EN20-01: A 24 Week Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Moderate to Severe Knee Osteoarthritis Pain.
Phase: PHASE2
Conditions: Knee Osteoarthritis
Sponsor: Maurizio Fava, MD

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EN20-01: A 24-WEEK STUDY TO EVALUATE THE SAFETY AND EFFICACY OF CNTX-6970 
IN SUBJECTS WITH MODERATE TO SEVERE KNEE OSTEOARTHRITIS PAIN. 
 
 
 
● Version: 9.0 22Jan2024 
 
● Amendment number(s) and date(s): 2.3 17Jun2021; 3.0 21Jul2021; 4.0 26Aug2021; 4.1 31Aug2021; 5.0 
02Sep2021; 5.1 13Sep2021; 5.2 22Sep2021; 5.3 04Jan2022; 6.0 15Apr2022; 7.0 23Sep2022 , 8.0 
19May2023, 8.1 18Jul2023, 8.2 04Oct2023, 9.0 22Jan2024 
 
 
● FDA IND#:  157811 
 
● NCT05025787 
 
 
 
 
 
Maurizio Fava, MD (Sponsor-Investigator) 
Psychiatrist-In-Chief 
Director, Division of Clinical Research of the MGH Research Institute  
Executive Director, Clinical Trials Network and Institute (CTNI) 
Massachusetts General Hospital (MGH) 
 
55 Fruit Street, Bulfinch 351 
Boston, MA 02114 
 
Robert Edwards, PhD (PPI) 
Associate Professor of Anesthesia, Pain Management Center 
Brigham and Women’s Hospital 
850 Boylston Street 
Chestnut Hill, MA 02467 
 
Thaddeus Tarpey, PhD (Statistician) 
Professor & PhD Program Director 
NYU Grossman School of Medicine 
180 Madison Avenue, 4th Floor, Suite 4-53 
New York, New York 10016 
 

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EPPIC-Net Clinical Coordinating Center Key Contacts 
 
Address:  
MGH Clinical Trials Network and Institute 
  
 
1 Bowdoin Square, 9th Floor 
 
 
Boston, MA 02114 
 
 
Study Contact/Project Manager: 
Name:  
Allison Campbell 
Email:  
acampbell17@mgh.harvard.edu    
Phone: 
(781) 422-4120 
 
Study Contact/Site Manager: 
Name:  
Megan Bubello 
Email:  
mbubello@mgh.harvard.edu  
 
 
Medical Monitor: 
Name:  
Mark Matza, MD 
 Email: 
mmatza@mgh.harvard.edu 
 
 
Lead Clinical Research Associate (CRA)/Monitor: 
Name:  
Miranda Williams, MS 
Email:  
MWilliams93@mgh.harvard.edu   
Phone: 
(863) 276-1178 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol/Amendment Signature Page 
Electronically Signed 21 CFR Compliant 
  
 
 
 
 
 
 
V9.0 22Jan2024 
 
Signatory of Protocol/Amendments: 
Name:  
Maurizio Fava, MD 
 
Signature: 
 
 
 
 
 
Signatory of Protocol/Amendments: 
Name:  
Robert Edwards, PhD 
 
Signature: 
 
 
 
 
 
 
Signatory of Protocol/Amendments: 
Name:  
Thaddeus Tarpey, PhD 
 
Signature: 
 
 

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TABLE OF CONTENTS 
 
Background and Introduction ............................................................................................................................... 8 
A.1. Preclinical Experience ............................................................................................................................................ 9 
A.2. Clinical Experience ............................................................................................................................................... 11 
A.1.1. 
First in Human Study: Single-Ascending Dose in Healthy Males ........................................................ 11 
A.1.2. 
Single- and Multiple-Ascending Dose in Healthy Subjects ................................................................. 11 
 
Study Rationale ................................................................................................................................................... 12 
 
Study Objectives ................................................................................................................................................. 13 
C.1. Primary Objective ................................................................................................................................................ 13 
C.2. Secondary Objective ............................................................................................................................................ 13 
C.3. Tertiary Objective ................................................................................................................................................ 14 
C.4. Note on Previous Protocol Versions .................................................................................................................... 15 
 
Study Design ....................................................................................................................................................... 15 
D.1. Overview.............................................................................................................................................................. 15 
D.2. Study Endpoints ................................................................................................................................................... 16 
D.1.1. 
Primary Safety Endpoint ..................................................................................................................... 16 
D.1.2. 
Primary Efficacy Endpoint ................................................................................................................... 16 
D.1.3. 
Secondary Endpoints .......................................................................................................................... 16 
 
Study Population ................................................................................................................................................. 17 
E.1. Recruitment Feasibility ........................................................................................................................................ 17 
E.2. Number of Subjects ............................................................................................................................................. 18 
E.3. Nature of Populations .......................................................................................................................................... 18 
E.4. Subject Eligibility .................................................................................................................................................. 18 
E.4.1. 
Inclusion Criteria ................................................................................................................................. 18 
E.4.2. 
Exclusion Criteria ................................................................................................................................ 20 
E.5. Rationale for the Inclusion/Exclusion Criteria ..................................................................................................... 23 
 
Study Assessments – Plan and Methods ............................................................................................................ 24 
F.1. Study Conduct ...................................................................................................................................................... 24 
F.1.1. 
Table 1: Schedule of Events ................................................................................................................ 24 
F.1.2. 
Study Assessment Overview ............................................................................................................... 30 
F.1.3. 
Screening Period (two – four weeks) .................................................................................................. 30 
F.1.4. 
Re-Screening ....................................................................................................................................... 34 
F.1.5. 
Visit 1 – Baseline (Day 0) ..................................................................................................................... 34 
F.1.6. 
Randomization .................................................................................................................................... 36 
F.1.7. 
Visit 2 (Week 3) ................................................................................................................................... 37 
F.1.8. 
Visit 3 (Week 6) ................................................................................................................................... 38 

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F.1.9. 
Visit 4 (Week 9) ................................................................................................................................... 39 
F.1.10. 
Visit 5 (Week 12) ................................................................................................................................. 40 
F.1.11. 
Visit 6 (Week 15) ................................................................................................................................. 41 
F.1.12. 
Visit 7 (Week 18) ................................................................................................................................. 42 
F.1.13. 
Visit 8 (Week 21) ................................................................................................................................. 43 
F.1.14. 
Visit 9 (Week 24 or Early Termination) ............................................................................................... 44 
F.2. Procedures ........................................................................................................................................................... 45 
F.2.1. 
Laboratory/Diagnostic Procedures ..................................................................................................... 45 
F.2.2. 
Blood and Synovial Fluid Biomarkers (Cytokines and Chemokines) ................................................... 49 
F.2.3. 
Biobanking – Blood and Stool Repository for Future Use .................................................................. 50 
F.2.4. 
Protocol Patient Measures ................................................................................................................. 50 
F.2.5. 
NIH HEAL Initiative Common Data Elements (CDEs) .......................................................................... 51 
F.2.6. 
Blinding Procedures ............................................................................................................................ 53 
F.2.7. 
Safety Measures ................................................................................................................................. 53 
F.3. Discontinuation .................................................................................................................................................... 54 
F.3.1. 
Discontinuation of Subjects ................................................................................................................ 54 
F.3.2. 
Discontinuation of Subjects who Stopped taking Study Medication ................................................. 55 
F.3.3. 
Discontinuation of Study .................................................................................................................... 56 
F.4. Specification of Safety Parameters ...................................................................................................................... 57 
F.4.1. 
Definition of an Adverse Event ........................................................................................................... 57 
F.4.2. 
Definition of Serious Adverse Events .................................................................................................. 58 
F.4.3. 
Definition of Life-Threatening ............................................................................................................. 58 
F.4.4.. 
Definition of Hospitalization ............................................................................................................... 58 
F.4.5. 
Definition of Disability or Permanent Damage ................................................................................... 59 
F.4.6. 
Definition of Medically Significant ...................................................................................................... 59 
F.4.7. 
Classification of an Adverse Event ...................................................................................................... 59 
F.4.8. 
Reporting Procedures ......................................................................................................................... 61 
F.5. Protocol Deviations and Violations ...................................................................................................................... 64 
 
Treatment ........................................................................................................................................................... 64 
G.1. Dosing Schedule .................................................................................................................................................. 64 
G.2. Study Drug Packaging, Labeling and Administration .......................................................................................... 64 
G.3. Study Drug Receipt, Accountability, and Storage Conditions ............................................................................. 65 
G.4. Possible Drug Interactions ................................................................................................................................... 66 
G.5. Analgesic and Rescue Medications ..................................................................................................................... 67 
G.6. Concomitant Medications ................................................................................................................................... 67 
G.6.1. 
Prohibited Medications ...................................................................................................................... 67 

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Ethical Considerations ........................................................................................................................................ 68 
H.1. Risk/Benefit Assessment ..................................................................................................................................... 68 
H.2. Safety ................................................................................................................................................................... 68 
H.2.1. 
CNTX-6970 .......................................................................................................................................... 68 
H.3. Informed Consent ................................................................................................................................................ 68 
H.4. IRB Review ........................................................................................................................................................... 69 
 
Data Handling and Recordkeeping ..................................................................................................................... 69 
I.1. New England Survey Systems (NESS) NEForm ...................................................................................................... 69 
I.2. Completion of EDC Forms ..................................................................................................................................... 70 
I.3. Procedure for Corrections .................................................................................................................................... 70 
I.4. Record Retention .................................................................................................................................................. 70 
I.5. Data Confidentiality .............................................................................................................................................. 70 
I.5.1. 
Certificate of Confidentiality ............................................................................................................... 70 
 
Monitoring and Oversight ................................................................................................................................... 71 
J.1. Evaluation of Study Sites ...................................................................................................................................... 71 
J.2. Initiation of Study Sites ......................................................................................................................................... 71 
J.3. Periodic Monitoring Visits .................................................................................................................................... 71 
J.4. Risk-Based Monitoring.......................................................................................................................................... 72 
J.5. Suspension and Early Termination of a Site ......................................................................................................... 72 
J.6. Direct Access to Source Data/Documents ............................................................................................................ 72 
J.7. Interim Analysis .................................................................................................................................................... 72 
J.8. Medical Monitoring .............................................................................................................................................. 72 
J.8.1. 
Urgent Clinical Situations .................................................................................................................... 73 
J.9. The Data and Safety Monitoring Board (DSMB) ................................................................................................... 73 
J.10. The Central IRB (Advarra) ................................................................................................................................... 74 
 
Data Analysis ....................................................................................................................................................... 74 
K.1. General statistical considerations ........................................................................................................................ 74 
K.2. Hypothesis testing ............................................................................................................................................... 75 
K.3. Exploratory analyses ............................................................................................................................................ 76 
K.4. Sample Size .......................................................................................................................................................... 77 
 
Publication Policy ................................................................................................................................................ 78 
 References .......................................................................................................................................................... 79 
 
Investigator Statement ....................................................................................................................................... 84 
 
Appendices ......................................................................................................................................................... 85 
Appendix I: BLINDED INFORMATION .......................................................................................................................... 85 
Appendix II: Cytokines & Chemokines (from the Inflammation MAP Multiplex panel): ............................................ 86 

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Appendix III: Concomitant Medications ..................................................................................................................... 87 
Appendix IV: Amylase and Lipase Normal Ranges_12Jan2024 .................................................................................. 95 
Appendix V: Glossary .................................................................................................................................................. 98 
 

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 BACKGROUND AND INTRODUCTION 
Chemokines are small chemotactic peptides that control the trafficking of leukocytes, and in particular 
monocytes, to their target tissue. Chemokine receptors (CCRs, CXCRs, or XCRs) form a growing family 
of receptors (CCR1 up to CCR10, CXCR1 up to CXCR7, CX3CR1, XCR1, etc.) (Hughes and Nibbs, 2018). 
Most of the receptors have several ligands, and therefore show considerable cross-talk and redundancy, 
making pharmacological intervention challenging. The study drug, CNTX-6970, is a highly selective CCR2 
and CCR5 antagonist (Centrexion Investigator’s Brochure, 2019); it is not an antagonist of chemokine 
receptor subtypes CCR3, CCR7, or CXCR4. This property makes it appealing as a targeted treatment for 
persistent pain conditions characterized by inflammatory processes. The main ligand of CCR2 is 
interchangeably called chemokine ligand-2 (CCL2), or monocyte chemoattractant protein 1 (MCP-1) 
(Koelink et.al, 2012). The endogenous ligand for the CCR5 receptor or RANTES is regulated upon 
activation, normal T-cell expressed, and secreted (Koelink et.al, 2012). The pharmacological effect of 
CNTX-6970 is expected to come primarily from blockade of CCR2, although higher concentrations will 
also inhibit CCR5 as demonstrated in the Phase 1 single ascending dose (SAD) study in ex vivo assays. 
Preclinical data suggest that CCR2 and MCP-1 are upregulated in cells responsible for the modulation of 
pain signals in peripheral nerves, dorsal root ganglia, dorsal horn of the spinal cord, and microglia (Bhangoo 
et al, 2007, White et al, 2009). Similar observations have been made for CCR5 in animal models of 
neuropathic pain (Matsushita et al, 2014).  The MCP-1/CCR2 axis appears also to play a role in the signaling 
of pain at the level of the joint.  
In mild and moderate osteoarthritis (OA), which is both quite common and highly disabling, the symptom 
of pain is the major contributing factor to functional impairment (Hunter et al, 2019).  With an aging and 
increasingly obese population, this condition is becoming even more prevalent than in previous decades 
(Hunter et al, 2019). The expectation is that CCR2 antagonism will not only reduce pain, but also lead to 
improvement of function, and thus be relevant for treating signs and symptoms of OA. Therefore, pain and 
function will be the primary therapeutic targets in this development program. The leading symptom of OA 
is chronic pain with acute flares, particularly activity-related flares (Parry et al, 2017).  CNTX-6970 has 
been shown to be effective in several animal models of OA, as demonstrated by increased tolerance of 
weight bearing in an experimentally injured knee or paw. These models may indicate analgesic effects and 
impact on function. On the other hand, no effect of CNTX-6970 on pain thresholds in healthy tissues, or on 
models of acute pain, have been observed, supporting the view that it will not interfere with protective pain 
reflexes and sensation of heat. 
Based upon the underlying pathophysiology, two main types of pain can be distinguished: neuropathic pain 
and nociceptive/inflammatory pain. The most pronounced effects of CNTX-6970 pertain to 
nociceptive/inflammatory pain, which is mediated by pain receptors (nociceptors) that activate afferent 
somatic or visceral pain pathways via afferent nerves. Chronic somatic nociceptive/inflammatory pain 
conditions include OA and rheumatoid arthritis (RA). While the symptoms of inflammation seem to be the 
primary cause and are most pronounced in RA, they are clearly important as well in most patients with OA. 
As it is unclear whether CNTX-6970 will result in relevant systemic anti-inflammatory effects in RA 
patients, OA is most suitable for initial evaluation of symptomatic treatment with CNTX 6970. 
The hallmark of OA is the damage and eventual loss of articular cartilage (Hunter et al, 2019) However, 
this damaged tissue is both aneural and avascular, making it an unlikely source of pain. Recent advances in 

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the understanding of OA have led to an appreciation that this disease involves all tissues of the synovial 
joint, not just the articular cartilage itself. Pain is likely generated in neurovascularized tissues within the 
joint, in particular the synovium and other soft tissues surrounding the joint (capsule, tendons, ligaments, 
muscles, and subchondral bone) (MacDonald et al, 2018). Although pain is considered the main source for 
functional impairment, it does not necessarily correlate well with degeneration and loss of function. At end 
stage degeneration, pain can be less pronounced, and functional impairment due to mechanical reasons is 
the leading symptom. Additionally, psychosocial comorbidities such as depression and anxiety commonly 
accompany chronic pain and can affect both the pain perception and tolerance thresholds. Additional 
biopsychosocial factors and personality traits may also contribute to perception of pain, which suggests that 
comprehensive phenotyping and careful selection of patients should be important components of 
osteoarthritis trials. This multifaceted pain matrix in OA (Read et al, 2008) may explain the limited effect 
sizes that common analgesics show, and open opportunities for individualized pharmacological approaches. 
Given that the pathophysiology of OA is poorly understood, there are currently no curative or disease-
modifying treatments approved for patients who are not yet at a stage of their condition at which total joint 
replacement is being considered. Overall, there are a few compounds and nutraceuticals for which there is 
questionable evidence of disease-modifying properties, highlighting the need for novel effective treatments 
in patients with this painful condition. 
The MCP-1/CCR2 axis appears to play a role in the egress of macrophages from the bone marrow to the 
periphery, in addition to the recruitment of macrophages to the site of inflammation (Tsou, 2007).  This role 
is supported by the clinical data from other CCR2 antagonists (Kalliomaki et al, 2013a; Kalliomaki et al, 
2013b). In toxicological testing of CNTX-6970 in rats, decreases in peripheral monocytes were observed. 
It is therefore likely that CNTX-6970 will show a similar effect in humans in clinical testing. Nonclinical 
evidence points to a role of CCR2 in the defense against microbial pathogens (Serbina et al, 2008).  
However, the clinical relevance of a CCR2 antagonist mediated reduction in peripheral monocyte count 
may be limited in the absence of impaired monocyte function. Importantly, activity is dependent on a 
mechanism that does not require penetration into the central nervous system. 
CCR2 antagonism has not been associated with any of the known safety issues of nonsteroidal anti-
inflammatory drugs (NSAIDs). One of the appealing features of CNTX-6970 is that it does not significantly 
cross the blood brain barrier and therefore is not expected to have any of the central nervous system side 
effects associated with opioids and many other analgesics.  Importantly the liability for addiction is very 
low.   
Although the pharmacological effect of CNTX-6970 is expected to come primarily from blockade of CCR2, 
at higher concentrations, CNTX-6970 also exhibits CCR5 antagonism (Centrexion Investigator’s Brochure, 
2019), which may contribute to some degree to its putative analgesic effects. 
A.1. Preclinical Experience 
A comprehensive summary of the pharmacology, absorption, distribution, metabolism and excretion, 
toxicology, and nonclinical experience with CNTX-6970 to date is provided in the Investigator’s Brochure 
(2019). 
CNTX-6970 is a highly selective antagonist for CCR2 from humans, rats, and monkeys. CNTX 6970 is 
also an antagonist to human and monkey CCR5, but with a higher inhibitory constant (Ki).  CNTX-6970 is 

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not an effective CCR5 antagonist in the rat. However, in the toxicology program, concentrations exceeded 
the rat Ki at the no observed adverse effect level (NOAEL).  Therefore, risks associated with CCR5 binding 
were covered with the high doses in the rat toxicology program. 
In rat models of pain varied with the model and was achieved in the dose range of 1 to 30 mg/kg.  In models 
of inflammatory or neuropathic pain, the minimum effective doses were in the range of 1 to 10 mg/kg. 
No relevant off-target pharmacological effects have been identified within the effective dose range. There 
was no evidence of a proarrhythmic risk of CNTX-6970 based on human Ether-à-go-go-related gene or 
papillary muscle studies. QTc prolongation was reported in the monkey at 250 mg/kg, but not at 50 mg/kg 
(maximum plasma concentration [Cmax] 5.67 µg/ml). 
CNTX-6970 is a moderate clearance compound (17 to 34 ml/min·kg) with a high volume of distribution in 
rats and monkeys (4 to 6 L/kg). Oral bioavailability was high in female rats (95%) and monkeys (62%) and 
moderate in male rats (34%). 
CNTX-6970 shows a moderate to low (~67 to 89%) binding to mouse, rat, cynomolgus monkey, and human 
plasma proteins. 
CNTX-6970 was predominantly metabolized by CYP2C9 with a minor contribution of CYP3A4. Drug-
drug interactions (DDIs) resulting from inhibition of transporters or cytochrome P450s (CYPs) are unlikely 
to occur in humans; the mean Cmax in humans after a single oral dose of 300 mg is at least 30-fold lower 
than the half maximal inhibitory concentrations for the transporters studied and the Ki for CYP2C9 
inhibition (Ki = 29.9 µM). 
In rats, CNTX-6970 was the dominant drug-related species in plasma, urine, feces, and bile. The major 
route of excretion for parent and metabolites was via bile and feces; urinary excretion only accounted for 9 
to 18% of the administered dose. 
In male and female rats, CNTX-6970 (20 mg/kg, 75 mg/kg, or 300 mg/kg) was given orally once daily 
(QD) for 4 weeks to assess toxicity and reversibility (4 weeks). At 300 mg/kg, gastric erosions and 
gastroesophageal reflux with lesions in the upper respiratory tract were considered related to the irritant 
potential of the test article. Foam cell aggregates (consistent with phospholipidosis) were identified in the 
gastrointestinal tract, liver, lungs, and mesenteric lymph nodes at 300 mg/kg. These changes were fully 
reversible with the exception of foam cell aggregates in the lungs of females. The NOAEL was 75 mg/kg 
where the mean Cmax was 3.97 and 6.61 µg/ml in males and females, respectively, and the mean area under 
the plasma concentration time curve (AUC) to the 24-hour time point (AUC0-24hr) was 15.8 and 32.6 
µg·hr/ml in males and females, respectively, on Day 28. 
In male and female monkeys, CNTX-6970 (10 mg/kg, 50 mg/kg, or 500/250 mg/kg) was given orally QD 
for 4 weeks to assess toxicity and reversibility (4 weeks). In the high-dose group (500 mg/kg), morbidity 
leading to euthanasia of 2 monkeys was caused by marked renal toxicity; following an off-dose period of 3 
days, there was a dose reduction to 250 mg/kg on Day 15 in the remaining monkeys in this group. 
Generalized dermal exfoliation was apparent in this group from Week 3 onwards and resolved after 3 weeks 
without treatment. Reversible increased neutrophil counts were recorded in individual high-dose animals 
after 4 weeks as well as individual increases in urea nitrogen and creatinine, perturbations in electrolytes, 
decreases in albumin, and increases in hepatic transaminases. Histologically, minimal tubular casts were 

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observed in 1 female at 4 weeks and minimal tubular degeneration/regeneration was noted in 1 male after 
the recovery period. Foamy macrophages were present in various lymphoid tissues (spleen, thymus, lymph 
nodes, gut-associated lymphoid tissue, sternal bone marrow, and jejunum), but were not seen in any tissues 
from recovery animals. Reversible epidermal hyperplasia and hyperkeratosis correlated with dermal 
exfoliation. No toxicity was observed in the lower dose groups. The NOAEL of 50 mg/kg CNTX-6970 was 
associated with combined gender mean Cmax of 6.18 µg/ml and a mean AUC0-24hr of 20.5 µg·hr/ml on 
Day 28. 
Genotoxicity, phototoxicity, and human epidermal irritation studies were all negative. 
A. 2. Clinical Experience 
CNTX-6970 has been evaluated in two Phase 1 studies in healthy volunteers. 
A.2.1 First in Human Study: Single-Ascending Dose in Healthy Males 
The first in human study was entitled: “Safety, tolerability and pharmacokinetics of single rising oral doses 
of CNTX-6970 (BI 416970) in healthy male volunteers in a partially randomized, single-blind, placebo-
controlled trial.” 
The objective of this study was to investigate the safety, tolerability, and pharmacokinetics (PK), including 
dose proportionality, of a single ascending dose (SAD) of 10mg, 25mg, 50mg, 100mg, 200mg, 400mg, or 
600mg of CNTX-6970 in 60 healthy male subjects. 
Results:  In total, 11 subjects (18.3%) reported adverse events (AEs) during the on-treatment period of the 
study. No dose-related trends were apparent for any AE and no major difference was observed when 
compared with placebo. No serious adverse events (SAEs) and no AEs leading to study discontinuation 
occurred. 
No clinically relevant findings in laboratory evaluations, physical examinations, vital signs, or 
electrocardiogram (ECG) measurements were reported.   
A.2.2. Single- and Multiple-Ascending Dose in Healthy Subjects 
The second Phase 1 study (CNTX-HV-102) was entitled: “A placebo-controlled, two-part study with single 
dose and multiple ascending oral dose to evaluate the safety, pharmacokinetics, and pharmacodynamics of 
CNTX-6970 in healthy subjects.”  
This was a two-part study with a primary objective to evaluate the safety, PK, and PD of CNTX 6970 
following repeated daily doses, and to determine if any age, sex, food, or formulation effects exist. 
The first part of the study evaluated the effects of food on single doses of enteric coated 100-mg tablets of 
CNTX-6970. This part of the study also evaluated the effect of enteric or film coating on the absorption and 
PK of the 100-mg dose of the drug in healthy subjects. 
The second part of the study evaluated the safety, PK, and PD of repeated doses of 100-mg, 300-mg, and 
600-mg tablets administered once daily (QD), and 300-mg tablets administered twice daily (BID) for 10 
days. The impact of age and sex on the PK of CNTX-6970 following repeated doses was also studied. 

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The PD measures in this study included the effects of repeated doses of CNTX-6970 on selected target 
systems (CCR-2 binding on CD14+ cells and CCR-5 binding on CD4+ cells) and the effects of repeated 
doses of CNTX-6970 on peripheral monocyte counts. 
Results:  No subjects experienced an SAE or AE that led to discontinuation from the study. There were no 
deaths in the study. There were no clinically meaningful changes from baseline in laboratory parameters, 
12-lead ECGs, or physical examination findings observed in the study.  
MCP-1/CCR-2 receptor binding inhibition by CNTX-6970 was observed to be concentration-dependent. 
Based upon the PD maximum effect, the greater extent of MCP-1/CCR-2 binding inhibition was observed 
as the dose increased in the once daily cohorts on both Day 1 and Day 10. Correspondingly, the PD area 
under the concentration-time curves (AUCs) increased as the dose increased. 
The mean inhibition on Day 1 was 80% for Cohort 3 (100 mg, once daily), 89% for Cohort 4 (300mg, QD), 
94% for Cohort 5 (600mg, QD), 90.6% for Cohort 6 (300mg, BID), and 91% for Cohort 7 (300mg, QD 
[elderly group]). The mean inhibition for the pooled placebo group was 8.9%. 
As expected, the RANTES/CCR-5 receptor binding inhibition by CNTX-6970 was not as robust as the 
CCR-2 inhibition. The mean inhibition on Day 1 was 45.6% for Cohort 3 (100mg, QD), 79% for Cohort 4 
(300mg, QD), 82% for Cohort 5 (600mg, QD), 89.6% for Cohort 6 (300mg, BID), and 72.7% for Cohort 7 
(300mg, QD [elderly group]). The mean inhibition for the pooled placebo group was 3.4%. 
Collectively, the results of these Phase I studies suggest that CTNX-6970 shows a favorable safety profile, 
produces minimal adverse events, and demonstrates substantial inhibition of the binding of monocyte 
chemoattractant protein-1 to its CCR-2 receptor in a concentration-dependent fashion across a range of 
daily doses.  
 STUDY RATIONALE 
CNTX-6970, a novel potent antagonist of CCR2 with lesser effects on CCR5, is being developed as a new 
treatment for chronic pain, including painful osteoarthritis of the knee. Preclinical studies with CNTX-6970 
demonstrate potent analgesia in multiple pain models including the CFA model of inflammatory pain, the 
MIA model of osteoarthritis pain, and the PNL model of nerve injury pain. In addition, the Phase 1 clinical 
studies have demonstrated excellent and dose-proportional target engagement and there have been no 
emergent safety issues observed in the SAD and MAD trials. CCR2 antagonists are under development for 
multiple 
indications 
including 
cancer, 
autoimmune 
disorders, 
atherosclerosis, 
stroke, 
and 
neurodegenerative diseases (Fantuzzi et al, 2019). The rationale for developing CNTX-6970 for the 
management of painful OA stems from mechanisms directly related to the affected joint as well as effects 
on neural signaling.  
The dose selected for this Phase 2 trial is based on the findings from the Phase 1 studies detailed above. A 
dose of 300mg BID demonstrated good tolerability and safety, as well as over 90% inhibition of the binding 
of monocyte chemoattractant protein-1 to its CCR-2 receptor. Moreover, this dose produced nearly 90% 
binding inhibition at the CCR-5 receptor as well.  
 

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 STUDY OBJECTIVES  
The first objective of this study is to evaluate the safety and efficacy of CNTX-6970 for the treatment of 
pain related to OA of the knee. One dose of CNTX-6970 will be tested, which has been previously studied 
in healthy volunteers. No adverse effects were noted during the short-term (10 days) administration of this 
dose. The dose studied in this investigation is 300mg BID. This objective is addressed by Aims 1 and 2.  
The second objective of this study is to evaluate the effects of  CNTX-6970 on general pain-related 
measures, such as physical and psychosocial functioning, as well as on biomarkers of pain and 
inflammation. This will offer a fuller efficacy profile of the CNTX-6970 dose, characterizing its effects on 
a wide range of patients’ experiences related to pain due to OA of the knee. This objective is addressed by 
Aims 3, 4, and 5.  
The third objective is to obtain deep phenotyping of the target population both prior to study enrollment, 
during treatment with the experimental agent, and during treatment with placebo and to identify moderators 
and mediators (mechanisms) of treatment effects, including biomarkers for treatment response. The features 
that we will assess include inflammatory markers in synovial fluid, inflammatory markers in plasma,  and 
daily assessments of patients’ pain and functioning.  This will allow us a) to study variability of 
characteristics associated with pain over time with active and placebo treatments as functions of CNTX-
6970; b) to evaluate the effect of CNTX-6970 on different features individually and jointly; and c) to 
discover biomarkers for treatment response by exploring the effects of the identified measures on the 
efficacy of CNTX-6970 evaluated under the first two objectives.  Combined with the first two objectives, 
this would move the field a step closer to personalized treatment and management of pain. This objective 
will be addressed by Aims 6 to 9. 
C.1. Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of 300mg BID CNTX-6970 for 
the treatment of pain related to OA of the knee compared to placebo. This objective will be accomplished 
through the following specific aims:  
Aim 1:  Assess the safety and tolerability of CNTX-6970 (300mg BID), and placebo.  
There will be no hypothesis testing under Aim 1. To achieve Aim 1, we will tabulate all AEs and SAEs and 
will classify them by severity and relatedness to treatment. We will estimate the frequency of AEs and 
SAEs in the active and placebo groups with point estimates and 95% CIs. Similarly, we will summarize 
relevant laboratory measures with appropriate estimates. 
Aim 2: Assess the efficacy of 300mg BID CNTX-6970 in comparison to placebo. The primary outcome 
measure used to assess efficacy will be patient-reported knee pain using the WOMAC Part A (Bellamy, et 
al., 1988).  
HYPOTHESIS 1. CNTX-6970 300mg BID will be more effective than placebo with respect to pain as 
measured by WOMAC-A (primary outcome measure). 
C.2. Secondary Objective 
The second objective of this study is to evaluate the effect of CNTX-6970 (300mg BID) on general pain-
related measures, including physical and psychosocial functioning, as well as biomarkers of pain and 
inflammation. This objective is addressed by the following specific aims:  

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Aim 3: Assess the efficacy of CNTX-6970 (300mg BID) in comparison to placebo with respect to 
secondary outcome measures related to OA on the knee: (a) WOMAC-C (function subscale) (Bellamy, et 
al., 1988); (b) Hospital Anxiety and Depression Scale (HADS) (Zigmond et al., 1983); (c) Patient Global 
Impression of Change (PGIC) (Kroenke et al., 2019); (d) PROMIS Sleep Disturbance Scale – 6A (Yu et 
al., 2011);  (e) Sleep Duration Question; and (f) Daily Knee Pain Intensity on a 0-10 Numeric Rating Scale 
(NRS). 
HYPOTHESIS 2: CNTX-6970 300mg BID will be superior to placebo with respect to symptoms measured 
by (a) WOMAC-C (function subscale); (b) Hospital Anxiety and Depression Scale (HADS); (c) Patient 
Global Impression of Change (PGIC); (d) PROMIS Sleep Disturbance Scale– 6A (Yu et al., 2011); (e) 
Sleep Duration Question; and (f) Daily Knee Pain Intensity on a 0-10 NRS. 
Aim 4: Assess the efficacy of CNTX-6970 (300mg BID) in comparison to placebo with respect to general 
outcomes of pain: (a) Pain Catastrophizing Scale –Short Form 6 (Sullivan et al., 1995); (b) PROMIS 
Physical Functioning Short-Form 6b (Schalet et al., 2016); (c) Patient Health Questionnaire – 2 item scale 
(PHQ-2) – Depression (Arroll et al., 2010); (d) Generalized Anxiety Disorder – 2 item scale (GAD-2) 
(Kroenke et al., 2007; Plummer et al., 2016); (e) Tobacco, Alcohol, Prescription medication, and other 
Substance use Tool (TAPS-1) (Gryczynski, et al., 2017); and (f) Opioid Use Questionnaire (OUQ).  
HYPOTHESIS 3: CNTX-6970 300mg BID will be superior to placebo with respect to outcomes measured 
by (a) Pain Catastrophizing Scale –Short Form 6; (b) PROMIS Physical Functioning Short-Form 6b; (c) 
Patient Health Questionnaire (PHQ) – Depression; (d) Generalized Anxiety Disorder – 2 item scale 
(GAD-2) and (e) Tobacco, Alcohol, Prescription medication, and other Substance use Tool (TAPS-1); 
and (f) Opioid Use Questionnaire.  
Aim 5: Assess the effect of CNTX-6970 (300mg BID) in comparison to placebo with respect to biomarkers 
of pain and inflammation: (a) Staircase-Evoked Pain Assessment; (b) serum and synovial fluid levels of 
chemokines and cytokines; and (c) synovial monocyte chemoattractant protein-1/CCR-2 receptor binding 
inhibition in blood and synovial fluid.  
 
HYPOTHESIS 4: Compared to placebo, CNTX-6970 300mg BID will result in greater improvement with 
respect to (a) Staircase-Evoked Pain Assessment; (b) serum and synovial fluid levels of chemokines and 
cytokines; and (c) synovial monocyte chemoattractant protein-1/CCR-2 receptor binding inhibition in 
blood and synovial fluid. 
C.3. Tertiary Objective 
The third objective of this study is to obtain deep phenotyping of the target population both prior to study 
enrollment and during treatment, and to identify biomarkers for treatment response. This objective will be 
accomplished through the following specific aims: 
Aim 6. If 300mg BID CNTX-6970 is more effective than placebo, evaluate the following characteristics of 
its effect: (a) onset of action; (b) carryover effect after treatment discontinuation.  
Aim 7. Identify biomarkers related to pain from OA of the knee and to response to treatment with CNTX-
6970 at 300mg BID. 
Aim 8:  Explore sociodemographic and clinical predictors of response to CNTX-6970. 

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C.4. Note on Previous Protocol Versions 
The design for previous protocol versions included two arms, 100 mg BID CNTX-6970 and Celecoxib (as 
an active comparator), that have been discontinued in this version of the protocol (n=22). The total number 
randomized overall will therefore be n=72 (up to 77) to include the discontinued arms.  These two arms 
were removed due to study drug supply issues and to aid recruitment feasibility.  The previous protocol 
stipulated that the analysis of data from these arms were to be analyzed separately and thus removal of these 
two arms does not impact the current study objectives (except one exploratory aim in the previous protocol 
versions did propose examining a possible dose response between the 100 mg and 300 mg CNTX-6970 
doses).   
The participants in these two arms will complete the trial and will be monitored for safety events.  A safety 
analysis for individuals in these two arms will be performed the same as for the 300 mg CNTX-6970 
arm.  For the efficacy objectives, exploratory analyses will be performed on the data from these two arms 
by computing summary statistics (e.g., means and standard deviations) comparing 100 mg CNTX-6970 to 
placebo (and comparing Celecoxib to placebo) for the different periods of the crossover study for the 
outcome measures.  Formal modeling of the data from these two arms will either not be possible or will 
provide only limited information due to the small sample size available in these two arms.  In the event that 
data becomes available from the biorepository samples from these two arms, that data will also be analyzed 
in an exploratory fashion. 
 
 STUDY DESIGN 
     D.1. Overview 
The study will employ a randomized, allocation-concealed, multicenter, placebo-controlled, multi-period 
crossover design (Schmid et al, 2018). This multi-period crossover randomized, controlled trial allows 
comparability and assessment of efficacy through repeated exposures within each subject to the active 
treatment and a control (placebo) in randomized sequence. Such multi-period crossover designs are ideal 
for treatments with rapid onset of action and short half-life such as the asset under study here. We have 
strived to minimize the complexity of this powerful design by using only 2 blocks with 2 periods each. The 
modest additional complexity of the proposed multi-period crossover design, compared to a parallel-groups 
design, is justified by the marked improvement in efficiency.  The gains in efficiency afforded by the multi-
period crossover design allow a substantial reduction in sample size without sacrificing statistical power.  
For example, our simulation experiments (with sample sizes ranging from 30 to 50, carryover effects 
ranging from 0 to 0.2, and an effect size of 0.4) indicated that the parallel design yields statistical power 
ranging from 0.20-0.25, whereas our proposed 2-block multi-period crossover design yields power ranging 
from 0.9-1.0. 
The trial will compare an active treatment vs. placebo. The study will employ a multi-period crossover 
design with two blocks. Each block will consist of two treatment periods with each period lasting 6 weeks.  
Treatment assignments (active drug versus placebo) will be randomized for each patient to the two periods 
within each block. The period length of 6 weeks was chosen based on several considerations:  (i) Most 
efficacious analgesic drugs demonstrate separation from placebo by 6 weeks; (ii) The decision to move 
CNTX-6970 forward to Phase 3 will require a clinically meaningful separation from placebo by 6 weeks; 
and (iii) In this Phase 2 study, implementing a treatment block longer than 6 weeks would make the overall 
design more challenging and burdensome by extending the duration of overall testing beyond 6 months.  

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In this study, the placebo will consist of inactive tablets identical to the active treatment tablets. Treatment 
assignments (active drug versus placebo) will be randomized for each patient to the two treatment periods 
within each block. (see Section F.1.6 for details about the randomization process; the unblinded 
randomization schema is available to unblinded study team members in Appendix I.  
This study is part of Early-Phase Pain Investigation Clinical Network (EPPIC-Net), under The Helping to 
End Addiction Long-termSM Initiative, or NIH HEAL InitiativeSM.  
D. 2. Study Endpoints 
D.2.1. Primary Safety Endpoint 
The primary safety endpoint is the incidence of treatment emergent adverse events (TEAEs), reported 
between the administration of study drug on Day 1 and the completion of the study at Week 24 or Early 
Termination. 
D.2.2. Primary Efficacy Endpoint 
The primary efficacy endpoint is pain in the index knee, measured weekly using the WOMAC-A (Pain 
subscale), (Bellamy et al, 1988). We will use the numerical rating scale version of the WOMAC-A, with 
the subject assessing each of 5 questions using an 11-point (0 to 10) scale; the total score is the sum of the 
individual item scores (range 0-50). A higher WOMAC-A score represents worse symptom severity.  
All WOMAC subscales show strong evidence of validity and reliability (Salafi et al, 2003), and are the 
most frequently used primary endpoints for OA trials because of their strong assay sensitivity (Jung et al, 
2018). Assessments during the last 2 weeks of each treatment period will be used to test the primary 
hypotheses in order to avoid possible carryover effects of unknown duration. All weekly measurements of 
WOMAC-A will be used to study the course of OA pain symptoms during treatment, including onset of 
action and carryover effects. 
D.2.3. Secondary Endpoints  
The following measures are considered secondary outcomes related to pain due to OA of the knee. They 
will be assessed at Baseline and at study visits through Week 24. See Section F.1.1 Schedule of Events for 
full description of procedure timepoints. The Daily Knee Pain Intensity on a 0-10 NRS which will be 
recorded daily the week prior to each study visit. For a full description of secondary endpoint scales and 
assessments, see Section F.2.4 and F.2.5. 
● Daily Knee Pain Intensity on a 0-10 Numeric Rating Scale (NRS).  
● WOMAC-C (Function subscale)  
● Hospital Anxiety and Depression Scale (HADS)  
● PROMIS Sleep Disturbance Scale – 6A **NIH HEAL Initiative CDE 
● Patient Global Impression of Change (PGIC) **NIH HEAL Initiative CDE 
The following measures are part of the NIH HEAL Initiative CDEs and are considered general pain-related 
outcomes. They will be assessed at Baseline and at Week 24/ET. For a full description of the CDE scales 
and assessments, see Section F.2.5. 
● Pain Catastrophizing Scale – Short Form 6  

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● PROMIS Physical Functioning Short-Form 6b  
● Sleep Duration Question.  
● Pain Health Questionnaire (PHQ) – Depression  
● Generalized Anxiety Disorder – 2 item scale (GAD-2)  
● Tobacco, Alcohol, Prescription medication, and other Substance use Tool (TAPS-1)  
● Opioid Use Questionnaire (OUQ)  
The following are physiological measures related to pain. They will be considered both as secondary 
outcomes and as potential biomarkers for pain and treatment response. For a full description of 
physiological pain scales and assessments, see Section F.2. 
● Staircase-Evoked Pain Assessment  
● Serum levels of cytokines and chemokines.  
● Monocyte chemoattractant serum protein-1(MCP-1)/CCR-2 receptor binding inhibition by CNTX-
6970  
● Synovial fluid levels of cytokines and chemokines. These will be assessed at the end of the first 
treatment period (week 6). A specific list is provided in Appendix II. 
● Monocyte chemoattractant protein-1 (MCP-1)/CCR-2 receptor binding inhibition by CNTX-6970 in 
synovial fluid. These will be assessed at the end of the first treatment period (week 6). 
 STUDY POPULATION 
This study is designed to evaluate changes in pain related to primary OA of the knee. Eligible subjects will 
have evidence of chronic knee OA with a history of moderate to severe pain in the designated index knee 
for a minimum of 6-months prior to Screening. Although this condition commonly affects multiple joints 
and subjects may have bilateral OA of the knee(s), the efficacy assessments will be conducted only on the 
index knee. 
E.1. Recruitment Feasibility 
Patients will be recruited through advertisement, as well as clinician referral and self-referral. Self-referred 
patients will call the study sites and will be screened over the phone by the study coordinators. Those 
deemed potentially eligible will be scheduled for a screening visit with one of the study physicians at the 
sites. Based on clinical and human subject protection considerations, a potential subject will, under no 
circumstance, be advised to taper his/her current medication regimen prior to the screening visit. 
Subjects will also be recruited through physician referral. Each site will recruit subjects via referral from 
primary care and specialty clinics from the communities surrounding each study site. Each site will utilize 
the experience of the MGH CCC to conduct outreach activities to community organizations, colleges, and 
other resources. Sites will regularly collaborate on strategies to recruit women and minorities, and sites will 
employ strategies specific to their local community, in ways that are culturally sensitive and specific to the 
local minority population. Retention will be enhanced with fair reimbursement (as deemed appropriate by 
the local IRB) for subjects’ time. Site specific recruitment details are located in each site’s recruitment plan. 

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E.2. Number of Subjects 
We expect to screen approximately 300 patients to randomize up to 55 patients.  
When the randomization target has been met, patients who have been screened but not yet randomized will 
be allowed to continue in the study unless they fail to meet randomization criteria. 
E.3. Nature of Populations 
Subjects must meet all of the following inclusion and none of the exclusion criteria (Section G.4.) to be 
eligible for participation in the study. 
Protocol waivers for eligibility will not be granted under any circumstances.  If, during the course of a 
subject’s post-randomization participation in the trial, it is discovered that the subject did not meet all 
eligibility criteria, the justification to allow the subject to continue in the trial will be made by the PPI, with 
medical input from the Medical Monitor and the site’s investigator(s), and will be documented in the 
patient’s record.  Whether or not the participant is allowed to remain in the trial, this will be reported as a 
major protocol deviation and not a waiver.  
E.4. Subject Eligibility 
E.4.1. Inclusion Criteria 
A subject will be eligible for study participation if they meet all of the following criteria: 
1. Individuals between 40 and 90 years of age (inclusive) at the time of the Screening Visit. 
2. Willing to use a mobile smart device during the study period. Individuals who do not have access 
to a mobile device will be provided with one for the duration of the study and trained in its use. 
3. Can understand the nature of the study and protocol requirements and is willing to comply with 
study drug administration requirements and discontinue prohibited concomitant medications before 
Baseline.  
4. Consents to participate in the study.  
a. Provides written informed consent using the current form approved by the institutional 
review board (IRB). 
5. Is capable of communicating with the site personnel, able to complete subject-reported outcome 
measures and can be reliably rated on assessment scales (in the opinion of the investigator).  
6. Radiography of both knees with a posterior-anterior, fixed-flexion view taken during the Screening 
visit.  The Index knee must show evidence of chronic OA with a K-L Grading Scale of 1, 2, 3, or 4. 
Such evidence will be provided by a central reading of the radiography of both knees from an expert 
radiologist of the CCC of EPPIC-Net.  
7. Moderate to severe pain in the Index knee associated with OA and stable for a minimum of 6 months 
prior to Screening in the opinion of the investigator. 
8. Confirmation of OA of the index knee: American College of Rheumatology (ACR) diagnostic 
criteria. 

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9. Subjects must have failed 2 or more prior therapies for knee OA pain. Failure is deemed to be 
inadequate relief in the opinion of the investigator. A knee OA pain therapy may be deemed to have 
been inadequate because of one or more of the following:   
a. Unacceptable adverse events (AEs) 
b. Inadequate response, or loss of response for chronic OA knee pain or 
o pain in the index knee was minimally improved, not improved, or was worse and/or 
o function, and/or stiffness in the index knee was minimally improved, not improved, 
or was worse 
c. Medical condition resulting in contraindication to the standard of care appropriate to the 
severity of the index knee OA pain. “Therapies” include, but are not limited to, each of the 
following: 
o   nonsteroidal anti-inflammatory drugs (NSAIDs) (including topical), opioids, 
duloxetine, other systemic therapy, intraarticular (IA) corticosteroids, IA 
viscosupplements 
o   physical therapy or bracing.   
10. A mid-to-high level summed pain score (0-50) for the Index knee on the WOMAC-A pain subscale, 
which will be completed by the subject every 3 days (+/-1 day window) during the Screening Period. 
Subject must complete at least 4 WOMAC-A pain subscales.  
Note: Criteria for pain intensity requirements are specified in Appendix I: Blinded Information. This 
is only available to unblinded study team members and will be assessed centrally. Additionally, 
eligibility per study pain intensity requirements will be confirmed by the CCC before a State, 
Assessibility, Face and Ecological Validity and the Rule of the 3 Ps [persistent, pervasive, 
pathological] (SAFER) interview is scheduled. 
11. Body mass index (BMI) of ≤ 40 kg/m2. 
12. Females are at least one of the following: 
a. Not of childbearing potential - defined as post-menopausal for at least 1 year, or surgically 
sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy); or 
b. Totally abstinent from heterosexual intercourse since the last menses before study drug 
administration; or 
c. Agree to concurrent use of at least two approved methods of birth control throughout their 
study participation. Approved methods of contraception are those that, alone or in 
combination, result in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly, listed below: 
1. Hormonal methods such as oral, implantable, injectable, or transdermal 
contraceptives for a minimum of 1 full cycle (based on the subject’s usual menstrual 
cycle period) before study drug administration. 
2. Intrauterine device (IUD) 
3. Barrier method (Condoms, sponge, cap, diaphragm with or without spermicidal 
jellies or cream) 
4. Withdrawal (coitus-interruptus) 
5. Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
6. Lactation amenorrhea method (LAM) 
7. Vasectomized partner (at least 3 months post-vasectomy) 
 

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13. Males are at least one of the following: 
a. Incapable of fathering a child – defined as surgical sterility (at least 3 months post-
vasectomy); or 
b. Totally abstinent from heterosexual intercourse beginning at study screening; or 
c. Agree to use of at least one of the following medically acceptable methods of birth control 
throughout their study participation:  
1. Barrier method (condoms, sponge, diaphragm).  
2. Male condoms with or without a spermicide coating are acceptable, as some women 
are allergic to spermicide. 
 
14. Willing and able to understand the study requirements, abide by the study restrictions, complete the 
study procedures, independently record responses on the pain scales and make daily/weekly entries 
using the NEForm (section K1), and independently communicate meaningfully with study 
personnel.  
15. Willing to refrain from illicit drug use during the study, and to have illicit drug testing at screening 
and at later time points, if illicit drug use is suspected during the study. Illicit drug use is defined as 
the use of any medication or substance that is prohibited by law and is outside the prescribed use of 
a medical professional (or equivalent), including medications that are prescribed but are not being 
used as prescribed.  
16. Complete the SAFER (State, Assessibility, Face and Ecological Validity and the Rule of the 3 Ps 
[persistent, pervasive, pathological]) interview, administered via teleconference by an MGH 
psychiatrist or psychologist, and receive a passing score which confirms pain history with knee OA 
medication history and a HADS score of <11 on both the depression and anxiety subscales.  
17. The End of Day Pain Ratings are completed on at least 5 days of the Screening Period.  
18. Patient-reported daily NRS (for average pain over the last 24 hours) meets the criteria specified in 
“Appendix I: Blinded Information” during the screening period. The algorithm is only available to 
unblinded study team members and will be assessed centrally. Additionally, screening NRS scores 
will be confirmed by the CCC before a SAFER interview is scheduled. 
E.4.2. Exclusion Criteria 
A subject will be excluded from the study if they meet any of the following criteria: 
1. Any form of joint replacement surgery (partial or total) of the index knee, or joint replacement 
surgery of the non-index knee within 12 months of Screening.  
2. Open surgery or arthroscopic surgery of the index knee/knee joint within 12 months of Screening. 
3. Any painful condition(s) of the index knee due to disease other than OA. For example, periarticular 
or referred pain involving the index knee, or from joint disease other than OA associated with the 
index knee. 
4. Other chronic pain anywhere in the lower extremities (e.g. hips, legs, feet) that is equal or greater 
in intensity or impairment than index knee pain. This includes radicular low back pain with radiation 
to the knee. 

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5. Secondary OA of the index knee due to acute or recurrent traumatic injury. 
6. Significant instability (e.g., cruciate ligament tear or rupture or previous repair) within the past 5 
years or current misalignment (>10 degrees varus or valgus) of the index knee.   
7. Documented history of neuropathic arthropathy in the knee. 
8. Imaging finding of bony fragmentation in the index knee (radiographic, computed tomography, or 
magnetic resonance imaging). 
9. Physical/occupational/chiropractic therapy for the lower extremities or acupuncture for the lower 
extremities within 30 days of Screening or need for such therapy during the study. 
10. Plans to have surgery, invasive procedures, or intra-articular (IA) injections of the index knee or 
procedure or surgery otherwise contraindicated for study participation while in the study. 
11. Use of pain medication (including non-steroidal anti-inflammatory drugs [NSAIDs]) less than 5 
days before Baseline or any time throughout the study, with the following exceptions (see Appendix 
III for additional information and MOP for maximum dosing and frequency): 
a. Concomitant Medications for Pain –  
i. Continuous use of one of the following medications prescribed for pain: tramadol, 
gabapentin, duloxetine, pregabalin, milnacipran, or tricyclic antidepressants that is:  
a. Chronic for at least 12 weeks; and  
b. At a stable dose for at least 4 weeks before Screening 
ii. Intermittent use of opioids that is: 
a. Ongoing for at least 4 weeks before Screening;  
b. At a frequency no more than 4 days/week; and 
c. Not be taken within 24 hours of a study visit 
 
iii. As needed use of acetaminophen 
iv. Continuous use of medical marijuana (or equivalent) that is chronic for at least 12 
weeks and at a stable dose for 4 weeks 
v. Topical creams (includes CBD topicals) 
a. Continuous use allowed if chronic and stable for at least 12 weeks 
b. Intermittent use allowed if at a frequency of no more than 4 days/week 
 
b. Concomitant Medications for Non-Pain Indications That May Impact Pain –  
i. Continuous use of medication for non-pain indications that are known to potentially 
impact pain, e.g. duloxetine for depression, that is at a stable dose for at least 12 
weeks prior to Screening. 
ii. Low-dose aspirin for the purposes of heart disease prophylaxis 
12. Corticosteroid injection in the index knee within 30 days of Screening (unless the injectable is a 
long-acting agent such as triamcinolone acetonide extended-release injectable suspension (Zilretta) 
in which case the injection cannot be within 90 days of screening)  
13. Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of Screening  

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14. Knee effusion requiring aspiration of the index or contralateral knee at time of screening. 
15. Radiofrequency ablation (RFA) of the knee within 6 months prior to Screening. 
16. Presence of any medical condition or unstable health status (including chronic or active infections) 
that, in the judgment of the investigator, might adversely affect the safety of the subject or the 
conduct of the study, or negatively affect the resulting data, including chronic conditions that are 
likely to alter the rate of healing or are likely to result in safety complications unrelated to the study 
medication, or significant compromise to key organ systems.      
17. Has a current malignancy or has received treatment for malignancy at any time within 5 years prior 
to Screening.  
a. History of resected basal cell carcinoma and squamous cell carcinoma of the skin is not 
exclusionary, so long as treatment is not currently ongoing.  
18. Ulcer or open wound anywhere in the region of the index knee. 
19. Clinically significant abnormal laboratory results at the Screening Visit (in the opinion of the 
investigator), or significant organ disease that would put the subject at undue risk or affect the ability 
of the subject to participate in the trial. 
20. Use of an investigational treatment, including investigational device(s), within 30 days of Screening, 
or 5 pharmacokinetic or pharmacodynamic half-lives (whichever is longer) or scheduled to receive 
such an agent while participating in the current study. 
21. Has any of the following characteristics: 
a. Active or historic substance use disorder within the previous year as defined by the 
Diagnostic and Statistical Manual for Mental Health Disorders, fifth edition, or  
b. Urine drug screen is positive for an illicit substance and subject is unable to provide a valid 
prescription from a medical professional.  
22. Has persistent moderate to severe depression or anxiety, as indicated by a score ≥ 11 on either 
subscale of the Hospital Anxiety or Depression Scale (HADS) at Screening. 
23. Female has a positive pregnancy test at the Screening or Baseline Visit, is planning to become 
pregnant, or is breastfeeding. 
24. Has ongoing litigation for workers’ compensation. 
25. Known diagnosis of long QT syndrome. 
26. Male has a QRS interval ≥120 ms and QTcF ≥460 ms OR female has a QRS interval ≥120 ms and 
QTcF ≥480 ms at Screening. 
27. Has moderate to severe congestive heart failure (New York Heart Association [NYHA] class III and 
class IV). 
28. Has a history of symptomatic cardiovascular disease. 
29. Current therapy with any immunosuppressive therapy, including corticosteroids (>5 mg/day of 
prednisone). 

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30. Moderate to severe hepatic impairment at the Screening Visit, as defined by any of the following:  
a. AST and ALT values that are ≥1.5 times ULN 
31. Moderate to severe renal impairment at the Screening Visit, as defined by either:  
a. An estimated glomerular filtration rate [eGFR] < 45 mL/min; or  
b. A serum creatinine level > 1.3 mg/dL. 
32. Use of CYP3A4 inhibitors (e.g., grapefruit juice, pantoprazole) or CYP3A4 inducers (e.g., 
omeprazole, carbamazepine, rifampin, St. John’s wort) within 7 days prior to the Baseline Visit. 
Please see Appendix III. Concomitant Medications.  
33. Use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole) or CYP2C9 inducers (e.g. 
carbamazepine, rifampin, St. John’s wort) within 7 days prior to the Baseline Visit.  Please see 
Appendix III. Concomitant Medications. 
34. Use of P-glycoprotein inhibitors (e.g., atorvastatin, azithromycin, carvedilol) within 7 days prior to 
the Baseline Visit or any time during study participation, unless taken for at least 3 months prior 
and at a stable dose for at least 1 month prior to the Baseline Visit. Please see Appendix III. 
Concomitant Medications.  
35. Is classified as a poor metabolizer via the CYP2C9 pathway as determined by genetic testing 
(CYP2C9 genotyping).  
36. Has clinically significant pulmonary disease such that chronic, daily use of medical treatment is 
required (e.g. COPD, asthma). 
37. Has any of the following blood counts: 
a. Monocyte count < 1 % of white blood cells (e.g., for WBC = 4,500/µL, exclude patient if 
monocyte count < 0.01 * 4,500 or 45/µL; for WBC = 11,000/µL, exclude patient if monocyte 
count < 0.01 * 11,000 or 110/µL) 
b. Platelet count, or 
i. Females (sex at birth): < 125,000/µL  
ii. Males (sex at birth): < 150,000/µL  
c. Hemoglobin: 
i. Females (sex at birth):  < 11.5 grams/dL  
ii. Males (sex at birth):  < 13.0 grams/dL  
E.5. Rationale for the Inclusion/Exclusion Criteria 
The main rationale for inclusion and exclusion criteria is to enroll Subjects who are generally in good health, 
with chronic pain related to stable clinical course of osteoarthritis of the index knee, and who will be able 
to participate in this study for the duration of 24 weeks. Subjects that show with renal or hepatic impairment 
or are poor CYP2C9 metabolizers are excluded for safety reasons. Subjects in this study must be able and 
willing to provide multiple assessments about their pain and function at home via smartphone using the 
New England Survey Systems (NESS) app and via tablet at the time of in-person clinic visits. Individuals 
without a smartphone can be lent one from NESS. 
 
 

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 STUDY ASSESSMENTS – PLAN AND METHODS 
F.1. Study Conduct 
Table 1: Schedule of Events 
Study Phase  
Screening  
Period 
Baseline 
(Day 0) 
Clinic Visits scheduled every 3 weeks (+/- 4 days) 
 
(14-28 days 
before 
Baseline) 
Study Week 
Screen 
Visit 
Screen 
Period 
Wk 0 
Wk    
0-3 
Wk 3 Wk 
3-6 Wk 6 Wk  
6-9 Wk 9 Wk   
9-12 Wk 12 Wk 
12-15 Wk 15 Wk  15-
18 
Wk 18 Wk  
18-21 Wk 21 Wk  
21-24 
Wk 24 
Final 
Visit/ET1 
Study Visit  
Screening  
Period 
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
 
V9 
Clinic (C) Visit or Mobile 
(M) Visit   
C 
M 
C 
M 
C 
M 
C 
M 
C 
M 
C 
M 
C 
M 
C 
M 
C 
M 
C      
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review Eligibility Criteria 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IXRS Drug Dispensing 
  
  
X 
 
X 
  
X 
 
X 
  
X 
 
X 
  
X 
 
X 
  
  
ASSESSMENTS 
Radiograph Imaging – Chest2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Radiograph Imaging – Both 
Knees 3 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
K-L Grade Confirmation by 
Central Radiologist3 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
12 – lead ECG 
X 
  
 X 
  
X 
  
X  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
CYP2C9 Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

EN20-01 
Page 25 
Protocol v9.0 22Jan2024 
Study Visit  
Screening  
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
 
V9 
Physical Examination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Vital Signs  
X 
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
Height and Weight BMI 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Contraceptive Use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Medical History, OA History 
X 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analgesic Rescue Medication 
Use4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
and Therapies5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SAFER Interview6 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Drug Accountability and 
Compliance 
  
  
X  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
PROTOCOL PATIENT MEASURES – NEForm (NESS) 
Distribute Smart Device (if 
applicable)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NEForm App Subject 
Training - Collection 
Procedures & Compliance 
(Retrain as Needed)7 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Placebo Response Mitigation 
Training 
X 
  
  
  
  
  
  
  
  
  
X  
  
  
  
  
  
  
  
  
WOMAC – A (Pain Scale)8 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hospital Anxiety and 
Depression Scale (HADS)9 
X 
  
 
  
 
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
Numeric Rating Scale (NRS) 
- Remote10 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
WOMAC – C (Functional 
Scale) 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 

EN20-01 
Page 26 
Protocol v9.0 22Jan2024 
Study Visit  
Screening  
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
 
V9 
Staircase-Evoked Pain 
Assessment  
  
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
Collect Smart Device (if 
applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
NIH HEAL Initiative COMMON DATA ELEMENTS (CDEs)11 
Pain Catastrophizing Scale – 
Short Form 6 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
PEG Scale  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
PROMIS Sleep Disturbance 
Scale – 6A 
  
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
  
 
  
X 
Sleep Duration Question 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
PROMIS Physical 
Functioning Short-Form 6b 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Patient Health Questionnaire 
(PHQ) – Depression 
  
 
 X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 X 
Generalized Anxiety 
Disorder- 2 item scale (GAD-
2)   
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Patient Global Impression of 
Change (PGIC) 
  
  
 
  
X 
  
 
  
 
  
 
  
 
  
 
  
 
  
X 
Tobacco, Alcohol, 
Prescription medication, and 
other Substance use Tool 
(TAPS-1) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Opioid Use Questionnaire 
(OUQ) 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
LABORATORY COLLECTION (BLOOD & URINE) 
Clinical Blood Lab Testing- 
Hematology12 
X 
  
 
 
 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Clinical Blood Lab Testing - 
Chemistry12  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

EN20-01 
Page 27 
Protocol v9.0 22Jan2024 
Study Visit  
Screening  
V1 
 
V2 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
 
V9 
Urine Drug Screen13 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Urine Pregnancy Test14 
X 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
Urine Dipstick/ Urinalysis15 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood for Biomarkers – 
Cytokines & Chemokines  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Blood Sampling - PK 
Analysis 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
BIOBANKING SAMPLES For Future Testing [OPTIONAL] (Subject must have consented to Biobanking)16 
Collect Whole Blood for 
Biobanking17 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Leftover Plasma & Serum Sent 
to Biobank - Exploratory 
Biomarkers18 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
Collect Stool Sample for 
Biobanking19 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SYNOVIAL FLUID [OPTIONAL] (Subject must have consented to Synovial Fluid Collection)20 
Synovial Fluid Collection 
(Cytokines & Chemokines) 21 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Leftover Synovial Fluid Sent 
to Biobank - Exploratory 
Biomarkers21 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: 
1. If a subject is discontinuing the study on or before Week 24, the assessments listed for an Early Termination visit should be completed. 
2. Chest radiography should be posterior-anterior view 
3. Radiographs of both knees (posterior-anterior, fixed-flexion views) will be obtained to confirm the diagnosis of OA of the knees, as part of assessing 
the Kellgren-Lawrence (K-L) grade of the identified index knee during the Screening Period. Quality of radiographs will be assessed, and radiographs 
may need to be repeated at the direction of the central imaging reader.  Only central reading of the K-L grade will be used to determine index knee 
eligibility, K-L grade of 1, 2, 3, or 4.  
4. Rescue medication use will be recorded daily by the subject using the NEForm (section K1) (number of tablets/dose taken each day) and provided to 
the study staff during each clinic visit.  Allowable rescue medications are outlined in Exclusion Criteria and Appendix III. 

EN20-01 
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Protocol v9.0 22Jan2024 
5. Concomitant medication use will be reviewed and captured at study visits.  Subjects will be informed at the Screening visit that they will have to stop 
taking any analgesic medications other than those allowed, per Appendix III, for the duration of the trial. 
6. An independent reviewer will conduct a remote SAFER interview to assess a patient's history of pain with OA, treatment history, and HADS score. 
7. Subjects should try and complete at least 80% of remote procedures in the NEForm app 
8. The WOMAC-A scale will be used to determine subject eligibility for enrollment. During the Screening period, the WOMAC-A will be completed 
every 3 days during the Screening period.  After screening, the WOMAC-A will be completed weekly (± 2 days), with every third assessment being 
conducted at the in-person clinic visit. 
9. A score ≥ 11 on either subscale of the HADS will exclude a participant from enrolling in the study. After randomization, investigators should monitor 
any HADS subscale scores ≥ 11; they should use clinical judgement to determine whether the participant should continue in the trial and whether 
intervention or treatment is needed. HADS may be repeated per PI discretion and MM approval. 
10. During the screening period, the Knee Pain Intensity NRS (0-10) will be collected once per day following the Screening Visit. After Baseline, the 
NRS will be completed daily for the seven days immediately preceding all study visits (e.g. Week 3, Week 6). Subjects should be instructed to record 
their average daily knee pain intensity each evening using the NEForm app. 
11. NIH HEAL CDEs can be collected from participant remotely to reduce in-person clinic time. This is optional. 
12. Clinical laboratory tests will include:  
a. Chemistry: sodium, potassium, chloride, calcium, phosphate, magnesium, bilirubin (total and direct), AST, ALT, GGT, ALK phosphatase, 
creatinine, eGFR, uric acid, BUN/Urea, glucose, amylase, lipase, total protein, and albumin 
i. eGFR value will be calculated automatically in the EDC system, once lab results have been entered. 
b. Hematology: White cell count with differential (absolute values of neutrophil, lymphocyte, monocyte, eosinophil, and basophil), red cell 
count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), MCH Concentration (MCHC) 
and platelets count 
If a laboratory result comes back as abnormal and/or exclusionary, the laboratory test can be repeated per PI discretion and Medical Monitor 
approval before the participant is screen failed or discontinued from study participation. 
13. Urine drug screen test results must be confirmed as negative for drugs of abuse prior to randomization. Use the drug screen kits provided by the study, 
testing for amphetamines, barbiturates, buprenorphine, benzodiazepines, cocaine, ecstasy, methamphetamine, methadone, marijuana, opiates, 
oxycodone, phencyclidine.   
If the subject tests positive for a substance but is able to provide a valid prescription from a medical professional, the Medical Monitor may give 
permission for the subject to enroll in the study. For this study medical marijuana (or equivalent) use is allowed depending on regional legality. 
14. Subjects will be tested for pregnancy if they are women of childbearing potential.  A serum pregnancy test will be performed if the urine pregnancy 
test is positive.  Subjects with positive serum pregnancy test results will be discontinued from study participation.   
15. At Baseline, all subjects will have a full urinalysis panel completed. After baseline, a urine dipstick analysis will initially be done to assess urine 
health. Microscopic examination (urinalysis) will only be performed if the dipstick test is abnormal for leukocyte, blood, nitrite or protein. If results 
come back as abnormal, the laboratory test can be repeated per PI discretion and Medical Monitor approval 
16. Confirm whether subject has signed consent for the optional biobanking sub-study. 

EN20-01 
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Protocol v9.0 22Jan2024 
17. 10 ml of blood will be collected and banked at NYU biorepository for the EPPIC-Net repository (see instructions for how to collect blood samples). 
18. Additional blood will not be collected. Leftover serum from the 8.5 ml Biomarker Blood Analysis (cytokines and chemokines) and left-over plasma 
from PK collection will be banked at each of the “Blood for Biomarkers” time points. Plasma not collected at V1. Leftover biomaterial from the 
Biomarker collection will be sent to NYU biobank. 
19. Stool will be collected and shipped by the patient directly to the NYU CBRD biobank 
20. An optional synovial fluid tap will be conducted on subjects who consent to the tap at the Visit 3 (week 6) clinic visit.   Approximately 1 cc of 
synovial fluid will be drawn for biomarker analysis. Sites who have opted out of collecting synovial fluid will not complete this. The WOMAC-A 
must be completed by the subject prior to the synovial fluid procedure. 
21. Additional synovial fluid will not be collected. If leftover synovial fluid is available, it will be sent to the biorepository if the subject consented to 
biobanking. Sites who have opted out of collecting synovial fluid will not complete this. 

 
 
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Protocol v9.0 22Jan2024 
F.1.2. Study Assessment Overview 
Subjects must provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the Schedule of Events 
(Section F.1.1). Throughout the study, every reasonable effort should be made by study personnel 
to follow the timing of assessments and procedures in the schedule of events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled as soon as possible.  
For cases of extreme circumstances where subjects are unable to make in person clinic visits, the 
site will thoroughly document the situation and collect data for use of rescue medication, 
concomitant medications, adverse events, and compliance with study medication via the telephone 
or video conference. Subjects will be asked to complete subject assessment surveys on their device 
using NEForm (See Section K.1). Study medication will be shipped to the subject per the site 
standard operating procedures. 
As indicated in the Manual of Procedures (MOP), direct data entry (DDE) is required in the EDC 
for several electronic case report forms (eCRFs). Site staff performing certain study procedures, 
according to the site’s Delegation of Authority (DOA) log, must enter the data directly into the 
electronic data capture (EDC) system at the time of the procedure. 
Please refer to the MOP, Appendix AC. “Investigator Source Documentation & DDE 
Expectations” for full list of DDE expectations. In the event of a technical EDC issue, paper 
documentation is allowable. 
DDE eCRFs Include: 
1. Adult Demographics 
2. Vital Signs 
3. Contraceptive Form 
4. Knee OA (med record if available – but some will be pt reported) 
5. Physical Exam  
6. Urine Drug  
7. Urine Pregnancy  
8. Urine Dipstick  
9. Eligibility Question  
10. Adverse Events 
11. Protocol Deviations  
F.1.3. Screening Period (two – four weeks)  
The Screening Period will be 2 weeks in duration with a +14-day window (14-28 days). 
Radiographs of both knees (posterior-anterior, fixed-flexion views) will be obtained to confirm the 
diagnosis of OA of the knees, as well as the Kellgren-Lawrence (K-L) grade of the identified index 
knee during the Screening Period. Quality of radiographs will be assessed, and radiographs may 

 
 
EN20-01 
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Protocol v9.0 22Jan2024 
need to be repeated at the direction of the central imaging reader.  Only central reading of the K-
L grade will be used to determine index knee eligibility.  
Subject eligibility for enrollment (moderate to severe knee pain) will be determined using the 
average WOMAC -A (pain subscale) scores across the Screening Period.  The scale will be 
completed every 3 days (± 1 days) during the Screening Period(Screening Visit and Days 3, 6, 9, 
12, etc.). A minimum of 4 WOMAC-A’s need to be collected during screening to determine the 
index knee. The subject can continue to try to complete the WOMAC-A’s until the required 
minimum of 4 WOMACs are obtained. An electronic device is used to enter data into NEForm 
(See Section K.1). The purpose of these assessments is to ensure that appropriate patients are 
entered into the study.  
The investigator will determine that the patients meet eligibility criteria and will collect the 
demographic and medical data permitting full characterization of the patients. Screening 
evaluations are to be conducted as outlined in the Study Schedule of Events (Table F.1.1). The in-
clinic screening visit procedures may be divided into two visits. 
Screening Visit(s)      
The screening visit should be conducted 14-28 days prior to the Baseline Visit. The in-clinic 
procedures can be split across two days, if necessary.  
For all visits, NEForm will be used to record the Patient Reported Outcome (PRO) scales.  All 
other data will be directly entered into the study database or collected externally and entered into 
the electronic data capture (EDC) system with source materials uploaded to Florence. Additional 
information and instructions on study activities can be found in MOP. 
1. Written informed consent – NEForm on Tablet  
a. Informed Consent – documents patient’s understanding and willingness to 
participate in the study; includes consent for optional biobanking and optional 
synovial fluid collection. Paper consent permitted if NEForm consent is not 
working properly. 
b. Participant Eligibility Affirmations – provides confirmation of patient-reported 
eligibility items, e.g. will refrain from using prohibited concomitant medications 
during the study. 
c. Post-Consent Checklist – documents appropriate consent process 
2. Protocol Patient Measures  
a. NEForm App. Introduction to the remote procedures app and training on how to 
use it. Patients will be instructed to complete the End of Day Pain Ratings daily for 
the first week of screening using the NEForm app.  If technical issues arise in the 
NEForm app, and the participant is unable to complete the at-home assessments 
during the first week of the screening period, they will be allowed to start the ePRO 
remote screening period once issues are resolved, as long as they are still within the 
screening period window.  Patients will be prompted to record their pain and 
functioning as well as document use of rescue medication(s) each day.  

 
 
EN20-01 
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Protocol v9.0 22Jan2024 
b. PROs – NEForm on Tablet 
i. HADS 
ii. WOMAC-A (Pain Subscale) 
 
 
3. Lab Collection 
a. Clinical blood labs – Chemistry, Hematology (Refer to Schedule of Events 
footnotes & F.2 Procedures for full list of labs to be collected) 
b. Central labs – CYP2C9 buccal swab, saliva, or blood sample (genotyping for poor 
metabolizers) 
c. Urine drug screen provided by the study 
i. If positive, work with MM to determine medical appropriateness of result, 
i.e. subject tested positive for a medication used as prescribed by a medical 
professional that is not otherwise excluded. 
d. Urine pregnancy test provided by the study, for women of childbearing potential 
(WOCBP) 
i. If positive, a serum pregnancy test will be done. 
4. Other Assessments 
a. Radiograph image taken using fixed flexion radiographic imaging of both knees. 
Posterior-anterior only. The fixed-flexion method of imaging is used as it has been 
shown to be more accurate than the standing-extended view in assessing Kellgren-
Lawrence (K-L) grading and joint space width. (Kan et al, 2017). Upload to NESS 
Image Portal. 
b. Confirmation of K-L grade (1, 2, 3, or 4) of the knees via central radiologist review 
in NESS Image Portal.  
c. Height and weight (BMI autocalculated by EDC). 
d. Review of analgesic rescue medication use, documented in EDC (Participant to 
document rescue medication daily in NEForm OA App) 
e. Demographics, documented in EDC.  
f. Contraceptive Use, documented in EDC 
g. Document Height & Weight – BMI in EDC 
h. Review of medical and OA history, including medical records and previous 
radiographic images of the knee, if available. Current and past knee OA treatments 
(including all previous pharmacologic, noninvasive, or invasive treatments) should 
all be documented in EDC. 
i. Vital signs – EDC. 
j. Complete physical examination – EDC.   
i. A pelvic or urogenital examination may be deferred, unless the investigator 
deems this to be clinically indicated. 

 
 
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Protocol v9.0 22Jan2024 
k. Concomitant Medication 
i. the study team will complete the Concomitant Medication Log in EDC, 
using generic names for each medication listed, and including dose and 
frequency of use). 
l. Placebo Response Mitigation Training, as a part of the NEForm (NESS) electronic 
assessments, patients will be presented with a placebo response mitigation 
transcript at the Screening and Week 12 visits. These instructions recommend 
patients answer questions while sitting alone in a quiet area free of distraction. The 
instruction also advises patients to focus only on pain in the index knee, ignoring 
pain in other areas and sensations in the index knee that are not painful (e.g. 
stiffness).   
m. ECG (12-Lead) – ERT/Clario – Upload ECG to ERT Portal for central review. Site 
to download report, and investigator to review report, assess clinical significance, 
and sign ECG report and upload to Florence 
n. Chest Radiograph – posterior-anterior only; upload report/image for remote 
monitoring review 
o. Adverse event collection and documentation in EDC.      
5. Review of inclusion/exclusion criteria. 
6. Review NEForm app Instructions. Walk the patient through the steps and have them 
confirm that the device is set-up by completing the single-question eCRF via the app.  
a. This will verify the device is appropriately linked to the study and gives the patient 
a chance to try to use the app while site staff are present to assist. 
7. Complete and send SAFER Scheduling Checklist to CCC  
Remote Screening Period  
The below list of assessments will be conducted remotely or via mobile device during the 
Screening Period.  Detailed instructions and processes can be found in the study’s MOP and its 
appendices.           
1. Protocol Patient Measures: Please educate patients on the importance of answering 
these prompts. Failure to do so during screening could result in ineligibility. If 
technical issues arise in the NEForm OA app, and the participant is unable to complete the 
at-home assessments beginning on Day 0, they will be allowed to start the ePRO remote 
screening period once issues are resolved, as long as they are still within the screening 
period window. Sites should contact CCC to approve of change.. 
a) PROs – Remotely via NEForm App 
1. End of Day Pain Ratings – NRS (0-10) 
● 
Completed once daily for the first seven days of the Screening 
Period 
2. WOMAC-A – completed on Screening Period days 3, 6, 9, and 12, etc. (±1 
day). A minimum of 4 are required to determine the index knee. 
 

 
 
EN20-01 
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Protocol v9.0 22Jan2024 
b) SAFER interview by an MGH CTNI rater will be conducted to confirm that the 
subject meets the history and current requirements for pain criteria stated above.  
1. Completed once by telephone; may only be scheduled after all Screening 
WOMAC-As have been completed. Contact CCC with scheduling 
concerns. The SAFER team will confirm the patient meets all other 
screening criteria, including blinded criteria prior to scheduling the patient 
for their SAFER interview. 
Note: eligibility criteria related to the remote measures, including pain intensity 
requirements are specified in Appendix I: Blinded Information and are only 
available to unblinded study team members. 
2. Other Assessments – captured once daily via NEForm App 
a) Concomitant rescue medication – capture use of analgesic medications                   
F.1.4. Re-Screening 
Subjects may re-screen up to a maximum of two times, for a total of three Screening Visits. Each 
rescreen visit may only be initiated with the documented permission of the Medical Monitor in 
NESS.  If a subject screen fails for knee radiography, rescreening is not recommended.  For a full 
list of rescreening procedures and timelines, please see the protocol MOP. 
F.1.5. Visit 1 – Baseline (Day 0)  
For all visits, NEForm will be used to record the Patient Reported Outcome (PRO) scales.  All 
other data will be directly entered into the study database or collected externally and entered into 
the EDC with source materials uploaded to Florence. Additional information and instructions on 
study activities can be found in the MOP. 
1. Review NEForm collection procedures/compliance with subjects  
Educate subjects to complete these forms. Subjects should try and complete at least 
80% of remote procedures in NESS. If subjects fall below the 80% completion rate, 
retrain the subject at the next study visit.  
2. Define index knee. Using the averaged screening period WOMAC-A scores by knee, the 
knee with the greater score at the end of screening is defined as the index knee going 
forward. 
3. Review of inclusion and exclusion criteria to ensure that the patient meets the requirements 
for the study.  
a) At the beginning of the visit, make sure subject did not take any prohibited 
medications or therapy prior to baseline. 
b) At the end of the visit, confirm all criteria have been met prior to randomizing the 
subject. 
4. Protocol Patient Measures – NEForm on Tablet 
a) PROs  

 
 
EN20-01 
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Protocol v9.0 22Jan2024 
▪ WOMAC-A (Pain Scale)  
▪ WOMAC-C (Functional Scale) 
b) Staircase-Evoked Pain Assessment 
 
5. NIH HEAL Initiative CDEs for chronic pain – NEForm  
Optional: Participants and site staff may complete CDEs remotely to reduce time at the 
in-person clinic visit 
a) PEG Scale 
b) Pain Catastrophizing Scale – Short Form 6 
c) PROMIS Sleep Disturbance Scale – 6A 
d) Sleep Duration Question 
e) PROMIS Physical Functioning Short-Form 6b 
f) PHQ – Depression 
g) GAD-2 
h) TAPS-1 
i) OUQ 
 
6. Lab Collection – enter data in EDC, upload reports for remote monitoring review 
a) Blood Draws: 
i. Chemistry (See Schedule of Events footnotes for full list) 
ii. Biomarkers – Cytokines & Chemokines (see section F.2.2) 
b) Urine Collection: 
i. Full Urinalysis Panel   
ii. Urine pregnancy test for WOCBP – EDC 
1. If positive, a serum pregnancy test should be performed before 
randomizing. If positive the subject should not randomize. 
 
c) Biobanking for Future Testing (See Section F.2.3 Biobanking – Blood and Stool 
Repository for Future Use; See MOP, Laboratory Manual).  
 
i. If a subject has opted out of biobanking, DO NOT collect.  
ii. Collect and freeze 10 ml whole blood for batch shipping to NYU’s 
biorepository 
iii. Collect and freeze any leftover biomarker aliquots for batch shipping to 
NYU’s biorepository 
iv. Give instructions for patient to collect and send standardized stool sample 
to NYU’s biorepository (See MOP for patient-facing instructions) 
 
7. Other Assessments 
a) Review concomitant medications (using generic names) in EDC. 
b) Review of analgesic rescue medication use since the last visit.  This information is 
recorded on the NEForm app by the patient daily. 
c) Record new adverse events and provide updates for existing adverse events. 
d) Vital signs – EDC. 

 
 
EN20-01 
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Protocol v9.0 22Jan2024 
e) ECG (12-lead) – ERT/Clario; upload ERT report for remote monitoring review 
 
8. Randomization (See Section F.1.6 below and MOP for additional details) 
a) If all criteria are met, the patient will be randomized via the Almac IXRS and a kit 
containing 2 bottles of study drug will be dispensed.  The first dose of drug, which 
includes one tablet from each bottle, should be taken at the visit, to be sure that the 
patient understands the procedure. If the subject’s first dose needs to be taken at 
home, the site will schedule a phone/teleconference meeting with the subject to 
ensure they understand the procedure before they take the first dose. 
b) Ensure Eligibility and Randomization eCRFs are completed in EDC. 
Remote procedures to be completed between V1/Baseline & V2/Week 3: 
9. Remote Protocol Patient Measures 
a) WOMAC-A – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10)  
i. Completed once daily for the seven days prior to the next visit 
 
10. Other Remote Assessments   
a) Concomitant Rescue Medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. Failure to document 6 consecutive doses (3 days) of study medication is 
grounds for early termination. Monitor for missed doses and reeducate 
patient as needed. 
 
F.1.6. Randomization 
For entry into the study and randomization, all eligibility criteria MUST be met (i.e., all inclusion 
criteria and no exclusion criteria). Patients who meet all eligibility criteria at the Baseline Visit 
(day 0) will be randomized.  After documentation of written informed consent and the completed 
screening period, clinical sites will confirm eligibility and complete randomization by accessing 
Almac’s centralized web-based system for randomization and drug management - the Interactive 
Web Response System (IXRS). Additional information and instructions can be found in the MOP 
and appendices. 
Patients will receive treatments (from among 300mg CNTX-6970 and placebo) in randomly 
assigned sequences. A block randomization will be used, stratifying by K-L grade to achieve 
balance on sequences.  The randomization will be implemented by Almac’s IXRS in consultation 
with the study statisticians. Blinding of the randomization sequence from trial subjects, staff from 
the Clinical Sites, CCC, and DCC will be ensured through the use of the IXRS and a designated 
unblinded statistician.  
After Randomization, drug will be dispensed.      

 
 
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F.1.7. Visit 2 (Week 3)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
1. Review remote forms completion rate with patient (confirm >80% forms completion rate or 
re-educate) 
2. Protocol Patient Measures (PROs): 
a) WOMAC-A (Pain Scale) 
b) WOMAC-C (Functional Scale) 
 
3. NIH HEAL CDE 
a) PGIC 
 
4. Blood Collection – Lab Chemistry 
 
5. Urine Collection – urine dipstick 
a) If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
6. Other Assessments 
a) Document concomitant medications (using generic names). 
b) Review of analgesic rescue medication with the patient 
c) ECG (12-Lead) 
d) Record adverse events 
e) Drug Accountability and Compliance 
 
7. Use Almac’s IXRS to get the next kit assignment. 
a) Dispensation of study drug (1 kit; 2 bottles) 
Remote procedures to be completed between V2/Week 3 & V3/Week 6: 
8. Remote Protocol Patient Measures – PROs – Use NEForm App 
a) WOMAC-A – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) - completed once daily for the week prior to 
the next visit 
9. Other Remote Assessments – completed once daily 
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. 
Failure to document 6 consecutive doses (3 days) of study medication is grounds 
for early termination. Monitor for missed doses and reeducate patient as needed. 

 
 
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F.1.8. Visit 3 (Week 6)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
1. Review remote forms completion rate with patient 
2. Protocol Patient Measures  
a) PROs  
i. 
WOMAC-A (Pain Scale) 
Must obtain WOMAC-A before synovial fluid collection procedure 
ii. WOMAC-C (Functional Scale). 
iii. HADS 
b) Staircase-Evoked Pain Assessment. 
 
3. Lab Draws/Collections 
a) Blood Draws: 
i. Chemistry 
ii. Hematology 
iii. PK Analysis (see section F.2.2) 
iv. Biomarker - Cytokines & Chemokines (see section F.2.2) 
b) Urine dipstick 
i. If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
c) Synovial Fluid (Knee) Collection  
i. If subject opted out of synovial fluid DO NOT collect 
ii. Collect and ship to Myriad Lab for analysis 
d) Biobanking (See Section F.2.3; See MOP, Laboratory Manual)  
i. If a subject has opted out of biobanking DO NOT collect  
ii. Collect and freeze leftover blood and synovial fluid samples to batch ship to 
NYU’s biorepository 
4. NIH HEAL Initiative CDEs for chronic pain (Use NEForm) 
a) PROMIS Sleep Disturbance Scale – 6A. 
 
5. Other Assessments 
a) Document concomitant medications (using generic names). 
b) Review of analgesic rescue medication  
c) Vital signs, as detailed in Section F.2.1     
d) ECG (12-Lead) 
e) Drug accountability and compliance. 
f) Record adverse events. 
6. Use Almac’s IXRS to get the next kit assignment. 
a) Dispensation of study drug (1 kit; 2 bottles)  

 
 
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Remote procedures to be completed between V3/Week 6 & V4/Week 9: 
7. Remote Protocol Patient Measures  
a) WOMAC-A (Pain Scale) – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) – completed once daily for the seven days 
prior to the next visit 
8. Other Remote Assessments – completed once daily  
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. Failure to document 6 consecutive doses (3 days) of study medication is grounds 
for early termination. Monitor for missed doses and reeducate patient as needed. 
F.1.9. Visit 4 (Week 9)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
 
1. Review remote forms completion rate with patient 
2. Protocol Patient Measures - PROs 
a) 
WOMAC-A (Pain Scale). 
b) WOMAC-C (Functional Scale) 
 
 
3. Blood Collection – Lab Chemistry 
 
4. Urine Collection – Urine Dipstick 
a) 
If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis 
 
5. Other Assessments 
a) 
Review concomitant medications (using generic names) 
b) Review of analgesic rescue medication 
c) 
ECG (12-Lead) 
d) Record adverse events 
e) 
Drug Accountability and Compliance 
 
6. Use Almac’s IXRS to get the next kit assignment. 
a) 
Dispensation of study drug (1 kit; 2 bottles)  
Remote procedures to be completed between V4/Week 9 & V5/Week 12: 
7. Remote Protocol Patient Measures 
a) WOMAC-A (Pain Scale) – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) - completed once daily for the seven days 
prior to the next visit 
 

 
 
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8. Other Remote Assessments – completed once daily 
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. 
Failure to document 6 consecutive doses (3 days) of study medication is grounds 
for early termination. Monitor for missed doses and reeducate patient as needed. 
F.1.10. Visit 5 (Week 12)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
1. Review remote forms completion rate with patient 
2. Protocol Patient Measures 
a) PROs  
i. WOMAC-A (Pain Scale). 
ii. WOMAC-C (Functional Scale). 
iii. HADS 
b) Staircase-Evoked Pain Assessment. 
 
3. NIH HEAL Initiative CDEs for chronic pain  
a) PROMIS Sleep Disturbance Scale – 6A. 
 
4. Lab Draws/Collection 
a) Blood Draws: 
i. 
Chemistry 
ii. 
Hematology 
iii. 
Biomarkers - Cytokines & Chemokines (See Section F.2.2) 
iv. 
PK Analysis (See Section F.2.2) 
b) Biobanking (See Section F.2.3; See MOP, Laboratory Manual) 
i. 
If a subject has opted out of biobanking DO NOT collect  
ii. 
Send leftover blood samples to NYU biorepository for future testing 
c) Urine dipstick analysis  
i. 
If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
d) Urine pregnancy test (kit provided by study) for WOCBP 
i. If positive, a serum pregnancy test should be performed. 
 
5. Other Assessments 
a) Document concomitant medications (using generic names). 
b) Vital signs, as detailed in Section F.2.1  
a) Review of analgesic rescue medication with patient using data from NEForm. 
c) ECG (12-lead). 
d) Drug Accountability and Compliance. 

 
 
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e) Record adverse events. 
f) Placebo Response Mitigation Training, as a part of the NEForm (NESS) electronic 
assessments, patients will be presented with a placebo response mitigation transcript 
at the Screening and Week 12 visits. These instructions recommend patients answer 
questions while sitting alone in a quiet area free of distraction. The instruction also 
advises patients to focus only on pain in the index knee, ignoring pain in other areas 
and sensations in the index knee that are not painful (e.g. stiffness).  
6. Use Almac’s IXRS to get the next kit assignment 
a) Dispensation of study drug (1 kit; 2 bottles) 
Remote procedures to be completed between V5/Week 12 & V6/Week 15: 
7. Remote Protocol Patient Measures  
a) WOMAC-A (Pain Scale) – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) -completed once daily for the seven days prior 
to the next visit 
8. Other Remote Assessments – completed once daily 
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. Failure to document 6 consecutive doses (3 days) of study medication is 
grounds for early termination. Monitor for missed doses and reeducate patient 
as needed. 
F.1.11. Visit 6 (Week 15)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
1. Review remote forms completion rate with patient 
2. Protocol Patient Measures -PROs 
a) WOMAC -A (Pain Scale) 
b) WOMAC-C (Functional Scale) 
 
3. Lab Draws/Collections: 
a) Blood Draw – Lab Chemistry 
b) Urine dipstick Urine dipstick analysis  
i. If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
4. Other Assessments 
a) Document concomitant medications (using generic names). 
b) Review of analgesic rescue medication with patient using data from NEForm. 
c) Record adverse events 
d) ECG (12-Lead) 

 
 
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e) Drug Accountability and Compliance 
 
5. Use Almac’s IXRS to get the next kit assignment 
a) Dispensation of study drug (1 kit; 2 bottles) 
 
 
Remote procedures to be completed between V6/Week 15 & V7/Week 18: 
6. Remote Protocol Patient Measures 
a) WOMAC-A (Pain Scale) – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) - completed once daily for the seven days 
prior to the next visit 
 
7. Other Remote Assessments – completed once daily  
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. Failure to document 6 consecutive doses (3 days) of study medication is grounds 
for early termination. Monitor for missed doses and reeducate patient as needed. 
F.1.12. Visit 7 (Week 18)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
1. Review forms completion rate with patient 
 
2. Protocol Patient Measures 
a) PROs  
i. WOMAC-A (Pain Scale). 
ii. WOMAC-C (Functional Scale). 
iii. HADS 
b) Staircase-Evoked Pain Assessment. 
 
3. NIH HEAL Initiative CDEs for chronic pain  
a) PROMIS Sleep Disturbance Scale – 6A. 
 
4. Lab Draws/Collection 
a) Blood Draws: 
i. Chemistry 
ii. Hematology 
iii. Biomarkers – Cytokines & Chemokines (see section F.2.2) 
iv. PK Analysis (see section F.2.2) 
b) 
Biobanking (See Section F.2.3; See MOP, Laboratory Manual) 

 
 
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i. 
If a subject has opted out of biobanking DO NOT collect 
ii. 
Send leftover blood samples to NYU biorepository for future testing  
c) 
Urine dipstick 
i. If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
 
 
5. Other Assessments 
a) Document concomitant medications (using generic names). 
b) Vital signs, as detailed in Section F.2.1. 
c) ECG (12-Lead) 
d) Review of analgesic rescue medication use  
e) Drug Accountability and Compliance 
f) Record adverse events. 
 
6. Use Almac’s IXRS to get the next kit assignment 
a) Dispensation of study drug (1 kit; 2 bottles) for Weeks 18-21 
Remote procedures to be completed between V7/Week 18 & V8/Week 21: 
7. Remote Protocol Patient Measures  
a) WOMAC-A (Pain Scale) – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) - completed once daily for the seven days 
prior to the next visit 
 
8. Other Remote Assessments – completed once daily 
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. Failure to document 6 consecutive doses (3 days) of study medication is grounds 
for early termination. Monitor for missed doses and reeducate patient as needed. 
F.1.13. Visit 8 (Week 21)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities can be found in 
the MOP. 
1. Review forms completion rate with patient 
 
2. Protocol Patient Measures -PROs 
a) WOMAC-A (Pain Scale) 
b) WOMAC-C (Functional Scale) 
 
3. Blood Collection – Lab Chemistry 
 
4. Urine dipstick 

 
 
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a) 
If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
 
5. Other Assessments 
a) Document concomitant medications (using generic names). 
b) Review of analgesic rescue medication with patient using data from NEForm. 
c) ECG (12-Lead) 
d) Record adverse events 
e) Drug Accountability and Compliance 
Remote procedures to be completed between V8/Week 21 & V9/Week 24 
6. Remote Protocol Patient Measures –  
a) WOMAC-A (Pain Scale) – completed once weekly 
b) End of Day Pain Ratings – NRS (0-10) -completed once daily for the seven days prior 
to the next visit 
 
7. Other Remote Assessments – completed once daily 
a) Concomitant rescue medication – captures use of acetaminophen and opioids daily 
b) Study Medication – captures time and confirms dosing twice daily 
i. Failure to document 6 consecutive doses (3 days) of study medication is 
grounds for early termination. Monitor for missed doses and reeducate patient 
as needed. 
F.1.14. Visit 9 (Week 24 or Early Termination)  
For all visits, NEForm will be used to record the PRO scales.  All other data will be directly entered 
into the study database or collected externally and entered into the EDC with source materials 
uploaded to Florence. Additional information and instructions on study activities, can be found in 
the MOP. 
1. Review forms completion rate with patient 
 
2. Protocol Patient Measures – NEForm on Tablet 
a) PROs  
i. WOMAC-A (Pain Scale) 
ii. WOMAC-C (Functional Scale) 
iii. HADS 
b) Staircase-Evoked Pain Assessment 
 
3. NIH HEAL Initiative CDEs for chronic pain – NEForm on Tablet 
a) PEG Scale. 
b) Pain Catastrophizing Scale – Short Form 6. 
c) PROMIS Sleep Disturbance Scale – 6A. 
d) Sleep Duration Question  
e) PROMIS Physical Functioning Short-Form 6b. 
f) PHQ – Depression. 

 
 
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g) GAD-2 
h) PGIC 
i) TAPS-1      
j) OUQ 
 
4. Lab Draws/Collection 
a) 
Blood Draws: 
i. Chemistry 
ii. Hematology 
iii. Biomarkers – Cytokines & Chemokines (See Section F.2.2) 
iv. PK Analysis (See Section F.2.2) 
b) Urine Dipstick 
i. If abnormal for leukocytes, blood, nitrite, or protein, complete full urinalysis. 
c) 
Urine Drug Screen – test kit provided by study 
d) Urine Pregnancy Test for WOCBP – if positive confirm with serum pregnancy test 
e) 
Biobanking (See Section F.2.3; See MOP, Laboratory Manual) 
i. If a subject has opted out of biobanking DO NOT collect 
ii. 10ml of whole blood will be collected and frozen to batch ship to NYU’s 
biorepository  
iii. Freeze leftover blood samples to batch ship to NYU’s biorepository  
5. Other Assessments 
a) Physical examination.   
i. A pelvic or urogenital examination may be deferred unless the investigator 
deems this to be clinically indicated. 
b) Document Concomitant medications (using generic names). 
c) Review of analgesic rescue medication use.  
d) Chest Radiograph - posterior-anterior only 
e) ECG (12-Lead) 
f) Vital signs, as detailed in Section F.2.1. 
g) Drug Accountability and Compliance 
h) Record adverse events. 
 
6. If applicable, collect NESS loaner device  from subjects. 
F.2. Procedures 
F.2.1. Laboratory/Diagnostic Procedures 
As outlined in Table 1, after the patient has signed the informed consent document, laboratory 
procedures will be conducted regularly to confirm subject safety. Urine and blood tests may be 
repeated per PI discretion and Medical Monitor approval before a subject is screen failed (during 
screening) or discontinued from study participation.      

 
 
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1. Urine Pregnancy Test: A urine pregnancy test will be performed at the Screening Visit, 
Baseline Visit, Week 12 (Visit 5), and Week 24/ET (Visit 9) using the test kit provided by 
the study.  
● In the event of a positive urine pregnancy test, a serum pregnancy test will be 
conducted to confirm.  
o If a urine pregnancy test is positive at the Baseline Visit, hold 
randomization until the serum pregnancy test can verify the results. 
● Subjects with a positive serum pregnancy test at Screening or Baseline will be 
excluded from the study. Subjects with positive serum pregnancy test results after 
Baseline will be discontinued from study participation. 
● Additional serum or urine pregnancy tests may be performed as determined 
necessary by the Investigator or required by local regulation, to establish the 
absence of any pregnancy any time during study participation. 
2. Urine Drug Screen: A urine drug screen will be conducted at the Screening Visit and Week 
24/ET (Visit 9) using the test kit provided by the study. The urine drug screen will include 
amphetamines, 
barbiturates, 
buprenorphine, 
benzodiazepines, 
cocaine, 
ecstasy, 
methamphetamine, methadone, marijuana, opiates, oxycodone, and phencyclidine. 
● If positive, the subject will have the opportunity to provide evidence of medical 
necessity for their result, e.g. positive for oxycodone due to prescribed 
intermittently for their OA pain. The Medical Monitor will make the final decision 
regarding medical support for any positive results.  
● For this study, continuing intermittent opioid use is allowed as a rescue analgesic 
medication. See Appendix III and MOP for additional information. 
● For this study, medical marijuana (or equivalent) use is allowed for use depending 
on regional legality.  
3. ECG: 12-lead ECGs will be measured at all in-clinic visits.  
● All ECG tracings should be checked for completeness and potential artifacts during 
the visit. If poor quality or otherwise indicated, additional ECG assessments can be 
made at the discretion of the investigator. 
● All ECG tracings will be uploaded to ERT (central ECG laboratory) and read at the 
scheduled time points by a central reader. The site will download the ECG report 
results from the ERT portal.  
● An investigator at the site is required to review all ECG reports to assess for 
potential safety concerns or exclusionary reasons.  Any abnormalities noted by the 
central reader must be assessed by the Investigator for clinical significance 
(CS/NCS) on the report with a date and signature or initials:  
o Abnormal and Not Clinically Significant (NCS) 
o Abnormal and potentially Clinically Significant (CS) 

 
 
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• Any ECG results that are judged by the Investigator to be potentially CS will be 
recorded on the ECG report and the eCRF. This would constitute an AE and should 
be entered on the Adverse Event Form and monitored as described in Section 
F.4.8.1 Adverse Event Reporting. Repeat or unscheduled samples may be taken for 
safety reasons or to address technical issues with the samples.  
● The site will upload the report with the investigator’s signature and assessment to 
Florence within 3-business days of receipt of the ERT report. If technical issues 
arise, please refer to the ERT manual for other methods of transmission. See MOP 
Appendix AC. Investigator Source Expectations and DDE Expectations for 
investigator requirements. 
4. Clinical Blood Lab Tests: Chemistry will be obtained at each in-clinic visit. Hematology 
will be obtained at the Screening Visit, and at the Weeks 6, 12, 18, and 24/ET Visits.   
● Chemistry: Sodium, potassium, chloride, calcium, phosphate, magnesium, 
glucose, urea nitrogen (BUN/Urea), creatinine, uric acid, bilirubin (total and 
indirect), alkaline phosphatase, AST, ALT, GGT, eGFR, amylase, lipase, total 
protein and albumin.  
o Estimated glomerular filtration rate [eGFR] will be calculated in the EDC 
system using Modification of Diet in Renal Disease (MDRD) Study 
equation and must be assessed by the Investigator for clinical significance 
(CS/NCS). 
● Hematology: White cell count with differential (absolute values of neutrophil, 
lymphocyte, monocyte, eosinophil, and basophil), red cell count, hemoglobin, 
hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), MCH Concentration (MCHC) and platelets count 
o The actual dates and times of sample collection must be recorded in the 
subject source notes or the laboratory requisition form. All clinical 
laboratory test results outside the reference range must be assessed by the 
Investigator for clinical significance (CS/NCS) on the report with a date and 
signature or initials: Abnormal and Not Clinically Significant (NCS) 
o Abnormal and potentially Clinically Significant (CS) 
Any laboratory test results that are judged by the Investigator to be potentially CS 
will be recorded on the /lab report  and the eCRF. This would constitute an AE and 
should be entered on the Adverse Event Form and monitored as described in 
Section F.4.8.1 Adverse Event Reporting. Repeat or unscheduled samples may be 
taken for safety reasons or to address technical issues with the samples.  
The site will upload the lab report with the investigator’s signature and assessment 
to Florence within 3-business days. See MOP Appendix AC. Investigator Source 
Expectations and DDE Expectations for investigator requirements.  
5. Vital Signs: Oral temperature, pulse, respiratory rate and blood pressure will be recorded 
at the Screening Visit, Baseline Visit, and at the Weeks 6, 12, 18, and 24/ET Visits.  
● Patients should be seated for 2 minutes prior to collecting pulse and blood pressure. 

 
 
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6. Physical Exam: At the Screening Visit and Week 24/ET (Visit 9), patients will have a 
physical examination.  
● Genitourinary evaluations will not be conducted, unless deemed necessary by the 
investigator. 
7. CYP2C9 Genotyping: At the Screening Visit, a buccal swab, saliva, or blood sample will 
be collected to identify and exclude poor CYP2C9 metabolizers. The results must be 
reviewed before a subject is randomized. 
8. Urine Testing: 
● At Baseline, a full urinalysis panel will be done for all subjects, including color, 
clarity, specific gravity, pH, leukocyte esterase, protein, glucose, ketones, bilirubin, 
blood, nitrite, urobilinogen. 
● After Baseline, a Urine Dipstick will be completed at all in-clinic visits and will 
include Calcium, Glucose, Protein, pH, Bilirubin, Blood, Urobilinogen, Micro 
albumin, Ascorbate, & Specific Gravity. If the dipstick test is abnormal for 
leukocyte, blood, nitrite or protein, a sample should be sent for a full urinalysis 
panel. 
The required laboratory tests are listed in Table 2, below. Laboratory tests will be performed at the 
site, and each site will provide their laboratory certificates and normal ranges to the coordinating 
center.  Reference ranges have been standardized across study sites for lipase and amylase due to 
institutional variability and are as follows, please refer to protocol Appendix IV Amylase and 
Lipase Normal Ranges Memo_12Jan2024 for additional information.  
F.2.1.1. Table 2: Frequency of Laboratory & Diagnostic Procedures 
Laboratory Test 
Frequency 
Hematology (local lab) # 
Screening and Week 6, 12, 18, and 24/ET 
Chemistry (local lab) #  
Screening, Baseline, Weeks 3, 6, 9, 12, 15, 18, 21, and 24/ET 
Urine Dip Stick ^ 
Weeks 3, 6, 9, 12, 15, 18, 21, and 24/ET 
Urinalysis (UA) ^ 
Complete UA panel at Baseline; for abnormals at Weeks 3, 6, 
9, 12, 15, 18, 21, and 24/ET 
Pregnancy test (urine) using 
kit provided * 
Screening, Baseline, and Weeks 12 and 24/ET 
Drug Screen (urine) using kit 
provided 
Screening and Week 24/ET 
CYP2C9 Genotyping 
Screening  

 
 
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#  For a full list of tests conducted, please see Section F.2.1. 
^ Microscopic examination will only be performed if the dipstick test is outside of the 
reference range for leukocyte, blood, nitrite, or protein. 
* Only for WOCBP. If urine pregnancy test is positive, a serum pregnancy test will be 
conducted. 
 
F.2.2. Blood and Synovial Fluid Biomarkers (Cytokines and Chemokines) 
At Baseline and Week 6, 12, 18, and 24/ET visits, 8.5 ml blood samples will be drawn. Serum will 
be separated and a commercially-available multiplex assay (the Myriad Human Inflammation 
MAP® 1.0) will be used to evaluate multiple inflammatory markers. In addition, we will assess: 
• Monocyte chemoattractant protein-1 (MCP-1)/CCR-2 receptor binding inhibition by 
CNTX-6970 (Baseline and Weeks 6, 12, 18 and 24). 
• Synovial fluid levels of cytokines and chemokines, assessed at the end of the first 
treatment period (Visit 3). 
• Monocyte chemoattractant protein-1 (MCP-1)/CCR-2 receptor binding inhibition by 
CNTX-6970 in synovial fluid, assessed at the end of the first treatment period (Visit 3). 
 
Extra (left over) blood samples not required to be sent to the lab for analysis will be frozen and 
batch shipped to NYU biobanking for future exploratory analysis. IF A SUBJECT HAS OPTED 
OUT OF SPECIMEN SAMPLING DO NOT SEND. See MOP for additional details. 
 
An optional synovial fluid tap will be conducted on the index knee on subjects at the week 6 clinic 
visit.  The synovial fluid tap is optional for both sites and participants. Approximately   1ml of 
synovial fluid will be withdrawn for biomarker analysis. Synovial fluid collection will be 
performed by a physician with training and experience. Synovial fluid analysis will include 
cytokines and chemokines as a part of establishing biomarker for treatment of OA pain with 
CNTX-6970.  
 
Extra (left over) Synovial fluid from the sample that is not required to be sent to the lab for analysis 
will be sent to NYU biobanking for future exploratory analysis. IF A SUBJECT HAS OPTED 
OUT OF SPECIMEN SAMPLING DO NOT SEND. 
F.2.2.1.      Blood Test for Pharmacokinetics (PK analysis at Weeks 6, 12, 18, and 24/ET [V3, V5, 
V7 and V9) 
Four (4) ml of Blood will be drawn. Pharmacokinetic/pharmacodynamics PK/PD analysis of this 
study will be conducted to determine dose relationship of CNTX-6970 and its analgesic effect in 
patients with OA. This determination will be obtained at the time when patients are at the steady 
state of CNTX-6970. Pharmacokinetic samples will be obtained at Week 6, Week 12, Week 18, 
and Week 24/ET Visits.  
Extra (left over) blood samples, beyond what was required to be sent to the lab for analysis, will 
be frozen and batch shipped to NYU biobanking for future exploratory analysis. IF A SUBJECT 

 
 
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HAS OPTED OUT OF SPECIMEN SAMPLING DO NOT SEND. See MOP for additional 
details. 
F.2.3. Biobanking – Blood and Stool Repository for Future Use  
The Informed Consent Form (ICF) will inform whether or not the subject has opted out of 
specimen biobanking. If the patient has opted out, no blood or stool sample for biobanking will be 
obtained.   
F.2.3.1. Whole Blood (Baseline and End of Study) 
The EPPIC-Net DCC’s NYU Center for Biospecimen Research and Development (CBRD) will 
store and manage biological samples (biosamples) collected in this clinical trial. The samples will 
be used for the present study and also for potential future research as permitted by the study-
specific informed consent form.  Biosamples stored for this study may include, but are not limited 
to: whole blood, plasma, serum, stool, synovial fluid and/or derivatives of these specimens.  The 
samples will be stored only for the period defined in the informed consent form, which may be 
indefinite.  Biospecimens may be shared in accordance with the protocol-defined data and sample 
sharing plan and the informed consent form. 
Biosamples will be documented in LabVantage, a secure network linking biospecimens to 
corresponding clinical and pathological data. LabVantage does not include any identifying 
personal health information (PHI). The CBRD and LabVantage meet all Good Laboratory Practice 
(GLP) and FDA guidelines. 
F.2.4. Protocol Patient Measures 
1. WOMAC-A (Pain subscale). Pain in the index knee, measured weekly by the WOMAC-
A (Pain subscale). We will use the numerical rating scale version of the WOMAC, with 
the subject assessing each of 5 questions using an 11-point (0 to 10) scale, and the total 
index score is the sum of the individual item scores (range 0-50). A higher WOMAC-A 
pain score represents worse pain. 
The WOMAC-A will be used to study the course of OA pain symptoms during treatment, 
including onset of action and carryover effects. 
 
2. WOMAC-C (Function subscale). The WOMAC-C physical function subscale contains 17 
items assessing daily functioning, each using an 11-point (0 to 10) numerical rating scale. 
The total index score (0-170) is the sum of the items. A higher WOMAC-C function 
score represents worse functioning and less ability to engage in daily activities. 
 
3. Daily Knee Pain Intensity on a 0-10 Numeric Rating Scale (NRS). Pain intensity is reported 
by patients with chronic pain as one of the most important targets of treatment, and daily 
pain intensity ratings are a recommended core outcome measure for clinical trials of 
treatments for chronic pain. Daily ratings are preferable to ratings of recalled pain over 
longer time periods such as a week, as daily ratings minimize the influence of recall biases 
(Dworkin et al., 2005). Subjects provide one-daily reports (at the end of the day) of their 

 
 
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average knee pain intensity on a 0-10 pain intensity NRS over the course of a week, and 
those daily ratings are averaged to compute a mean knee pain intensity score.  
 
4. HADS (Hospital Anxiety and Depression Scale). The HADS is a 14-item self-report 
questionnaire designed to assess symptoms of anxiety and depression in those with medical 
illness (Norton et al, 2013). It has well-established reliability and validity in the assessment 
of symptoms of depression and emotional distress, and it has been used in numerous 
clinical trials. It does not include somatic symptoms, such as fatigue and sleeplessness, 
which may otherwise be attributable to physical illness, and it has been standardized among 
large community samples. It has also been validated in several medical illness populations 
with good sensitivity and specificity for predicting DSM-IV major depression or 
generalized anxiety disorder diagnoses. The HADS has been recommended as a 
psychosocial phenotyping measure in clinical trials of treatments for chronic pain (Edwards 
et al, 2016). 
 
5. Staircase-Evoked Pain Assessment: This procedure consists of stepping fully up and down 
onto an 8in (20.32cm) high platform with both feet a total of 24 times. The lead leg is 
alternated between each up/down cycle. Subjects are instructed to use their normal gait for 
completing this task and are encouraged to complete the task despite increasing pain, 
without stopping if possible. The procedure is timed, and current knee pain intensity on a 
0-10 NRS is assessed immediately before and following the procedure while the subject is 
in a seated, resting position. 
 
6. SAFER Interview: The SAFER Interview (Targum et al, 2008) is a validated, structured, 
clinician-rated scale that is used to facilitate the identification of appropriate and valid 
patients for clinical trials. The interview will confirm that identified patients have 
symptoms that reflect the current state of illness and that these symptoms can be assessed 
with the appropriate rating instruments. The SAFER and the HADS will be administered 
to the patients remotely via telephone by psychiatrists and psychologists from the CCC.  
After the assessments are evaluated, the CCC will notify the study center, indicating 
whether the patient meets all criteria and is eligible to continue. Study center staff will 
schedule the telephone assessment (SAFER interview) with staff at the CCC. Patients 
who do not meet the SAFER criteria will be discontinued from the study and considered 
a screen failure. The information collected by the CCC clinicians will be copied and 
transmitted to the study centers to retain as source documentation.  
F.2.5. NIH HEAL Initiative Common Data Elements (CDEs) 
1. PEG Scale. The PEG consists of 3 items assessing pain intensity, interference of pain with 
enjoyment of life, and interference of pain with general activity. PEG scores range from 0-
10, with higher scores representing a greater burden of pain.  
 
2. Pain Catastrophizing Scale – Short Form 6. Catastrophizing is a pain-specific psychosocial 
construct comprising cognitive and emotional processes such as helplessness, pessimism, 

 
 
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rumination about pain-related symptoms, and magnification of pain reports. The short-
form Pain Catastrophizing Scale is a 6-item, self-report measure of catastrophic thinking 
associated with pain (McWilliams, et al, 2015).  Scores range from 0-24, with higher scores 
indicating more catastrophizing.  
 
3. The Patient-Reported Outcomes Measurement Information System (PROMIS) Physical 
Functioning Short-Form 6b. The PROMIS Physical Functioning short form is a 6-item 
scale which is widely used in pain research. It is a unidimensional scale that shows broad 
coverage of the physical function construct, good construct validity, and high levels of 
temporal stability (Schalet et al, 2016). The PROMIS Physical Function Scale is 
expressed as a T-score, with a population mean of 50 and SD of 10. Higher scores 
represent better physical functioning; possible T scores in this distribution range from 21 
to 59 
(http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Physical_Function_
Scoring_Manual.pdf). 
 
4. PROMIS Sleep Disturbance Short Form. The PROMIS Sleep Disturbance short form is a 
convenient 6-item scale that correlates strongly with the longer forms. It shows greater 
measurement precision for assessing sleep disturbance than other commonly-used (and 
much longer) questionnaires such as the Pittsburgh Sleep Quality Index and the Epworth 
Sleepiness Scale; its brevity and convenience are a major advantage for both research and 
clinical settings (Yu et al, 2011). The PROMIS Sleep Disturbance Scale is expressed as a 
T-score, with a population mean of 50 and SD of 10. Possible T scores in this distribution 
range from 31.7 to 76.1; higher scores represent a greater disruption of sleep (i.e., lower 
sleep quality). 
 
5. Patient Health Questionnaire (PHQ) – Depression. The 2-item PHQ-2 is a brief depression 
screening tool that correlates strongly with PHQ-9 scores and shows good sensitivity for 
identifying individuals with depressive disorders in the general population and in a variety 
of medical samples (Arroll et al, 2010). Scores range from 0-6, with higher scores 
indicating more depressive symptomatology. 
 
6. Generalized Anxiety Disorder – 2 item scale (GAD-2). The GAD-2 is a 2-item screening 
tool that is widely used to screen for clinically significant anxiety symptoms and anxiety 
disorders in clinical settings. It shows good sensitivity and specificity as a screening tool 
for anxiety disorders (Kroenke et al, 2007). Scores range from 0-6, with higher scores 
indicating more anxiety symptomatology. 
 
7. Tobacco, Alcohol, Prescription medication, and other Substance use Tool (TAPS-1). The 
TAPS-1 is the screening component of the TAPS tool and consists of a single stem question 
with four items covering frequency of past-12-month use of tobacco, alcohol, illicit drugs, 
and non-medical use of prescription medications. Scores range from 0-4; higher scores 
indicate a higher likelihood of problematic substance use. The TAPS-1 shows good 
sensitivity and specificity for identifying substance use disorders (Gryczynski, et al, 2017). 
 

 
 
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8. Opioid Use Questionnaire (OUQ). The OUQ is an indicator of past or present use of any 
of the listed opioid medications. There are a total of three yes/no items where a yes 
indicates the use of such medications. 
F.2.6. Blinding Procedures 
Eligible subjects will be randomized through an interactive web response system (IXRS). The 
randomization will be stratified by K-L grade. Blinding will be assured by restricting access of site 
and Sponsor personnel and/or designees to the treatment codes, and by providing identical tablets 
and packaging for the placebo and CNTX-6970 tablets. Subjects will be provided with 2 bottles 
(CNTX-6970 100mg or placebo; CNTX-6970 200mg or placebo) at each clinic visit. 
For the final analysis, the treatment sequence codes for all subjects will be released after all 
subjects have completed the study and the clinical database is locked. 
For the DSMB safety reviews, the treatment sequence codes will be released to an independent 
statistician and a programmer to produce unblinded reports.  The Sponsor and the investigators 
will remain blinded. 
Unblinding of individual treatment sequence during the study is discouraged.  The PI at a site may 
break the blind for a given subject in the event of a medical emergency, where knowledge of the 
subject’s treatment sequence must be known in order to facilitate appropriate emergency medical 
treatment.  If reasonable, the investigator should attempt to contact the study Medical Monitor 
before unblinding a subject’s treatment sequence identity in order to obtain concurrence that 
unblinding a subject’s treatment sequence assignment is necessary.  If not reasonable prior to 
unblinding, investigators should notify the Medical Monitor as soon as possible after an unblinding 
event. Details of the process to be followed are provided in a separate Almac IXRS manual. Once 
unblinded, a subject must be permanently withdrawn from study participation. 
F.2.7. Safety Measures 
Laboratory values will be recorded in the electronic case report form (eCRF). Abnormal laboratory 
values will be recorded as AEs only if deemed clinically significant. Abnormal laboratory values 
(clinically significant and not clinically significant), will be reviewed by the Medical Monitor and 
PPI for trends. The presence of any side effect or adverse event that would not be deemed as 
exclusionary will be carefully documented at screen (for the past week) and at every subsequent 
visit using the patient’s self-report to the study staff.  Reasons for premature discontinuation, 
including intolerable side effects, will be recorded. 
The primary safety endpoint for the study is the following: Percent of adverse events and serious 
adverse events in the final 2 weeks of each treatment period. Vital signs (heart rate, blood pressure, 
etc.) will be obtained regularly throughout the study at the time of study visits. Height and weight 
will be collected during the screening period and at the subject’s final study visit. Blood chemistry 
and hematology panels will also be obtained regularly at study visits. All ECGs will be documented 
by recording date, time, heart rate, QRS duration, PR interval, RR interval, QT, and QTcF on the 
eCRF.  Paper strips will be maintained in the patient file.  If indicated, additional ECG assessments 
can be made at the discretion of the investigator. 

 
 
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Because CNTX-6970 is metabolized by CYP2C9 and CYP3A4 (to a lesser extent), use of 
inhibitors and inducers of those two genes are excluded for the duration of participation in the trial. 
CYP2C9 genotyping will be used to exclude poor metabolizers. As a P-glycoprotein (P-gp) 
substrate, introduction of any new P-gp inhibitor is also exclusionary for the duration of study 
participation – P-gp use must have been chronic for at least 3 months and stable for at least 1 month 
prior to Baseline.  Additionally, until more is known about the hepatic metabolization and renal 
excretion of CTNX-6970, individuals with moderate to severe impairment in hepatic or renal 
functioning will be excluded from participation. 
ECGs will be done at each in-clinic visit to assess heart health. Urine dipstick/urinalysis and liver 
functioning tests (AST, ALT, GGT, total bilirubin, direct bilirubin, ALK phosphatase) will be 
collected at each in-clinic visit to monitor the subject’s health throughout the study. 
F.3. Discontinuation 
F.3.1. Discontinuation of Subjects 
In accordance with the Declaration of Helsinki and other applicable regulations, subjects have the 
right to withdraw from the study at any time, and for any reason, without prejudice to their future 
medical care. Subjects may be discontinued or withdrawn from the study for any of the following 
reasons: 
• Serious adverse event.  
• The investigator determines that continuation in the study would be detrimental to a 
subject’s well-being, including criteria under F.3.1.1 
• Subject fails to comply with protocol requirements. 
• Subject misses more than 6 consecutive doses of study medication. 
• Subject is lost to follow-up. 
• Subject becomes pregnant. 
F.3.1.1. Automatic Stopping Criteria for Subjects 
If a subject meets any of the following criteria at any time during the study, they must be 
discontinued from the study drug and withdrawn from participation, in accordance with the 
procedures outlined in Section F.3.2. 
a. 1) ALT and/or AST >3x ULN with total bilirubin >2x ULN (unless elevated bilirubin is 
related to confirmed Gilbert’s Syndrome). Subjects with total serum bilirubin >2x above 
ULN will be followed until resolution. 2) Confirmed AST and/or ALT >5x ULN for more 
than 2 weeks. 
 
b. Serum creatinine >1.5 × ULN or Grade 2 (moderate) value based on Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials. 
 

 
 
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c. ECGs (minimum criteria): absolute QTcF ≥500 ms; absolute QTcF <320 ms (clinically 
significant QTc shortening); prolongation in repeated, averaged ECG measures of PR or 
QRS of >40 ms from the Baseline Visit. 
 
d. Monocyte count <1% of white blood cells (e.g., for WBC = 4,500/µL, stop if monocyte 
count  <0.01 * 4,500 or 45/µL), hemoglobin <11 g/dL (Grade 2 in females) or <12.4 g/dL 
(Grade 2 in males), platelets <100,000/μL on 2 consecutive blood draws. A confirmatory 
blood draw will be completed at an in-clinic unscheduled visit. Discontinuation will be 
confirmed by the consecutive blood draw at the next in-clinic visit. 
F.3.2. Discontinuation of Subjects who Stopped taking Study Medication 
Should a patient discontinue study medication and decide to withdraw consent, an EOS visit should 
be scheduled at the earliest convenience to complete the EOS study procedures, unless the subject 
agrees to schedule it for the next study visit. 
Should a patient discontinue study medication, but not withdraw consent, best efforts should be 
made by the site to collect all study data at the regular study assessment times through the closest 
of the following study visits:  Week 6, Week 12, Week 18 or Week 24/ET.  At this clinic visit, all 
assessments outlined for the EOS visit should be conducted. 
Should the subject decline to come into the site for an ET visit, an abbreviated version of the Week 
24/ET visit should be performed over the telephone. Sites should complete as many as the patient 
is willing/able to complete remotely. If the subject is unable or unwilling to complete any of these 
assessments, it will not be considered a protocol deviation. The following assessments are listed 
in order of importance and should be completed in that order, dependent on the subject’s 
willingness and capabilities: 
1. WOMAC – A (pain scale)  
2. WOMAC – C (functional scale)  
3. Patient Global Impression of Change (PGIC)  
4. Assessment of Analgesic Medication Use  
5. Concomitant Medications and Therapies 
6. Hospital Anxiety and Depression Scale (HADS)  
7. Drug Compliance  
8. Adverse Events 
9. Pain Catastrophizing Scale – Short Form 6  
10. PEG Scale  
11. PROMIS Sleep Disturbance Scale – 6A  
12. Sleep Duration Question  
13. PROMIS Physical Functioning Short-Form 6b  
14. Patient Health Questionnaire (PHQ)  
15. Depression Generalized Anxiety Disorder – 2 item scale (GAD-2)  
16. Tobacco, Alcohol, Prescription medication, and Other Substance use Tool (TAPS-1)  
17. Opioid Use Questionnaire (OUQ)  

 
 
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The eCRF Completion Guidelines and MOP will provide further instructions on data collection 
for the end of study visits.  
Failure to collect follow-up data despite best efforts will not be counted as a protocol deviation. 
Action items, instructions and script will be provided to site coordinators for tracking down and 
obtaining data from those patients who discontinued treatment. Logs will be kept for actions taken 
to reach each patient who discontinued treatment. 
If a subject is lost to follow-up, every effort should be made to contact the subject by telephone.  
Two phone calls followed by a certified letter should be documented before considering the subject 
lost to follow-up. 
For subjects who continue to be followed for safety, adverse events should continue to be reported 
as described in Section F.4. 
F.3.3. Discontinuation of Study 
This study may be suspended or discontinued in part or in whole, at any time. The study may be 
discontinued for a number of reasons, including but not limited to those listed below:      
● Excessive AE(s) - serious [i.e., an SAE]  
● It is determined that continuation in the study would be detrimental to subjects’ well-
being 
● At the discretion of a study oversight body, such as NINDS, IRB, DSMB, etc. 
● Loss of funding from the NIH 
F.3.3.1. Automatic Pausing/Stopping Criteria for Study 
If the study meets any of the following criteria at any time, the study must be stopped, and the data 
reviewed. These criteria will be monitored by the unblinded statistician or designee. 
a. If ≥ 2 serious adverse events (SAEs) occur in the CNTX-6970 300 mg / placebo cohort that 
are deemed to be possibly, probably or definitely related to the study drug, dosing will be 
stopped and available safety information will be reviewed to evaluate whether dosing in 
that arm should continue.  
b. If ≥ 2 subjects in the CNTX-6970 300 mg / placebo cohort experience Grade 3 or 4 AEs 
for vital signs, systemic effects, or laboratory abnormalities that are deemed to be possibly, 
probably or definitely related to the study drug as defined in the following guidance for 
industry, Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, available at, https://www.fda.gov/media/73679/download, 
dosing will be stopped and available safety information will be reviewed to evaluate 
whether the study should continue. 
The table below should be referred to when determining severity for non-systemic effects or if an 
AE is not listed in the FDA guidance. 
 

 
 
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Grade 
Grade Category 
Intensity Definition 
1 
Mild 
An AE that is usually transient and may 
require only minimal treatment of therapeutic 
intervention.  The event does not generally 
interfere with usual activities of daily living.) 
2 
Moderate 
An AE that is usually alleviated with 
additional specific therapeutic intervention.  
The event interferes with usual activities of 
daily living, causing discomfort but poses no 
significant or permanent risk of harm to the 
research subject 
3 
Severe 
An AE that interrupts usual activities of daily 
living, or significantly affects clinical status, 
or 
may 
require 
intensive 
therapeutic 
intervention 
4 
Potentially Life Threatening: Emergency Room visit or 
hospitalization 
 
c. Clinical study will be terminated if any death attributable to the 300 mg CNTX-6970 
treatment occurs. 
F.4. Specification of Safety Parameters 
F.4.1. Definition of an Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (CDER, 2012). 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. 
 
An adverse reaction means any adverse event that was likely to have been caused by a drug.  
Adverse reactions are a subset of all suspected adverse reactions for which there is reason to 
conclude that the drug caused the event. A suspected adverse reaction is any adverse event for 
which there is a reasonable possibility that the drug caused the adverse event. For this study, all 
events, whether or not related to the study drug, will be captured. 
 
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 baseline. 

 
 
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● Overdose of either study drug or concomitant medication without any signs or 
symptoms unless the subject is hospitalized for observation. 
● Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred). 
● Symptoms that are an expected part of knee OA, unless a significant change in severity 
or duration. 
● Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form.  
 
Adverse events will be recorded from the time informed consent is obtained. AEs should be 
assessed at each visit. All AEs for randomized patients must be either resolved or stable at the end 
of the study.  If ongoing at the end of the study, the subject should be referred for appropriate 
treatment.   
F.4.2. Definition of Serious Adverse Events 
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 immediately life threatening 
● Results in disability or permanent damage 
● Requires hospitalization 
● Prolongs existing hospitalization 
● Is a congenital anomaly or birth defect (in an offspring) 
● Is medically significant  
● 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. 
F.4.3. 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. 
F.4.4. Definition of Hospitalization  
Hospitalization is defined by NINDS as a full admission to the hospital for diagnosis and treatment.  
This includes prolongation of an existing in-patient hospitalization.  Hospitalization may include 
social hospitalization, defined as inadequate family support or care at the subject’s primary 
residence that results in the subject being admitted to the hospital (i.e., wound care, nutrition).  

 
 
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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, and protocol procedures 
F.4.5. 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. 
F.4.6. 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. 
F.4.7. Classification of an Adverse Event 
The description of each AE should use the following definitions: 
F.4.7.1. Severity of Event – as determined by the Investigator 
The severity of each AE will be graded on a 4-point scale and reported in detail as indicated on 
the eCRF. Vital signs, systemic effects, and laboratory abnormalities will be graded using the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, available at https://www.fda.gov/media/73679/download (See MOP 
Appendix M). 
As noted in the FDA guidance listed above, institutional laboratory reference ranges should be 
used when determining the severity of abnormal lab results, if appropriate. Due to variability in 
institutional laboratory reference ranges for amylase and lipase, ranges have been standardized 
across study sites. 
Please refer to protocol Appendix IV Amylase and Lipase Normal Ranges Memo_12Jan2024 for 
additional information.  
The table below should be referred to when determining severity for non-systemic effects or if an 
AE is not listed in the FDA guidance.  
 
Grade 
Grade Category 
Intensity Definition 
1 
Mild 
An AE that is usually transient and may require only minimal 
treatment of therapeutic intervention.  The event does not 
generally interfere with usual activities of daily living.) 

 
 
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F.4.7.2. Relationship to Study Agent – as determined by the Investigator 
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). 
• Definitely related 
• Probably related 
• Possibly related 
• Probably not related 
• Definitely not related 
 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 
• Response to cessation (de-challenge) or re-challenge 
• Compatibility with known drug class effects 
• Known effects of concomitant medications 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
F.4.7.3. Duration 
The duration of the AE should be recorded using the following criteria: 
• Start:  Date of the first episode of the AE or date of significant sustained worsening in 
severity 
• Stop:  Date when AE either ceased permanently or changed in severity 
o If AE has not resolved/recovered, document as ongoing 
In the event that a subject is withdrawn from the study because of an AE, the subject should be 
followed and treated by the investigator until the AE has resolved, stabilized, or a new chronic 
baseline has been established.  
2 
Moderate 
An AE that is usually alleviated with additional specific 
therapeutic intervention.  The event interferes with usual 
activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject 
3 
Severe 
An AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive 
therapeutic intervention 
4 
Potentially Life Threatening: Emergency Room visit or hospitalization 

 
 
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F.4.7.4. Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single:  Experienced once, without recurrence 
• Recurrent:  More than one discrete episode with the same severity 
F.4.7.5. Action Taken with Regard to Study Medication 
• Dose not changed 
• Drug withdrawn 
• Drug interrupted 
• Not applicable 
F.4.7.6. Outcome 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Fatal:  Death related to adverse event 
• Unknown 
F.4.7.7. Seriousness 
See Section F.4.2. for additional information about determining the seriousness of an AE. 
• Not serious 
• 
Serious 
F.4.7.8. Expectedness – as determined by the Investigator 
An AE is deemed unexpected (in terms of nature, severity, or frequency), given the information 
provided in research-related documents, such as the Investigator’s Brochure (IB), and the 
characteristics of the subject population being studied. 
An adverse event or suspected adverse reaction is considered "unexpected" if the event/reaction 
is: 
• Not listed in the IB;       
• Listed in the IB, but not at the specificity or severity that has been observed; or       
• Not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application (per 21CFR312.32). 
F.4.8. Reporting Procedures 
F.4.8.1. Adverse Event Reporting 
The investigator or designee must record all observed AEs and all reported AEs.  At each visit, the 
investigator or designee should ask the subject a nonspecific question (e.g., “Have you noticed 

 
 
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anything different since your last visit?”) to assess whether any AEs have been experienced since 
the last report or visit.  
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 as 
described above. 
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. 
F.4.8.2. Serious Adverse Event Reporting 
The reporting of serious adverse events (SAEs) to the NINDS, the IRB, and Food and Drug 
Administration (FDA) is a regulatory requirement. The EPPIC-Net CCC and DCC are responsible 
for reporting SAEs to NINDS. Each site is responsible for reporting SAEs at their site to the cIRB 
and their local IRB, as applicable. CCC is responsible for the reporting of SAEs to the FDA.  Each 
Regulatory Authority has established a timetable for reporting SAEs based upon established 
criteria. 
The investigator or designee will immediately report to the CCC any SAE, whether or not 
considered study intervention related. All SAEs, even those that are listed as expected in the 
protocol or IB, should be reported and must include an assessment of causality/relationship to 
study drug. The CCC will inform Centrexion of any SAEs that need to be reported for the 
Investigational New Drug (IND). 
All SAEs will be followed until satisfactory resolution or until the investigator deems the event to 
be chronic or the patient is stable. Other supporting documentation of the event may be requested 
by the DCC, CCC, NINDS, or Centrexion and should be provided as soon as possible.  
F.4.8.2.1. SAE Reporting Timeline 
The EPPIC-Net CCC will be responsible for notifying: 
● the FDA of any unexpected, fatal or life-threatening, suspected adverse reaction as soon as 
possible, but in no case later than 7 calendar days after CCC’s initial receipt of the 
information.   
● the FDA and all participating investigators in an IND safety report of potential serious 
risks, from clinical trials or any other source, as soon as possible, but in no case later than 
15 calendar days after the CCC determines that the information qualifies for reporting. 
For this study, sites will complete the electronic SAE and/or Pregnancy eCRF for initial reporting 
and any subsequent follow-up information.  The EDC system will send an automatic notification 
to the PI, the Medical Monitor, and any other study personnel, as required. 
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 

 
 
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experiencing an SAE will be seen by the investigator or designee as soon as is feasible following 
the report of the SAE. 
SAEs that occur after the study follow-up period 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.   
F.4.8.3. Unanticipated Problem Reporting 
An unanticipated problem is any incidence, experience, or outcome that is: 
• Unexpected (in terms of nature, severity, or frequency) given the information provided 
in research-related documents and the characteristics of the subject population being 
studied; 
• Related or possibly related to participation in the research; and 
• Suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
Advarra uses the following to determine whether something is an unanticipated problem involving 
risk to subjects or others: 
• Unanticipated or unexpected at the time of IRB approval; 
• Involved new or increased risk to subjects or others; and 
• Related to the research. 
F.4.8.4. Elective Procedures and Surgeries 
As a part of consenting, subjects are asked to affirm that are not planning to have any surgeries, 
invasive procedures, or IA injections of the index knee or any surgeries/procedures that are 
otherwise contraindicated during their participation the study (exclusion criterion #10).   
For the purposes of this protocol, the following conventions will apply for SAE reporting of 
elective procedures and surgeries: 
• A prescheduled elective procedure or a routinely scheduled treatment is not to be 
considered an SAE, even if the subject is hospitalized, provided the site stipulates that:  
o The condition requiring the prescheduled elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress 
between the subject’s consent to participate in the clinical trial and the time 
of the procedure or treatment. 
o The prescheduled elective procedure or routinely scheduled treatment is the 
sole reason for admission and intervention. 
• An untoward medical event occurring during the pre-scheduled elective procedure or 
routinely scheduled treatment should be recorded as an AE or an SAE.  Any concurrent 
medications should also be recorded on the eCRF. 
F.4.8.5. Other Reportable Information  
In addition, and for the purposes of monitoring, the following should be reported via the AE, SAE, 
and/or Pregnancy reporting forms, as appropriate: 

 
 
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• A new diagnosis of cancer 
• Instances of overdose of study drug (where there are associated symptoms) 
• Any occurrence of pregnancy (with or without AEs) 
F.4.8.6. Reporting of Pregnancy 
Women of childbearing potential are permitted in this study.  Women of non-childbearing potential 
are defined as those who have been postmenopausal for at least 12 months, who do not have a 
uterus, have had a bilateral tubal ligation, have undergone bilateral salpingectomy, and/or have 
had both ovaries removed. 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
discontinued from study treatment and the pregnancy must be reported on the pregnancy form.  
Any female subject who becomes pregnant during the study will be followed through the first well-
baby visit. Any AEs that are the consequence of pregnancy and that meet the criteria for serious 
should also be reported via the AE/SAE forms. 
F.5. Protocol Deviations and Violations 
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 under 
any circumstances.  If, during the course of a subject’s post-randomization participation in the trial, 
it is discovered that the subject did not meet all eligibility criteria, s/he 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 study investigator, with medical input from the PPI and 
the Medical Monitor and will be documented.  Whether or not the participant is allowed to remain 
in the trial, this will be reported as a major protocol deviation and not a waiver.   
All follow-up safety assessments must be completed and documented as outlined in the protocol.  
Protocol deviations and violations will be recorded in the eCRF (non-patient specific deviations 
will be documented in a log on Florence) and a monthly report will be generated by the DCC for 
review.  
 TREATMENT 
G.1. Dosing Schedule 
Study medication will be taken orally twice a day by the subject, with or without food. The  study 
medication will consist of two tablets. Doses should be taken at least 8 hours apart, but as close to 
12 hours apart as possible. 
G.2. Study Drug Packaging, Labeling and Administration 
CNTX-6970 will be provided as off-white, oval tablets in strengths of 100mg and 200mg and with 
matching placebo tablets. 
Sites will be provided with two (2) different kit types, each kit containing two (2) 60-count bottles 
as follows: 

 
 
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*PTM = Placebo to Match 
Each kit will contain the following information on the label:  
• Study number and IND number 
• Unique Kit number  
• Drug treatment label (each kit will include two bottles):  
o Bottle 1: CNTX-6970 100mg or placebo  
o Bottle 2: CNTX-6970 200mg or placebo  
• Route of administration 
• Directions for use 
• Storage conditions 
• Space for investigator name, telephone, dispensing date and subject number 
• Space for study subject identifier 
• Label statement “Caution:  New Drug-Limited by federal law to investigational 
use” 
• Label statement “Caution:  Keep out of reach of children” 
• Name and address of study drug distribution center 
 
Subjects will be instructed to take a tablet from each of the two bottles (bottles 1 and 2) twice a 
day with or without food. 
The first dose of the drug will be administered on site, to ensure that the patient understands the 
procedure. If the subject cannot take the first dose on site due to drug supply issues, the first dose 
can be taken at home. The site will schedule a phone or video teleconference (preferred) to ensure 
the participant understand the procedure before taking the first dose. 
G.3. Study Drug Receipt, Accountability, and Storage Conditions 
Study drug, or Investigational Product (IP), supplies will be received by the investigator or other 
authorized study personnel at the study site, managed and stored safely and properly, and kept in 
a secured location with restricted access. Shipping records, signed receipts, and IP inventory 
records should be maintained for all shipments of IP. Study staff with responsibility for drug 
management will keep accurate and complete records of study drug received by the site, dispensed 
to study subject, and used and returned by study subject.  If the site’s local policies do not require 
use of the research pharmacy, IP may be stored and managed by trained study team members, so 

 
 
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long as storage conditions are restricted/locked access, temperatures are monitored regularly, and 
the IP-related documentation is maintained appropriately. 
Study drug is to be stored at 20⁰C to 25⁰C (68⁰F to 77⁰F). Excursions are allowed between 15⁰C to 
30⁰C (59⁰F to 86⁰F). If a temperature excursion lasts longer than 24 hours or exceeds the allowed-
excursion range, the study drug should be quarantined and the study CCC Project Manager should 
be contacted immediately upon identification. The drug should remain in quarantine until it is 
confirmed by the CCC PM to be safe to use.  
Study drug will be dispensed by appropriately qualified staff as designated by the PI’s delegation 
of authority log. Subjects will self-administer the study drug at home following the instructions 
provided to the subject at the study visit. The PI or designee will retain returned study drug, or 
study drug supplies not dispensed to subjects, until the CCC provides written approval for 
disposition.  
The study case report forms and source documents will include prompts to record study subject 
eligibility to receive study drug, study drug dispensed, dosing start date, dosing end date, missing 
doses, and study drug returned. 
In accordance with local regulatory requirements, the investigator, designated site staff, or head of 
the medical institution (where applicable) must document the amount of investigational product 
dispensed and/or administered to study subjects, the amount received from the central 
pharmacy/site, and the amount destroyed upon completion of the study. If institutional policy does 
not allow the retention of IP for review prior to destruction, the site must have written approval 
from the CCC detailing how IP accountability will be handled in the absence of monitor review. 
The PI or designee is responsible for ensuring product accountability records are maintained 
throughout the course of the study. The inventory will include details of study drug received and 
dispensed to subjects. The site must receive written approval from the CCC prior to either 
destroying the remaining study drug or returning it to the Central Pharmacy or manufacturer. An 
accounting must be made of any drug deliberately or accidentally destroyed. Discrepancies 
between the amount of study drug received and dispensed drug must be reconciled. 
G.4. Possible Drug Interactions 
Drug-drug interactions (DDI) resulting from inhibition of transporters or cytochrome P450 (CYP) 
are unlikely to occur in humans; the mean maximum plasma concentration (Cmax) in humans after 
a single oral dose of 600mg is at least 18-fold lower than the concentration at 50% inhibition for 
the transporters studied. Additionally, CNTX-6970 was predominantly metabolized by CYP2C9 
with a minor contribution of CYP3A4. Concomitant use of CYP2C9 and CYP3A4 inducers and 
inhibitors is prohibited within 7 days of Baseline and during participation in this trial. P-
glycoprotein inhibitors are also prohibited, as CNTX-6970 is a P-glycoprotein substrate, unless 
use has been chronic for at least 3 months and stable for at least 1 month prior to Baseline. 

 
 
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G.5. Analgesic and Rescue Medications 
Subjects may continue use of tramadol, gabapentin, duloxetine, pregabalin, milnacipran, or a 
tricyclic antidepressant, if prescribed for pain and use is chronic for at least 12 weeks and at a 
stable dose for at least 4 weeks prior to Screening. Other continuous, chronic analgesic treatments 
are exclusionary.  
Some medications that may impact pain are used to treat non-pain indications. For this trial, 
continuous use of such medications, e.g. duloxetine for depression, may be continued throughout 
study participation, if the dose has been stable for at least 12 weeks prior to Screening. 
Additionally, continued use of low-dose aspirin for heart disease prophylaxis is allowed. 
Starting with the first visit, the only allowable analgesic rescue medications that can be taken for 
pain are acetaminophen and opioids (see Appendix III and MOP for additional details, including 
maximum daily dosing).  Intermittent use of opioids must have started at least four weeks prior to 
Screening; introduction of new opioid treatment during the study is prohibited. The amount of 
rescue medication(s) taken each day will be recorded by the subject in the NEForm app. 
G.6. Concomitant Medications 
For a full list of concomitant medications and their restrictions for use, please see Appendix III: 
Concomitant Medications.  
All concomitant medications taken during the study will be recorded in the Concomitant 
Medication Log for each patient, along with dosage information and start and stop dates. Allowed 
concomitant medications include any prescription or over-the-counter medication not specifically 
excluded by the protocol. In the present study, acetaminophen, opioids, and select anticonvulsants 
are the only permitted concomitant/rescue analgesic medication. Patients requiring excluded drugs 
will be discontinued from the study. If there are any questions regarding concomitant medications, 
contact the Medical Monitor. 
G.6.1. Prohibited Medications 
Subjects will be prohibited from using any experimental or investigational drug and/or use an 
experimental or investigational medical device within 30 days, or within a period of less than 5 
times the experimental drug’s half-life, prior to screening, whichever is longer, or may still be 
experiencing pharmacodynamic effects from an experimental drug as stated in the inclusion 
exclusion criteria. 
Subject will be prohibited from receiving therapy that is known to interfere significantly with drug 
metabolism or transport (within 7 days, or 5 half-lives (whichever is longer) of dosing with study 
drug. Exceptions will only be made if the rationale is clearly documented by the investigator, and 
discussed with the Medical Monitor. 
Medications that are not included in the above, but that may reasonably be expected to interfere 
significantly with the metabolism or excretion of CNTX-6970, that may be associated with a 
significant drug interaction with CNTX-6970, or that may pose a significant risk to the subject’s 

 
 
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participation in the study will be assessed on a case by case basis to determine, to the extent 
possible from the published literature, if they should be prohibited. 
The direct FDA link for all CYP2C9, CYP3A4, and P-GP interactions is: Drug Development and 
Drug Interactions | Table of Substrates, Inhibitors and Inducers | FDA 
 ETHICAL CONSIDERATIONS 
H.1. Risk/Benefit Assessment 
Subjects must be capable of understanding the nature of this study and its potential risks, 
discomforts, and benefits. Study physicians will obtain consent after they have fully explained the 
study purpose and its procedures, and potential Subjects have demonstrated an understanding of 
the protocol, willingness to participate, and competency to consent. 
H.2. Safety 
H.2.1. CNTX-6970 
The potential for reproductive and developmental toxicity with CNTX-6970 has been assessed in 
multiple species in several studies. All studies were negative indicating that there was no evidence 
of in vitro or in vivo genotoxicity. Similarly, studies conducted to evaluate potential for 
phototoxicity, dermal toxicity (sensitivity), immunotoxicity, and reproductive and developmental 
toxicity found no evidence for concern. In addition, there is little to no evidence of a proarrhythmic 
or cardiovascular risk of CNTX-6970. In human studies, CNTX-6970 was well tolerated at all 
doses tested and there were no potential or identified risks established for the drug. The most 
commonly reported adverse event was headache, which was mild in nature, and was reported by 
under 20% of Subjects. In the Phase I trials of CNTX-6970, no subjects experienced an SAE or 
AE that led to discontinuation from the study. There were no deaths in the study. There were no 
clinically meaningful changes from baseline in laboratory parameters, 12-lead ECGs, or physical 
examination findings observed in the study. Collectively, the safety profile of the drug appears to 
pose minimal risk. 
H.3. Informed Consent 
The investigator or delegated study team member must ensure that patients are clearly and fully 
informed about the purpose, potential risks, and other critical issues regarding clinical trials in 
which they volunteer to participate. Preparation of the consent form is the responsibility of the PI 
and must include all elements required by 21 CFR §50.25 and the central IRB. 
All subjects will receive the consent form for the study. These documents will be read by the 
patients and also reviewed by the patient with a delegated study team member on the research staff 
prior to participating in the study. Any questions, concerns, or ambiguities will be clarified by the 
PI or another study clinician prior to the patient signing consent. Subjects will sign informed 
consent and only then will begin participation in the study. 

 
 
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H.4. IRB Review 
Before study initiation, the PI must have written and dated approval/favorable opinion from the 
central IRB for the protocol, consent form, patient recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to patients. 
The PI will ensure the central IRB is provided with reports, updates, and other information (e.g., 
Safety Updates, Amendments, and Administrative Letters) according to regulatory requirements 
and institutional procedures. 
A detailed list of required regulatory documents also to be submitted to EPPIC-Net Clinical 
Coordinating Center will be sent upon final approval of the protocol. 
 DATA HANDLING AND RECORDKEEPING 
I.1. New England Survey Systems (NESS) NEForm 
Radiology image uploads, radiology image review data, SAFER Rater data, electronic Patient 
Reported Outcomes (ePROs), and electronic Informed Consent (eConsent/eICF) will be collected 
using a validated electronic data capture system (NEForm by NESS). NEForm has been 
successfully deployed in Medical/Dental Operations as well as Clinical Trials. NEForm is fully 
validated and compliant to 21 CFR Part 11, HIPAA, GDPR, and other standards.   
Data collected on the secure mobile application are stored locally on the mobile device, synced to 
a central server, and backed up on an off-location server. Data collected on the secure website are 
stored on a central server and backed up on an off-location server. Data collected are encrypted 
and uploaded/synced via additionally encrypted transmission to secure servers where access is 
limited according to the protocol.  Strict operating procedures are enforced to protect the 
confidentiality, integrity, and access of Protected Health Information (PHI) when it is stored, 
transmitted, and maintained. When any PHI is collected in NEForm and uploaded to NESS, such 
PHI data are ONLY accessible to designated staff at NESS and handled in accordance with NESS 
SOPs.  Such data are also only accessible to designated staff at the sponsor or the sponsor’s 
designee when such access is properly requested.  In such cases, the sponsor or sponsor’s designee 
would follow their own SOPs. 
The ePROs will be programmed by NESS and will include a notification system to patients 
reminding them to complete study activities.  Data will be maintained by NESS and provided to 
the DCC at specific time points throughout the study.  NESS will provide a dashboard that sites 
may access in order to ensure that patients are completing PROs at the appropriate timepoints.  
Sites are only able to see their own data.  The DCC and CCC will be able to review all sites’ data. 
Additionally, automated and text message reminders will be sent by NESS to remind study patients 
about off-site ePROs, rescue medication use, and IP compliance. 
For all data expected to be entered directly into NESS, paper source is permitted in the event of 
technical difficulties or other approved situational events. 

 
 
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I.2. Completion of EDC Forms  
An Investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
with the investigational product or entered as a control in the investigation. 
TrialMaster will be used as the Electronic Data Capture (EDC) system and managed by the DCC. 
The EDC system will include eCRFs designed to capture study information, which are completed 
by trained site staff. Patient reported outcomes and additional eCRFs will be captured in the NESS 
EDC system. Data entered directly into the eCRFs via a tablet or other data entry device will be 
considered as source.  Specific details of the procedures for Data Management are found in the 
Data Management Plan. 
For all data expected to be entered directly into TrialMaster, paper source is permitted in the event 
of technical difficulties or other approved situational events. 
 
I.3. Procedure for Corrections 
Query resolution will be performed and tracked within the EDC system, and completed by trained 
site staff. Specific details regarding EDC query flow are found in the Data Management Plan.  
I.4. Record Retention 
The PI must retain investigational product disposition records, case report forms, and source 
documents for the minimum period required by applicable regulations and guidelines or 
institutional procedures, and at least for 10 years. If the PI withdraws from the study (e.g., 
relocation, retirement), the records shall be transferred to a mutually agreed upon designee (e.g., 
another investigator, IRB, EPPIC-Net). Notice of such transfer will be given in writing to the 
EPPIC-Net CCC and NINDS. 
I.5. Data Confidentiality 
Potential risks to data confidentiality will be mitigated by requirements for the de-identification of 
all study data and by security protocols for all data capture systems. All users of the EDC system 
will be tracked and provided access in a secure fashion following established Standard Operating 
Procedures (SOPs) for this process. 
As with all research data, information gathered by the study will be used only for aggregate 
analysis; it will not be released with any information that identifies research Subjects. The data 
managers, statisticians, and PPI do not have access to the identities of patients. That information 
is retained only at the clinical sites. Uses and risks related to data collection will be outlined in the 
informed consent form and reviewed with the subjects. 
I.5.1. Certificate of Confidentiality 
This research is covered by a Certificate of Confidentiality (CoC) from the National Institutes of 
Health. The CoC protects subjects from the release or use of information, documents, or samples 

 
 
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without permission, including federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings. An example would be a court subpoena. The CoC does not prevent the subjects 
from willingly releasing information about their involvement in this research. 
 MONITORING AND OVERSIGHT 
Central IRB approval will be obtained and documented prior to subject enrollment and screening. 
J.1. Evaluation of Study Sites 
Potential study sites will be evaluated by EPPIC-Net to determine suitability for the proposed 
study. Information reviewed will include, but is not limited to, facility details and site capabilities, 
past performance in similar studies, investigator and staff experience, ongoing studies at the site, 
projected enrollment in this study, and FDA or other agency audit findings. Study sites may be 
asked to complete a study-specific Site Selection Questionnaire and other documents for 
consideration for participation and EPPIC-Net or clinical study monitors may make a Site 
Qualification Visit prior to completing the evaluation process. Upon completion of this evaluation, 
EPPIC-Net will invite the chosen sites for participation. 
J.2. Initiation of Study Sites 
Prior to subject enrollment, a study initiation visit will be completed at each investigational site to 
ensure the following: central IRB approval has been obtained and documented prior to subject 
screening, the investigators and study personnel are appropriately trained and clearly understand 
the study, the investigators and study personnel accept the obligations incurred in undertaking this 
clinical investigation. 
J.3. Periodic Monitoring Visits  
Qualified clinical monitors or qualified contract monitors representing EPPIC-Net will conduct 
investigational site monitoring visits to ensure that all investigators conduct the study in 
compliance with the protocol and applicable regulations. The site will receive notification prior to 
each monitoring visit during the course of the study. It is expected that the PI and/or Sub-
Investigator(s) and other appropriately trained study staff are available on the day(s) of the visit in 
case any questions might arise. 
Periodic monitoring visits will be made in accordance with the approved monitoring plan at all 
active study sites throughout the clinical study to assure that the PI obligations are fulfilled and all 
applicable regulations and guidelines are being followed. These visits will assure that the facilities 
are still acceptable, the protocol and investigational plan are being followed, the central IRB has 
been notified of approved protocol changes as required, complete records are being maintained, 
appropriate and timely reports have been made to the EPPIC-Net and the central IRB, and the PI 
is executing all agreed activities. 
EPPIC-Net retains the right to remove either the PI or the investigational site from the study for 
issues of non-compliance with the protocol or regulatory requirements, in accordance with its 
SOPs. 

 
 
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On one or more occasions, the study site may be inspected or audited by an EPPIC-Net 
representative or a third party. The PI will be informed in advance of this visit. 
J.4. Risk-Based Monitoring 
EPPIC-Net will employ a protocol-specific Risk Based Monitoring (RBM) plan to ensure a 
robust quality control method for determining and enabling dynamic management of study risks 
and facilitating ongoing improvement in the trial conduct and oversight. The Acuity RBM 
system uses tools and dashboards to identify Key Risk Indicators (KRIs), which highlight 
potential issues with (for example) trial conduct, safety, data integrity, compliance, and 
enrollment, that may require further monitoring from a qualified contract monitor.  
J.5. Suspension and Early Termination of a Site 
The policies and procedures for the suspension or early termination of a study at a Clinical 
Study Site (i.e. Hub or Spoke participating in a particular clinical trial) are described in EPPIC-
Net SOP Suspension and Early Termination of a Site. Circumstances that may necessitate 
invoking early termination or suspension of a site include but are not limited to: 
• Enrollment at a site below expectation  
• Protocol violations at the study site that place study subjects at risk of serious harm 
or that render the study data from that site untrustworthy or invalid 
• Continuing or serious noncompliance by study investigators with regard to the 
protocol or regulations 
• Any other site event that increases Subject risk of serious harm or undermines the 
integrity of the study 
• Request of the site 
The study can be suspended or terminated unilaterally at a site by the NIH, FDA, the central 
IRB, the local IRB (if applicable), or upon recommendation from the NINDS Data and Safety 
Monitoring Board (DSMB). The EPPIC-Net Study Trial Committee will receive concerns 
about site study suspension or termination, investigate, and determine if study should be 
suspended or terminated at a site, based on the above criteria. 
J.6. Direct Access to Source Data/Documents 
Subcontracts with study sites will specify that EPPIC-Net or its representatives will have direct 
access to source data and documents for study monitoring. Additionally, the central IRB, NINDS, 
and FDA may review source data following appropriate guidelines for this process. 
J.7. Interim Analysis 
No interim analysis is planned for this study.  
J.8. Medical Monitoring 
The Medical Monitor for this trial will be designated by EPPIC-Net. The Medical Monitor will 
review all adverse events, assess the benefits and risks of protocols on an ongoing basis, and work 

 
 
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in collaboration with the PPI to identify safety signals and trends, in accordance with the approved 
medical monitoring plan. 
In addition, the Medical Monitor will be available to sites for questions regarding 
inclusion/exclusion criteria, protocol conduct, and safety. Trained and qualified EPPIC-Net staff 
physicians will be available to provide coverage during times when the Medical Monitor is 
unavailable. Sites will be provided with the Medical Monitor’s cell phone number for emergency 
situations. Otherwise, sites are instructed to contact the Medical Monitor through email. Each 
month the Medical Monitor will receive a listing of protocol violations for review and 
identification of possible trends. 
Serious adverse events will be reported to EPPIC-Net by the site within 24 hours of the site’s 
knowledge of the event. In addition, the Medical Monitor may request individual patient records, 
including laboratory data, clinical records, and other study related data, to evaluate these events 
against the known safety profile of the study treatment and the disease. Any records sent to the 
Medical Monitor by the site will be redacted for any identifying information before transmission. 
The Medical Monitor may recommend actions including partial or complete unblinding, and/or 
modifying or terminating the study. In addition to safety monitoring, the Medical Monitor may 
review enrollment data, demographic information, retention status, and other reports prepared by 
the study statistician that describe study performance and progress.  
J.8.1. Urgent Clinical Situations 
During the course of the study, a patient will be reassessed for continued participation based on 
clinical judgment of the investigators. All subjects will be offered access to 24/7 coverage for 
medical emergencies through the clinical staff at each site. Treatment options and their risks and 
benefits, including continued study participation and other treatment options, will be sensitively 
explained. All study investigators have extensive clinical experience in the treatment knee OA, 
and can make the decision (while blinded) as to removal of subjects from the trial, particularly in 
the event of clinical deterioration. When a patient is removed from the trial based on clinical 
judgment, investigators will implement an appropriate treatment plan and arrange for follow-up 
for the patient. 
J.9. The Data and Safety Monitoring Board (DSMB)  
The NINDS DSMB will review the progress of the study and will monitor patient intake, 
outcomes, adverse events, and other issues related to patient safety. Interim, independent, and 
unbiased reviews of the study's ongoing progress will be provided. The DSMB will consist of 
experts in the study’s subject matter field(s), clinical trials, biostatistics, and ethics. These 
individuals will not be Subjects in the trial and will not have participated in the planning of the 
protocol. The DSMB will consider safety or other circumstances as grounds for early termination, 
including either compelling internal or external evidence of treatment differences or the 
infeasibility of addressing the study hypothesis (e.g., poor patient intake, poor adherence to the 
protocol).  
At each of its meetings during the study period, the DSMB will review the randomization rates 
and assess the difference between the actual and the projected rates, as well as the impact of these 

 
 
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assessments on overall trial size. If the study enrollment is inadequate, the reasons for exclusion 
may be scrutinized and actions may be suggested. An assessment of whether the trial should be 
continued will be made. The DSMB makes recommendations after each meeting to the NINDS 
Director about whether the study should continue or be stopped. 
J.10. The Central IRB (Advarra) 
The Central IRB will be the IRB of record for all sites. They will monitor the study’s serious 
adverse events and review deviations on a continual basis. They will conduct annual reviews of 
the study.  
 DATA ANALYSIS 
K.1. General statistical considerations 
The general approach for inference for most of our aims will utilize a mixed-effects multi-period 
crossover model with 2 blocks and 2 treatment periods per block (of length 6 weeks). This model 
will be used to access the efficacy CNTX-6970 (300mg BID). Data will be analyzed on an intent-
to-treat (ITT) basis with a per protocol analysis set used as a supportive analysis. Additionally, 
modified ITT (mITT) data sets will be prepared for supportive analyses to access the impact of the 
changes in the eligibility criteria across the different protocol versions. 
In order to account for possible carryover effects, the multi-crossover model will incorporate 
carryover effect terms when appropriate. Only carryover effects from active to placebo will be 
formally tested, but a carryover effect from placebo to active will be studied in an exploratory 
fashion. 
A patient who remains in the study for the first two treatment periods or for all four treatment 
periods will receive a balanced exposure to treatments randomized to receive.  If patients 
discontinue treatment prior to completing the entire 24 weeks of study, all their data (including 
weekly assessments) from their time in the study will be used in the analyses. Because the main 
analysis is based on maximum likelihood estimation using a mixed-effects multi-period crossover 
model, the inferences will be unbiased under missing at random assumptions. No imputation of 
missing data is planned for this study, unless intensive investigations indicate that reliable and 
valid data imputation is possible, in which case multiple imputation will be performed and the 
analysis of the imputed data sets will serve as a sensitivity check of the results from the primary 
analysis based on the mixed-effects models (van Buuren et al, 2011).  
All analyses will adjust for age, sex, K-L grade, and site. 
All hypothesis tests will be two-sided using 5% significance level, and p-values unadjusted for 
multiple testing will be reported. The justification for this decision is that this is a Phase II 
investigation and all assessed outcomes are of specific and unique interest. Much more important 
than testing hypotheses is the efficient estimation of all quantities of interest, and this will be 
carried out throughout the analyses. Point estimates, 95% confidence intervals and standardized 
effect sizes (e.g., Cohen’s d) will be reported for all estimated effects, regardless of whether the 
null hypotheses were rejected or not. 

 
 
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K.2. Hypothesis testing 
Aim 1: Assess the safety of CNTX-6970 (300mg BID).  
There will be no formal hypothesis testing under Primary Study Aim 1. All AEs and SAEs 
observed during different treatment periods will be summarized based on severity and relation to 
the active treatment (CNTX-6970 300mg BID). The reports will include tabulation of the AEs and 
SAEs by period, block, and treatment; point estimates and 95% CIs will be reported. Similarly, we 
will summarize relevant laboratory measures (see Section F.2.1) with appropriate estimates.  
 
Aim 2: Assess the efficacy of CNTX-6970 (300mg BID) in comparison to placebo with respect to 
the primary outcome measure for pain due to osteoarthritis of the knee - WOMAC Part A. 
WOMAC Part A (WOMAC-A) assessed only in the last two weeks of each 6-weeks treatment 
period will be used for this primary analysis in order to avoid any carryover effects, which are 
expected to vanish after 4 weeks; the specific carryover effect of the two doses of CNTX-6970 
will be studied under Aim 3.  
HYPOTHESIS 1: CNTX-6970 300mg BID is superior to placebo with respect to symptoms 
measured by WOMAC Part A.  
The hypothesis testing is based on the WOMAC-A assessed only in the last 2 weeks of each 6-
week treatment period.  This provides a more than adequate 4-week washout interval.  The 
adequacy of this 4-week period is based on extensive pharmacokinetics (PK) and 
pharmacodynamics (PD) of the study agent. The PK/PD analyses were performed for single dose 
and multiple ascending dose (MAD) studies using both QD and BID dosing regimens. For the 
single dose study, the PK study showed that the mean half-life ranged from 15.8 to 16.6 hours.  
For PD, the CNTX dossier reports that “… based on the half-life of CNTX-6970 determined in 
humans it is estimated that the duration of the PD may be between 8-12 hours.”  Specifically, after 
two doses of 300mg the plasma level is 10ng/ml 36 hours after dosing.  The PD effect is less than 
50% at 10ng/ml based on the MCP-1 interaction with CCR2. Hence, we anticipate a more than 
adequate washout period. Additionally, under Aim 6 (see below), we explicitly study the potential 
carryover effects in the statistical modeling.  The statistical models will utilize a standard approach 
to adjust for carryover effects in a multi-period crossover design when estimating treatment effects, 
and allows for testing for the existence of carryover effect (Chen and Chen, 2014). 
Aim 3: Assess the efficacy of CNTX-6970 (300mg BID) in comparison to placebo with respect to 
secondary outcome measures related to OA of the knee: (a) WOMAC-C (function subscale), (b) 
Hospital Anxiety and Depression Scale (HADS), (c) Patient Global Impression of Change (PGIC), 
(d) PROMIS Sleep Disturbance Scale – 6A, (e) Sleep Duration Question, and (f) Daily Knee Pain 
Intensity on a 0-10 NRS. 
HYPOTHESIS 2: CNTX-6970 300mg BID is superior to placebo with respect to symptoms 
measured by (a) WOMAC-C (function subscale), (b) Hospital Anxiety and Depression Scale 
(HADS), (c) Patient Global Impression of Change (PGIC), (d) PROMIS Sleep Disturbance Scale– 
6A, (e) Sleep Duration Question, and (f) Daily Knee Pain Intensity on a 0-10 NRS. 

 
 
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Outcomes (a) and (f) are assessed at baseline and each study visit through week 24. Outcome (b) 
will be assessed at each in-person visit except baseline. Outcome (c) will be assessed at week 3 
and week 24 only. Outcome (d) will be assessed at baseline and each in-person visit through week 
24. Outcome (e) will be assessed at baseline and week 24 only. The analysis plan for outcomes 
(a), (b), (d), and (f) will be similar to the analysis for aim 2 except that the model will adjust for 
possible carryover effects in placebo-treated periods that are preceded periods with the active drug 
treatment; the analysis plan for outcomes (c) and (e) will follow the same approach as in aim 4 
below. 
Aim 4: Assess the efficacy of CNTX-6970 (300mg BID) in comparison to placebo with respect to 
general outcomes of pain: (a) Pain Catastrophizing Scale –Short Form 6, (b) PROMIS Physical 
Functioning Short-Form 6b, (c) Patient Health Questionnaire (PHQ) – Depression, (d) Generalized 
Anxiety Disorder – 2 item scale (GAD-2); (e) Tobacco, Alcohol, Prescription medication, and 
other Substance use Tool (TAPS-1); and (f) Opioid Use Questionnaire.  
HYPOTHESIS 3: CNTX-6970 300mg BID is superior to placebo with respect to outcomes 
measured by (a) Pain Catastrophizing Scale –Short Form 6, (b) PROMIS Physical Functioning 
Short-Form 6b, (c) Patient Health Questionnaire (PHQ) – Depression, (d) Generalized Anxiety 
Disorder – 2 item scale (GAD-2), (e) Tobacco, Alcohol, Prescription medication, and other 
Substance use Tool (TAPS-1), and (f) Opioid Use Questionnaire.  
Outcomes (a)-(f) are assessed at baseline and week 24. Testing hypotheses for these outcomes will 
not benefit from the multi-period crossover design because they are assessed only at baseline and 
week 24. Instead, we will test the hypotheses by comparing subjects taking active drug versus 
placebo at the last treatment period ending on week 24, controlling for the baseline value of the 
outcome.   
Aim 5: Assess the efficacy of CNTX-6970 (300mg BID) in comparison to placebo with respect to 
biomarkers of pain and inflammation: (a) Staircase-Evoked Pain Assessment, (b) Serum and 
synovial fluid levels of chemokines and cytokines; and (c) Synovial monocyte chemoattractant 
protein-1/CCR-2 receptor binding inhibition in blood and synovial fluid. 
 
 
HYPOTHESIS 4: Compared to placebo, CNTX-6970 300mg BID will result in more improvement 
with respect to (a) Staircase-Evoked Pain Assessment, (b) Serum and synovial fluid levels of 
chemokines and cytokines; and (c) Synovial monocyte chemoattractant protein-1/CCR-2 receptor 
binding inhibition in blood and synovial fluid. 
 
The Staircase-Evoked Pain Assessment will be assessed at Baseline and each in-person study visit 
through Week 24 (Week 3, 6, 9, 12, 15, 18, 21, and 24/ET visits).  
 
Hypothesis 4 will be tested with the same approach as for testing the hypotheses under Aim 3.  
K.3. Exploratory analyses 
Aim 6. If CNTX-6970 is more effective than placebo, evaluate the following characteristics of its 
effect: (a) onset of action; (b) carryover effect after treatment discontinuation.  

 
 
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We will study the change of symptoms over time using a time trend in our statistical models within 
each of the 6-week treatment periods to model the weekly WOMAC-A measure.  
Under this aim, the interest is not in hypothesis testing, but rather in understanding the progression 
and magnitude of onset of action and the carryover effects of the CNTX-6970 compound. This 
approach will allow an elucidation of the nature of action of the compound.  
Aim 7. Identify biomarkers related to pain from OA of the knee, course of the disease, and response 
to treatment with CNTX-6970.  
Statisticians on the study team have published methods for analysis of complex multimodal data, 
such as EEG and brain imaging for developing optimal treatment decision (e.g., Ciarleglio et al, 
2018; Jiang et al, 2020; Park et al, 2020a; Park et al, 2020b; Petkova et al, 2020), one of the 
objectives of precision medicine. Although this previous work has been primarily motivated by 
mental health research (e.g., depression), the methodologies developed apply equally to pain and 
other medical conditions. As necessary, new methodologies will be developed for the joint analysis 
of outcome measures.  
 
The results of these investigations are expected to be features (for example, the variability of pain 
across days) or combinations of features that constitute biosignatures for specific response to 
CNTX-6970, placebo response, or non-specific response to both an active agent and placebo.  For 
all indices and estimates, we will perform extensive internal cross-validation. All results from these 
discovery analyses will be reported as exploratory and subject to independent validation. The 
interpretation of the results will also be in the context of all analyses that were performed, and will 
emphasize the discovery nature of the work. 
  
Aim 8:  Explore sociodemographic and clinical predictors of response to CNTX-6970. 
 
The rich data collection will allow for exploration of the relationship between treatment with 
CNTX-6970 and placebo, and sociodemographic and clinical covariates. No hypotheses will be 
tested under this aim. Rather various research questions will be addressed, such as:  
 
Q1: Do women show a greater reduction in pain ratings following CNTX-6970 compared to 
placebo, relative to men? 
Q2: Do patients with high levels of psychological distress show a greater reduction of pain with 
CNTX-6970, relative to patients who do not have high levels of psychological distress?  
K.4. Sample Size 
The sample size for this study was determined based on the primary efficacy aim to detect a 
significant effect of each dose of CNTX-6970 compared to placebo in the multi-period crossover 
design model.  Power was computed for effect sizes ranging from 0.25 to 0.50 using Monte Carlo 
simulation. Data were simulated from multi-period crossover models with block, period, and 
carryover effects, and varying within and between subject variability.  Although carryover effects 
can be efficiently isolated and estimated in the analysis stage by using mixed-effects models, 
power for the primary hypothesis was computed using only WOMAC-A assessed during the last 
2 of 6 weeks per treatment period to minimize carryover effects. The power of the test depends on 

 
 
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the relationship of the between-subject variability to the within-subject variability. In general, the 
between-subject variability is larger than the within-subject variability, but we investigated a range 
of Between/Within (B/W) variance ratios (5/1, 2/1). With a total sample size of n=55, there will 
be more than adequate power for the study using a two-sided Type I error rate of α=0.05. A power 
analsyis was conducted with n=50 and the power to detect an effect size (for an active treatment 
vs. placebo) of Cohen’s d=0.35 is approximately 95% when the ratio B/W=2/1.  Assuming a 15% 
early termination rate during each of the 4 periods will yield a sample size of n=26 with complete 
observations at all treatment periods for this simulation. If we conservatively assume that only 
subjects with complete data will be analyzed, the corresponding power with n=26 is approximately 
81%. Because we will use all available data from all enrolled subjects in the analysis, the actual 
power in the case of 15% early termination rate per treatment period will be larger than 81%, and 
anywhere between 81% and 95%.   If the ratio B/W is larger than 2, say B/W=3, 4 or 5, the power 
for detecting the treatment effects is much larger. For example, with only 26 patients, if B/W=5, 
the power to detect an effect of magnitude Cohen’s d=0.35 is 0.96. Note that the reported test-
retest reliability of the WOMAC-A measure is 0.86, which corresponds to a B/W=7.  
 
Figure 2: Power versus Cohen’s d effect size. B/W indicates the ratio of between-subject to within-
subject variance of the WOMAC-A measure.   Assuming that only data from completers will be 
used in the analysis gives a lower bound of the power that can be achieved for the given range of 
effect sizes. 
 PUBLICATION POLICY 
See EPPIC-Net Publication Policy. 
 
 
 

 
 
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 INVESTIGATOR STATEMENT 
 
EN20-01: A 24-WEEK STUDY TO EVALUATE THE SAFETY AND EFFICACY OF 
CNTX-6970 IN SUBJECTS WITH MODERATE TO SEVERE KNEE OSTEOARTHRITIS 
PAIN 
VERSION 9.0 22JAN2024 
 
Principal Investigator Signature Page 
I confirm that I have read the above EN20-01 protocol version 9.0, dated 22Jan2024.  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 GCP and as described in 21 CFR parts 50, 54, 56, and 312 
and according to applicable local requirements. I will ensure all site staff delegated to the study 
are appropriately trained on this version of the protocol. 
 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal 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 NINDS. 
 
Principal Investigator: 
 
 
 
Signature 
 
Date 
 
 
 

 
 
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 APPENDICES 
Appendix I: BLINDED INFORMATION 
Available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix II: Cytokines & Chemokines (from the Inflammation MAP Multiplex panel): 
Adiponectin 
 
Alpha-1-Antitrypsin 
Alpha-2-Macroglobulin 
 
Apolipoprotein(a) 
Beta-2-Microglobulin  
Brain-Derived Neurotrophic Factor 
C-Reactive Protein 
 
Complement C3 
EN-RAGE 
 
Eotaxin-1 
Factor VII 
 
Ferritin 
Fibrinogen 
 
Granulocyte-Macrophage Colony-
Stimulating Factor 
Haptoglobin  
Immunoglobulin A 
Immunoglobulin M 
 
Intercellular Adhesion Molecule 1 
Interferon gamma 
 
Interleukin-1 alpha 
Interleukin-1 beta 
 
Interleukin-1 receptor antagonist 
Interleukin-10  
Interleukin-12 Subunit p40 
Interleukin-12 Subunit p70 
 
Interleukin-17 
Interleukin-18  
Interleukin-2 
Interleukin-23  
Interleukin-3 
Interleukin-4  
Interleukin-5 
Interleukin-6  
Interleukin-7 
Interleukin-8  
Macrophage Inflammatory Protein-1 alpha 
Macrophage Inflammatory Protein-1 beta 
Matrix Metalloproteinase-3 
Matrix Metalloproteinase-9  
Monocyte Chemotactic Protein 1 
Myoglobin 
 
Plasminogen Activator Inhibitor 1 
Pulmonary and Activation-Regulated 
Chemokine 
 
Serum Amyloid P-Component 
Stem Cell Factor 
 
T-Cell-Specific Protein RANTES 
Thyroxine-Binding Globulin  
Tissue Inhibitor of Metalloproteinases 1 
Tumor Necrosis Factor alpha  
Tumor Necrosis Factor beta 
Tumor necrosis factor receptor 2 
 
Vascular Cell Adhesion Molecule-1 
Vascular Endothelial Growth Factor  
Vitamin D-Binding Protein 
von Willebrand Factor 
 
 

 
 
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Appendix III: Concomitant Medications 
Subjects who take prohibited concomitant medications during the trial 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 a site investigator (PI, 
clinical Sub-I), and will be documented.  Whether or not the participant is 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.  Medications within each class include, but are not limited to, examples 
listed in this table.  Any questions regarding prohibited and restricted medications should be 
discussed with the Medical Monitor or appropriate designee. 
The direct FDA link for all CYP2C9, CYP3A4, and P-GP interactions is: Drug Development and 
Drug Interactions | Table of Substrates, Inhibitors and Inducers | FDA 
Drug Name or 
Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Analgesics 
Y 
Y 
Acetaminophen, opioids, and select anticonvulsants 
are allowed as a rescue medication (as described in the 
respective sections). Other analgesics as specified 
below:  
Continuous use of one of the following medications 
prescribed for pain is allowed: tramadol, gabapentin, 
duloxetine, pregabalin, milnacipran, or tricyclic 
antidepressants. Use must be chronic for at least 12 
weeks and at a stable dose for at least 4 weeks before 
Screening. 
Intermittent use of opioids is allowed if use is ongoing 
for at least 4 weeks before Screening, and at a 
frequency no more than 4 days/week, and the opioid is 
not taken within 24 hours of a study visit. 
As needed use of acetaminophen is allowed. 
Continuous use of medical marijuana (or equivalent) 
that is chronic for at least 12 weeks and at a stable 
dose for 4 weeks is allowed. 
Continuous use of topical creams (includes CBD 
topicals) is allowed if use is chronic and stable for at 
least 12 weeks. 
Intermittent use of topical creams is allowed if at a 
frequency of no more than 4 days/week. 
Other analgesics (for example, NSAIDS) are not 
allowed. 

 
 
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Drug Name or 
Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Anesthetics, 
general 
Y 
— 
If procedures requiring general anesthesia are to 
occur/have occurred, please contact MGH CTNI to 
report the medical condition(s). 
Anesthetics, local 
Y 
N 
— 
Anorexics 
N 
N 
— 
Antacids 
Y 
Y 
— 
Antiacne 
Y 
Y 
Topical agents only, including topical antibiotics. 
Isotretinoin (Accutane) is not allowed. 
Antianginal 
agents 
N 
 
 
N 
 
 
Calcium agonists (e.g. diltiazem, nifedipine, 
verapamil) and beta blockers (e.g. carvedilol, 
propranolol, metoprolol) are excluded if used to 
treat angina.— 
 
 
Antiarrhythmics 
N 
N 
Amiodarone is excluded. 
Antiasthma agents 
Y 
N 
— 
Antibiotics 
Y 
Y 
Chronic use of topical antibiotics for acne is 
allowed, except for the MAOI linezolid (Zyvox) 
and isoniazid, which are not allowed. Erythromycin, 
clarithromycin, rifampin, and azithromycin are 
excluded. 
Anticoagulants 
N 
N 
Common drugs include: Warfarin (Coumadin) is not 
allowed. Antiplatelet agents are allowed (see 
“Antiplatelets”). 
Anticholinergics 
Y 
Y 
Except for scopolamine, which is not allowed. 
Anticonvulsants 
N 
Yb 
Gabapentin, and pregabalin are allowed. Other 
anticonvulsants are not allowed, including 
lamotrigine and carbamazepine. 
 

 
 
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Drug Name or 
Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Antidepressants 
N 
Yb 
Monoamine oxidase inhibitors (which may have 
unknown drug-drug interactions) are excluded.  
Concomitant use of trazodone (up to 200mg daily),
nefazodone or duloxetine are allowed No dose 
changes are allowed during the study. 
Antidiarrheal 
preparations 
Y 
N 
Only 
loperamide 
HCl 
(Imodium), 
bismuth 
subsalicylate 
(Pepto-Bismol), 
and 
kaolin 
preparations are allowed. 
Antifungals, 
systemic 
N 
N 
 
Antifungals, 
topical 
Y 
Y 
 
Antihistamines 
Y 
Y 
The 
use 
of 
combinations 
containing 
pseudoephedrine or phenylephrine is not allowed. 
Combination 
products 
containing 
the 
word 
nighttime or are specifically marketed for before 
sleep routinely include an antihistamine and are not 
allowed. Combination products ending in “-D” 
routinely contain a stimulant such as phenylephrine, 
and the appropriate limits above apply to them. (See 
“Cough and Cold Preparations” for combination 
products.) 
Antihypertensives 
N 
Y 
Diltiazem, verapamil are excluded 
Anti-impotence 
medications 
Y 
Y 
— 
Anti-
inflammatory 
drugs 
Y 
N 
Indomethacin (Indocin) and systemic 
corticosteroids are not allowed for PRN or chronic 
use. NSAID use is exclusionary. 
Antimigraine 
N 
N 
Common one includes: Triptans not allowed. 
 
 
 
 

 
 
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Drug Name or 
Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Antinauseants/ 
Antiemetics 
Y 
N 
Phosphoric 
acid 
preparations 
(Emetrol, 
Emecheck), bismuth subsalicylate (Pepto-Bismol), 
cola syrup, 5-HT3 receptor antagonists (e.g., 
ondansetron), 
and 
prokinetic 
agents 
(metoclopramide) are allowed only for PRN.  
Scopolamine is not allowed for PRN or chronic use 
(see section on antihistamines). 
Antineoplastics/ 
Immunosuppressa
nt agents 
N 
N 
Common drugs include: Interferons, methotrexate, 
and other immunosuppressant agents are not 
allowed. Call MGH CTNI for approval for certain 
cases in cancer remission maintaining therapy. 
Antiobesity/ 
Appetite 
suppressants 
N 
N 
Common drugs include: OTC Alli (Xenical), 
sibutramine (Meridia), and phentermine (Adipex-P 
and others) are not allowed. 
Antiplatelet 
agents 
N 
Yb 
Aspirin (maximum 325 mg/day) and clopidogrel 
(Plavix) are allowed. Note that use of an SSRI or of 
a triple uptake inhibitor may increase bleeding 
times and possibly prothrombin times. 
Antipsoriatic 
treatments 
Y 
Y 
Only topical agents are allowed. Acitretin 
(Soriatane) is not allowed. 
Antipsychotics 
N 
N 
— 
Antismoking 
medications 
N 
N 
Common drugs include: Varenicline (Chantix) is 
not allowed. Chronic nicotine replacement may be 
allowed in certain cases after review with MGH 
CTNI. 
 
 
 
 
 
 
 
 
 

 
 
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Drug Name 
or Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Antiviral agents 
Y 
Y 
Only oral or topical agents are allowed.  
Only 
acyclovir, 
famciclovir, 
valacyclovir, 
penciclovir, docosanal, trifluridine, and vidarabine 
are allowed.  
Amantadine, rimantadine, indinavir, nelfinavir, 
ritonavir, saquinavir are not allowed. Tamiflu 
(oseltamivir phosphate), and Relenza (zanamivir) 
inhalants are permitted for influenza prophylaxis but 
use is limited to a 7- to 14-day course in accordance 
with prescribing information. 
Interferons are not allowed. Boceprevir (Victrelis®) 
is not allowed. 
Anxiolytics 
N 
Y 
Chronic, stable treatment with benzodiazepines is 
allowed. Stable in dosing at least four weeks prior to 
randomization is required. 
Barbiturates 
N 
N 
Benign prostatic 
hyperplasia 
treatments 
N 
Yb 
Male patients who have symptoms of obstructed 
voiding should not be included in the study. 
Surgically or medically treated patients must be 
asymptomatic and receiving a stable dosage of 
allowed medications (α-1 blockers, finasteride, or 
dutasteride) for 1 month before screening. 
Buspirone 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Cough/cold 
preparations 
Y 
N 
Use of cough and cold preparations containing 
pseudoephedrine or dextromethorphan is not allowed, 
as are those containing phenylephrine. Combination 
products ending in “-D” routinely contain a stimulant 
such as phenylephrine, and the appropriate limits 
apply to them. (See “Antihistamines”.) 
Diuretics 
Y 
Yb 
Episodic use of diuretics is restricted to treatment of 
premenstrual symptoms. For chronic use, medication 
and dosage should be stable for 1 month before 
screening. 

 
 
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Drug Name 
or Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Dopaminergics 
N 
Y 
Common drugs include: Dopamine agonists for 
restless leg syndrome are allowed for chronic use. 
Gastrointestinal: 
● H2-blockers/ 
● proton pump 
inhibitors/ 
● prokinetic 
agents 
Y 
Y 
Cimetidine 
(Tagamet),) 
metoclopramide, 
omeprazole and pantoprazole are not allowed within 
7 days of Baseline. 
Hormonal 
(noncontraceptive
) therapies 
N 
Y 
See below. 
Hormone 
suppressants 
N 
Yb 
Only finasteride (Proscar) and dutasteride (Avodart) 
are allowed for chronic use. 
Bromocriptine (Cycloset, Parlodel) is not allowed 
Hormones: 
reproductive 
N 
Y 
Systemic 
hormonal 
contraceptives 
(oral 
contraceptives 
of 
estrogen 
and 
progestin 
combinations, depot injections such as Depo-Provera, 
the contraceptive implant Implanon, or transdermaslly 
delivered contraceptives such as Ortho Evra) are 
allowed 
Hormones: 
thyroid 
N 
Y 
Thyroid hormone replacement is allowed (dosage of 
thyroid medication should be stable for 3 months 
before screening).  
Hypoglycemic 
agents 
N 
Y 
Oral and injectable hypoglycemic agents are allowed.
Insulin is not allowed 
Hypolipidemics 
N 
Yb 
Common drugs includes: Ezetimibe (Zetia) is allowed
for chronic use. 
Hypolipidemics: 
bile acid 
sequestrants 
N 
N 
— 
Hypolipidemics: 
fibrates 
N 
Yb 
Common drugs include: Gemfibrozil and fenofibrate 
are allowed for chronic use. 
Hypolipidemics: 
niacin 
N 
N 
Common drugs include: Oral niacin and niacinamide 
are not allowed 
Hypolipidemics: 
statins 
N 
Yb 
Lovastatin, simvastatin, pravastatin, fluvastatin, and 
rosuvastatin are allowed 

 
 
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Drug Name 
or Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Laxatives 
Y 
Ya 
Only fiber-based products and docusate sodium 
(Colace) are allowed 
Lithium 
N 
Y 
Stable in dosing at least four weeks prior to 
randomization is allowed. 
Muscle relaxants 
N 
N 
— 
NMDA receptor 
antagonist 
N 
N 
Common drugs include: Memantine is not allowed. 
Opioid 
agonists/analgesic
s (e.g., codeine, 
hydrocodone, 
methadone, 
morphine, 
maperidine, 
propoxyphene) 
and antagonists 
(e.g., naltrexone, 
naloxone, 
nalmefene) 
Y 
N 
Intermittent use allowed, if the following criteria are 
met:  
• use has been ongoing for at least 4 weeks 
prior to Screening, 
• frequency is no more than 4 days/week, and 
• no dosing within 24 hours of a study visit. 
Proton pump 
inhibitors or H2  
receptor blockers 
Y 
Y 
Sedatives/hypnoti
cs 
N 
Y 
Ongoing, stable hypnotic therapy (e.g., zolpidem, 
zaleplon, benzodiazepine hypnotics, and low-dose
trazodone 50-200mg) will be allowed during the 
study. Eszopiclone is not allowed. 
Steroids/systemic 
Y 
N 
Systemic steroid treatment will be allowed only for 
medical emergencies, such as severe allergic reactions
Steroids/topical 
and inhalant 
Y 
Y 
— 
Steroids/intra-
articular 
N 
N 
— 

 
 
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Drug Name or 
Class 
Episodic 
Use (PRN) Chronic Use 
Restrictions/Comments 
Stimulants 
N 
Y 
Chronic use allowed if taken for at least 12 weeks and 
at a stable dose for 4 weeks. 
The use of combinations containing pseudoephedrine 
or phenylephrine is not allowed. 
Supplement and 
herbals 
N 
N 
The 
following 
are 
the 
only 
exclusionary 
supplements/herbals: 
St. 
John’s 
Wort, 
garlic, 
chamomile, grapefruit and pineapple juice  
Vaccines 
Y 
NA 
— 
a If being taken prior to enrolling in the study. 
b If being taken for at least 3 months prior to enrolling in the study and the dose has been 
stable for at least 1 month. 
 
 
 

 
 
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Appendix IV: Amylase and Lipase Normal Ranges_12Jan2024 
January 12, 2024 
 
Thank you for contacting me concerning normal values on amylase and lipase across institutions. As 
mentioned on the call and emails, I reviewed all of the active sites lab reference ranges for lipase and 
amylase. I reviewed the normal values programmed into the EDC and compared the values to the 
reference ranges you have on file in the TMF (collected with regulatory documents), and cross-checked 
both ranges against the ranges listed on recent lab source documents. As stated by you, out of the 14 
open sites (113 is not included as they have not randomized a subject), 5 sites were flagged to have 
inconsistent ranges: 
 
Site 
PI 
Amylase 
Reference 
Range 
Programm
ed into 
EDC (U/L) 
Amylase 
Referen
ce 
Range 
listed in 
Lab 
Normal 
Values 
(U/L) 
Lipase 
Reference 
Range 
Programm
ed into 
EDC (U/L) 
Lipase 
Referen
ce 
Range 
listed in 
Lab 
Normal 
Values 
(U/L) 
Values 
match 
most 
recent 
subjec
ts lab 
source
? 
Comments 
Date of Normal Values (or date 
confirmed on recent source)  
101 
- 
UWisc 
Sehgal 
25-125 
25-125 
8-78 
8-78 
No 
Lipase range from recent 
subject visit (13Dec23) 0-
60 
 10/2021 
102 
- 
UCSD 
Wallace 
28-100 
28-100 
13-60 
13-60 
Yes 
  
2023 
104 
- 
MGH 
Mao 
3-100 
3-100 
13-60 
13-60 
Yes 
  
9/14/2023 
106 - UPN 
Asburn 
29-103 
29-103 
11- 82 
11- 82 
Yes 
  
11/22/2023 
107 - UFL 
Przkora 
28-100 
28-100 
0-70 
0-70 
Yes  
  
11/1/2022 
108 
- 
UWA 
Stacey 
27-106 
27-106 
0-70 
0-70 
Yes 
  
3/6/2023 
109 
- 
MSM 
Robinson-
Papp 
30-110 
31-110 
8 -78 
14-72  
No 
Lipase range from recent 
subject visit (08Nov23) 
13-78 
2023 
111 - URO 
Philip 
28-100 
28-100 
13-60 
13-60 
Yes 
  
12/4/2023 
114 - UTS 
Jain 
25-125 
25-125 
0-60 
0-60 
Yes 
  
12/19/2023 
117 - UPT 
Wasan 
0-65 
0-65 
15-70 
15-70 
Yes 
  
11/15/2023 
118 - NYU 
Samuels 
25-125 
25-125 
7-78 
7-78 
No 
Lipase range from recent 
subject visit (27Nov23) 8-
78 
3/1/2023 
119 - UCD 
Wise 
33-130 
28-130 
13-51 
13-606 
No 
Lab values on source 
match lab normal values 
in TMF, not in EDC 
4/26/2023 

 
 
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Protocol v9.0 22Jan2024 
130 
- 
MMC 
Canaan 
23-103 
23-103 
11-82 
11-82 
No 
Amylase 
range 
from 
recent 
subject 
visit 
(20Nov23): 25-125 
9/15/2023 
132 - HRN 
Reed 
21-101 
21-101 
7-60 
7-60 
Yes 
  
10/13/2023 
 
My review and recommendations are as follows. Note all values described below are U/L. 
  
Reference ranges for lab tests are set by each individual laboratory based on the specific 
method/instrument used (which may differ from lab to lab), normal range data if a formal reference range 
study was performed, manufacturer provided data, literature reviews, national standards (e.g. HbA1c, 
LDL) patient characteristics (e.g. age, gender, etc) and potentially many other factors. For most routine 
chemistry tests the expected normal values across labs are often quite similar albeit minor but clinically 
irrelevant differences are commonly observed. The key is to differentiate between minor variations of no 
significance versus variations that are clinically significant. In this specific case I assume you are looking 
for potential evidence of pancreatitis. Considering this the following observations can be made. 
 
1. The greatest outlier shown on the table above is amylase at UPT (0-65). I spoke with the lab 
director and this was an historical range set many years ago and they realize it is inappropriate 
for their method and plan to change it to 31-118 in February of 2023. 
 
2. On the low end of both amylase and lipase there is no significance in your clinical scenario of 
hypoamylasemia or hypolipasemia. To avoid unnecessary flagging of “abnormal” low results 
which are not real or significant, I would suggest setting your multicenter lower range at 0 or 3 
for amylase and 0 for lipase.  
 
3. Given the intention of UPT to change their ranges that leaves us with the upper end of normal 
for amylase and lipase. Given the inherent accuracy and imprecision of these tests and variation 
in ranges between institutions, there is no meaningful difference between an amylase of 100 
versus 130 or a lipase of 60 versus 82. For example, in one guideline “an amylase of greater than 
3 times the upper limit of normal supports the diagnosis of acute pancreatitis”. In the case of 
lipase, “if the sample has 3 to 10 times the normal level of lipase, then it's likely to be acute 
pancreatitis” according to various sources. Again, to avoid unnecessary flagging of “abnormal” 
values of no significance I would set the upper range for the study at 130 for amylase and 82 for 
lipase.  
 
4. Amylase itself is not optimal for the diagnosis of acute pancreatitis. As stated in one guideline 
“Current guidelines and recommendations indicate that lipase should be preferred over total 
and pancreatic amylase for the initial diagnosis of acute pancreatitis and that the assessment 
should not be repeated over time to monitor disease prognosis”. Although it may not be 
important at this time to eliminate amylase from the study protocol its use is not necessary for 
detecting pancreatitis. 
 

 
 
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5. Of note we are currently standardizing normal values for all routine tests across the many 
hospitals at Mass General Brigham to avoid the confusion over what is normal resulting from 
minor difference in reference ranges.  
 
Please let me know if you need further information or analysis. Note for regulatory purposes I am the CLIA 
Medical Director for the laboratories at MGH.  
 
 
Kent Lewandrowski, MD 
 
 
Kent Lewandrowski, M.D., FCAP 
Associate Chief of Pathology 
Director of Clinical Laboratories and  
Molecular Medicine 
Professor, Harvard Medical School 
Editor, Point of Care Journal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Appendix V: Glossary 
GLOSSARY: 
Abbreviation 
Entity 
ACR 
American College of Rheumatology 
AE 
Adverse Event  
ALK 
Alkaline phosphatase level 
ALT 
Alanine Aminotransferase Test 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BID 
Twice daily 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CABG 
Coronary Artery Bypass Graft 
CBD 
Cannabidiol 
CBRD 
Center for Biospecimen Research and Development (at NYU) 
CCC 
Clinical Coordinating Center 
CCC/PI 
Principal Investigator of the Clinical Coordinating Center 
CCC/PM 
Project Manager of the Clinical Coordinating Center 
CCL 
Chemokine Ligand 
CCR 
Chemokine receptor 
CDE 
Common Data Element 
CDER 
Center for Drug Evaluation and Research 
CFA 
Complete Freund’s Adjuvant (animal model of inflammatory joint pain) 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
cIRB 
Central Institutional Review Board 
Cmax 
Mean maximum plasma concentration  
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CXCR 
Chemokine receptor 
DCC 
Data Coordinating Center 
DCC/PI 
Principal Investigator of the Data Coordinating Center 
DCC/PM 
Project Manager of the Data Coordinating Center 
DDE 
Direct Data Entry 
DDI 
Drug-drug interactions  
dL 
Deciliters 
DSM-IV 
Diagnostic and Statistical Manual, Fourth Edition 
DSMB 
Data Safety and Monitoring Board 
ECG 
Electrocardiogram 

 
 
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eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EPPIC-Net      Early Phase Pain Investigation Clinical Network 
ET  
Early Termination 
FDA 
US Food and Drug Administration 
GAD-2 
Generalized Anxiety Disorder – 2 item scale  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GI 
Gastrointestinal 
GGT 
Gamma-Glutamyl Transferase 
GLP 
Good Laboratory Practice 
HADS 
Hospital Anxiety and Depression Scale 
HEAL 
Helping to End Addiction Long-term 
HIPAA 
Health Insurance Portability and Accountability Act 
hr 
Hour 
IA 
Intra-articular 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IXRS 
Interactive [Web/Phone] Response System 
kg 
Kilograms 
K-L 
Kellgren-Lawrence System for Classification of Osteoarthritis 
KRI 
Key Risk Indicators 
m 
Meter 
MAD 
Multi-Ascending Dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
MCH Concentration 
MCP 
Monocyte Chemoattractant Protein 
MCV 
Mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
mg  
Milligrams 
µg 
Micrograms 
MGH 
Massachusetts General Hospital is the Clinical Coordinating Center 
MIA 
Mono-Iodoacetate (animal model of osteoarthritic pain) 
mL 
Milliliters 
µL 
Microliters 
MOP 
Manual of Procedures 
NESS 
New England Survey System 

 
 
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NIH 
National Institutes of Health 
NINDS 
National Institute of Neurological Disorders and Stroke 
NOAEL 
No Observed Adverse Effect Level 
NRS 
Numeric Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
NYU 
New York University is the Data Coordinating Center 
OA 
Osteoarthritis 
OUQ 
Opioid Use Questionnaire 
PD 
Pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change  
P-gp 
P-glycoprotein 
PHI 
Protected Health Information 
PHQ 
Patient Health Questionnaire  
PI 
Principal Investigator of a clinical site 
PK 
Pharmacokinetic(s) 
PNL 
Partial Sciatic Nerve Ligation (animal model of nerve injury pain) 
PM 
Project Manager 
PPI 
Protocol Principal Investigator 
PRN 
As needed 
PRO 
Patient-Reported Outcome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
QD 
Once a Day 
QTcF 
QT Correction using Fredericia’s Formula 
RA 
Rheumatoid arthritis 
RANTES 
T-cell specific protein  
RBM 
Risk Based Monitoring 
RFA 
Radiofrequency Ablation 
SAD 
Single-Ascending Dose 
SAE 
Serious Adverse Event 
SAFER 
State, Assessibility, Face and Ecological Validity and the Rule of the 3 Ps 
[persistent, pervasive, pathological] 
SAP 
Statistical Analysis Plan 
TAPS-1 
Tobacco, Alcohol, Prescription medication, and other Substance use Tool 
TC 
Trial Committee, formerly ENMOC 
TEAEs 
Treatment emergent adverse events  
UA 
Urinalysis 
ULN 
Upper Limit of Normal 
V [#] 
Visit [Number] 
WOCBP 
Woman/Women of Childbearing Potential 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
XCR 
Chemokine receptor 

 
 
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