP-044 at 100 and 300 mg/kg significantly 
increased joint compression thresholds, to approximately the same degree as celecoxib. It is 
unknown, 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., 800 mg BID or 400 mg QID) 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. If the 
study shows treatment with ACP-044 is effective, this could lead to further clinical 
development of this treatment for pain associated with OA.  
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 subjects, 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 management of pain associated with OA of the knee. 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 pain associated with osteoarthritis (OA) of the knee. 
2.1.1 
Primary Endpoint 
The primary endpoint is change from Baseline to Week 4 in the weekly average of the daily 
average Numeric Rating Scale (NRS) pain intensity scores. 
2.2 
Secondary Objective 
The secondary objective of the study is to evaluate the efficacy of ACP-044 compared with 
placebo in the treatment of pain associated with OA of the knee. 
2.2.1 
Secondary Endpoints 
The key secondary endpoints are: 
• Patient Global Impression of Change (PGIC) at Week 4 with reference to baseline 
status 
• Change from Baseline to Week 4 in Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) total score and individual subscale scores for pain, 
stiffness, and physical function  
• Proportion of subjects who are responders as defined by 30% and 50% reduction from 
Baseline to Week 4 in the weekly average of the daily average NRS pain intensity 
scores 
Additional secondary endpoints are: 
• Change from Baseline to Week 4 in: 
o Weekly average of the daily worst NRS pain intensity scores 
o Brief Pain Inventory–Short Form (BPI-sf) 
o 12-item Short Form Survey (SF-12) 


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2.3 
Exploratory Objective 
The exploratory objective of the study is to evaluate the use of rescue medication in subjects 
with pain associated with OA of the knee treated with ACP-044 compared with placebo. 
2.3.1 
Exploratory Endpoints 
The exploratory endpoints are: 
• Comparison of average daily rescue medication use 
• Hospital Anxiety and Depression Scale (HADS) 
2.4 
Safety Objective 
The safety objective of the study is to evaluate the safety and tolerability of ACP-044 
compared with placebo in the treatment of pain associated with OA of the knee. 
2.4.1 
Safety Endpoints 
Safety will be evaluated by analyses of the following: 
• Treatment-emergent adverse events (TEAEs) 
• Vital signs 
• Electrocardiograms (ECGs) 
• Physical examination results 
• Clinical laboratory tests 
• Columbia–Suicide Severity Rating Scale (C-SSRS) 
2.5 
Pharmacokinetic Objectives 
The PK objective of the study is to characterize the PK profile of ACP-044 in subjects with 
pain associated with OA of the knee. 
2.5.1 
Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• Plasma concentrations of ACP-044 using sparse sampling on the following study days: 
Baseline (Week 0), Week 1, Week 2, and Week 4 (EOT)/ET 
• ACP-044 PK parameters determined using a population PK approach 
2.6 
Pharmacokinetic/Pharmacodynamic Objective 
The pharmacokinetic/pharmacodynamic (PK/PD) objective of the study is to characterize the 
exposure-response relationship using appropriate modelling and simulation methods. 


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2.6.1 
Pharmacokinetic/Pharmacodynamic Endpoints 
• Guided by exploratory analyses, appropriate ACP-044 exposure-response relationship: 
o for efficacy using the primary endpoint 
o for safety using the most frequent and other relevant TEAEs 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of ACP-044 in subjects with pain associated with 
radiographically confirmed OA of the knee. The study will compare active treatment groups, 
receiving either 800 mg ACP-044 BID or 400 mg ACP-044 QID, with a placebo group. The 
Sponsor, subjects, and Investigators will be blinded to treatment assignment. 
Up to approximately 50 sites in the United States (US) will screen approximately 
480 subjects and approximately 240 subjects are planned for randomization (80 subjects per 
treatment group). 
The duration of participation for individual study subjects will be approximately 13 weeks, 
consisting of a screening period of up to 4 weeks, a 7-day baseline pain assessment period, a 
4-week double-blind treatment period, and a safety follow-up period of approximately 
30 (+4) days. 
The study periods are: 
• Screening: up to 4 weeks 
• Baseline Pain Assessment: a 7-day period during which baseline pain assessments will 
be recorded for 7 days. Additional 3-day window may be added, if needed. 
• Double-blind treatment: 4 weeks 
• Safety follow-up: approximately 7 days after end of treatment (EOT)/early termination 
(ET) and approximately 30 days after the last dose of study drug 
The study start date is defined as the date the first subject is enrolled, which is the date the 
first subject is randomized. 
The primary completion date is the last date that subject data was collected for the primary 
outcome measure. 


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The study completion date is defined as the last date that subject data was collected for the 
primary outcome measure, secondary outcome measure(s), and adverse events, which 
includes the safety follow-up telephone call visit.  
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. All subjects must 
have radiographically confirmed OA of the knee, including review of imaging and 
confirmation of a Kellgren-Lawrence (K-L) score of 2 or 3. Subjects who have had an X-ray 
of the index knee within 12 weeks of Screening may provide a historical image for central 
reading to confirm eligibility, or imaging can be done during Screening at protocol-trained 
radiological sites. Randomization visits cannot occur until there is confirmation from the 
central reader that there are no exclusionary findings on the knee joint images. The index 
knee is defined as the most painful knee at Screening. 
Prohibited analgesic medications must be discontinued during the Screening period. 
Investigators must not withdraw a subject’s prohibited medication other than analgesics 
solely 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. 
All pain medication, except for the rescue medication (acetaminophen), will be discontinued 
7 days or 5 half-lives, whichever is longer, prior to the Baseline Pain Assessment Period. In 
the event of inadequate pain relief, acetaminophen may be taken with a maximum daily dose 
of 2500 mg. 
Rescreening of a subject will be allowed, with the approval of the Medical Monitor. 
3.1.2 
Baseline Pain Assessment Period (1 Week) 
Following eligibility at screening, subjects will complete a Baseline Pain Assessment Period 
that will occur approximately 7 days before randomization; an additional 3-day window may 
be added, if needed. During the Baseline Pain Assessment Period, subjects will be instructed 
in the use of a handheld device (electronic diary [eDiary]) to record their daily pain scores 
and rescue medication use. Compliance with recording of pain score and use of rescue 
medication will be assessed for continued study eligibility. 
Subjects must discontinue taking study-provided rescue medication during the Baseline Pain 
Assessment Period and for at least 24 hours prior to the start of study visits. Rescue 


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medication use during the Baseline Pain Assessment Period through Visit 3 and within 
24 hours of the study visits (Visits 5, 6, and 8) will be documented in the electronic data 
capture (EDC). 
Subjects who enter the Baseline Pain Assessment Period will not be allowed to rescreen. 
Subjects who experience technical issues with the device and their pain scores were not 
assessed may be rescreened and the Baseline Pain Assessment Period may be extended, if 
needed and with permission of the Sponsor. 
3.1.3 
Treatment Period (4 Weeks) 
At Baseline (Week 0), eligible subjects will be randomly assigned in a 1:1:1 ratio to receive 
ACP-044 800 mg BID, ACP-044 400 mg QID, or placebo, according to a randomization 
schedule. Randomization will be stratified by sex and baseline K-L score (2 or 3).  
All efficacy assessments will be completed and a PK blood sample will be taken at the 
Baseline visit prior to administration of the first dose of study drug (Table S–1). Subjects will 
continue daily entry into the eDiary of pain scores, compliance with ingestion of study 
medication, and rescue medication use from Week 0 through to Week 4/EOT/ET.  
Subjects will receive their first dose at the study site after all Baseline assessments have been 
completed and a PK blood sample will be taken approximately 1 hour after dosing. Dosing is 
four times a day. 
During the treatment period (Week 0 through Week 4), subjects will be permitted to use only 
acetaminophen as rescue medication. Subjects will record their use of acetaminophen in their 
eDiary. Subjects must discontinue acetaminophen use for at least 24 hours prior to the start of 
study visits in order to minimize the confounding effects of the rescue medication on efficacy 
measurements.  
A PK sample will be taken at each study visit according to the schedule described in the 
Section 6.7. 
At the Week 4 visit, end of treatment (EOT) procedures will be completed. 
See Section 4.5 for subjects who discontinue early from the study. 
3.1.4 
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. During this in-clinic visit, pain intensity, adverse 
events (AEs), and concomitant medications will be assessed, since the EOT/ET. Then, a 
follow-up telephone call will occur approximately 30 (+4) days after the last dose of study 
drug to assess AEs and concomitant medications. 


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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 subjects ≥18 and <65 years of age at the time of Screening  
2. Able to understand and provide signed informed consent 
3. Has a body mass index (BMI) ≤39 kg/m2 at Screening 
4. Confirmed history of pain associated with OA in the index knee  
5. Clinical diagnosis of OA in at least one knee joint (i.e., the index knee) based on the 
American College of Rheumatology Criteria with radiographic evidence of OA 
(K-L score of 2 or 3) at Screening 
Note: K-L scores of 1 or 4 are exclusionary  
6. Willing to maintain current activity and exercise levels throughout the study 
7. Willing and able to comply with clinic visits and study-related procedures 
8. Consent to allow all radiographs and medical/surgical/hospitalization records of care 
received elsewhere to be shared with the Investigator and third parties who will 
examine the images (i.e., central x-ray reader) 
9. Negative urine drug screen result at Screening, Baseline Pain Assessment Period, and 
Baseline. A positive urine drug test for a prescribed medication that is permitted at 
Screening, but not in the study, is acceptable if it has been prescribed. The subject will 
need to washout from this medication, if appropriate, and have a negative screen for 
this medication prior to randomization. Investigators must not withdraw a subject’s 
prohibited medication other than analgesics solely 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. 
10. Must have a negative COVID-19 diagnostic polymerase chain reaction (PCR) test at 
Screening. Not planning to receive a COVID-19 vaccine during Screening through 
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 1 week before the Screening visit and be symptom 
free. If subjects have received a COVID-19 booster shot, they will need to have 
completed the shot at least one week before Screening and have no residual symptoms. 


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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. 
11. 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 
12. 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. 
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 at Baseline. 
Inclusion Criteria Specific to Baseline Pain Assessment Period 
13. Baseline Pain Assessment Period weekly average daily pain score ≥4  
14. Has no more than 1 day with a pain score of 10 during the Baseline Pain Assessment 
Period 
15. Has a standard deviation of <1.6 for average daily pain score diary entries during the 
Baseline Pain Assessment Period  
16. Able to complete logging of pain scores for at least 6 of the last 7 days of the Baseline 
Pain Assessment Period 


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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. Pain anywhere else in the body which is greater than or equal to OA pain in the index 
knee, or likely to interfere with subject’s assessment of pain throughout the study, as 
judged by the Investigator 
2. History or presence on imaging of knee arthropathy (osteonecrosis, subchondral 
insufficiency fracture, rapidly progressive OA type 1 or type 2), recent fall, injury, or 
trauma affecting the index knee, ligament tear, neuropathic joint arthropathy, knee 
dislocation (patella dislocation is eligible), extensive subchondral cysts, Baker’s cyst, 
evidence of bone fragmentation or collapse, or primary metastatic tumor with the 
exception of chondromas, or pathological fractures during the Screening Period 
3. History or presence at Screening of non-OA inflammatory joint disease (e.g., 
rheumatoid arthritis, lupus erythematosus, psoriatic arthritis, pseudo-gout, gout, 
spondyloarthropathy, joint infections within the past 5 years, Paget’s disease of the 
spine, pelvis, or femur, neuropathic disorders, multiple sclerosis, fibromyalgia, tumors 
or infections of the spinal cord, or renal osteodystrophy) or any condition that would 
interfere with the rating of OA pain 
4. Recent arthroscopic surgery within 1 month of Screening; or has any planned surgery or 
procedure during the study 
Concomitant Treatments 
5. Use of monoamine reuptake inhibitors, tricyclic antidepressants, anticonvulsants, and/or 
serotonin norepinephrine reuptake inhibitors within 4 weeks prior to Screening. 
6. Unwilling to discontinue current use of analgesic medication following Screening and 
to adhere to study requirements for rescue treatments (acetaminophen to be taken as 
needed with a maximum daily dose of 2500 mg), including, but not limited to, 
non-steroidal anti-inflammatory drugs (NSAIDs), opioids, selective cyclooxygenase 
2 inhibitors, or combinations thereof, within 7 days or five half-lives of the drug prior to 
the Baseline Pain Assessment Period, whichever is longer 
Note: only the rescue medication, i.e., acetaminophen, is allowed for OA pain in the 
knee; aspirin, at a dose of up to 81 mg per day, is allowed for prophylaxis of coronary 
and cerebrovascular events if stable for 30 days prior to Screening and the dose is 
expected to remain the same throughout the duration of the study 
7. Use of immediate- or extended-release or controlled-release opioids (e.g., oxycontin), 
transdermal fentanyl, or methadone within 3 months prior to Screening 


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8. Use of opioids, for the treatment of pain other than OA of the knee, with a morphine 
equivalent dose of ≥30 mg per day for more than 2 days per week within 1 month prior 
to Screening 
9. Use of systemic (i.e., oral) corticosteroids or intra-articular corticosteroids in any joint 
within 30 days prior to the screening visit (topical, intranasal, and inhaled 
corticosteroids are permitted) 
10. Intra-articular injection of any approved (i.e., hyaluronic acid and corticosteroids) or 
unapproved treatments (e.g., platelet-rich plasma, capsaicin) into the index knee within 
3 months of Screening 
11. Physical/occupational/chiropractic therapy for the lower extremities or acupuncture for 
the lower extremities within 30 days of Screening, or the need for such therapy during 
the study 
Medical History, Laboratory Studies, Vital Signs, and Electrocardiograms 
12. Has current evidence, or history within the previous 12 weeks prior to Screening, of a 
serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, endocrinologic, or other medical disorder, 
that in the judgment of the Investigator and/or Medical Monitor would jeopardize the 
safe participation of the subject in the study 
13. 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 
14. Has any 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. Has one or more clinical laboratory test values outside the range 
specified below at Screening or Baseline:  
a. aspartate aminotransferase (AST) ≥1.5 × the upper limit of normal range 
(ULN) 
b. alanine aminotransferase (ALT) ≥1.5 × ULN 
c. total bilirubin (TBL) >ULN range or has a known condition that is associated 
with hyperbilirubinemia (e.g., Gilbert’s syndrome) 
15. Has moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 
<60 mL/min/1.73 m2 from screening clinical laboratory tests) 
16. Has an ECG QTcF result >480 ms at Screening or Baseline  
17. Has a history of uncontrolled hypertension, as defined by: 
a. Systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg 
at Screening or Baseline 


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b. Systolic blood pressure of 160-179 mmHg or diastolic blood pressure of 
100-109 mmHg at Screening or Baseline, AND a history of end-organ damage 
(including history of left ventricular hypertrophy, heart failure, angina, 
myocardial infraction, stroke, transient ischemic attack, renal failure, 
peripheral arterial disease and moderate to advanced retinopathy [hemorrhages 
or exudates, papilledema]) 
c. Known clinical diagnosis of orthostatic hypotension 
d. Evidence of orthostatic hypotension at Baseline, defined as a decrease in 
systolic blood pressure ≥20 mmHg or diastolic blood pressure ≥10 mmHg 
after transitioning from the supine position (after resting for 5 minutes) to 
standing at 1 or 3 minutes. Subjects unable to stand may be assessed while 
sitting upright.  
18. Congestive heart failure with New York Heart Classification of stage III or IV 
(Appendix A) 
19. Transient ischemic attack or cerebrovascular accident within the past 12 months prior to 
Screening, or myocardial infarction, or acute coronary syndromes within the past 
6 months prior to Screening  
20. 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 
21. Beck Depression Inventory–II (BDI-II) score ≥29 at Screening  
22. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or Type 2 DM, or 
glycosylated hemoglobin (HbA1c) >8.0% at Screening 
23. Known history of human immunodeficiency virus (HIV) infection 
24. Known history of infection with hepatitis B virus. 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 
25. Known history of infection with the hepatitis C virus. Subjects with a history of 
hepatitis C are eligible if there is documentation of a negative hepatitis C virus RNA 
test 
26. Has a known or suspected history of drug abuse or a recent (within the last 5 years) 
history of alcohol abuse 


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27. Use of medicinal or recreational marijuana or cannabidiol (CBD) within 1 month prior 
to Screening. The use of these substances are not allowed throughout the study 
Other Criteria 
28. Subject is unlikely to be able to swallow double-blind study drug (i.e., swallowing 
tablets 4 times per day, including two tablets at the first and third dosing) 
29. Subject is unwilling or unable to comply with the use of the handheld devices  
30. Has a significant sensitivity or allergic reaction to ACP-044 or its excipients, or rescue 
medication 
31. Has participated in or is participating in a clinical research study evaluating ACP-044 or 
has received another investigational product within 30 days or 5 half-lives, whichever is 
longer, prior to Screening 
32. Is an employee or is a family member of an employee of Acadia Pharmaceuticals Inc. 
or the clinical research site or the CRO administering this study 
4.3 
Screen Failures 
Rescreening of a subject will be allowed, with the approval of the Medical Monitor. 
Subjects may be rescreened following a COVID-19 infection as long as they have 
no sequelae from COVID-19 infection, per Exclusion Criterion 12. 
Subjects who enter the Baseline Pain Assessment Period will not be allowed to rescreen. 
Subjects who experience technical issues with the device and their pain scores were not 
assessed, may be rescreened and the Baseline Pain Assessment Period may be extended, if 
needed and with permission of the Sponsor. 
The minimum information that will be captured for screen failures includes date informed 
consent is signed, demography, screen failure details, and any adverse event (AE)/serious 
adverse event (SAE). 
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 the subject decides to withdraw consent from all components in 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 visit and/or at 
safety follow-up (whichever 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 


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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). 
Individual subject and aggregate safety data will be reviewed regularly throughout the study 
to determine whether the study should be stopped, modified, or continued based on the 
review of cumulative data. This review will include analysis of similar clinically significant 
laboratory findings/abnormalities, ECG abnormalities, vital sign abnormalities and AE’s 
among subjects in order to assess all potential risks from blinded investigational product. 
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 


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• Frequently-occurring, similar serious adverse events that increases risk for all subjects 
from continued participation in the study 
• Frequently-occurring, similar clinically significant laboratory findings/abnormalities, 
ECG abnormalities, and/or vital sign abnormalities that increases risk for all subjects 
from continued participation in the study 
• 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. 
See Section 4.5.2 for handling of subjects who discontinue and for any further evaluations 
that need to be completed. 
4.5.1.1 
Liver Chemistry Stopping Criteria 
Discontinuation of study drug for abnormal liver tests is required by the Investigator when a 
subject meets one of the conditions outlined below. The Investigator can discontinue study 
drug in the presence of abnormal liver chemistries not meeting protocol-specified stopping 
rules if they believe that it is in best interest of the subject. 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 × upper limit 
of normal (ULN)  
o if there is an elevation of >2 x ULN, the laboratory assessment should be 
repeated 
o If ALT or AST is ≥3 × ULN, international normalized ratio (INR) should 
be tested 


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o If a subject is discontinued from the study because of ALT or AST ≥3 × 
ULN, every reasonable attempt should be made to follow the subject until 
the value(s) normalize or until the Investigator deems it to be chronic or 
stable. 
• 
Total bilirubin (TBL) ≥1.5 × ULN   
• Creatine kinase (CK)/creatine phosphokinase (CPK) ≥5 × ULN for more than 1 week 
4.5.1.2 
Cardiovascular-Related Stopping Criteria 
If a clinically significant finding of orthostatic hypotension, bradycardia, or change in QTcF, 
as defined below, is identified after enrollment, the Investigator or qualified designee and 
Medical Monitor will determine if the subject can continue in the study and if any change in 
subject management is needed. 
• Orthostatic hypotension – decrease in systolic blood pressure (SBP) ≥20 mmHg or 
diastolic BP (DBP) ≥10 mmHg after transitioning from the supine position (after 
resting for 5 minutes) to standing at 1 or 3 minutes with or without symptoms such as 
light headedness or dizziness and not explained by dehydration, illness, or medications 
• 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 >470 ms for males and >480 ms for females or QTcF increases ≥60 ms 
from Baseline 
4.5.1.3 
Adverse Event Stopping Criteria 
If a clinically significant finding of any below-mentioned or any other medically-concerning 
AE that is considered by the Investigator and Sponsor to be causally related to study drug is 
identified after enrollment, the Investigator or qualified designee and Medical Monitor will 
determine if the subject can continue in the study and if any change in subject management is 
needed. 
• life-threatening event 
• immediate drug reaction (e.g., Stevens-Johnson syndrome) 
• QT prolongation 
• acute renal insufficiency 
• cardiopulmonary arrest 


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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 Week 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 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 second 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 second 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). 
The Investigator may prescribe appropriate medication to treat AEs. 


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Drugs that confound the potential analgesic response and are prohibited (Appendix B) 
include: 
• monoamine reuptake inhibitors, antidepressants, anticonvulsants, and/or serotonin 
norepinephrine reuptake inhibitors 
• Analgesics (other than rescue medication, i.e., acetaminophen), including NSAIDs, 
opioids, selective cyclooxygenase 2 inhibitors, or combinations thereof 
Note: only the rescue medication, i.e., acetaminophen, is allowed for OA pain in the 
knee (not combinations including acetaminophen); aspirin, at a dose of up to 81 mg 
per day, is allowed for prophylaxis of coronary and cerebrovascular events if stable for 
30 days prior to Screening and the dose is expected to remain the same throughout the 
duration of the study. Aspirin should not be used with an anticoagulant. 
• systemic corticosteroids or intra-articular corticosteroids 
• intra-articular injection of any approved (i.e., hyaluronic acid) or unapproved 
treatments (e.g., platelet-rich plasma, capsaicin) 
Additional restriction (Appendix B) includes: 
• HMG-CoA reductase inhibitors (statins) are restricted and cannot be initiated after 
Screening and throughout the study. Subjects who are on a stable dose of a statin at 
Screening may be eligible for enrollment. 
4.8 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Week 4 (EOT)/ET as specified in Appendix B. 
Permitted concomitant medications should remain at a stable dose throughout the study. 
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. 


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4.8.1 
Rescue Medications, Treatments, and Procedures 
Subjects are encouraged to limit the amount of rescue medication (i.e., acetaminophen) taken 
during the study. Subjects must discontinue taking study-provided rescue medication during 
the Baseline Pain Assessment Period and for at least 24 hours prior to the start of study visits 
in order to minimize the confounding effects of the rescue medication on efficacy 
measurements. Rescue medication use during the Baseline Pain Assessment Period through 
Visit 3 and within 24 hours of the study visits (Visits 5, 6, and 8) will be documented in the 
EDC. The total daily dose of acetaminophen should not exceed 2500 mg (5 tablets). 
4.9 
Lifestyle Considerations 
4.9.1 
Activity 
Subjects should maintain the same activity level throughout the study duration. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational products are ACP-044 400 mg tablets 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, tablets will be administered orally 
four times per day for 4 weeks. 
Doses to be studied are: 
• ACP-044 800 mg total dose delivered two times a day (provided as 2×400 mg 
ACP-044 tablets) 
• ACP-044 400 mg total dose delivered four times a day (provided as 1×400 mg 
ACP-044 tablet) 
• Placebo, size- and color-matched to ACP-044 tablets 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply ACP-044 400 mg tablets and matching placebo tablets provided in 
blister cards. 
ACP-044 is a white to off-white powder. ACP-044 400 mg tablets include the active 
compound (ACP-044) and the following excipients: 
 
 
. The drug product is formulated with standard pharmaceutical 
excipients at 400 mg strength (454.5 mg of ACP-044). 


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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 (59°F to 86°F) [See USP controlled conditions] in a secure 
area with restricted access and according to local and national regulations. 
5.1.3 
Rescue Medication 
The sponsor will provide acetaminophen 500 mg tablets for the Baseline Pain Assessment 
Period and the Double-blind Period. The bottles of acetaminophen will be labeled with a 
protocol-specific label regarding the maximum allowable daily dose for the study. All rescue 
medication will be stored per commercially labeled conditions. 
5.1.4 
Dosing and Administration 
At Baseline (Week 0), eligible subjects will be randomly assigned in a 1:1:1 ratio to receive 
ACP-044 800 mg BID, ACP-044 400 mg QID, or placebo (Table 5-1). In order to maintain 
the double-blind design of the study, all subjects will take the same number of tablets per day. 
Dosing is to occur in the morning (2 tablets), noon (1 tablet), evening (2 tablets), and night 
(1 tablet) and should occur at the same time each day over the duration of the study. 
The first dose of study drug will be administered in the clinic, subjects will be instructed on 
administration of study drug, and subjects will be sent home with blinded study drug in 
blister cards. 
Table 5-1 
Blinded Daily Dosing Regimen 
 
First 
Daily Dose 
Second 
Daily Dose 
Third 
Daily Dose 
Fourth 
Daily Dose 
Placebo 
PP 
P 
PP 
P 
ACP-044 
400 mg (four times a day) 
XP 
X 
XP 
X 
ACP-044 
800 mg (twice a day) 
XX 
P 
XX 
P 
Abbreviations: P=ACP-044 placebo tablet; X=ACP-044 400 mg tablet 
 


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5.1.5 
Method of Assigning Subjects to Treatment Groups 
At Baseline (Week 0), eligible subjects who meet inclusion and do not meet exclusion criteria 
will be randomized in a 1:1:1 ratio to receive ACP-044 800 mg BID, ACP-044 400 mg QID, 
or placebo, according to a randomization schedule. 
5.1.6 
Blinding 
Treatment assignments will be blinded to all study subjects, Investigators, site personnel, and 
Sponsor personnel. In the event of a potential SUSAR, in 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. 
5.1.7 
Study Drug Compliance 
The Investigator or designated study center personnel will maintain a log of all study drug 
dispensed and returned during the study. Study drug supplies for each subject will be 
inventoried and accounted for throughout the study to verify the subject’s compliance with 
the dosage regimen. Subjects will be counseled regarding compliance at every visit. Subjects 
who have <80% or >120% compliance may be discontinued from the study. If a subject 
shows significant undercompliance (<80%) between any two scheduled visits, the Medical 
Monitor should be notified to determine if the subject remains eligible for the study and 
whether the incident should be considered a protocol deviation. 
If a subject misses a dose, they should not take an extra dose. 
5.1.8 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment (i.e., study drug or 
rescue medication) 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 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, 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 and rescue 
medication supplied is for use in this study only and should not be used for any other 
purpose. A clinical research associate (CRA) will be responsible for monitoring product 
accountability procedures and tablet counts by the site staff. 


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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 rescue medication 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 rescue medication 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. 
6.1 
Remote Assessments or Visits 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when a study 
visit at the clinic may not be possible. In those cases, study visit 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 in advance 
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, medication (including past OA treatments), 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 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. 


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Any medication reported as taken on or after Baseline (Week 0) will be captured as 
concomitant medication. 
6.2.2 
Beck Depression Inventory–II 
The BDI is a 21-item, self-report rating inventory that measures characteristic attitudes and 
symptoms of depression (Beck et al. 1961). Like the BDI, the BDI-II also contains 
21 questions, each answer being scored on a scale value of 0 to 3. Higher total scores indicate 
more severe depressive symptoms. The standardized cutoffs used differ from the original: 
• 0-13: minimal depression 
• 14-19: mild depression 
• 20-28: moderate depression 
• 29-63: severe depression 
The BDI-II will be completed at Screening. 
6.2.3 
Verified Clinical Trials Registry 
The Verified Clinical Trials LLC (VCT) Research Subject Database (VCT Registry) is used 
at study sites to help determine whether a subject is already participating in or has recently 
participated in another clinical trial. Subjects will be given detailed information about the 
processing of their personal data through the VCT Registry in a separate patient information 
and consent form (Verified Clinical Trials LLC Research Subject Database Declaration of 
Consent for the Processing of Personal Data) and will be asked to give explicit consent by 
signing this separate patient information and consent form. Where allowed under local laws 
and regulations, such consent from subjects is a precondition for being able to participate in 
this clinical study. No personal data will be entered into or processed through the 
VCT Registry, unless the relevant subject has given explicit consent. 
The VCT Registry is used to help prevent dual enrollment at the time of screening and 
throughout the duration of the study. 
6.3 
Baseline Pain Assessment Period 
Approximately 7 (+3) days prior to randomization, subjects will complete a Baseline Pain 
Assessment Period. During this period, subjects will be instructed in the use of a handheld 
device (eDiary) to record their daily pain scores and use of rescue medication.  
Prior to beginning the Baseline Pain Assessment Period, to ensure accurate reporting of OA 
knee pain, subjects will receive Accurate Symptom Response Training (ASR) and Placebo 
Response Reduction (PRR) Training. 


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Compliance with recording of pain score and use of rescue medication will be assessed for 
continued study eligibility. 
6.3.1 
Accurate Symptom Reporting Training 
The Accurate Symptom Reporting (ASR) training instructs subjects how to report pain scores 
accurately and reliably, and on the proper use of pain scales, with the aim of increasing the 
reporting accuracy of subject pain. 
Subjects will receive training via eDiary at Visit 1 and Visit 3; additional training may be 
performed at Visits 5, 6, and/or 8 on an as needed basis and the need will be determined by 
Participant Scorecard recommendations. 
6.3.2 
Placebo Response Reduction Training 
The Placebo Response Reduction (PRR) training teaches the subject about the appropriate 
expectations of personal benefit while participating in a clinical trial. The purpose is to 
provide subjects with truthful information that will neutralize the typically excessive 
expectations that drive high placebo responses in clinical studies. 
Subjects will receive training via eDiary at Visit 1 and Visit 3; additional training may be 
performed at Visits 5, 6, and/or 8 on an as needed basis and the need will be determined by 
Participant Scorecard recommendations. 
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 throughout the study. Subjects will be 
required to assess and record daily in the eDiary their knee pain intensity and daily use of 
rescue medication. Subjects will be rating both the average daily pain as well as their worst 
daily pain. 
Knee pain intensity will be assessed by describing their knee pain at the present time from 
0 to 10 where “0” means “no pain at all” and “10” means “the worst pain imaginable”. 
Pain intensity assessments are to be recorded in the evening prior to their 4th dose of the day. 
Subjects must discontinue acetaminophen use for at least 24 hours prior to the start of study 
visits in order to minimize the confounding effects of the rescue medication on efficacy 
measurements.  
6.4.2 
Patient Global Impression of Change 
The self-report measure Patient Global Impression of Change (PGIC) reflects a subject’s 
belief about how their pain has changed since start of study treatment. PGIC is a 7-point scale 


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depicting a subject’s rating of overall improvement. Subjects rate their change as “very much 
improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” 
“much worse,” or “very much worse”. 
The PGIC will be completed at Week 1, Week 2, and Week 4 (EOT)/ET. At study visits, the 
PGIC should be performed before blood sample collection, ECG, and other procedures. 
6.4.3 
Western Ontario and McMaster Universities Osteoarthritis Index 
The WOMAC is widely used in the evaluation of hip and knee osteoarthritis (Collins et al. 
2011) and rates pain during the last 48 hours. It is a self-administered questionnaire 
consisting of 24 items divided into three subscales: 
• Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing 
upright 
• Stiffness (2 items): after first waking and later in the day 
• Physical Function (17 items): using stairs, rising from sitting, standing, bending, 
walking, getting in/out of a car, shopping, putting on/taking off socks, rising from bed, 
lying in bed, getting in/out of bath, sitting, getting on/off toilet, heavy domestic duties, 
light domestic duties 
The test questions are scored on a scale of 0-4, which correspond to: None (0), Mild (1), 
Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with 
a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. The 
sum of the scores for all three subscales provides the total WOMAC score. Higher scores on 
the WOMAC indicate worse pain, stiffness, and functional limitations. 
The WOMAC will be completed at Baseline (Week 0), Week 1, Week 2, and Week 4 
(EOT)/ET. At study visits, the WOMAC should be performed before blood sample collection, 
ECG, and other procedures. 
6.4.4 
Brief Pain Inventory–Short Form 
The BPI is a self-report measure used to assess the severity of pain and its impact on 
functioning in patients with chronic diseases (Cleeland and Ryan 1994). The short form 
version uses a 24-hour recall period (i.e., assesses pain and its impact over the previous 
24 hours). 
The BPI uses a 0 (no pain) to 10 (pain as bad as you can imagine) numeric rating scale to 
measure how much pain has interfered with seven daily activities, including general activity, 
walking, work, mood, enjoyment of life, relations with others, and sleep. 


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The BPI will be completed at Baseline (Week 0), Week 1, Week 2, and Week 4 (EOT)/ET. At 
study visits, the BPI should be performed before blood sample collection, ECG, and other 
procedures. 
6.4.5 
12-Item Short Form Survey 
The SF-12 survey, version 2 (SF-12v2), is a shortened form (12 items) of the SF-36 Health 
Survey (Ware et al. 1996). It is a self-reported general assessment of health-related quality of 
life from the subject’s perspective. The SF-12 has eight domains including physical health 
summary measures: physical functioning, role–physical, bodily pain, and general health and 
mental health summary measures: vitality, social functioning, role–emotional, and mental 
health. From the evaluation of these domains, algorithms are used to generate physical and 
mental health composite summary scores, PCS and MCS, respectively, for comparison to 
normative data. In normative data, the mean score is set to 50; thus, scores >50 indicate better 
physical or mental health than the mean scores and scores <50 indicate worse health. The 
timeframe for this scale is the past 4 weeks. 
The SF-12 will be completed at Baseline (Week 0) and Week 4 (EOT)/ET. 
6.4.6 
Hospital Anxiety and Depression Scale 
The HADS was developed to detect states of anxiety or depression (Zigmond and Snaith 
1993). The questionnaire focuses on non-physical symptoms so that it can be used to 
diagnose depression in people with significant physical ill-health. The questionnaire 
comprises seven questions for anxiety and seven questions for depression, which are each 
scored separately. Each item on the questionnaire is scored from 0 (No, not at all) to 
3 (Yes definitely), for a total score between 0 to 21 for either anxiety or depression. The 
timeframe for this scale is the past week. 
The HADS will be completed at Screening, Baseline (Week 0), and Week 4 (EOT)/ET. 
6.4.7 
Participant Scorecard  
The Participant Scorecard presents subjects with data on key tasks reflecting their own 
performance in the study, plus automated and customized tips for how to improve their 
performance. Scores are assigned for study metrics that serve as markers of data quality and 
accurate symptom reporting, and have been shown to affect accuracy of study endpoints. 
Scores are typically shown for medication adherence, eDiary compliance, and accuracy of 
symptom reporting, although other domains may be included. Although study staff are urged 
to be present with the subject during the scorecard review, human intervention is not required 
but may be needed. For instance, scorecard scores that are within the limits of the signal 
analysis are displayed in green and require no human intervention. The scores that are outside 


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of signal thresholds are shown in yellow or red and require human intervention. Reviewing 
scorecards in this manner improves efficiency and timeliness of recommendations, while 
decreasing the biases and burdens introduced by filtering re-training through site staff. For-
cause re-training on Accurate Symptom Reporting (Section 6.3.1) may be triggered on the 
platform in response to subject scores. The scorecard and as-needed re-training must be 
viewed by the subject prior to the completion of visit assessments, and reviewed by the 
Investigator during the subject’s visit.  
The scorecard is viewed by the subject and reviewed by the Investigator at Visits 5, 6, and 
8/EOT/ET. 
6.5 
Safety Assessments 
6.5.1 
Physical Examination 
A complete, general physical examination will be conducted at Screening and a brief physical 
exam will be conducted at Baseline (Week 0) and Week 4 (EOT)/ET. Height will only be 
measured and reported at Screening and weight will be measured and recorded at Screening, 
Baseline (Week 0), and Week 4 (EOT)/ET. 
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, supine and standing 
systolic and diastolic blood pressure, and pulse rate. Blood pressure and pulse rate 
measurements will be taken after the subject rests for 5 minutes in the supine position. The 
subject will then be asked to stand and blood pressure and pulse rate will be taken after the 
subject stands for 1 minute and then again after 3 minutes. Subjects unable to stand may be 
assessed while sitting upright. A drop in SBP of ≥20 mmHg or in DBP of ≥10 mmHg or if the 
subject is experiencing lightheadedness or dizziness is considered abnormal and orthostasis 
should be considered (further detail is provided in Section 4.5.1.2). 
Vital signs will be evaluated at all designated study visits. A 15-minute window is permitted 
for vital sign measurements.  


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Vital signs should be measured prior to (PK and laboratory) blood draws. 
6.5.3 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings. A single 
12-lead ECG will be performed at Screening, at Baseline (Week 0) both predose and 1 hour 
postdose (the first dose of the day), Week 1, Week 2, and Week 4 (EOT)/ET. A 1-hour 
window is permitted for the predose ECG; a 20-minute window is permitted for the postdose 
ECGs. Electrocardiograms should be performed prior to blood sampling (or at least 
30 minutes after blood sampling) and vital signs but after pain assessments are completed. 
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. All 
ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF, and QTcB intervals) will be 
included in the subject’s record. 
At Screening, if the ECGs have 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. 
At Baseline (Week 0), 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). 
C-SSRS will be completed at all designated study visits. 


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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) 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca),carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid,  
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) 
 INR to be evaluated, as needed (described in Section 4.5.1.1) 
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) 
• Pregnancy test 


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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 at Baseline (Week 0) and Week 4 
(EOT)/ET (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 
• COVID-19 test:  
o COVID-19 diagnostic PCR test at Screening 
• Urinalysis (UA) 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, nitrates  
• Urine drug screen (UDS) with reflex testing 
o A urine drug screen will test for controlled substances at Screening, Baseline Pain 
Assessment Period, and at Week 4/EOT/ET. A dipstick urine drug screen will be 
performed at Baseline (Week 0) for rapid detection of controlled substances and 
for certain prescription medications in order to determine if the subject continues 
to meet subject eligibility. The following controlled substances will be tested for 
with a urine drug screen and/or urine dipstick according to the schedule presented 
in Table 6–1: amphetamine, barbiturates, benzodiazepines, buprenorphine, 
cocaine, ecstasy (MDMA), methadone, morphine/opiates, methamphetamine, 
marijuana (THC), phencyclidine (PCP), propoxyphene, tricyclic antidepressants. 
Negative drug screens are required for study eligibility. 
 If there is a positive urine drug screen for an analgesic medication 
that is not allowed per protocol, the subject must washout of 
medication, if appropriate, prior to the Baseline Pain Assessment 
Period. 
 If there is a positive urine drug screen for a medication that is 
allowed per protocol (e.g., metformin leading to a false positive for 
amphetamine), the subject must have a valid prescription for such 
medication, and if the subject denies use of the positive prohibited 
medication (e.g., amphetamine), 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. 


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Table 6–1 
Safety Laboratory Evaluations 
Visit 
Tests 
Screening 
CHEM, CBC, UA, COVID-19a, serum pregnancy, and urine drug 
screen 
Baseline Pain 
Assessment Period 
Urine drug screen 
Baseline (Week 0) 
predose 
CHEM, CBC, UA, urine pregnancy, and urine dipstick testb 
Day 3 
CHEMc 
Week 1 
CHEM, CBC, UA 
Week 2 
CHEM, CBC, UA 
Week 3 
CHEMc 
Week 4 (EOT/ET) 
CHEM, CBC, UA, urine pregnancy, and urine drug screen 
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 
b 
Urine dipstick test will be administered which must be negative for any non-permitted medications or drugs 
in order for the subject to continue in the study 
c 
Full chemistry (CHEM) panel of clinical laboratory tests will be completed, excluding glucose and the 
CHEM tests noted in Section 6.5.5 to only be performed at Screening 
 
6.6 
Electronic Clinical Outcome Assessments  
The electronic Clinical Outcome Assessment (eCOA) devices will be used during the 
Baseline Pain Assessment Period and throughout the Double-blind study period. Subjects will 
complete electronic-based assessments using handheld devices during the study, specifically, 
a tablet device will be used during clinic visits and an eDiary will be provided for subjects to 
take home. The eDiary, will be provided to all subjects to record pain scores, compliance 
with ingestion of study medication, and use of rescue medication.  
During the Baseline Pain Assessment Period, subjects will record their daily pain scores and 
rescue medication use. Compliance with recording of pain score and use of rescue medication 
will be assessed for continued study eligibility. 
Subjects will continue daily entry into the eDiary of pain scores, rescue medication use, and 
compliance with ingestion of study medication from Baseline (Week 0) through to Week 4 
(EOT)/ET. 


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6.7 
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. 
At each predefined timepoint, PK samples will be obtained for measurement of 
concentrations of ACP-044 at the following visits: 
• Baseline (Week 0) visit (Visit 3; both before dosing and approximately 1 hour after 
dosing) 
• Visit 5 
• Visit 6 
• Visit 8/or upon early termination (ET) 
Pharmacokinetic blood samples taken at Visits 5, 6, and 8 should be collected at one of the 
following time intervals: 
• 2-5 hours after morning dosing  
• 6-9 hours after morning dosing  
• 10-12 hours after morning dosing  
Every effort should be made to collect PK samples at distinct time intervals during Visits 5, 
6, and 8. However, if the interval is the same across these visits, then the collection time 
should vary within that interval. The following scenario is only for illustrative purposes, a 
number of other scenarios are possible.  
• For example, if the time interval of 6-9 hours after morning dosing is used for Visits 5, 
6, and 8, then every effort should be made to collect PK samples at 6, 7, and 8 hours 
after morning dosing at each of these visits, respectively. 
When possible, an additional PK sample (approximately 4 mL 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 all PK samples (scheduled and unscheduled), with the exception of those taken following 
an AE or SAE, the dates and times of administration of the last three doses of the study drug 
should be recorded. 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. 


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6.7.1 
Blood Sampling 
Five (5) 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. 
6.7.2 
Specimen Preparation, Handling, Storage, and Shipment 
Pharmacokinetic 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 timepoint, 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. 
6.8 
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. 
Safety will be further assessed during a follow-up visit to occur in the clinic approximately 
7 (±3) days after EOT/ET procedures. During this in-clinic visit, pain intensity (i.e., subjects 
will rate both the average daily pain as well as their worst daily pain over the past week and 
the data will be entered into EDC), adverse events (AEs), and concomitant medications will 
be assessed, since the EOT/ET. Then, a follow-up telephone call will occur approximately 
30 (+4) days after the last dose of study drug to assess AEs and concomitant medications. 
6.9 
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, C-SSRS, and measurement of vital signs. If an 
unscheduled visit is required for safety reasons, a 12-lead ECG and all appropriate clinical 


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laboratory tests are also to be performed. 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. 
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 time 
of consent, or scheduled surgery/procedure. 
• Overdose of concomitant medication without any signs or symptoms will not be 
considered an AE, but 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 
For subjects who discontinue from the study, AEs will be recorded from the time informed 
consent is obtained until 30 (+4) days after the last dose of study drug. 


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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. 
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. 


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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 
• 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 


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• 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 at same severity 
• 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 
• 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 


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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. 
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. 


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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 
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 


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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 (i.e., study drug or 
rescue medication) at a dose higher than the maximum recommended dose per protocol. It 
must be reported to the Sponsor or 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 5.1.8). 
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. 


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9.2 
Statistical Hypotheses 
Let Δi ( 𝝁𝝁𝐴𝐴𝐴𝐴𝐴𝐴_𝑖𝑖−𝝁𝝁𝑃𝑃𝑃𝑃𝑃𝑃) be the difference in the mean change from Baseline to Week 4 in the 
weekly average of the daily average pain between each of the ACP-044 (µAct_i) dose groups 
and placebo (µPBO) group. 
The null hypothesis is: ∆𝑖𝑖= 0;  
The alternative hypothesis is: ∆𝑖𝑖≠0; 𝑖𝑖= 1, 2. 
9.3 
Sample Size Determination 
Approximately 240 subjects will be randomized in a 1:1:1 ratio to ACP-044 800 mg BID 
dose, ACP-044 400 mg QID dose, or placebo. Assuming a treatment difference of 0.85 and a 
common standard deviation of 1.7 between an ACP-044 dose arm and placebo, 64 subjects 
per arm is needed to provide approximately 80% power to detect this treatment difference 
using a 2 sample t-test at 2-sided alpha level of 0.05. Assuming a discontinuation rate of 
20%, 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 (FAS) includes all randomized subjects who received at least one dose 
of study drug and with baseline pain assessments and at least one post-baseline pain 
assessment. Subjects will be analyzed based on the treatment to which they are assigned. The 
Full Analysis Set will be used for the analysis of all 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 
For continuous variables, descriptive statistics will include the following information: the 
number of subjects with data values (n), mean, standard error of the mean, median, standard 
deviation, minimum, and maximum. For categorical or ordinal data, frequencies and 
percentages will be displayed for each category. All statistical hypotheses will be tested at the 
0.05 significance level. 
Demographic and baseline characteristics, including medical history and exposure to study 
drug will be summarized descriptively by treatment group and by all subjects combined. 


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9.5.2 
Primary Analyses 
The primary efficacy variable will be analyzed using an analysis of covariance model 
(ANCOVA) based on the FAS with treatment, sex, and baseline K-L score (randomization 
strata) as factors and baseline weekly average of daily average pain score as a covariate in the 
model. The primary comparison will be between each ACP-044 dose group versus the 
placebo group. The comparison between the average of the means of the two ACP-044 dose 
groups versus the mean of placebo group will also be conducted. Missing data will be 
imputed using multiple imputation based on missing at random assumption (MAR) with an 
exception of missing data from subjects who are treated with ACP-044 and discontinue the 
study due to lack of efficacy or adverse events. Their missing data will be imputed using the 
data from placebo group. The details of missing data imputation and multiplicity adjustment 
will be described in the SAP. 
Sensitivity analysis using pattern mixture model and tipping point approach with multiple 
imputation to impute missing data will be performed to assess the robustness of the results 
due to treatment discontinuation and other intercurrent events. 
9.5.3 
Secondary Analyses 
For analysis of continuous secondary endpoints, the analysis method will be the same as that 
used for the primary variables except for PGIC which will be analyzed using analysis of 
variance (ANOVA) with treatment, sex, and baseline K-L score as factors. For analysis of 
categorical variables in secondary endpoints, e.g., proportions of subjects with ≥30% 
reduction from baseline to Week 4 in the weekly average of the daily average NRS score; the 
Cochran Mantel Haenszel approach stratified by the randomization strata will be used for 
subjects with missing data considered as non-responders. 
9.5.4 
Exploratory Analyses 
The analysis of the exploratory variables will be described in the SAP. 
9.5.5 
Safety Analyses 
Safety data 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), TEAEs leading to discontinuation, 
TEAEs related to study drug, TEAEs by maximum severity, fatal TEAEs, SAEs, SAEs 
related to study drug, and TEAEs of special interest (AESI) will all be summarized. 
Descriptive statistics for ECGs, vital signs and weight, and clinical laboratory parameters, 
including changes from Baseline (prior to first dose), will be tabulated by timepoint and by 


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treatment group. The incidence of subjects with prolonged QTc intervals and changes in QTc 
intervals in accordance with ICH guidelines will also be summarized by treatment group. 
Additional safety analysis details will be specified in the SAP. 
9.5.6 
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. 
9.5.7 
Pharmacokinetic/Pharmacodynamic Analyses 
Guided by exploratory analyses, PK/PD models to describe the exposure-response 
relationship between ACP-044 exposure parameters and the relevant efficacy and safety 
endpoints will be developed using appropriate PK/PD methods. Results will be presented in a 
separate report per a prespecified data analysis plan. 
9.5.8 
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 
At Baseline (Week 0), eligible subjects who meet inclusion and do not meet exclusion criteria 
will be randomized in a 1:1:1 ratio to receive ACP-044 800 mg BID, ACP-044 400 mg QID, 
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. 
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. 
9.7.1 
Masking Procedures 
This unmasked protocol version provides details of certain study design elements, 
procedures, and statistical methods that are not available in the masked version of the 
protocol. 
This document is intended for use only by the unmasked Sponsor and restricted clinical 
service providers and their designated agents for purposes of regulatory document 


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preparation in conjunction with review by IRBs, IECs, and regulatory authorities. Access to 
this document by other entities may be considered on a case-by-case basis by the Sponsor. 
The information contained herein is UNMASKED and CONFIDENTIAL. Therefore, it must 
NOT be shared with or communicated to any individual at an investigational site or from site 
facing members of the clinical operations team of the contract research organization except 
with explicit and fully documented authorization from the Sponsor. 
The key elements revealed herein but that are masked in the masked protocol are the 
ACP-044 dosing regimens and inclusion criteria specific to the Baseline Pain Assessment 
Period. 
Investigators will receive the masked version of the clinical study protocol. 
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 


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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. 
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, 


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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. 
If, during the course of a subject’s post-enrollment participation in the trial it is discovered 
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 6.8). 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: 


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• 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 
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 


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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 (or remote) 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, 
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.  


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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. 
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. 


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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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16 APPENDICES 
Appendix A New York Heart Association Class Guidelines 
The NYHA heart failure functional classifications are provided below. 
 
NYHA Class I (mild): Patients with cardiac disease but without resulting in limitation of 
physical activity. Ordinary physical activity does not cause undue fatigue, palpitation (rapid 
or pounding heart beat), dyspnea (shortness of breath), or anginal pain (chest pain). 
NYHA Class II (mild): Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
NYHA Class III (moderate): Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
NYHA Class IV (severe): Patients with cardiac disease resulting in the inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is increased. 
Source: New York Heart Association 1994 
 


Study: ACP-044-005 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 UNMASKED VERSION 
Date: 16 February 2022 
 
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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 
• Only acetaminophen (not combinations 
including acetaminophen) is allowed as rescue 
medication for OA pain in the knee (at a 
maximum daily dose of 2500 mg) 
• Subjects are encouraged to limit the amount of 
rescue medication (i.e., acetaminophen) taken 
during the study. Subjects must discontinue 
taking study-provided rescue medication during 
the Baseline Pain Assessment Period and for at 
least 24 hours prior to the start of study visits. 
Rescue medication use during the Baseline Pain 
Assessment Period through Visit 3 and within 
24 hours of the study visits (Visits 5, 6, and 8) 
will be documented in the EDC.  
Anticonvulsants  
PROHIBITED 
• gabapentin 
• pregabalin 
• carbamazepine 
• Prohibited use within 4 weeks prior to Screening 
and throughout the study 
Antidepressants 
PROHIBITED 
• tricyclic antidepressants 
• duloxetine 
• monoamine reuptake 
inhibitors 
• Prohibited use within 4 weeks prior to Screening 
and throughout the study  
 


Study: ACP-044-005 
 
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Medication Class 
 
Medicationa 
Prohibition/restrictions 
• serotonin norepinephrine 
reuptake inhibitors 
Anxiolytics  
 
PROHIBITED 
• chlordiazepoxide  
• diazepam  
• flurazepam  
• alprazolam  
• clonazepam  
• lorazepam  
• oxazepam  
• temazepam  
• midazolam  
• triazolam 
• Prohibited at study entry and throughout the 
study 
HMG-CoA 
reductase inhibitor 
(Statin) 
RESTRICTED 
• HMG-CoA reductase inhibitors are restricted 
and cannot be initiated after screening and 
throughout the study. Subjects who are on a 
stable dose of a statin at screening may be 
eligible for enrollment. 
Miscellaneous 
PROHIBITED 
• intra-articular injections 
into the index knee, 
approved and unapproved 
(i.e., hyaluronic acid and 
corticosteroids) 
• unapproved treatments 
(e.g., platelet-rich plasma, 
topical capsaicin, 
lidocaine, and diclofenac) 
• cannabidiol (CBD) 
• COVID-19 vaccine 
 
• Prohibited use within 3 months of Screening and 
throughout the study 
 
 
• Prohibited throughout the study 
 
 
 
• Use of CBD is prohibited within 1 month prior 
to Screening and throughout the study 
• Subject must not be planning to receive a 
COVID-19 vaccine during Screening through 
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 1 week before 
the Screening visit and be symptom free 
Nonsteroidal anti-
inflammatory drugs 
(NSAIDs) 
PROHIBITED 
• ibuprofen 
• Prohibited use following Screening 
• Prohibited use within 7 days or five half-lives of 
the drug prior to the Baseline Pain Assessment 
Period, whichever is longer 


Study: ACP-044-005 
 
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Medication Class 
 
Medicationa 
Prohibition/restrictions 
RESTRICTED 
• aspirin 
 
• Aspirin, at a dose of up to 81 mg per day, is 
allowed for prophylaxis of coronary and 
cerebrovascular events if stable for 30 days prior 
to Screening and the dose is expected to remain 
the same throughout the duration of the study 
• Aspirin should not be used with an anticoagulant 
Opioids 
PROHIBITED 
• methadone 
• oxycodone 
• codeine 
• morphine 
• hydrocodone 
• fentanyl 
• Prohibited use following Screening 
• Prohibited use within 7 days or five half-lives of 
the drug prior to the Baseline Pain Assessment 
Period, whichever is longer 
• Prohibited use of immediate- or extended-
release or controlled-release opioids, 
transdermal fentanyl, or methadone within 
3 months of Screening 
• Use of opioids, for the treatment of pain other 
than OA of the knee, with a morphine equivalent 
dose of ≥30 mg per day for more than 2 days per 
week within 1 month prior to Screening 
Steroids and 
immunosuppressant 
drugs 
PROHIBITED 
• oral corticosteroids 
• Prohibited use within 30 days prior to the 
screening visit 
• 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 in Subjects With Pain Associated With 
Osteoarthritis of the Knee 
NCT Number: NCT05008835 
Document Date: 21 September 2022 
 


Protocol ACP-044-005 
Version 1.0 
Statistical Analysis Plan 
21 September 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.  Page 1 of 44 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-044-005 
Protocol Title: 
A Phase 2, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Efficacy and Safety of 
ACP-044 in Subjects With Pain Associated With 
Osteoarthritis of the Knee 
Drug: 
ACP-044 
Sponsor:  
Acadia Pharmaceuticals Inc. 
 
Version No. and Date 
Version 1.0, 21 September 2022 
 
 
 


Protocol ACP-044-005 
Version 1.0 
Statistical Analysis Plan 
21 September 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.  Page 2 of 44 
SIGNATURE/APPROVAL PAGE 
AUTHOR 
 
_____________________________________________ 
____________ 
 
       Date 
Senior Director, Biostatistics  
Acadia Pharmaceuticals Inc. 
 
 
APPROVERS 
 
_____________________________________________ 
____________ 
                                                                                           Date 
Executive Director, Clinical Science  
Acadia Pharmaceuticals Inc. 
 
_____________________________________________ 
____________ 
  
        Date 
Executive Director, Biostatistics 
Acadia Pharmaceuticals Inc. 
 
 
 
 
 


Signature Page for ACP-044-005 SAP v1.0
Signature Page for ACP-044-005 SAP v1.0
Approve
26-Sep-2022 18:25:27 GMT+0000
Approve
s
26-Sep-2022 21:02:13 GMT+0000
Approve
30-Sep-2022 22:32:35 GMT+0000


Protocol ACP-044-005 
Version 1.0 
Statistical Analysis Plan 
21 September 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.  Page 4 of 44 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................... 7 
ABBREVIATIONS .................................................................................................................... 8 
1 INTRODUCTION ............................................................................................................... 9 
2 OBJECTIVES ...................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Secondary Objective ........................................................................................................ 9 
2.3 
Exploratory Objective .................................................................................................... 10 
2.4 
Safety Objective ............................................................................................................ 10 
2.5 
Pharmacokinetic Objective ............................................................................................ 10 
2.6 
Pharmacokinetic/Pharmacodynamic Objective ............................................................. 10 
3 STUDY DESIGN ............................................................................................................... 10 
3.1 
General Study Design .................................................................................................... 10 
3.2 
Schedule of Assessments ............................................................................................... 13 
3.3 
Randomization ............................................................................................................... 13 
3.4 
Blinding ......................................................................................................................... 13 
3.5 
Determination of Sample Size ....................................................................................... 14 
3.6 
Coronavirus Disease 2019 ............................................................................................. 14 
4 ANALYSIS SETS .............................................................................................................. 15 
5 DATA HANDLING CONVENTIONS .............................................................................. 15 
5.1 
General Data Reporting Conventions ............................................................................ 15 
5.2 
Derived Variables........................................................................................................... 16 
5.2.1 
Numeric Rating Scale (NRS) of Pain Intensity Scores ............................................. 16 
5.2.2 
Patient Global Impression of Change (PGIC) ........................................................... 16 
5.2.3 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) ........ 17 
5.2.4 
Brief Pain Inventory – Short Form (BPI-sf) .............................................................. 17 
5.2.5 
12-item Short Form Survey (SF-12) .......................................................................... 17 
5.2.6 
Hospital Anxiety and Depression Scale (HADS) ...................................................... 18 
5.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 19 
5.3 
Data Presentation Conventions ...................................................................................... 19 


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Statistical Analysis Plan 
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5.4 
Study Day ...................................................................................................................... 19 
5.5 
Baseline Definition ........................................................................................................ 20 
5.6 
Analysis Visit Windows ................................................................................................. 20 
5.6.1 
Unscheduled Assessments ......................................................................................... 20 
5.6.2 
Multiple Measurements within Visit Windows ......................................................... 20 
5.7 
Missing or Incomplete Date for Last Dose of Study Drug ............................................ 20 
5.8 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ........... 21 
5.9 
Missing or Incomplete Dates for Adverse Events ......................................................... 21 
5.10 Missing Severity Assessment for Adverse Events ......................................................... 21 
5.11 Missing Relationship to Study Drug for Adverse Events .............................................. 21 
5.12 Character Values of Clinical Laboratory Variables ....................................................... 21 
6 SUBJECT DISPOSITION ................................................................................................. 21 
7 PROTOCOL DEVIATIONS .............................................................................................. 22 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 22 
9 MEDICAL HISTORY ....................................................................................................... 23 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 23 
10.1 Exposure to Study Drug ................................................................................................ 23 
10.2 Treatment Compliance ................................................................................................... 23 
11 CONCOMITANT AND POST-TREATMENT MEDICATION ....................................... 23 
12 EFFICACY ANALYSES ................................................................................................... 24 
12.1 Efficacy Variables .......................................................................................................... 24 
12.2 Adjustment for Covariates ............................................................................................. 24 
12.3 Handling of Missing Data .............................................................................................. 25 
12.4 Multiple Comparisons / Multiplicity ............................................................................. 25 
12.5 Examination of Subgroups ............................................................................................ 25 
13 METHODS OF EFFICACY ANALYSES ........................................................................ 26 
13.1 Primary Efficacy Endpoints ........................................................................................... 26 
13.1.1 
Primary Efficacy Endpoints ....................................................................................... 26 
13.1.2 
Sensitivity Analyses ................................................................................................... 27 
13.1.3 
Supportive Analyses .................................................................................................. 27 
13.2 Key Secondary Efficacy Endpoints ............................................................................... 27 
13.3 Secondary Efficacy Endpoints ....................................................................................... 27 


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13.4 Exploratory Efficacy Endpoints .................................................................................... 28 
14 SAFETY ANALYSES ....................................................................................................... 28 
14.1 Adverse Events .............................................................................................................. 28 
14.2 Clinical Laboratory Variables ........................................................................................ 29 
14.3 Vital Signs ...................................................................................................................... 34 
14.4 Electrocardiogram (ECG) .............................................................................................. 35 
14.5 Physical Examination .................................................................................................... 37 
14.6 Other Safety Variables ................................................................................................... 37 
14.6.1 
Suicidality Based on C-SSRS .................................................................................... 37 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 37 
15.1 Pharmacokinetic Endpoints ........................................................................................... 37 
15.2 Pharmacokinetic/Pharmacodynamic Endpoints ............................................................ 37 
16 INTERIM ANALYSIS ....................................................................................................... 38 
17 DATA MONITORING/REVIEW COMMITTEE ............................................................. 38 
18 COMPUTER METHODS ................................................................................................. 38 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 38 
20 REFERENCES .................................................................................................................. 39 
21 APPENDICES ................................................................................................................... 40 
Appendix A 
Schedule of Events and Assessments .............................................................. 40 
Appendix B 
Summary of Version Changes ......................................................................... 44 
 


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LIST OF TABLES 
Table 1 Blinded Daily Dosing Regimen .................................................................................. 14 
Table 2  Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry .................................................................................................. 32 
Table 3  Criteria for Potentially Clinically Important Laboratory Values - Urinalysis ............ 33 
Table 4  Criteria for Potentially Clinically Important Vital Signs ........................................... 35 
Table 5  Criteria for Potentially Clinically Important ECG Values ......................................... 37 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .............................................................................. 13 
 


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ABBREVIATIONS 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BID 
twice daily 
BMI 
body mass index 
BPI-sf 
Brief Pain Inventory - Short Form 
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 
GSD 
Guidance for Site Documentation and Data Management Querying of 
Data Impacted by COVID-19 
HADS 
Hospital Anxiety and Depression Scale 
K-L 
Kellgren-Lawrence 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
milliseconds 
NRS 
numerical rating scale 
OA 
osteoarthritis 
PCI 
potentially clinically important 
PGIC 
Subject Global Impression of Change 
QID 
four times daily 
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 
SAS® 
Statistical Analysis System 
SD 
standard deviation 
SE 
standard error 
SF-12 
12-item Short Form Survey 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 


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Statistical Analysis Plan 
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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 Amendment 
4 dated 16 February 2022. This trial was terminated on 8 August 2022 with 61 patients 
randomized. 
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 pain associated with osteoarthritis (OA) of the knee. 
The primary endpoint is:  
The primary endpoint is change from Baseline to Week 4 in the weekly average of the daily 
average Numeric Rating Scale (NRS) pain intensity scores. 
2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the efficacy of ACP-044 compared with 
placebo in the treatment of pain associated with osteoarthritis (OA) of the knee. 
The key secondary endpoints are: 
• Patient Global Impression of Change (PGIC) at Week 4 with reference to baseline status 
• Change from Baseline to Week 4 in Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) total score and individual subscale scores for pain, 
stiffness, and physical function 
• Proportion of subjects who are responders as defined by 30% and 50% reduction from 
Baseline to Week 4 in the weekly average of the daily average NRS pain intensity scores  
Additional secondary endpoints are:  
• Change from Baseline to Week 4 in:  
o Weekly average of the daily worst NRS pain intensity scores 
o Brief Pain Inventory–Short Form (BPI-sf)  


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o 12-item Short Form Survey (SF-12) 
2.3 
Exploratory Objective 
The exploratory objective of this study is to evaluate the use of rescue medication in subjects 
with pain associated with OA of the knee treated with ACP-044 compared with placebo. 
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 pain associated with OA of the knee. 
2.5 
Pharmacokinetic Objective 
The PK objective of the study is to characterize the PK profile of ACP-044 in subjects with 
pain associated with OA of the knee. 
2.6 
Pharmacokinetic/Pharmacodynamic Objective 
The pharmacokinetic/pharmacodynamic (PK/PD) objective of the study is to characterize the 
exposure-response relationship using appropriate modelling and simulation methods. 
3 STUDY DESIGN 
3.1 
General Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of ACP-044 in subjects with pain associated with 
radiographically confirmed OA of the knee. The study will compare active treatment groups, 
receiving either 800 mg ACP-044 BID or 400 mg ACP-044 QID, with a placebo group. The 
Sponsor, subjects, and Investigators will be blinded to treatment assignment. 
The study periods are: 
• Screening: up to 4 weeks 
• Baseline Pain Assessment: a 7-day period during which open-label placebo will be 
taken and baseline pain assessments will be recorded. Additional 3-day window may 
be added, if needed. 
• Double-blind treatment: 4 weeks 
• Safety follow-up: approximately 7 days after end of treatment (EOT)/early 
termination (ET) and approximately 30 days after the last dose of study drug 
Screening Period (Up to 4 weeks) 
During the Screening period, subjects will be assessed for study eligibility. All subjects must 
have radiographically confirmed OA of the knee, including review of imaging and 


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Statistical Analysis Plan 
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confirmation of a Kellgren-Lawrence (K-L) score of 2 or 3. Subjects who have had an X-ray 
of the index knee within 12 weeks of Screening may provide a historical image for central 
reading to confirm eligibility, or imaging can be done during Screening at protocol-trained 
radiological sites. Randomization visits cannot occur until there is confirmation from the 
central reader that there are no exclusionary findings on the knee joint images. The index 
knee is defined as the most painful knee at Screening.  
Prohibited analgesic medications must be discontinued during the Screening period. 
Investigators must not withdraw a subject’s prohibited medication other than analgesics 
solely 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. 
All pain medication, except for the study-provided rescue medication (acetaminophen), will 
be discontinued 7 days or 5 half-lives, whichever is longer, prior to the Baseline Pain 
Assessment Period. In the event of inadequate pain relief, acetaminophen may be taken with 
a maximum daily dose of 2500 mg. 
Rescreening of a subject will be allowed, with the approval of the Medical Monitor. 
Baseline Pain Assessment Period (1 Week) 
Following eligibility at screening, subjects will complete a Baseline Pain Assessment Period 
that will occur approximately 7 days before randomization; an additional 3-day window may 
be added, if needed. During the Baseline Pain Assessment Period, subjects will be instructed 
in the use of a handheld device (electronic diary [eDiary]) to record their daily pain scores 
and rescue medication use. Compliance with recording of pain score and use of rescue 
medication will be assessed for continued subject eligibility. 
Subjects must discontinue taking study-provided rescue medication during the Baseline Pain 
Assessment Period and for at least 24 hours prior to the start of study visits. Rescue 
medication use during the Baseline Pain Assessment Period through Visit 3 and within 
24 hours of the study visits (Visits 5, 6, and 8) will be documented in the electronic data 
capture (EDC). 
Subjects who enter the Baseline Pain Assessment Period will not be allowed to rescreen. 
Subjects who experience technical issues with the device and their pain scores were not 
assessed may be rescreened and the Baseline Pain Assessment Period may be extended, if 
needed and with permission of the Sponsor. 


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Treatment Period (4 Weeks) 
At Baseline (Week 0), eligible subjects will be randomly assigned in a 1:1:1 ratio to receive 
ACP-044 800 mg BID, ACP-044 400 mg QID, or placebo, according to a randomization 
schedule. Randomization will be stratified by sex and baseline K-L score (2 or 3).  
All efficacy assessments will be completed and a PK blood sample will be taken at the 
Baseline visit prior to administration of the first dose of study drug. Subjects will continue 
daily entry into the eDiary of pain scores, compliance with ingestion of study medication, and 
rescue medication use from Week 0 through to Week 4/EOT/ET.  
Subjects will receive their first dose at the study site after all Baseline assessments have been 
completed and a PK blood sample will be taken approximately 1 hour after dosing. Dosing is 
four times a day.  
During the treatment period (Week 0 through Week 4), subjects will be permitted to use only 
acetaminophen as rescue medication. Subjects will record their use of acetaminophen in their 
eDiary. Subjects must discontinue acetaminophen use for at least 24 hours prior to the start of 
study visits in order to minimize the confounding effects of the rescue medication on efficacy 
measurements.  
A PK sample will be taken at each study visit according to the schedule described in the 
Pharmacokinetic Assessments section.  
At the Week 4 visit, end of treatment (EOT) procedures will be completed. 
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. During this in-clinic visit, pain intensity, adverse 
events (AEs), and concomitant medications will be assessed, since the EOT/ET. Then, a 
follow-up telephone call will occur approximately 30 (+4) days after the last dose of study 
drug to assess AEs and concomitant medications.  
The study design schematic is presented in Figure 1. The schedule of assessments is provided 
in Appendix A. 


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Figure 1 
Schematic of Study Design 
 
Abbreviations: BID=twice daily; EOT=end of treatment; QID=four times daily; R=randomization 
3.2 
Schedule of Assessments 
Schedule of events and assessments can be found in Appendix A. 
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 ACP-044 800 mg BID, ACP-044 400 mg QID, or 
placebo, according to a randomization schedule. Randomization will be stratified by sex and 
baseline K-L score. 
Approximately 50 United States (US) sites will participate in this study. 
3.4 
Blinding 
Treatment assignments will be blinded to all study subjects, Investigators, site personnel, and 
Sponsor personnel. 
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. 
The investigational products are ACP-044 400 mg tablets, or matching placebo (size- and 
color-matched) tablets. Study drug doses are to be administered orally for 4 weeks. 
Doses to be studied are: 
• ACP-044 800 mg dose delivered two times a day (provided as 2×400 mg ACP-044 
tablets) 
• ACP-044 400 mg dose delivered four times a day (provided as 1×400 mg ACP-044 
tablet) 


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• Placebo, size- and color-matched to ACP-044 tablets 
Blinded drug will be provided in blister cards. All subjects will take the same number of 
tablets per day in order to maintain the blinded study design. 
Dosing is to occur in the morning (2 tablets), noon (1 tablet), evening (2 tablets), and night 
(1 tablet) and should occur at the same time each day over the duration of the study. 
Table 1 Blinded Daily Dosing Regimen 
 
First Daily Dose 
Second Daily 
Dose 
Third Daily 
Dose  
Fourth Daily 
Dose  
Placebo  
PP  
P  
PP  
P  
ACP-044 400 mg QID 
(four times daily)  
XP 
X  
XP  
X  
ACP-044 800 mg BID 
(twice daily)  
XX  
P  
XX  
P  
Abbreviations: P=ACP-044 placebo table; X=ACP-044, 400 mg tablet 
3.5 
Determination of Sample Size 
Approximately 240 subjects will be randomized in a 1:1:1 ratio to ACP-044 800 mg BID 
dose, ACP-044 400 mg QID dose, or placebo. Assuming a treatment difference of 0.85 and a 
common standard deviation of 1.7 between an ACP-044 dose arm and placebo, 64 subjects 
per arm is needed to provide approximately 80% power to detect this treatment difference 
using a 2 sample t-test at 2-sided alpha level of 0.05. Assuming a discontinuation rate of 
20%, 80 subjects per treatment group will be randomized. 
The planned sample size is 240 subjects randomized (80 subjects per treatment group).  
3.6 
Coronavirus Disease 2019  
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
implementation of urgent safety measures designed to ensure subject safety. 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] in 
the Data Management Plan).  
The impact of COVID-19 on the statistical analysis is discussed in each of the relevant 
sections of this SAP. 
Subjects who remained in this study who could not attend clinic visits were allowed to 
participate in remote visits via telephone or video, or site staff conducted the visit in a 
subject’s home. Sites were required to document details of all visits that are administered 
remotely. 


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4 ANALYSIS SETS 
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 and with baseline pain assessments and at least one post-baseline pain assessment. 
The Full Analysis Set will be used for the analysis of all efficacy endpoints. Subjects will be 
analyzed based on their randomized treatment assignment.  
Pharmacokinetics Analysis Set 
The Pharmacokinetics Analysis Set includes all subjects with at least one measurable 
ACP-044 plasma concentration. The Pharmacokinetics Analysis Set will be used for 
ACP-044 plasma concentration summaries. 
5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
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, 
maximum and quartiles when necessary. 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.  
Duration in months will be calculated as ([the number of days / 365.25] *12).  


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Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at 
the significance level of 5% for main effects 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). 
5.2.1 
Numeric Rating Scale (NRS) of Pain Intensity Scores 
A 0 to 10 NRS will be used to assess the subject’s pain throughout the study. Subjects will be 
required to assess and record daily in the eDiary their knee pain intensity and daily use of 
rescue medication. Subjects will be rating both the average daily pain as well as their worst 
daily pain. 
Knee pain intensity will be assessed by describing their knee pain at the present time from 
0 to 10 where “0” means “no pain at all” and “10” means “the worst pain imaginable”. 
Pain intensity assessments are to be recorded in the evening prior to their 4th dose of the day. 
Subjects are encouraged to refrain from acetaminophen use for at least 24 hours prior to the 
start of study visits in order to minimize the confounding effects of the rescue medication on 
efficacy measurements. At study visits, pain assessments should be performed before blood 
sample collection, ECG, and other procedures  
5.2.2 
Patient Global Impression of Change (PGIC) 
The self-report measure Patient Global Impression of Change (PGIC) reflects a subject’s 
belief about how their pain has changed since start of study treatment. PGIC is a 7-point scale 
depicting a subject’s rating of overall improvement. Subjects rate their change as “very much 
improved” = 1, “much improved” =2 “minimally improved”=3 “no change” = 4 “minimally 
worse” = 5 “much worse” = 6 or “very much worse” = 7. 
 The PGIC will be completed at Week 1, Week 2, and Week 4 (EOT)/ET. At study visits, the 
PGIC should be performed before blood sample collection, ECG, and other procedures. 


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5.2.3 
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) 
The WOMAC is widely used in the evaluation of hip and knee osteoarthritis (Collins et al. 
2011) and rates pain during the last 48 hours. It is a self-administered questionnaire 
consisting of 24 items divided into three subscales: 
• Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing 
upright  
• Stiffness (2 items): after first waking and later in the day 
• Physical Function (17 items): using stairs, rising from sitting, standing, bending, 
walking, getting in/out of a car, shopping, putting on/taking off socks, rising from 
bed, lying in bed, getting in/out of bath, sitting, getting on/off toilet, heavy domestic 
duties, light domestic duties  
The test questions are scored on a scale of 0-4, which correspond to: None (0), Mild (1), 
Moderate (2), Severe (3), and Extreme (4). The scores for each subscale are summed up, with 
a possible score range of 0-20 for Pain, 0-8 for Stiffness, and 0-68 for Physical Function. The 
sum of the scores for all three subscales provides the total WOMAC score. Higher scores on 
the WOMAC indicate worse pain, stiffness, and functional limitations.  
The WOMAC will be completed at Baseline (Week 0), Week 1, Week 2, and Week 4 
(EOT)/ET. At study visits, the WOMAC should be performed before blood sample collection, 
ECG, and other procedures. 
5.2.4 
Brief Pain Inventory – Short Form (BPI-sf) 
The BPI is a self-report measure used to assess the severity of pain and its impact on 
functioning in subjects with chronic diseases. The short form version uses a 24-hour recall 
period (i.e., assesses pain and its impact over the previous 24 hours). 
 The BPI uses a 0 (no pain) to 10 (pain as bad as you can imagine) numeric rating scale to 
measure how much pain has interfered with seven daily activities, including general activity, 
walking, work, mood, enjoyment of life, relations with others, and sleep. 
The BPI will be completed at Baseline (Week 0), Week 1, Week 2, and Week 4 (EOT)/ET. At 
study visits, the BPI should be performed before blood sample collection, ECG, and other 
procedures. 
5.2.5 
12-item Short Form Survey (SF-12) 
The SF-12 survey, version 2 (SF-12v2), is a shortened form (12 items) of the SF-36 Health 
Survey (Ware et al. 1996). It is a self-reported general assessment of health-related quality of 
life from the subject’s perspective. The SF-12 has eight domains including physical health 


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summary measures: physical functioning, role–physical, bodily pain, and general health and 
mental health summary measures: vitality, social functioning, role–emotional, and mental 
health. From the evaluation of these domains, algorithms are used to generate physical and 
mental health composite summary scores, PCS and MCS, respectively, for comparison to 
normative data. In normative data, the mean score is set to 50; thus, scores >50 indicate better 
physical or mental health than the mean scores and scores < 50 indicate worse health. The 
timeframe for this scale is the past 4 weeks. 
Scales of SF-12 (health survey) Physical Component Summary (PCS) and Mental 
Component Summary (MCS) will be derived using the weights provided in the SF-12 manual 
developed by J. Ware, M. Kosinski and S. Keller. 
For variable 12 (Physical Component Summary (PCS) and Mental Component Summary 
(MCS) of SF-12), PCS and MCS are created from the SF-12 survey in this way.  First, 
subjects with missing answer to any one of the 12 items will be ignored, i.e., will have their 
PCS-12 and MCS-12 scores missing.  Indicator variables (1/0) will be created for all choices 
of each the 12 items, except that the choice associated with the best health status under each 
item.  Thus totally 35 indicator variables will be created.  For example, for item “In general, 
would you say your health is”, indicator variables will be created for each of the choices 
“Poor”, “Fair”, “Good”, and “Very Good”, but not the choice “Excellent”.  This means that if 
a subject marks “Good” under this item, the indicator variable for “Good” will have a value 
1, and the indicator variables for “Poor”, “Fair” and “Very Good” will have value 0.  If a 
subject marks “Excellent” for this item, all indicator variables under this item will have value 
0.  Then all these indicator variables will be weighted based on the SF-12 Manual for the 
PCS-12 and MCS-12 separately.  Summing of these indicator variables based on their weight, 
and plus the constant (56.57706 for PCS-12 and 60.75781 for MCS-12) will provide the 
PCS-12 and MCS-12 scores for each subject. 
The SF-12 will be completed at Baseline (Week 0) and Week 4 (EOT)/ET. 
5.2.6 
Hospital Anxiety and Depression Scale (HADS) 
The HADS was developed to detect states of anxiety or depression (Zigmond and Snaith 
1983). The questionnaire focuses on non-physical symptoms so that it can be used to 
diagnose depression in people with significant physical ill-health. The questionnaire 
comprises seven questions for anxiety and seven questions for depression, which are each 
scored separately. Each item on the questionnaire is scored from 0 (No, not at all) to 3 (Yes 
definitely), for a total score between 0 to 21 for either anxiety or depression. The timeframe 
for this scale is the past week.  
The HADS will be completed at Screening, Baseline (Week 0), and Week 4 (EOT)/ET. 


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5.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Baseline, Day 7, Day 14, and Day 28 (EOT/ET).  
The C-SSRS version assessing information since the last visit will be completed at all visits 
(including the Baseline visit).  
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 
suicidal behavior. 
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 
Data Presentation Conventions 
• 1 year = 365.25 days. Year is calculated as (days/365.25) and will be rounded to 
1 digit after the decimal point (tenths) for presentation purposes.  
• 1 month = 30.4375 days. Month is calculated as (days/30.4375) and will be rounded 
to 1 digit after the decimal point (tenths) for presentation purposes.  
• 1 pound = 0.454 kg and 1 kg = 2.2 pounds.  
• 1 inch = 2.54 cm and 1 cm = 0.3937 inches.  
• Body mass index (BMI) calculated as [weight (kg)/height (m)2] 
5.4 
Study Day 
If the date of assessment occurs on or after the first dose date of double-blind study 
medication, then study day will be calculated as (date of assessment – date of first 
double-blind dose) + 1. If the date of assessment occurs prior to the first double-blind dose 
date, then study day will be calculated as (date of assessment – date of first double-blind 
dose). There is no study day 0. 


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5.5 
Baseline Definition 
Baseline data 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 Study Day -1, the value closest to and 
prior to the receipt of the first dose, whether scheduled or unscheduled, will be used as the 
Baseline value. 
The baseline of the average of the daily average NRS pain intensity score will be the average 
of the scores during the baseline pain assessment period which is 7 consecutive days prior to 
the first dose of study medication. 
5.6 
Analysis Visit Windows  
Assessment nominal visit window will be applied. 
5.6.1 
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. 
5.6.2 
Multiple Measurements within Visit Windows 
In the event that more than one assessment falls within a given window, the assessment closest to 
the target study day will be selected for the by-visit analysis. If two assessments are equidistant 
from the target study day, then the chronologically last assessment will be used. Exceptions may 
be made for incomplete assessments, in which case, more complete assessments may be 
given priority. Details are provided in a separate programming conventions document. 
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. 
5.7 
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 
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5.8 
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. 
5.9 
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. 
5.10 Missing Severity Assessment for Adverse Events 
If the severity is missing for a treatment-emergent AE, a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
and the actual values will be presented in data listings. 
5.11 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. 
5.12 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. 
6 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 


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(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 
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 and Full Analysis Sets. All subjects excluded from the Safety, Full Analysis 
Sets, and the reason(s) for exclusion will be listed.  
7 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 will be presented by treatment group for the Randomized Analysis Set in three 
ways: all protocol deviations, COVID-19-PHE related protocol deviations, and 
non-COVID 19-PHE related protocol deviations. Three data listings of all protocol 
deviations, COVID-19-PHE related protocol deviations, and non-COVID-19-PHE related 
protocol deviations will be provided.  
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and Baseline characteristics will be summarized for the Safety Analysis Set 
using descriptive statistics. Variables include age, age group (18-40 years and >40 years), sex, 
primary race, ethnicity, height, weight, and body mass index (BMI). 
Race will also be categorized by White vs. Non-White. The eCRF reported age reflects a 
subject’s age at the Baseline visit date. 


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9 MEDICAL HISTORY 
Medical history data will be coded using Medical Dictionary for Regulatory activities 
(MedDRA) version 23.0. 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. 
A listing of the SOC, preferred term, body system, 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 
The number of doses dosed, the number of morning doses dosed, the number of missed 
doses, the number of missed morning 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 and the number of missed morning doses will be summarized as a 
categorical variable. 
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 2020 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 


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usage by a subject in the same category will be counted only once. 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 will 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). 
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 
• Change from Baseline to Week 4 in the average of the daily average Numeric Rating 
Scale (NRS) pain intensity scores 
Key Secondary Efficacy Endpoints 
• Patient Global Impression of Change (PGIC) at Week 4 with reference to 
baseline status 
• Change from Baseline to Week 4 in Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) total score and individual subscale scores for pain, 
stiffness, and physical function 
• Proportion of subjects who are responders as defined by 30% and 50% reduction from 
Baseline to Week 4 in the average of the daily average NRS pain intensity scores 
Additional Secondary Efficacy Endpoints 
Change from Baseline to every study visit in: 
• Weekly average of the daily worst NRS pain intensity scores 
• Brief Pain Inventory–Short Form (BPI-sf) 
• 12-item Short Form Survey (SF-12) 
Exploratory Endpoints 
• Comparison of average daily rescue medication use 
• Hospital Anxiety and Depression Scale (HADS) 
12.2 Adjustment for Covariates 
The baseline average of daily average pain score as a covariate in the model. 


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12.3 Handling of Missing Data 
Weekly Mean Pain Intensity Scores 
If a subject reports at least 3 days with non-missing pain intensity scores within a particular 
week, the weekly mean pain intensity score will be derived using the non-missing scores 
only. This is identical to imputing the missing scores as the mean of the non-missing scores. 
If the subject reports less than 3 days with non-missing pain intensity scores within a 
particular week, the weekly mean pain intensity score will be treated as missing data.  
Missing weekly mean pain intensity scores will be imputed using multiple missing data and 
pattern mixture methodology as detailed in Section 13. Sensitivity analyses will be conducted 
exploring different patterns for missing data.  
WOMAC Index Total Score  
If at least 50% of items within a subscale are non-missing, the missing items of the WOMAC 
score at a weekly visit will be imputed using the mean of non-missing items within the same 
subscale. Otherwise, the item, the subscale score and the total score will all remain missing. 
The total and subscale scores will be derived as the sum of all respective observed and 
imputed scores. If all values of a particular subscale are missing at a particular week then the 
total and corresponding subscale score will be treated as missing.  
12.4 Multiple Comparisons / Multiplicity 
The primary efficacy endpoint is change from baseline to week 4 in the average of the daily 
average Numeric Rating Scale (NRS) pain intensity scores. For the primary efficacy analysis, 
the null hypothesis is that there is no treatment effect between 400 mg QID and placebo 
during the study versus the alternative hypothesis that there is a treatment effect. Similar 
hypothesis applies to the comparison of 800 mg BID to placebo. 
The overall Type I error is controlled by a hierarchical testing procedure. The procedure is to 
test the difference of the treatment effect between 400 mg QID versus placebo first, at 
significant level α=0.05. If this test is significant, then comparison for 800 mg BID versus 
placebo will be performed at α=0.05 level. 
12.5 Examination of Subgroups 
No subgroup analyses for primary endpoint are planned. 


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13 METHODS OF EFFICACY ANALYSES 
13.1 Primary Efficacy Endpoints 
13.1.1 Primary Efficacy Endpoints 
Estimand 
The primary estimand has the following attributes: 
• Population: all randomized subjects who received at least one dose of study drug and 
with baseline pain assessments and at least one post-baseline pain assessment. 
• Endpoint: change from baseline to week 4 in the average of the daily average 
Numeric Rating Scale (NRS) pain intensity scores 
• Intercurrent events: premature discontinuation from the study, the hypothetical 
estimand is to evaluate the pharmacological effect as if no withdrawals had occurred. 
• Treatment condition: one of the randomized treatment groups of the following per 
protocol: 1600 mg total dose (provided as 2×800 mg tablets), 1600 mg total dose 
(provided as 4×400 mg tablets), or placebo. 
• Population-level summary: difference in mean of endpoint between treatment 
conditions. 
Statisitical Hypotheses 
The primary endpoint is the change from baseline to week 4 in the average of the daily 
average Numeric Rating Scale (NRS) pain intensity scores. 
The mean change from baseline to week 4 daily average NRS score will be compared 
between each of the ACP-044 dose groups (400 mg QID, 800 mg BID) to the placebo group. 
The null hypothesis is the mean change from baseline to week 4 in the average of the daily 
average Numeric Rating Scale (NRS) pain intensity scores using ACP-044is equal to that of 
placebo in subjects with pain associated with osteoarthritis of the knee. 
The alternative hypothesis is the mean change from baseline to week 4 in the average of the 
daily average Numeric Rating Scale (NRS) pain intensity scores using ACP-044 is not equal 
to that of placebo in subjects with pain associated with osteoarthritis of the knee. 
Primary Estimator 
The primary efficacy variable will be analyzed using an analysis of covariance model 
(ANCOVA) based on the FAS with treatment, sex, and baseline K-L score (randomization 
strata) as factors and baseline weekly average of daily average pain score as a covariate in the 
model. The primary comparison will be between each ACP-044 dose group versus the 


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placebo group. The comparison between the average of the means of the two ACP-044 dose 
groups versus the mean of placebo group will also be conducted. Missing data will be 
imputed using multiple imputation based on missing at random assumption (MAR) with an 
exception of missing data from subjects who are treated with ACP-044 and discontinue the 
study due to lack of efficacy or adverse events. Their missing data will be imputed using the 
data from placebo group.  
13.1.2 Sensitivity Analyses 
No sensitivity analyses are planned for primary efficacy endpoint. 
13.1.3 Supportive Analyses 
No supportive analyses are planned for primary efficacy endpoint. 
13.2 Key Secondary Efficacy Endpoints 
Patient Global Impression of Change (PGIC) at Week 4 with reference to baseline status 
The PGIC will be summarized as both a categorical and continuous variable (including 
95% CI for the mean) at every study visit week. This endpoint will be analyzed using 
analysis of variance (ANOVA) with treatment, sex, and baseline K-L score as factors on 
LOCF data. The comparison at week 4 will be viewed as key secondary. 
The proportion of patients with PGIC scores of “very much improved” and “much improved” 
will also be summarized and compared between treatments using a logistic regression with 
treatment, sex and baseline K-L score as factors. Additionally, this proportion will be 
compared using a Cochran-Mantel-Haenzel test stratified by baseline K-L score and sex. 
Change from Baseline to Week 4 in Western Ontario and McMaster Universities 
Osteoarthritis Index (WOMAC) total score 
The change from baseline in the WOMAC Index total score will be analyzed using analysis 
of covariance (ANCOVA) with baseline WOMAC score as covariate, treatment, sex, and 
baseline K-L score as main effects on LOCF data.  
Proportion of subjects who are responders as defined by 30% and 50% reduction from 
Baseline to Week 4 in the average of the daily average NRS pain intensity scores will be 
evaluated by the Cochran-Mantel-Haenszel (CMH) General Association Test, missing data 
considered as “non-respond”, controlling for baseline K-L score and sex. 
13.3 Secondary Efficacy Endpoints 
Change from Baseline to every study week visit in: 
Weekly average of the daily worst NRS pain intensity scores will be evaluated using 
ANCOVA with baseline SF-12 score as covariate, treatment, baseline K-L score and sex as 
main effects on LOCF data. 


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Brief Pain Inventory–Short Form (BPI-sf) will be evaluated using ANCOVA with baseline 
SF-12 score as covariate, treatment, baseline K-L score and sex as main effects on LOCF 
data. 
12-item Short Form Survey (SF-12)  The change from baseline to week 4 will be evaluated 
using ANCOVA with baseline SF-12 score as covariate, treatment, baseline K-L score and 
sex as main effects on LOCF data. 
13.4 Exploratory Efficacy Endpoints 
Comparison of average daily rescue medication use 
The average daily number of acetaminophen tablets used during the study will be compared 
between treatments using a Wilcoxon Rank Sum Test stratified by baseline K-L score and 
sex. 
Hospital Anxiety and Depression Scale (HADS)  The change from baseline to week 4 will be 
evaluated using ANCOVA with baseline HADS score as covariate, treatment, baseline K-L 
score, sex as main effects on LOCF data. 
14 SAFETY ANALYSES 
All safety analyses will be performed using the actual treatment 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 interest, will be summarized separately by SOC and 
preferred term. The adverse events of interest evaluation will be based on the following 
prespecified preferred terms of aspartate aminotransferase increased, alanine 
aminotransferase increased, gamma-glutamyltransferase increased, blood alkaline 
phosphatase increased, blood bilirubin increased, hyperbilirubinaemia, liver function test 
increased, blood creatine phosphokinase increased, rash, hypotension, blood pressure 
decreased , presyncope, hypotension, orthostatic hypotension, pre-syncope, syncope, and 
bradycardia. 
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 Baseline and Week 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, 
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) 
 INR to be evaluated, as needed 
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) 
• 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 at Baseline (Week 0) and Week 4 
(EOT)/ET 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 
• COVID-19 test: 


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o COVID-19 diagnostic PCR test at Screening 
• Urinalysis (UA) 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, nitrates 
• Urine drug screen (UDS) with reflex testing 
o A urine drug screen will test for controlled substances at Screening, Baseline 
Pain Assessment Period, and at Week 4/EOT/ET. A dipstick urine drug screen 
will be performed at Baseline (Week 0) for rapid detection of controlled 
substances and for certain prescription medications in order to determine if the 
subject continues to meet subject eligibility. The following controlled 
substances will be tested for with a urine drug screen and/or urine dipstick 
according to the schedule presented in Table 6–1 in protocol: amphetamine, 
barbiturates, benzodiazepines, buprenorphine, cocaine, ecstasy (MDMA), 
methadone, morphine/opiates, methamphetamine, marijuana (THC), 
phencyclidine (PCP), propoxyphene, tricyclic antidepressants. Negative drug 
screens are required for study eligibility. 
 If there is a positive urine drug screen for an analgesic medication that 
is not allowed per protocol, the subject must washout of medication, if 
appropriate, prior to the Baseline Pain Assessment Period.  
 If there is a positive urine drug screen for a medication that is allowed 
per protocol (e.g., metformin leading to a false positive for 
amphetamine), the subject must have a valid prescription for such 
medication, and if the subject denies use of the positive prohibited 
medication (e.g., amphetamine), they can be included in the study and 
it will not be considered a protocol deviation. 
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 


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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 Table 2 and Table 3. The number and percentage of subjects 
with post-Baseline PCI values for each of the categories in Table 3 and Table 4 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. 
Table 2  Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry 
 
Analyte 
Conventional 
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 


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Table 2  Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry (Continued) 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
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 
 
Table 3  Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥ Moderate 
Protein 
Not Applicable 
≥ 100 mg/dL 
Glucose 
Not Applicable 
≥ 500 mg/dL 
 
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  


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• 
AST (SGOT) ≥ 2x ULN U/L 
• 
Gamma Glutamyl Transferase ≥ 2x ULN U/L  
• 
Alkaline Phosphatase ≥ 2x ULN IU/L 
• 
Creatine Kinase (CK) ≥ 5x ULN 
14.3 Vital Signs 
Vital signs will include body temperature, resting respiration rate, supine and standing 
systolic and diastolic blood pressure, and pulse rate. Blood pressure and pulse rate 
measurements will be taken after the subject rests for 5 minutes in the supine position. The 
subject will then be asked to stand and blood pressure and pulse rate will be taken after the 
subject stands for 1 minute and then again after 3 minutes. Subjects unable to stand may be 
assessed while sitting upright. A drop in SBP of ≥20 mmHg or in DBP of ≥10 mmHg or if the 
subject is experiencing lightheadedness or dizziness is considered abnormal and orthostasis 
should be considered.  
Vital signs will be evaluated at all designated study visits. A 15-minute window is permitted 
for vital sign measurements.  
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 4. 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 
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 4  Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Systolic blood pressure 
(standing or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Diastolic blood pressure 
(standing or sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Systolic blood pressure 
(supine to standing) 
mmHg 
 
Decrease ≥ 20 mmHg 
Diastolic blood pressure 
(supine to standing) 
mmHg 
 
Decrease ≥ 10 mmHg 
Pulse (supine) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
 
Decrease of ≥7% 
Pulse (standing or sitting) 
bpm 
≥120            
And 
Increase of ≥15 
 
≤50             
And 
Decrease of ≥15 
 
 
Decrease of ≥7% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change 
from baseline. 
 
In addition, the following additional PCI criteria for orthostatic hypotension, significant 
bradycardia will be flagged, listed, and summarized:  
• 
Orthostatic hypotension: decrease in systolic blood pressure (SBP) ≥20 mmHg or 
diastolic blood pressure (DBP) ≥10 mmHg after transitioning from the supine 
position (after resting for 5 minutes) to standing at 1 or 3 minutes with or without 
symptoms such as light headedness or dizziness and not explained by dehydration, 
illness, or medications.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. 
14.4 Electrocardiogram (ECG) 
12-lead ECGs are collected at Baseline (Week 0) both predose and 1 hour postdose (the first 
dose of the day), Week 1, Week 2, and Week 4 (EOT)/ET. Observed values of ECG variables 
(e.g., heart rate, PR interval, QRS interval, QT interval, and QTc interval) and the changes 


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from Baseline 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-Baseline maximum: 
• Observed: ≤450, 451 - ≤480, 481 - ≤500, and >500; >450; >480. 
• Change from Baseline: ≤10, 11 – 30, 31 – 60, and >60; >30. 
• QTcF result >470 ms for males, >480 ms for females. 
• QTcF increases ≥60 ms from Baseline. 
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 
Table 5. 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. 
 


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Table 5  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 Baseline (Week 0), Week 4 (EOT)/ET. 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. 
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. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
15.1 Pharmacokinetic Endpoints 
The PK endpoints of the study are: 
• Plasma concentrations of ACP-044 using sparse sampling on the following study 
days: Baseline (Week 0), Week 1, Week 2, and Week 4 (EOT)/ET  
• 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 
• ACP-044 exposure-response relationship: 
o for efficacy using the primary endpoint and selected secondary endpoints 


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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. 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Due to early termination of the ACP-044 program, the changes to the planned analyses are: 
• 
Primary efficacy endpoint will be analyzed using an analysis of covariance model 
(ANCOVA) based on the FAS with treatment, sex, and baseline K-L score 
(randomization strata) as main factors and baseline weekly average of daily average 
pain score as a covariate in the model. The missing data will be imputed using 
baseline observed data carried forward (BOCF). 
• 
Key secondary efficacy endpoints, the observed data will be provided in descriptive 
statistics including point estimates and listings. 
• 
Secondary efficacy endpoints, the observed data will be provided in descriptive 
statistics and listings, no statistical inferences will be applied. 
• 
Exploratory efficacy endpoints, the observed data will be provided in descriptive 
statistics and listings, no statistical inferences will be applied. 


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20 REFERENCES 
Centers for Disease Control and Prevention. 2018 Annual Surveillance Report of 
DrugRelated 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. 
 
Collins NJ, Misra D, Felson DT, Crossley KM, Roos EM. Measures of knee function. 
Arthritis Care Res. 2011;63(S11):S208-S228. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic Guidance for Industry, Investigators, and Institutional Review Boards (March 
2020)  
 
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 
 
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. 
  
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand 
1983;67(6):361-370


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21  APPENDICES 
Appendix A Schedule of Events and Assessments 
 
Screening 
Period 
Baseline Pain 
Assessment 
Period 
Double-Blind Treatment Period 
 
Safety 
Follow-up Period 
Visit Day/Week 
Days -35 
to -8 
Days -7 to -1 
Baseline 
Week 0  
Day 3 Week 1  Week 2  Week 3 
Week 4  
Unscheduled 
Visitr 
Clinic 
visit 
Telephone 
call 
7 days 
after 
EOT 
30 days 
after last 
dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 (EOT/ET) 
 
 
 
Visit window (# days) 
 
+3 
0 
±1 
±3 
±3 
±3 
±3 
 
±3 
+4 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Medical, medication, and surgical 
history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
 
 
 
 
X 
 
 
 
Vital signs (including orthostatic 
changes)a 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Height, weight, and BMI calculationb 
X 
 
X 
 
 
 
 
X 
 
 
 
12-lead ECGc 
X 
 
Xc 
 
X 
X 
 
X 
 
 
 
Clinical laboratory tests 
X 
 
X 
Xd 
X 
X 
Xd 
X 
 
 
 
Pregnancy teste 
X 
 
X 
 
 
 
 
X 
 
 
 
Urine drug screen 
X 
X 
Xf 
 
 
 
 
X 
 
 
 
COVID-19 testg 
X 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
 
X 
X 
 
X 
X 
 
 
Beck Depression Inventory–II 
X 
 
 
 
 
 
 
 
 
 
 
Verified Clinical Trials Subject Registry 
X 
 
 
 
 
 
 
 
 
 
 
Central Imagingh 
X 
 
 
 
 
 
 
 
 
 
 
Issue eDiary and train on usei 
 
X 
 
 
 
 
 
 
 
 
 
Collect eDiary 
 
 
 
 
 
 
 
X 
 
 
 


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Appendix A Schedule of Events and Assessments (Continued) 
 
Screening 
Period 
Baseline Pain 
Assessment 
Period 
Double-Blind Treatment Period 
 
Safety 
Follow-up Period 
Visit Day/Week 
Days -35 
to -8 
Days -7 to -1 
Baseline 
Week 0  Day 3 
Week 1  Week 2  Week 3 
Week 4  
Unscheduled 
Visitr 
Clinic 
visit 
Telephone 
call 
7 days 
after 
EOT 
30 days after 
last dose 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
 
 
 
Visit window (# days) 
 
+3 
0 
±1 
±3 
±3 
±3 
±3 
 
±3 
+4 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
PK blood sample collectionj 
 
 
Xk 
 
Xl 
Xl 
 
Xl 
 
 
 
eDiary completion: Numeric Rating 
Scale Daily Pain Score (Average and 
Worst)m 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
PGICn 
 
 
 
 
X 
X 
 
X 
 
 
 
WOMACn 
 
 
X 
 
X 
X 
 
X 
 
 
 
BPI-sfn 
 
 
X 
 
X 
X 
 
X 
 
 
 
SF-12 
 
 
X 
 
 
 
 
X 
 
 
 
HADS 
X 
 
X 
 
 
 
 
X 
 
 
 
Participant Scorecardo 
 
 
 
 
X 
X 
 
X 
 
 
 
Accurate Symptom Reporting (ASR) 
Training – subject facing 
X 
 
X 
 
Xp 
Xp 
 
Xp 
 
 
 
Placebo Response Reduction (PRR) 
Training – subject facing 
X 
 
X 
 
Xp 
Xp 
 
Xp 
 
 
 
Study drug dispensing/accountability 
 
 
X 
 
X 
X 
 
X 
 
 
 
eDiary completion: Rescue 
medication 
dispensing/accountabilityq 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Protocol ACP-044-005 
Version 1.0 
Statistical Analysis Plan 
 
21 September 2022 
 
 
                                   Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.   
 
Page 42 of 44 
Abbreviations: ASR=accurate symptom reporting; BMI=body mass index; BPI-sf=Brief Pain Inventory–Short Form; COVID-19=coronavirus disease 2019; 
C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; eDiary=electronic diary; EOT=end of treatment; ET=early termination; 
HADS=Hospital Anxiety and Depression Scale; PGIC=Subject Global Impression of Change; PK=pharmacokinetic; PRR=placebo response reduction; 
SF-12=12-item Short Form Survey; WOMAC=Western Ontario and McMaster Universities Osteoarthritis Index 
a 
Vital signs will include body temperature, resting respiration rate, supine and standing systolic and diastolic blood pressure, and pulse rate. Blood pressure 
and pulse rate will be measured after the subject rests for 5 minutes in the supine position. The subject will then be asked to stand and blood pressure and 
pulse rate will be taken after standing for 1 minute and then again after 3 minutes. Subjects unable to stand may be assessed while sitting upright. The same 
position and arm should be used each time vital signs are measured for a given subject. 
b 
Height will only be measured at the Screening visit, and BMI will be calculated based on height and weight measurements at Screening. Weight will also be 
measured at any unscheduled visit. 
c 
A single 12-lead ECG will be performed at Screening, at Baseline (Week 0) both predose and at 1 hour postdose (the first dose of the day), Week 1, Week 2, 
and EOT/ET. A 1-hour window is permitted for the predose ECG and a 20-minute window is permitted for the postdose ECGs. Electrocardiograms should 
be performed before blood sampling or at least 30 minutes after blood sampling.  
d 
A full chemistry (CHEM) panel of clinical laboratory tests will be completed, excluding glucose and the CHEM tests noted in Section 6.5.5 to only be 
performed at Screening. 
e 
Applicable to women of childbearing potential. A serum pregnancy test should be performed at Screening and a urine test must be performed at all other 
designated visits. 
f 
At Baseline, urine drug screen will be performed using a dipstick test which must be negative for any non-permitted medications or drugs in order for the 
subject to continue in the study.  
g 
COVID-19 diagnostic PCR test at Screening. 
 
h 
Randomization visit cannot occur until there is confirmation from the central reader that there are no exclusionary findings. 
i 
Subjects will be instructed on the use of and will complete electronic clinical outcome assessments using handheld devices during the study. An eDiary, will 
be used to record pain scores, compliance with ingestion of study medication, and use of rescue medication.  
j 
A PK sample (approximately 4 mL) should also be taken from subjects who experience SAEs or AEs leading to discontinuation, as soon as possible after the 
occurrence of the event. 
k 
A predose PK blood sample must be collected before administration of study drug. A postdose PK blood sample will be collected at the end of ECG 
assessment approximately 1 hour after study drug administration. 
l 
PK samples at Visits 5, 6, and 8 will be collected at one of the following time intervals: 1) 2-5 hours after morning dosing OR 2) 6-9 hours after morning 
dosing OR 3) 10-12 hours after morning dosing. Every effort should be made to collect the PK samples at distinct time intervals during Visits 5, 6, and 8. 
However, if the interval is the same across these visits, then the collection time should vary within that interval.  
m 
Pain intensity assessments are to be recorded in the evening during the Baseline Assessment Period and prior to their 4th dose of the day during the 
Double-blind period. Subjects will be rating both the average daily pain as well as their worst daily pain. At the Safety Follow-up Clinic Visit (7 days after 
EOT), subjects will rate both the average daily pain as well as their worst daily pain over the past week and the data will be entered into EDC. 
n 
At study visits, PGIC, WOMAC, and BPI-sf should be performed before blood sample collection, ECG, and other procedures. 


Protocol ACP-044-005 
Version 1.0 
Statistical Analysis Plan 
 
21 September 2022 
 
 
                                   Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.   
 
Page 43 of 44 
o 
Participant Scorecard is viewed by the subject and reviewed by the Investigator at the designated study visits. The Investigator or designee, will 
acknowledge the scorecard review on the training platform, aLearn. 
p 
ASR and PPR training at Visits 5, 6, and/or 8 is on an as needed basis and the need for training will be determined by Participant Scorecard intervention 
recommendations. 
q 
Record rescue medication use in eDiary. 
r 
The Investigator may perform any additional evaluations deemed to be clinically indicated. If an unscheduled visit is required for safety reasons, a 12-lead 
ECG and all appropriate clinical laboratory tests are to be performed. 
 
 


Protocol ACP-044-005 
Version 1.0 
Statistical Analysis Plan 
 
21 September 2022 
 
 
                                   Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.   
 
Page 44 of 44 
Appendix B Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original Version 
 
21 September 2022