Conditions: Knee Osteoarthritis
Keywords: osteoarthritis knee pain non opioid analgesic capsaicin pain intra-articular
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 854
Healthy volunteers: no

Brief summary:
An Open-label, 8-Week Study to Compare the Comfort and Ease of Use of Five Different Treatment Regimens for CNTX 4975-05 Intra-articular Injection in Subjects with Chronic, Moderate-to-Severe Osteoarthritis Knee Pain.

Detailed description:
This is an open-label, single injection (per knee), 8-week study to evaluate the comfort and ease of use of 5 different treatment regimens, and to evaluate the efficacy and safety of a single intra-articular (IA) injection, in one or both knees, of CNTX-4975-05 in subjects with chronic, moderate-to-severe knee OA pain. Procedural pain associated with IA injection of the investigational product, CNTX-4975-05, will be controlled primarily through adjunct controlled joint cooling and secondarily by pre-medication with IA lidocaine.

Arms:
arm 1: Subject receives 2% lidocaine and CNTX-4975-05 with cooling device Breg ice water pump. arm 2: Subject receives 2% lidocaine and CNTX-4975-05 with cooling device Elasto-Gel. arm 3: Subject receives 2% lidocaine and CNTX-4975-05 with cooling device Elasto-Gel. arm 4: Subject receives 2% lidocaine and CNTX-4975-05 with cooling device Elasto-Gel. arm 5: Subject receives 1% lidocaine and CNTX-4975-05 with cooling device Elasto-Gel.

Interventions: intervention 1: CNTX-4975-05 intervention 2: Lidocaine without epinephrine intervention 3: ElastoGel intervention 4: Breg Ice Water Pump
Intervention descriptions: intervention 1: Osteoarthritis (OA) intra-articular injection of CNTX-4975-05 intervention 2: 15 mL lidocaine intra-articular injection intervention 3: Cooling Device intervention 4: Cooling Device

Protocol document:
Prot_SAP_000.pdf: 




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1 
SYNOPSIS 
PRODUCT 
NAME/NUMBER 
CNTX-4975-05 
PROTOCOL 
NUMBER 
CNTX-4975i-OA-303 
DEVELOPMENT 
PHASE 
Phase 3 
PROTOCOL TITLE 
An Open-label, 8-Week Study to Compare the Comfort and Ease of Use of Five 
Different Treatment Regimens for CNTX 4975-05 Intra-articular Injection in Subjects 
with Chronic, Moderate-to-Severe Osteoarthritis Knee Pain 
INDICATION 
Knee pain due to osteoarthritis (OA) 
OBJECTIVES 
The objectives of this study in subjects with moderate-to-severe pain due to knee OA 
are as follows: 
Primary Efficacy Objective:  
To determine the optimal procedures for administering CNTX 4975-05 as a single intra-
articular (IA) injection into knee(s) with OA, balancing comfort and ease of use of 
methods of cooling and administration. 
Secondary Efficacy Objectives:  
• 
To describe the clinical benefit of CNTX-4975-05 treatment at Week 8 in a 
single knee with OA  
• 
To describe the clinical benefit at Week 8 of treating bilateral knee OA with a 
single injection to each knee 
• 
To describe the clinical benefit at Week 8 of treating a single knee with OA in 
subjects with partial or total joint replacement (PJR/TJR) in the contralateral 
knee  
• 
To evaluate subject satisfaction (SS) with the overall benefit of 
CNTX-4975-05 
• 
To evaluate SS with IA CNTX-4975-05 relative to SS with contralateral knee 
PJR or TJR 
• 
To evaluate subject and investigator satisfaction (IS) with different treatment 
regimens 
• 
To evaluate the responders to treatment through 8 weeks 
Exploratory Efficacy Objectives: 
• 
To explore the likelihood of the need for joint replacement surgery, based on 
clinical benefit and the subject’s assessment of their improvement at Week 8 
• 
To explore the effect of subject characteristics (including Kellgren-Lawrence 
[K-L] grade, sex, body mass index [BMI], age, unilateral versus bilateral knee 
OA, unilateral versus bilateral injections, and history of contralateral PJR or 
TJR) on the clinical benefit of IA CNTX-4975-05 at each study visit through 
Week 8 
• 
To explore changes in the frequency of use of background analgesic 
medication for pain in the injected knee(s) throughout the study period 


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Safety Objective: 
•
To further evaluate the safety of a single IA injection of 
CNTX-4975-05 to one or both knees in subjects with chronic moderate to
severe unilateral or bilateral knee OA pain
STUDY DESIGN 
This is an open-label, single injection (per knee), 8-week study to evaluate the comfort 
and ease of use of 5 different treatment regimens, and to evaluate the efficacy and safety 
of a single IA injection, in one or both knees, of 
 CNTX-4975-05 in subjects 
with chronic, moderate-to-severe knee OA pain. Procedural pain associated with IA 
injection of the investigational product, CNTX-4975-05, will be controlled primarily 
through adjunct controlled joint cooling and secondarily by pre-medication with IA 
lidocaine. 
Types of Subjects: 
The study population will contain 3 types of subjects, with a targeted minimum of 
150 subjects of each type: 
1.
Subjects with unilateral or bilateral OA of the knee, with one knee (the index
knee) with moderate to severe pain (K-L grade 1-4) and the other knee (the
contralateral knee) with no to mild pain. These subjects will receive an
injection of CNTX-4975-05 into the index knee only.
2.
Subjects with bilateral OA of the knees, with both knees having moderate to
severe pain (K-L grade 1-4, with worse pain being the index knee). These
subjects will receive an injection of CNTX-4975-05 into each knee (1 week
apart, most painful knee [index knee] first, then the following week, the
contralateral knee).
3.
Subjects who have unilateral or bilateral OA of the knee, with one knee with
moderate to severe pain (the index knee [K-L grades 1-4]) and previous PJR or
TJR in the other knee (the contralateral knee). These subjects will receive an
injection of CNTX-4975-05 into the index knee only.
All subjects will receive 
 CNTX-4975-05 injected into the index knee; 
subjects with bilateral OA will receive an injection into both knees (injections will be 
separated by 1 week). Subjects will be followed for 8 weeks.  
Pre-Medication: 
Prior to the injection procedure, the investigator may, at his or her discretion, pre-
medicate subjects with an oral dose of an opioid or non-steroidal anti-inflammatory 
drug (NSAID). The skin at the point of the anticipated injection(s) may also be 
infiltrated with 1 to 2 mL of lidocaine and/or a topical analgesic such as ethyl chloride 
spray. It is recommended not to use more than 2 methods of local analgesia about the 
knee(s) to be injected. 
Injection of CNTX-4975-05: 
ALL subjects are required to be administered an IA injection of a full 15 mL of 
lidocaine (without epinephrine) (1% or 2%, depending on the assigned treatment 
regimen) to ensure: 1) the local targeted concentration of CNTX-4975 in the joint; 
2) distension of the joint capsule to improve access of CNTX-4975 to the joint space;
and 3) to provide some analgesia. The full 15 mL of lidocaine (without epinephrine)
and the full 2 mL of CNTX-4975-05 must be injected into the knee joint, as directed.
The 5 flexion-extension moves of the knee after IA CNTX-4975-05 is injected into the
knee also improve access of CNTX-4975 to the entire joint space. The lidocaine may
have some modest effect on pain, but the concentration and dispersion of CNTX-4975
into the joint are the primary reasons for lidocaine use.


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The use of ultrasound for IA injections is recommended, but not required. If not using 
ultrasound guided IA injection, then with a clinical IA injection, joint fluid must be 
identified within the needle hub before injection of 2% lidocaine (without epinephrine) 
and CNTX-4975-05. After injection of CNTX-4975, the knee joint will be passively 
flexed and extended 5 times over 1 minute to facilitate distribution of the CNTX-4975 
within the knee. All subjects must be monitored for at least 30 minutes (or longer, as 
required by the protocol) after study drug injection to ensure that they do not have a 
hypersensitivity reaction/anaphylaxis.   
The duration of cooling and the knee pain upon discontinuation of cooling must be 
entered into the electronic case report form [eCRF]. If cooling must be reapplied, the 
time and knee pain level must be recorded in the eCRF, and timing of subsequent pain 
assessments should be on the standard time lines in the eCRF. 
Each site will be randomly assigned 1 of the following 5 treatment regimens to be 
employed for ALL subjects at that site:  
Group 
Cooling 
Device 
• Pre-cool 
• Lidocaine % 
• Post-lido cool 
Needle 
Post-
dose 
cooling 
1. Breg Cooling 
Control Group 
Breg ice 
water 
pump  
• 15 mins 
• 2% lidocaine 
• 30 mins 
Separate needles 
for lidocaine and 
CNTX-4975-05 
30 to 90 
mins as 
needed 
2. Gel Pack Cooling 
Group 
Elasto-
Gel 
• 40 mins 
• 2% lidocaine 
• 10 mins 
Separate needles 
for lidocaine and 
CNTX-4975-05 
10 to 90 
mins as 
needed 
3. Shortened Gel 
Pack Cooling Group 
Elasto-
Gel 
• 30 mins 
• 2% lidocaine 
• 5 mins 
Separate needles 
for lidocaine and 
CNTX-4975-05 
up to 90 
mins as 
needed 
4. Single Needle 
Injection Gel Pak 
Cooling Group-2% 
Lidocaine 
Elasto-
Gel 
• 45 mins 
• 2% lidocaine 
• no cooling 
Single needle for 
lidocaine and 
CNTX-4975-05 
up to 90 
mins as 
needed 
5. Single Needle 
Injection Gel Pack 
Cooling Group-1% 
Lidocaine 
Elasto-
Gel 
• 45 mins  
• 1% lidocaine 
• no cooling 
Single needle for 
lidocaine and 
CNTX-4975-05  
up to 90 
mins as 
needed 
 
See study manual for specific instructions on the use of the Breg Cooling Wrap and the 
Elasto-Gel Cooling Wrap. 
 
1. Breg Cooling Control Group (used in protocols CNTX-4975i-OA-301 and 
CNTX-4975i-OA-304 for comfort and blinding of the protocols)  
a. 
Controlled joint cooling wrap with an ice water pump system (Breg 
Cooler) will be applied 15 minutes prior to IA injection of the full 
15 mL 2% lidocaine (without epinephrine) into the knee joint using 
standard aseptic techniques.  
b. Inject IA the full 15 mL of 2% lidocaine (without epinephrine) into 
the knee joint using appropriate aseptic techniques. 
c. 
Controlled cooling will be resumed for a further 30 minutes after the 
IA injection of the full 15 mL 2% lidocaine (without epinephrine) into 
the knee joint.  
d. The cooling device will be removed, and CNTX-4975-05 IA injection 
will be administered using standard aseptic techniques.  


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e. 
Controlled cooling will be reapplied for a minimum of 30 minutes, 
and up to 90 minutes, as needed, after CNTX-4975-05 injection, 
depending on the subject’s comfort. The cooling may be discontinued 
after a minimum of 30 minutes after IA CNTX-4975-05 injection, if 
the subject has a pain level that is acceptable for the subject and 
investigator (0-4 scale: none, mild, moderate, moderately severe, and 
severe). 
2. Gel Pack Cooling Group 
a. 
Gel pack cooling applied for 40 minutes to the knee using the gel 
pack over a stockinette or light-weight pants. This may be outside of 
the exam room, but at the investigator’s discretion, may be done in 
the exam room. If done outside the exam room, subject may be 
moved to the exam room ± 5 minutes of the 40-minute cooling (with 
gel pack remaining on the knee). 
b. Inject IA the full 15 mL 2% lidocaine (without epinephrine) into the 
knee joint using appropriate aseptic techniques.  
c. 
Gel pack cooling is applied for 10 minutes to the knee using the gel 
pack over a stockinette or light-weight pants. 
d. The gel pack will then be removed, and CNTX-4975-05 IA injection 
will be administered using appropriate aseptic techniques.  
e. 
Gel pack cooling will be reapplied for a minimum of 10 minutes, and 
up to 90 minutes, as needed, after CNTX-4975-05 injection, 
depending on the subject’s comfort. The cooling may be discontinued 
after a minimum of 10 minutes after IA CNTX-4975-05 injection. If 
the subject has a pain level that is acceptable for the subject and 
investigator (0-4 scale: none, mild, moderate, moderately severe and 
severe). 
3. Shortened Gel Pack Cooling Group  
a. 
Gel pack cooling applied for 30 minutes to the knee using the gel 
pack over a stockinette or light-weight pants. This may be outside of 
the exam room, but at the investigator’s discretion, may be done in 
the exam room. If done outside the exam room, subject may be 
moved to the exam room ± 5 minutes of the 30-minute cooling (with 
gel pack remaining on the knee). 
b. Inject IA the full 15 mL 2% lidocaine (without epinephrine) into the 
knee joint using appropriate aseptic techniques. 
c. 
Gel pack cooling is applied for 5 minutes to the knee using the gel 
pack over a stockinette or light-weight pants. 
d. The gel pack will then be removed, and CNTX-4975-05 IA injection 
will be administered using appropriate aseptic techniques.  
e. 
Gel pack cooling may be reapplied for up to 90 minutes, as needed, 
after CNTX-4975-05 injection, depending on the subject’s comfort. 
The subject may remain in the exam room, or be moved to a more 
comfortable area with the gel pack. The gel pack may be discontinued 
after IA CNTX-4975-05 injection if the subject has a pain level that is 
acceptable for the subject and investigator (0-4 scale: none, mild, 
moderate, moderately severe and severe). 
4. Single Needle Injection Gel Pack Cooling Group-2% IA Lidocaine 
a. 
Gel pack cooling applied for 45 minutes to the knee using the gel 
pack over a stockinette or light-weight pants. This may be outside of 
the exam room, but at the investigator’s discretion, may be done in 
the exam room. If done outside the exam room, subject may be 


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moved to the exam room ± 5 minutes of the 45-minute cooling (with 
gel pack remaining on the knee).   
b. Inject IA the full 15 mL 2% lidocaine (without epinephrine) into the 
knee joint using appropriate aseptic techniques.   
c. 
After the 2% lidocaine IA injection, CNTX-4975-05 IA injection, 
using the same needle, will be injected into the knee joint using 
appropriate aseptic techniques after 3 minutes of the 2% lidocaine 
(without epinephrine).  
d. Gel pack cooling may be reapplied for up to 90 minutes, as needed, 
after CNTX-4975-05 injection, depending on the subject’s comfort. 
The subject may remain in the exam room, or be moved to a more 
comfortable area with the gel pack. The gel pack may be discontinued 
after a minimum of 10 minutes after IA CNTX-4975-05 injection if 
the subject has a pain level that is acceptable for the subject and 
investigator (0-4 scale: none, mild, moderate, moderately severe and 
severe). 
5. Single Needle Injection Gel Pack Cooling Group-1% IA Lidocaine 
a. 
Gel pack cooling applied for 45 minutes to the knee using the gel 
pack over a stockinette or light-weight pants. This may be outside of 
the exam room, but at the investigator’s discretion, may be done in 
the exam room. If done outside the exam room, subject may be 
moved to the exam room ± 5 minutes of the 40-minute cooling (with 
gel pack remaining on the knee).   
b. Inject IA the full 15 mL 1% lidocaine (without epinephrine) into the 
knee joint using appropriate aseptic techniques.   
c. 
After the 1% lidocaine IA injection, CNTX-4975-05 IA injection, 
using the same needle, will be injected into the knee joint using 
appropriate aseptic techniques after 3 minutes of the 1% lidocaine 
(without epinephrine).  
d. Gel pack cooling may be reapplied for up to 90 minutes, as needed, 
after CNTX-4975-05 injection, depending on the subject’s comfort. 
The subject may remain in the exam room, or be moved to a more 
comfortable area with the gel pack. The gel pack may be discontinued 
after IA CNTX-4975-05 injection if the subject has a pain level that is 
acceptable for the subject and investigator (0-4 scale: none, mild, 
moderate, moderately severe and severe). 
Subjects should not take a hot bath or shower, or expose the injected knee(s) to external 
heat, within 12 hours after the injection.  
On Day 3 post-injection, study staff will call subjects to assess adverse events (AEs), 
subject assessment of procedure pain and satisfaction, knee pain with walking, and the 
use of rescue medication (for bilateral knee injections, calls will occur 3 days after each 
injection). Subjects will return to the clinic at Weeks 4 and 8 for study assessments.  
Efficacy will be assessed on the OA index knee (and contralateral knee in bilateral knee 
injection subjects) using a numeric pain rating scale (NPRS); the Knee Injury and 
Osteoarthritis Outcome Score (KOOS), which includes subscales for pain, other 
symptoms, activities of daily living, sports and recreation, and quality of life; a joint 
replacement questionnaire; a subject satisfaction questionnaire; an investigator 
satisfaction questionnaire; and rescue medication use. Pain with walking will also be 
collected and assessed for the contralateral knee. 
For subjects with bilateral knee injections, the contralateral knee will be assessed using 
the same scales as the index knee, and the effect of bilateral knee injections will be 


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combined as a composite score to examine the overall benefit. The index knee in these 
subjects is the one with worse pain with walking. Where both knees have equal pain 
with walking, then the knee on the subject’s dominant side will be designated the index 
knee. 
Safety will be assessed by injection site assessments (erythema and edema), assessment 
of procedure pain, AEs, physical examination findings, vital sign measurements, 
12-lead electrocardiograms (ECGs), clinical laboratory test results, and sensory testing. 
PLANNED NUMBER 
OF SUBJECTS 
Approximately 850 subjects will be enrolled.  
STUDY ENTRY 
CRITERIA 
Inclusion Criteria: 
1. Male or female subjects between 40 and 95 years of age (inclusive)  
2. Confirmation of OA of the knee: radiography of both knees using standard standing 
films (scored by the investigator) or using the fixed flexion method, taken during 
the Screening Visit (prior radiographs of the knees of sufficient quality that have 
been taken within 2 years of the Screening Visit may be used for K-L grading). The 
index knee must show evidence of chronic OA with a K-L grade of 1, 2, 3 or 4. 
Subjects who were screen failures for the United States (US) CNTX-4975i-OA-301 
or CNTX-4975i-OA-304 trials may be considered for this trial if the K-L grade of 
the index knee is 1-4, inclusive. 
3. Confirmation of OA of the index knee: American College of Rheumatology (ACR) 
diagnostic criteria (ACR confirmation of bilateral knee OA for subjects who will 
have bilateral knee injections of CNTX-4975-05). 
4. For subjects for monoarticular knee injection, the index knee must have moderate 
to severe pain (≥5 and ≤9) at screening associated with OA, which must be stable 
for a minimum of 6 months prior to Screening, as assessed by the investigator. 
These subjects may have: 
a) unilateral or bilateral OA, with the index knee having moderate to severe pain, 
and the contralateral knee having none to mild pain, OR 
b) unilateral or bilateral OA, with the index knee having moderate to severe pain 
and the other knee having had a PJR or TJR within 5 years of the Screening 
Visit. The knee with the PJR/TJR is not to be injected with CNTX-4975-05. 
For subjects for bilateral knee injection, the index knee must have moderate to 
severe pain (≥5 and ≤9) at screening associated with OA, and greater pain in the 
index knee than in the contralateral knee. Their pain must be stable for a minimum 
of 6 months prior to Screening, as assessed by the investigator. The index knee in 
these subjects is the one with the worst pain with walking. Where both knees have 
equal pain with walking, then the knee on the subject’s dominant side will be 
designated the index knee. 
For qualifying knee pain with walking, subjects will use an NPRS (0-10; 0=no 
pain, 10=worst possible pain) to rate their knee pain with walking (both knees, 
except knees with PJR/TJR). The PJR/TJR pain should be rated using the NPRS 
scale, but will not be a qualifying pain score. 
5. Body mass index ≤45 kg/m2. 
6. Subjects must have failed 2 or more prior therapies. Failure is deemed to be 
inadequate relief in the opinion of the investigator. A therapy may be deemed to 
have been inadequate because of one or more of the following:  
a) unacceptable AEs;  


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b) initial failure to achieve clinically adequate pain relief;  
c) initial pain relief that was not maintained; and/or 
d) 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: NSAIDs 
(including topical), opioids, duloxetine, other systemic therapy, IA corticosteroids, 
IA visco-supplements, physical therapy, bracing, and orthotics.  
7. Females not of childbearing potential, defined as post-menopausal for at least 
1 year, or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy), or practicing one of the following medically acceptable methods of 
birth control throughout the study period:  
• 
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 CNTX-4975-05 administration 
• 
Total abstinence from sexual intercourse since the last menses before 
CNTX-4975-05 administration 
• 
Intrauterine device 
• 
Double barrier method (condoms, sponge, diaphragm, with spermicidal jellies 
or cream). 
8. Able to speak, read, and understand the language of the study used for the informed 
consent.  
9. Willing and able to:  
a) understand the study requirements 
b) abide by the study restrictions and requirements 
c) complete the study procedures 
d) be compliant and independently (i.e., without assistance) record responses on 
the efficacy scales during clinic visits 
e) independently communicate meaningfully with the study personnel. 
10. Signed informed consent form approved by the institutional review board (IRB)/ 
independent ethics committee (IEC). 
11. Subjects may come into the study with a single analgesic of their choice for their 
OA knee pain (prescription or OTC). The current pain medication must be 
identified as that taken only for pain in the knee OA or pain in the PJR/TJR, and 
not for another pain indication. The subjects will complete a daily paper diary of 
their background knee analgesic medications during the screening period and 
throughout the trial. Other analgesics may be taken for occasional pain but should 
not be taken within 24 hours of a clinic visit; these are to be recorded as 
concomitant medications, not as rescue/background medication for knee 
osteoarthritis. 
Exclusion Criteria:  
1. Joint replacement surgery of the index knee at any time, or open surgery of the 
index knee in the past 24 months. Joint replacement of the contralateral knee is 
permitted for subjects who will not receive an injection in the contralateral (natural) 
knee. For subjects with bilateral knee OA who will receive an injection into both 


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knees, joint replacement surgery of both knees at any time, or open surgery of the 
index knee in the past 24 months, is excluded. 
2. Prior arthroscopic surgery of the index knee within 6 months of Screening. 
3. Any painful conditions of the index knee due to joint disease other than OA. For 
example, radicular or referred pain involving the index knee or from joint disease 
other than OA involving the index knee, such as, but not restricted to 
chondromalacia patellae, inflammatory diseases (e.g., rheumatoid arthritis, 
psoriatic arthritis), metabolic diseases, gout/pseudogout, hemochromatosis, 
acromegaly, etc.  
4. Periarticular pain from any cause, including referred pain, bursitis, tendonitis, soft 
tissue tenderness, or subacute/acute pain from injury. 
5. Other chronic pain anywhere in the body that requires the use of chronic analgesic 
medications, including, but not limited to, local painful areas, myofascial pain 
syndromes, fibromyalgia, genetic, metabolic abnormalities, hematologic, or 
neuropathic pain. 
6. Instability of the index or contralateral knee (e.g., cruciate ligament tear or rupture, 
significant protruding meniscus, substantial ligamentous laxity, unstable PJR or 
TJR).  
7. Misalignment (>10 degrees varus or valgus) of the index knee on standing. 
8. Documented history of neuropathic arthropathy or finding of bony fragmentation in 
the index knee with imaging (radiographic, computed tomography, or magnetic 
resonance imaging). 
9. Physical/occupational/chiropractic therapy for the lower extremities or acupuncture 
for the lower extremities within 15 days of Screening, or need for such therapy 
during the study. 
10. Plans to have surgery, other invasive procedures, or IA injections (other than 
CNTX-4975-05) for either knee while participating in the study. 
11. Current use of opioids for any condition other than for OA of the knees injected 
with CNTX-4975-05) (maximum dose of 15 mg of hydrocodone [or equivalent] per 
day).  
12. Corticosteroid injection into the index or contralateral knee within 90 days of 
Screening. 
13. Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of 
Screening. 
14. History of allergic reaction to the planned local anesthesia/analgesic regimens, 
ethylenediaminetetraacetic acid, Kolliphor HS 15, butylated hydroxytoluene, or 
capsaicin. 
15. Presence of any medical condition or unstable health status that, in the judgment of 
the investigator, might adversely impact 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 significantly compromise key organ systems. 
For any question regarding eligibility, it is strongly recommended that the 
investigator discuss the subject with the medical monitor. 
16. Is pregnant or is breast feeding. 


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17. Has a malignancy, a history of malignancy, or has received treatment for 
malignancy at any time, with exception of resected and cured basal cell carcinoma 
and squamous cell carcinoma of the skin.  
18. Regular use of anticoagulant blood thinners (except low-dose aspirin, Dabigatran 
150 mg once daily [qd], Enoxaparin 40 mg qd, Rivaroxaban 10 mg qd, or Apixaban 
2.5 mg twice daily, or clopidogrel 75 mg qd, which are allowed).  
19. Active cutaneous disease at the anticipated site of CNTX-4975-05 injection that 
would prevent the safe administration of CNTX-4975-05. 
20. Ulcer or open wound anywhere on the index knee. 
21. Specific laboratory abnormalities: 
• 
Hemoglobin <11.0 g/dL 
• 
White blood cells <2.5 × 109/L 
• 
Neutrophils <1.5 × 109/L 
• 
Platelets <100 × 109/L 
• 
Aspartate transaminase or alanine transaminase >2 × upper limit of normal 
• 
Creatinine >1.6 mg/dL 
• 
Glucose (fasting) >250 mg/dL 
• 
Hemoglobin A1c (HgbA1c) >9.0% 
22. Clinically significant abnormal laboratory result 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. For any 
question regarding eligibility, it is strongly recommended that the investigator 
discusses the subject with the medical monitor. 
23. Use of an investigational medication 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. 
24. Prior participation in an ALGRX 4975 or CNTX-4975 study. 
25. Has any of the following characteristics: 
• 
Active or historic substance use disorder within the previous year, as defined 
by the Diagnostic and Statistical Manual for Mental Health Disorders, fifth 
edition 
• 
Test is positive upon urine drug screen for a substance of abuse (prescribed 
opioids acceptable) 
• 
Has a history, at any time, or currently, of suicidal ideation, suicide attempt, or 
increased risk of suicide 
• 
Has an unacceptable level of depression or anxiety as measured by the 
Hospital Anxiety and Depression Scale (HADS) (a score of ≥11) 
• 
Has unacceptable chronic pain as measured by the Fibromyalgia Symptom 
Scale Score (FSS) (a score of ≥13) 
• 
Has a positive pregnancy test at the Screening or either Treatment Visit 
• 
Has ongoing litigation for workers’ compensation 


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• 
Has any condition, or is taking any medication, that would be contraindicated 
for study participation. 
INVESTIGATIONAL 
PRODUCT 
Name: CNTX-4975-05 (trans-capsaicin injection), provided as a pre-filled syringe 
  
TREATMENT 
REGIMENS 
All subjects will receive a single clinical or ultrasound-guided IA injection of either 1% 
or 2% lidocaine (without epinephrine), followed by CNTX-4975-05 
 on Study 
Day 1 (Treatment), along with controlled cooling. Subjects with bilateral moderate to 
severe OA knee pain, who have not had joint replacement and who qualify to have 
bilateral IA injections of CNTX-4975-05, will receive an injection in both knees 
(injections will be separated by 1 week). 
PLANNED STUDY 
SITES 
No more than 45 concurrent study sites in the US, Germany, Spain and the United 
Kingdom.  
CRITERIA FOR 
EVALUATION 
Primary efficacy endpoint:  
The primary endpoint is assessment of the CNTX-4975-05 treatment regimens, with the 
Breg Cooling Control Group as the standard, using a combination of 3 assessments of 
the index knee: 1) pain 30 minutes after CNTX-4975-05 injection (using the 0-4 scale 
of none, mild, moderate, moderately severe, and severe); 2) subject satisfaction with the 
treatment regimen (SS); and 3) investigator satisfaction with the treatment regimen (IS).  
Secondary efficacy endpoints:  
• 
Assessment of the primary combined outcome using the contralateral knee for 
the subjects who received bilateral injections and the index knee for all other 
subjects 
• 
Assessment of the primary combined outcome for each subject type 
• 
Assessment of the primary combined outcome, using the contralateral knee for 
the subjects who received bilateral injections 
• 
Percent of Outcome Measures in Rheumatology-Osteoarthritis Research 
Society International (OMERACT-OARSI) responders at Week 8 for subjects 
with a single CNTX-4975-05 joint injection (index knee, moderate-to-severe 
pain; index knee, pain not >3 for contralateral knee) 
• 
Percent of OMERACT-OARSI responders at Week 8 for subjects with 
bilateral knee injections of CNTX-4975-05 (index knee, moderate-to-severe 
pain index knee; both knees meeting OMERACT-OARSI responder criteria) 
• 
Percent of OMERACT-OARSI responders at Week 8 for subjects with a single 
CNTX-4975-05 joint injection (population with index knee, moderate-to-
severe pain index knee; non-index knee with PJR/TJR) 
• 
For each of the 3 types of subjects, the absolute change; the number of subjects 
who have ≥30%, ≥50%, ≥70%, or ≥90% improvement area under the curve; 
and landmark analysis on the 5 subscales of the KOOS through Week 8 using 
the average of both knees: 
o 
Pain 
o 
Other symptoms 
o 
Activities of daily living 
o 
Sports and recreation 


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o 
Quality of life 
• 
Assess the SS of treatment with CNTX-4975-05 IA injection for each of the 
3 types of subjects, and all subjects in the trial 
• 
For subjects with a PJR/TJR, assess their satisfaction with the CNTX-4975-05 
IA injection versus their satisfaction with their PJR/TJR 
Exploratory Efficacy Endpoints: 
Exploratory efficacy endpoints include: 
• 
Likelihood of the need for joint replacement surgery, based on KOOS 
subscales and SS outcomes, from Baseline through Week 8 
• 
Subject satisfaction with the treatment of the index knee through Week 8 of the 
trial (7-point Likert Scale where 1=completely dissatisfied and 7=completely 
satisfied) 
• 
The effect of subject characteristics (including K-L grade, sex, BMI, age, 
unilateral/bilateral knee OA, bilateral knee OA treatment, and history of 
contralateral PJR/TJR) on the analgesic efficacy of CNTX-4975-05, using the 
KOOS subscales at each study visit through Week 8 
• 
Frequency of use of background analgesic medication for pain in the injected 
knee(s) throughout the study period. 
• 
Assessment of the mean of the individual outcome measures, using the average 
of both knees for the subjects who received bilateral knee injections 
Safety endpoints: 
• 
Adverse events 
• 
Vital signs 
• 
Clinical laboratory evaluations (hematology, chemistry, and urinalysis) 
• 
12-lead ECGs 
• 
Physical examination (including the presence or absence of an effusion in the 
index knee, periarticular pain/tenderness) 
• 
Concomitant medications and therapies 
• 
Degree of procedure pain (not recorded as AEs) 
• 
Local physical findings after injection of the index knee  
• 
Injection site assessment of erythema and edema  
• 
Sensory testing 
STATISTICAL 
METHODS 
The primary analysis will compare each experimental treatment regimen to the Breg 
Cooling Control Group using an equally-weighted, combined score calculated from the 
following 3 measures: 1) pain 30 minutes after CNTX-4975-05 injection (using the 0-4 
scale of none, mild, moderate, moderately severe, and severe), 2) SS with the treatment 
regimen; and 3) IS with the treatment regimen, all assessed on the index knee. Ratios of 
the mean values of test/control will have 95% confidence intervals constructed for each 
treatment regimen versus the Breg Cooling Control Group. For a treatment regimen to 
be considered clinically acceptable, it must be no more than 30% worse than the Breg 
Cooling Control Group and the lower limit of the 95% confidence interval for the 
treatment regimen must be greater than 0.7. This analysis will be performed on the ITT 
population.  


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For analysis, satisfaction scores (SS and IS) and 30 minute pain after CNTX-4975-05 
injection will be transformed to equivalent scales, and 30 minute pain after CNTX-
4975-05 injection will be reverse-scored so that higher scores represent lower pain, in 
order to have the 3 components on the same scale before they are combined by 
summing the 3 scores for a composite score. A sensitivity analysis will be performed 
that creates a composite score using the original scales (with the pain scores still 
reverse-scored to ensure the direction of the effect remains the same), using the ITT 
population. 
All other continuous secondary and exploratory efficacy endpoints will be summarized 
using descriptive statistics by subject type, experimental injection procedure, and 
week/visit, as appropriate, and analyzed using a mixed-model repeated measures 
analysis or by analysis of covariance, as appropriate. Categorical endpoints will be 
compared between treatments using Pearson’s chi-square or Fisher’s exact test, as 
appropriate.  
Safety analyses will be conducted using data from the safety population.   
SAMPLE SIZE 
DETERMINATION 
Approximately 850 subjects will receive CNTX-4975-05 in an open-label manner. This 
sample size was chosen based on the need to fulfill safety requirements for regulatory 
review.  
STUDY AND 
TREATMENT 
DURATION 
The overall study duration is expected to be 13 months, with 10 months of active 
enrollment and about 3 months for screening and treatment follow-up. The sequence 
and maximum duration of the study periods will be as follows: 
• 
Screening Period up to 15 days.  
• 
Treatment Period (open-label): 1 day per knee treated, maximum 2 days 
• 
Post-treatment period: 8 weeks from the first CNTX-4975-05 IA injection  
The maximum CNTX-4975-05 treatment for each subject is 2 days. 
The maximum study duration for each subject is approximately 10 weeks. 
 


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2 
SCHEDULE OF EVENTS 
Table 2-1: Schedule of Events 
 
Screening  
Visit 
Treatment  
#1  
(single 
knee)* 
Phone  
F/U 
Treatment  
#2  
(Bilateral 
knees 
only)*  
Phone  
F/U 
(Bilateral 
knees only)  
Efficacy 
Safety 
Efficacy 
Safety/ Early 
Termination 
Visit 
Clinic Visit (V) or Telephone Visit (TV) 
V1 
V2 
TV3a 
V4b 
TV5a,b 
V6 
V7 
Study Day/Week 
Day -14 
to Day 1c 
Day 1 
Day 3 
±1d  
Day 7 
(Week 2) 
(-2/+5 d) 
V4 +3d  
±1d 
Week 4 
±5d  
Week 8 
± 7dd 
Informed consent 
X 
 
 
 
 
 
 
Confirmation of OA of the knee (K-L grade 1- 4) based on 
radiographse 
X 
 
 
 
 
 
 
Confirmation of OA of the knee based on American 
College of Rheumatology diagnostic criteria 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Height and weight (including body mass index) 
X 
 
 
 
 
 
 
History of cancer 
X 
 
 
 
 
 
 
Knee pain with walking (last 24 hours; NPRS of 0-10)  
X 
Xh 
X 
Xh 
X 
X 
X 
Demographics, medical history, OA medications & 
treatment historyf 
X 
 
 
 
 
 
 
Hospital Anxiety and Depression Scale (HADS) 
X 
 
 
 
 
 
 
Fibromyalgia Symptom Scale Score (FSS) 
X 
 
 
 
 
 
 
Knee circumference  
X 
 
 
 
 
 
 
Physical examinationg 
X 
Xh 
 
Xh 
 
 
X 
12-Lead electrocardiogram 
X 
Xh 
 
 
 
 
X 
Clinical laboratory testingi 
X 
 
 
Xi 
 
 
X 
Urine drug screenj 
X 
Xh 
 
 
 
X 
X 
Urine pregnancy testk 
X 
Xh 
 
Xh 
 
X 
X 
Vital signs  
X 
Xl 
 
Xl 
 
X 
X 


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Screening  
Visit 
Treatment  
#1  
(single 
knee)* 
Phone  
F/U 
Treatment  
#2  
(Bilateral 
knees 
only)*  
Phone  
F/U 
(Bilateral 
knees only)  
Efficacy 
Safety 
Efficacy 
Safety/ Early 
Termination 
Visit 
Clinic Visit (V) or Telephone Visit (TV) 
V1 
V2 
TV3a 
V4b 
TV5a,b 
V6 
V7 
Study Day/Week 
Day -14 
to Day 1c 
Day 1 
Day 3 
±1d  
Day 7 
(Week 2) 
(-2/+5 d) 
V4 +3d  
±1d 
Week 4 
±5d  
Week 8 
± 7dd 
Issue/review/collect paper diary 
X 
Xh 
 
Xh 
 
X 
X 
Sensory testing  
 
Xh 
 
Xh 
 
 
X 
CNTX-4975-05 injection (dosing)l 
(30-minute post-injection observation required) 
 
X 
 
X 
 
 
 
Injection site assessment (erythema, edema)n 
 
X 
 
X 
 
X 
 
Subject assessment of procedure pain (scale of 0-4) o 
 
X 
X 
X 
X 
 
 
Knee Injury and Osteoarthritis Outcome Score (KOOS) 
 
Xw 
 
 
 
X 
X 
Subject satisfaction with treatment procedurep 
 
X 
X 
X 
X 
X 
X 
Subject satisfaction with PJR/TJR (as applicable)p 
 
 
 
 
 
X 
X 
Retreatment questionq 
 
 
 
 
 
 
X 
Investigator satisfaction questionnairer  
 
X 
 
X 
 
 
X 
Joint replacement questionnaires 
 
X 
 
 
 
 
X 
Adverse eventst 
 
X 
X 
X 
X 
X 
X 
Review use of background, analgesic, rescue, and other 
concomitant medications and therapiesu,v 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; d=day; eCRF=electronic case report form; ET=early termination; f/u=follow-up; IA=intra-articular; K-L=Kellgren-Lawrence; 
NPRS=numeric pain rating scale; NSAID=non-steroidal anti-inflammatory drug; OA=osteoarthritis; PI=principal investigator; PJR=partial joint replacement; 
TJR=total joint replacement; TV=telephone visit; V=clinic visit 
* Sites where crash carts and ACLS-certified personnel are not immediately available will have a window of +/- 14 business days to schedule injections. Once a 
crash cart and ACLS-certified personnel are available at these sites then all standard windows apply.  
 
a. 
On Day 3 post-injection (±1 day), study staff will call subjects to assess OA pain, AEs, subject assessment of procedure pain and satisfaction, knee pain with 
walking, and the use of rescue medication (for bilateral knee injections, calls will occur 3 days after each injection). 
b. Only subjects receiving bilateral knee injections will have Visit 4 and Telephone Visit 5. 
c. 
If subjects are unable to complete the screening assessments due to technical issues, the site is permitted a 3 business day window to complete the 
assessments (Screening Period of up to 17 days instead of 14 days). 


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d. If a subject is discontinuing the study before Week 8, the assessments listed for the Week 8/ET Visit should be completed. 
e. 
A pre-screening radiograph of both knees must show evidence of chronic OA with a K-L grade of 1 to 4 in the index knee as determined by the site PI or 
radiologist. If the subject has radiographs from Centrexion study CNTX-4975i-OA-301 or CNTX-4975i-OA-304, those radiographs and K-L grading should 
be used for this study. 
f. 
Medical history and demographics, as outlined in the eCRFs. OA medications should note all therapies, including doses and regimen when known, and all 
should note if the medications were over the counter or prescriptions. Treatments to be recorded include non-invasive treatments (e.g., physical therapy) and 
previous invasive treatments (e.g., arthrotomy, arthroscopy – with procedure, if known). 
g. A complete physical examination (excluding a genitourinary examination) will be performed by the investigator at the Screening Visit and at the final clinic 
visit (Week 8/ET). A partial physical examination will be performed by the investigator before each injection). The physical examinations will also evaluate 
the soft tissue of the index knee for periarticular painful sites, which will be entered onto the case report form.  
h. To be performed before injection of CNTX-4975-05.   
i. 
Clinical laboratory tests will include chemistry, hematology, and urinalysis. Additional tests, including fibrinogen and prothrombin time/partial 
thromboplastin time, will be done at Screening only. Hemoglobin A1c will be done at the Screening and Week 8/ET Visits. Subjects are to fast prior to the 
laboratory sample collections performed at the Screening Visit. If the subject is receiving a second knee injection (in the contralateral knee), labs are not 
required to be repeated if the injection is within 30 days of the screening lab draw (at the investigator’s discretion). 
j. 
Urine drug screen must be confirmed as negative for drugs of abuse prior to treatment. For subjects being treated bilaterally, a Urine Drug Screen is not 
required prior to the second injection. 
k. 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 urine pregnancy test results will not be enrolled or will be discontinued from study participation. These subjects will be 
followed until the pregnancy is completed, and the health of the infant is known. 
l. 
Vital signs are to be performed standing and sitting within approximately 5 minutes before the injection of IP, and sitting-only vital signs within approximately 
5, 15, and 30 minutes minutes after the injection of IP.  
m. Each site is to follow their assigned, protocol-specified treatment regimen and the protocol-specified CNTX-4975-05 administration procedures. 
n. The injection site will be examined and assessed for erythema and edema by site personnel (using a categorical 4-point scale of none, mild, moderate, or 
severe [0-3]) on Study Day 1 (Treatment) before injection, after the injection at 1 and 2 hours post-dose, and at the Week 4 Visit. For bilateral knee 
injections, injection site examinations will be performed before and after each injection. Significant bruising or other clinically significant injection site 
reactions will be recorded as AEs.  
o. Procedure pain will be assessed by asking subjects to rate their index knee pain (1) at rest prior to pre-medication; (2) prior to IA lidocaine (without 
epinephrine); (3) at rest 10 minutes (± 2 minutes) after IA lidocaine (without epinephrine); (4) at 30 minutes (± 5 minutes) after IA injection of 
CNTX-4975-05; and (5) at rest at the 1-hour and 2-hour time points after IA injection of CNTX-4975-05 (± 10 minutes).  
p. Immediately prior to leaving the clinic, the subject will be asked how satisfied they were with the treatment procedure at that visit, using a 7-point Likert 
Scale where 1=completely dissatisfied and 7=completely satisfied. Subjects with a PJR/TJR will also compare their satisfaction with PJR/TJR versus the 
CNTX-4975-05 treatment. 
q. Subjects will be asked whether they would undergo the study treatment again. 
r. 
The investigator will rate their satisfaction with each subject’s study treatment (at V2 and V4 if applicable) and the treatment procedure (at V7). 
s. 
The investigator will judge the likelihood of the need for joint replacement surgery, based on KOOS subscales and subject satisfaction outcomes. The subject 
will judge the likelihood of the desire for joint replacement surgery, based on their personal response to treatment with CNTX-4975-05. 
t. 
Collection of AEs will begin from the time of signing the informed consent form through the Week 8/ET Visit. On Day 1, the AE assessment must be 
performed pre-dose. Treatment-emergent AEs will be collected from the time of the injection of CNTX-4975-05 through the Week 8/ET Visit. Potentially 


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related AEs that are ongoing at the Week 8/ET Visit will be followed until they are stable, resolved, no longer clinically significant (in the opinion of the 
investigator), or until 4 weeks after the study is completed.  
u. Subjects may come into the study with a single analgesic of their choice for their OA knee pain (prescription or OTC). The current pain medication must be 
identified as that taken only for OA knee pain, not for another pain indication. The subjects will complete a daily paper diary of their background knee 
analgesic medications during the screening period and throughout the trial. 
v. Subjects may take rescue medication for pain of the index knee as needed. Subjects should not take rescue medication within 24 hours prior to a clinic visit. 
Data on the type of rescue medication, and the daily dose of rescue medication, will be collected and will be recorded each day in their paper diary. 
Additional rescue medication details will be collected at study visits and follow-up telephone calls and recorded in the source documents and eCRF. 
w. For subjects being treated bilaterally, KOOS will be assessed on both knees prior to the first injection but is not required to be completed prior to the second 
injection.


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3 
TABLE OF CONTENTS 
APPROVAL SIGNATURES...........................................................................................................2 
1 
SYNOPSIS ...............................................................................................................................3 
2 
SCHEDULE OF EVENTS .....................................................................................................15 
3 
TABLE OF CONTENTS .......................................................................................................19 
3.1 
LIST OF TABLES ........................................................................................................23 
REASONS FOR AMENDMENT .................................................................................................24 
SUMMARY OF AMENDED SECTIONS ....................................................................................25 
AMENDED PROTOCOL .............................................................................................................29 
4 
LIST OF ABBREVIATIONS.................................................................................................30 
5 
INTRODUCTION ..................................................................................................................32 
5.1 
Background and Rationale ............................................................................................32 
5.1.1 Capsaicin for Injection (CNTX-4975-05) .........................................................32 
5.1.2 Clinical Experience ...........................................................................................32 
5.1.3 Pharmacokinetics of Qutenza® Topical 8% Capsaicin Patch versus 
Intra-articular CNTX-4975-05 ..........................................................................34 
5.2 
Summary of Potential Risks and Benefits .....................................................................35 
6 
OBJECTIVES .........................................................................................................................36 
6.1 
Primary Efficacy Objective ...........................................................................................36 
6.2 
Secondary Efficacy Objectives .....................................................................................36 
6.3 
Exploratory Efficacy Objectives ...................................................................................36 
6.4 
Safety Objective ............................................................................................................36 
7 
STUDY DESIGN ...................................................................................................................37 
7.1 
Overall Study Design and Plan .....................................................................................37 
7.2 
Discussion of Study Design ..........................................................................................38 
7.3 
Study Site(s) ..................................................................................................................38 
8 
SUBJECT POPULATION .....................................................................................................39 
8.1 
Selection of Study Population .......................................................................................39 
8.2 
Study Entry Criteria ......................................................................................................39 
8.2.1 Inclusion Criteria ...............................................................................................39 
8.2.2 Exclusion Criteria ..............................................................................................41 
8.3 
Premature Subject Withdrawal .....................................................................................43 
8.4 
Subject Replacement Criteria ........................................................................................43 
9 
TREATMENTS ......................................................................................................................44 
9.1 
Identification of Investigational Product(s) ..................................................................44 
9.2 
Labeling and Packaging ................................................................................................44 
9.3 
Treatments Administered ..............................................................................................44 


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9.3.1 Pre-Medication ..................................................................................................44 
9.3.2 Joint Treatment Regimens .................................................................................44 
9.3.3 Injection of CNTX-4975-05 ..............................................................................47 
9.4 
Dispensing and Storage .................................................................................................48 
9.5 
Method of Assigning Subjects to Treatment Groups ....................................................48 
9.6 
Blinding and Unblinding Treatment Assignment .........................................................48 
9.7 
Selection of Dose in the Study ......................................................................................48 
9.8 
Dose Adjustment Criteria ..............................................................................................49 
9.9 
Selection of Timing of Dose for Each Subject..............................................................49 
9.10 Drug Accountability ......................................................................................................49 
9.11 Treatment Compliance ..................................................................................................49 
9.12 Permitted and Prohibited Therapies ..............................................................................49 
9.12.1 Rescue Medication for OA Knee Pain ..............................................................49 
9.12.2 Prohibited Therapies ..........................................................................................50 
9.13 Treatment After End of Study .......................................................................................51 
10 STUDY PROCEDURES ........................................................................................................52 
10.1 Study Visits ...................................................................................................................52 
10.1.1 Screening Visit, Day -14 to Day 1, Visit 1 ........................................................52 
10.1.2 Treatment, Day 1, Visit 2 ..................................................................................53 
10.1.3 Day 3, Telephone Visit 3 ...................................................................................54 
10.1.4 Day 1 of Treatment 2 (Bilaterally Treated Subjects Only), Visit 4 ..................54 
10.1.5 Day 3 of Treatment 2 (Bilaterally Treated Subjects Only), Telephone Visit 5 .55 
10.1.6 Week 4 Follow-up, Visit 6 ................................................................................55 
10.1.7 Week 8, Visit 7 (or Early Termination) ............................................................55 
10.2 Study Duration ..............................................................................................................56 
10.2.1 Overall Study Schedule .....................................................................................56 
10.3 Assessments ..................................................................................................................56 
10.3.1 Efficacy .............................................................................................................56 
10.3.1.1 Average Walking OA Knee Pain (NPRS) ............................................56 
10.3.1.2 Knee Injury and Osteoarthritis Outcome Score (KOOS) ......................56 
10.3.1.3 Joint Replacement Questionnaire ..........................................................57 
10.3.1.4 Subject Satisfaction Questionnaire .......................................................57 
10.3.1.5 Investigator Satisfaction Questionnaire ................................................57 
10.3.1.6 Rescue Medication Use .........................................................................57 
10.3.2 Clinical Pharmacology ......................................................................................58 
10.3.3 Safety .................................................................................................................58 
10.3.3.1 Laboratory Safety Assessments ............................................................58 
10.3.3.2 Clinical Examinations ...........................................................................59 


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10.3.3.3 Assessment of Procedure Pain ..............................................................60 
11 ADVERSE EVENTS..............................................................................................................61 
11.1 Definitions .....................................................................................................................61 
11.1.1 Adverse Events ..................................................................................................61 
11.1.2 Unexpected Adverse Event ...............................................................................61 
11.1.3 Serious Adverse Events .....................................................................................61 
11.1.4 Significant Adverse Events ...............................................................................62 
11.1.5 Treatment-Emergent Adverse Events ...............................................................62 
11.2 Management of Adverse Events ...................................................................................62 
11.2.1 Adverse Event of Special Interest: Severe Allergic Reaction – Anaphylaxis/ 
Anaphylactoid Reaction ....................................................................................62 
11.2.2 Collection ..........................................................................................................64 
11.2.3 Evaluation ..........................................................................................................64 
11.2.3.1 Severity of Adverse Events ...................................................................64 
11.2.3.2 Seriousness ............................................................................................64 
11.2.3.3 Action(s) Taken .....................................................................................64 
11.2.3.4 Outcome at the Time of Last Observation ............................................65 
11.2.3.5 Adverse Event Relationship to Investigational Product........................65 
11.2.4 Documentation ..................................................................................................66 
11.2.5 Treatment of Adverse Events ............................................................................66 
11.2.6 Follow-up ..........................................................................................................66 
11.2.7 Notification ........................................................................................................67 
11.2.7.1 Serious Adverse Events.........................................................................67 
11.2.7.2 Non-serious Adverse Events .................................................................68 
11.3 Special Considerations ..................................................................................................68 
11.3.1 Pregnancy ..........................................................................................................68 
11.3.2 Overdose ............................................................................................................68 
12 DATA SAFETY MONITORING BOARD ...........................................................................70 
13 STATISTICS ..........................................................................................................................71 
13.1 Study Endpoints ............................................................................................................71 
13.1.1 Primary Efficacy Endpoint ................................................................................71 
13.1.2 Secondary Efficacy Endpoints ..........................................................................71 
13.1.3 Exploratory Efficacy Endpoints ........................................................................72 
13.1.4 Safety Endpoints ................................................................................................72 
13.2 Sample Size Determination ...........................................................................................72 
13.3 Analysis Populations .....................................................................................................73 
13.4 Statistical Analyses .......................................................................................................73 
13.4.1 Study Subjects and Demographics ....................................................................73 


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13.4.1.1 Disposition and Withdrawals ................................................................73 
13.4.1.2 Protocol Deviations ...............................................................................73 
13.4.1.3 Demographics and Other Baseline Characteristics ...............................73 
13.4.2 Exposure and Compliance .................................................................................74 
13.4.3 Efficacy Analyses ..............................................................................................74 
13.4.3.1 Primary Analysis ...................................................................................74 
13.4.3.2 Secondary and Exploratory Analyses ...................................................74 
13.4.4 Safety and Tolerability Analyses ......................................................................75 
13.4.4.1 Adverse Events......................................................................................75 
13.4.4.2 Clinical Laboratory Evaluations ...........................................................75 
13.4.4.3 Vital Signs .............................................................................................75 
13.4.4.4 Electrocardiograms ...............................................................................76 
13.4.4.5 Physical Examination Findings .............................................................76 
13.4.4.6 Injection Site Assessment .....................................................................76 
13.4.4.7 Sensory Testing .....................................................................................76 
13.4.4.8 Procedure Pain ......................................................................................76 
13.4.5 Interim Analyses ................................................................................................76 
14 STUDY CONDUCT ...............................................................................................................77 
14.1 Sponsor and Investigator Responsibilities ....................................................................77 
14.1.1 Sponsor Responsibilities ...................................................................................77 
14.1.2 Investigator Responsibilities .............................................................................77 
14.2 Site Initiation .................................................................................................................77 
14.3 Screen Failures ..............................................................................................................78 
14.4 Study Documents ..........................................................................................................78 
14.4.1 Investigator’s Regulatory Documents ...............................................................78 
14.4.2 Case Report Forms ............................................................................................78 
14.4.3 Source Documents .............................................................................................79 
14.5 Data Quality Control .....................................................................................................79 
14.5.1 Monitoring Procedures ......................................................................................79 
14.5.2 Data Management ..............................................................................................79 
14.5.3 Quality Assurance/Audit ...................................................................................80 
14.6 Study Termination .........................................................................................................80 
14.7 Study Site Closure .........................................................................................................80 
14.7.1 Record Retention ...............................................................................................80 
14.8 Changes to the Protocol ................................................................................................81 
14.9 Use of Information and Publication ..............................................................................81 
15 ETHICAL AND LEGAL CONSIDERATIONS ....................................................................82 
15.1 Declaration of Helsinki and Good Clinical Practice .....................................................82 


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15.2 Subject Information and Informed Consent ..................................................................82 
15.3 Approval by Institutional Review Board ......................................................................82 
15.4 Finance and Insurance ...................................................................................................82 
16 REFERENCES .......................................................................................................................83 
17 ATTACHMENTS ...................................................................................................................84 
17.1 Investigator’s Agreement ..............................................................................................85 
18 APPENDICES ........................................................................................................................86 
A. 
Study Specific Requirements ........................................................................................87 
B. 
Regulations and Good Clinical Practice Guidelines .....................................................88 
1. 
Regulations ........................................................................................................88 
2. 
Good Clinical Practice Guidelines ....................................................................88 
C. 
Severe Allergic Reaction – Anaphylaxis/ Anaphylactoid Reaction .............................89 
1. 
 .............................................................89 
2. 
Sampson et al. (2006) ........................................................................................89 
3.1 
LIST OF TABLES 
Table 2-1: Schedule of Events .......................................................................................................15 
 


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REASONS FOR AMENDMENT 
1. The addition of acute allergic/anaphylactic/anaphylactoid reaction as an adverse event of 
special interest, with new precautions, clinical criteria, assessments, and treatment protocols. 
2. The addition of vital sign assessments 15 and 30 minutes after injection of study drug. 
3. The addition of a 30-minute post-injection observation period to ensure that subjects do not 
have a hypersensitivity reaction/anaphylaxis. 
4. The addition of crash carts and ACLS-certified personnel to the requirements at each study 
site. 
 
 
 










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AMENDED PROTOCOL 
The following are the amended protocol and appendices, including all revisions specified above. 


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4 
LIST OF ABBREVIATIONS 
ACLS 
Advanced Cardiac Life Support  
ACR 
American College of Rheumatology  
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical class 
AUC 
area under the curve 
AUC0-last 
maximum systemic exposure  
bid 
twice daily 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CRA 
clinical research associate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FSS 
Fibromyalgia Symptom Scale Score 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale  
HgbA1c 
hemoglobin A1c 
HR 
heart rate 
IA 
intra-articular 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
IP 
investigational product 
IRB 
Institutional Review Board 
IS 
investigator satisfaction 


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ITT 
intent-to-treat 
K-L 
Kellgren-Lawrence 
KOOS 
Knee Injury and Osteoarthritis Outcome Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-model repeated measures  
NPRS 
numeric pain rating scale  
NSAID 
non-steroidal anti-inflammatory drug 
OA 
osteoarthritis 
OARSI 
Osteoarthritis Research Society International 
OMERACT 
Outcome Measures in Rheumatology 
OTC 
over the counter 
PJR 
partial joint replacement 
qd 
once daily 
QOL 
quality of life 
QTc 
QT interval corrected for heart rate 
RR 
respiratory rate 
SAE 
serious adverse event 
SD 
standard deviation 
SS 
subject satisfaction 
t½ 
half-life 
TJR 
total joint replacement 
TRPV1 
transient receptor potential vanilloid subfamily member 1 
UAE 
unexpected adverse event  
US 
United States 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 








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dose exposure, relative to the total 
 exposure of CNTX-4975-05, and approximately a -fold 
safety margin for the single application, as the capsaicin systemic exposure is less than one day. 
5.2 
Summary of Potential Risks and Benefits 
The potential benefits of study participation are that subjects with painful OA of the knee 1) may 
experience a reduction in acute and chronic, moderate-to-severe pain as a result of treatment with 
CNTX-4975-05, and 2) will understand that they are contributing to the scientific knowledge that 
may lead to expansion of the treatment options for subjects with OA. No other benefits of 
participation are anticipated. 
The potential risks of study participation include those associated with exposure to CNTX-4975-05 
and the risks of medical evaluation, including venipuncture and IA injection. Subjects will be 
injected with 1% or 2% lidocaine (without epinephrine) to provide distension of the joint capsule 
for access to the whole joint for CNTX-4975-05 and secondarily for sensory blockade. In principle, 
subjects with substantial reduction of pain and improvement in function after injection could 
overuse the joint and subject the index joint to overuse and an acceleration of the knee OA. 
A summary of the pharmaceutical properties and known potential risks of CNTX-4975 is provided 
in the current version of the investigator’s brochure (IB).3 The investigator must become familiar 
with all sections of the CNTX-4975-05 IB before the start of the study. 






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On Day 3 post-injection, study staff will call subjects to assess AEs, subject assessment of 
procedure pain, knee pain with walking, and the use of rescue medication (for bilateral knee 
injections, calls will occur 3 days after each injection). Subjects will return to the clinic at Weeks 4 
and 8 for study assessments.  
Efficacy will be assessed on the OA index knee (and contralateral knee in bilateral knee injection 
subjects) using a numeric pain rating scale (NPRS); the Knee Injury and Osteoarthritis Outcome 
Score (KOOS), which includes subscales for pain, other symptoms, activities of daily living, sports 
and recreation, and quality of life (QOL); a joint replacement questionnaire; a subject satisfaction 
questionnaire; an investigator satisfaction questionnaire; and rescue medication use. Pain with 
walking will also be collected and assessed for the contralateral knee. 
For subjects with bilateral knee injections, the contralateral knee will be assessed using the same 
scales as the index knee, and the effect of bilateral knee injections will be combined as a composite 
score to examine the overall benefit. The index knee in these subjects is the one with worse pain 
with walking. Where both knees have equal pain with walking, then the knee on the subject’s 
dominant side will be designated the index knee. 
Safety will be assessed by injection site assessments (erythema and edema), assessment of 
procedure pain, AEs, physical examination findings, vital sign measurements, 12-lead 
electrocardiograms (ECGs), clinical laboratory test results, and sensory testing. 
7.2 
Discussion of Study Design 
This open label study, CNTX-4975i-OA-303, is an 8-week study to evaluate the efficacy and 
safety of a single IA injection (per knee, as applicable) of CNTX-4975-05 in subjects with chronic, 
moderate-to-severe OA knee pain. Procedural pain associated with IA injection of CNTX-4975-05 
will be controlled primarily through adjunct controlled joint cooling and secondarily by 
pre-medication with IA lidocaine. The planned safety and tolerability and efficacy assessments are 
standard and appropriate. 
7.3 
Study Site(s) 
The study will take place at no more than 45 concurrent sites in the US, Germany, Spain and the 
United Kingdom. Each site is anticipated to screen a sufficient number of subjects to be able to 
enroll approximately 18 subjects. A study site with an acceptable recruitment rate and acceptable 
quality metrics may be allowed to recruit more subjects if other sites have low enrollment.  


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8 
SUBJECT POPULATION  
8.1 
Selection of Study Population 
Based on the mechanism of action and use of trans-capsaicin for the treatment of pain, there are 
no gender-specific adverse effects known or to be expected. Thus, male and female subjects will 
be included in the study. A screening log of potential study candidates and/or an enrollment log of 
enrolled subjects must be maintained at each study site. 
8.2 
Study Entry Criteria 
8.2.1 Inclusion Criteria 
A subject will be eligible for study participation if the subject meets all of the following criteria: 
1. Male or female subjects between 40 and 95 years of age (inclusive). 
2. Confirmation of OA of the knee: radiography of both knees using standard standing films 
(scored by the investigator) or using the fixed flexion method, taken during the Screening 
Visit (prior radiographs of the knees of sufficient quality that have been taken within 2 years 
of the Screening Visit may be used for K-L grading). The index knee must show evidence of 
chronic OA with a K-L grade of 1, 2, 3 or 4. Subjects who were screen failures for the US 
CNTX-4975i-OA-301 or CNTX-4975i-OA-304 trials may be considered for this trial if the 
K-L grade of the index knee is 1-4, inclusive. 
3. Confirmation of OA of the index knee: American College of Rheumatology (ACR) 
diagnostic criteria (ACR confirmation of bilateral knee OA for subjects who will have 
bilateral knee injections of CNTX-4975-05). 
4. For subjects for monoarticular knee injection, the index knee must have moderate to severe 
pain (≥5 and ≤9) at screening associated with OA, which must be stable for a minimum of 
6 months prior to Screening, as assessed by the investigator. These subjects may have: 
a) unilateral or bilateral OA, with the index knee having moderate to severe pain, and the 
contralateral knee having none to mild pain, OR 
b) unilateral or bilateral OA, with the index knee having moderate to severe pain and the 
other knee having had a PJR or TJR within 5 years of the Screening Visit. The knee with 
the PJR/TJR is not to be injected with CNTX-4975-05. 
For subjects for bilateral knee injection, the index knee must have moderate to severe pain 
(≥5 and ≤9) at screening associated with OA, and greater pain in the index knee than in the 
contralateral knee. Their pain must be stable for a minimum of 6 months prior to Screening, 
as assessed by the investigator. The index knee in these subjects is the one with the worst 
pain with walking. Where both knees have equal pain with walking, then the knee on the 
subject’s dominant side will be designated the index knee. 
For qualifying knee pain with walking, subjects will use an NPRS (0-10; 0=no pain, 
10=worst possible pain) to rate their knee pain with walking (both knees, except knees with 
PJR/TJR). The PJR/TJR pain should be rated using the NPRS scale, but will not be a 
qualifying pain score. 
5. Body mass index ≤45 kg/m2. 


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6. Subjects must have failed 2 or more prior therapies. Failure is deemed to be inadequate relief 
in the opinion of the investigator. A therapy may be deemed to have been inadequate because 
of one or more of the following:  
a) unacceptable AEs;  
b) initial failure to achieve clinically adequate pain relief;  
c) initial pain relief that was not maintained; and/or  
d) 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, the following: NSAIDs (including topical), 
opioids, duloxetine, other systemic therapy, IA corticosteroids, IA viscosupplements, 
physical therapy, bracing, and orthotics.  
7. Females not of childbearing potential, defined as post-menopausal for at least 1 year, or 
surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or 
practicing one of the following medically acceptable methods of birth control throughout the 
study period:  
• 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 CNTX-4975-05 administration 
• Total abstinence from sexual intercourse since the last menses before CNTX-4975-05 
administration 
• Intrauterine device 
• Double barrier method (condoms, sponge, diaphragm, with spermicidal jellies or cream). 
8. Able to speak, read, and understand the language of the study used for the informed consent.  
9. Willing and able to:  
a) understand the study requirements 
b) abide by the study restrictions and requirements 
c) complete the study procedures 
d) be compliant and independently (i.e., without assistance) record responses on the efficacy 
scales during clinic visits 
e) independently communicate meaningfully with the study personnel 
10. Signed informed consent form (ICF) approved by the institutional review board 
(IRB)/independent ethics committee (IEC). 
11. Subjects may come into the study with a single analgesic of their choice for their OA knee 
pain. The current pain medication must be identified as that taken only for pain in the knee 
OA or pain in the PJR/TJR, and not for another pain indication. The subjects will complete a 
daily paper diary of their background knee analgesic medications during the screening period 
and throughout the trial. Other analgesics may be taken for occasional pain but should not be 


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taken within 24 hours of a clinic visit; these are to be recorded as concomitant medications, 
not as rescue/background medication for knee osteoarthritis. 
8.2.2 Exclusion Criteria 
A subject will be excluded from the study if the subject meets any of the following criteria: 
1. Joint replacement surgery of the index knee at any time, or open surgery of the index knee in 
the past 24 months. Joint replacement of the contralateral knee is permitted for subjects who 
will not receive an injection in the contralateral (natural) knee. For subjects with bilateral 
knee OA who will receive an injection into both knees, joint replacement surgery of both 
knees at any time, or open surgery of the index knee in the past 24 months, is excluded. 
2. Prior arthroscopic surgery of the index knee within 6 months of Screening. 
3. Any painful conditions of the index knee due to joint disease other than OA. For example, 
radicular or referred pain involving the index knee or from joint disease other than OA 
involving the index knee, such as, but not restricted to chondromalacia patellae, 
inflammatory diseases (e.g., rheumatoid arthritis, psoriatic arthritis), metabolic diseases, 
gout/pseudogout, hemochromatosis, acromegaly, etc.  
4. Periarticular pain from any cause, including referred pain, bursitis, tendonitis, soft tissue 
tenderness, or subacute/acute pain from injury. 
5. Other chronic pain anywhere in the body that requires the use of chronic analgesic 
medications, including, but not limited to, local painful areas, myofascial pain syndromes, 
fibromyalgia, genetic, metabolic abnormalities, hematologic, or neuropathic pain. 
6. Instability of the index or contralateral knee (e.g., cruciate ligament tear or rupture, 
significant protruding meniscus, substantial ligamentous laxity, unstable PJR or TJR).  
7. Misalignment (>10 degrees varus or valgus) of the index knee on standing. 
8. Documented history of neuropathic arthropathy or finding of bony fragmentation in the index 
knee with imaging (radiographic, computed tomography, or magnetic resonance imaging). 
9. Physical/occupational/chiropractic therapy for the lower extremities or acupuncture for the 
lower extremities within 15 days of Screening, or need for such therapy during the study. 
10. Plans to have surgery, other invasive procedures, or IA injections (other than 
CNTX-4975-05) for either knee while participating in the study. 
11. Current use of opioids for any condition other than for OA of the knees injected with 
CNTX-4975-05) (maximum dose of 15 mg of hydrocodone [or equivalent] per day).  
12. Corticosteroid injection into the index or contralateral knee within 90 days of Screening. 
13. Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of Screening. 
14. History of allergic reaction to the planned local anesthesia/analgesic regimens, 
ethylenediaminetetraacetic acid, Kolliphor HS 15, butylated hydroxytoluene, or capsaicin. 
15. Presence of any medical condition or unstable health status that, in the judgment of the 
investigator, might adversely impact 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 
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medication, or significantly compromise key organ systems. For any question regarding 
eligibility, it is strongly recommended that the investigator discuss the subject with the 
medical monitor. 
16. Is pregnant or is breast feeding. 
17. Has a malignancy, a history of malignancy, or has received treatment for malignancy at any 
time, with exception of resected and cured basal cell carcinoma and squamous cell carcinoma 
of the skin.  
18. Regular use of anticoagulant blood thinners (except low-dose aspirin, Dabigatran 150 mg 
once daily [qd], Enoxaparin 40 mg qd, Rivaroxaban 10 mg qd, or Apixaban 2.5 mg twice 
daily [bid], or clopidogrel 75 mg qd, which are allowed).  
19. Active cutaneous disease at the anticipated site of CNTX-4975-05 injection that would 
prevent the safe administration of CNTX-4975-05. 
20. Ulcer or open wound anywhere on the index knee. 
21. Specific laboratory abnormalities: 
• Hemoglobin <11.0 g/dL 
• White blood cells <2.5 × 109/L 
• Neutrophils <1.5 × 109/L 
• Platelets <100 × 109/L 
• Aspartate transaminase or alanine transaminase >2 × upper limit of normal 
• Creatinine >1.6 mg/dL 
• Glucose (fasting) >250 mg/dL 
• Hemoglobin A1c (HgbA1c) >9.0% 
22. Clinically significant abnormal laboratory result 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. For any question regarding eligibility, it is 
strongly recommended that the investigator discusses the subject with the medical monitor. 
23. Use of an investigational medication 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. 
24. Prior participation in an ALGRX 4975 or CNTX-4975 study. 
25. Has any of the following characteristics: 
• Active or historic substance use disorder within the previous year, as defined by the 
Diagnostic and Statistical Manual for Mental Health Disorders, fifth edition 
• Test is positive upon urine drug screen for a substance of abuse (prescribed opioids 
acceptable) 
• Has a history, at any time, or currently, of suicidal ideation, suicide attempt, or increased 
risk of suicide 


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• Has an unacceptable level of depression or anxiety as measured by the Hospital Anxiety 
and Depression Scale (HADS) (a score of ≥11) 
• Has unacceptable chronic pain as measured by the Fibromyalgia Symptom Scale Score 
(FSS) (a score of ≥13) 
• Has a positive pregnancy test at the Screening or either Treatment Visit 
• Has ongoing litigation for workers’ compensation 
• Has any condition, or is taking any medication, that would be contraindicated for study 
participation 
8.3 
Premature Subject Withdrawal 
All subjects will be advised that they are free to withdraw from participation in this study at any 
time, for any reason, and without prejudice. Every reasonable attempt should be made by the 
investigator to keep subjects in the study. However, subjects must be withdrawn from the study if 
they withdraw consent to participate. Investigators must attempt to contact subjects who fail to 
attend scheduled visits by telephone or other means to exclude the possibility of an AE being the 
cause of withdrawal. Should this be the cause, the AE must be documented, reported, and followed 
as described in Section 11.2. 
The sponsor reserves the right to request the withdrawal of a subject due to protocol deviations or 
other reasons. 
The investigator also has the right to withdraw subjects from the study at any time for lack of 
therapeutic effect that is intolerable or otherwise unacceptable to the subject, for intolerable or 
unacceptable AEs, intercurrent illness, noncompliance with study procedures, administrative 
reasons, or in the investigator’s opinion, to protect the subject’s best interest. 
If a subject is withdrawn before completing the study, the reason for withdrawal and the date of 
discontinuation will be recorded on the appropriate page of the electronic case report form (eCRF). 
Whenever possible and reasonable, the evaluations that were to be conducted at the completion of 
the study should be performed at the time of premature discontinuation. 
8.4 
Subject Replacement Criteria 
Withdrawn subjects will not be replaced. If a substantial number of subjects are withdrawn from 
the study, the sponsor will evaluate the need for developing replacement criteria. 
Enrolled subjects withdrawn from the study may not reenter. The subject number for a withdrawn 
subject will not be reassigned to another subject. 




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Each site will be randomly assigned 1 of the following 5 treatment regimens to be employed for 
ALL subjects at that site:  
Group 
Cooling 
Device 
• Pre-cool 
• Lidocaine % 
• Post-lido cool 
Needle 
Post-
dose 
cooling 
1. Breg Cooling Control 
Group 
Breg ice 
water 
pump  
• 15 mins 
• 2% lidocaine 
• 30 mins 
Separate needles for 
lidocaine and CNTX-
4975-05 
30 to 90 
mins as 
needed 
2. Gel Pack Cooling 
Group 
Elasto-
Gel 
• 40 mins 
• 2% lidocaine 
• 10 mins 
Separate needles for 
lidocaine and CNTX-
4975-05 
10 to 90 
mins as 
needed 
3. Shortened Gel Pack 
Cooling Group 
Elasto-
Gel 
• 30 mins 
• 2% lidocaine 
• 5 mins 
Separate needles for 
lidocaine and CNTX-
4975-05 
up to 90 
mins as 
needed 
4. Single Needle 
Injection Gel Pak 
Cooling Group-2% 
Lidocaine 
Elasto-
Gel 
• 45 mins 
• 2% lidocaine 
• no cooling 
Single needle for 
lidocaine and CNTX-
4975-05 
up to 90 
mins as 
needed 
5. Single Needle 
Injection Gel Pack 
Cooling Group-1% 
Lidocaine 
Elasto-
Gel 
• 45 mins  
• 1% lidocaine 
• no cooling 
Single needle for 
lidocaine and CNTX-
4975-05  
up to 90 
mins as 
needed 
See study manual for specific instructions on the use of the Breg Cooling Wrap and the Elasto-Gel 
Cooling Wrap. 
1. Breg Cooling Control Group (used in protocols CNTX-4975i-OA-301 and 
CNTX-4975i-OA-304 for comfort and blinding of the protocols)  
a. Controlled joint cooling wrap with an ice water pump system (Breg Cooler) will 
be applied 15 minutes prior to IA injection of the full 15 mL 2% lidocaine 
(without epinephrine) into the knee joint using standard aseptic techniques.  
b. Inject IA the full 15 mL of 2% lidocaine (without epinephrine) into the knee joint 
using appropriate aseptic techniques. 
c. Controlled cooling will be resumed for a further 30 minutes after the IA injection 
of the full 15 mL 2% lidocaine (without epinephrine) into the knee joint.  
d. The cooling device will be removed, and CNTX-4975-05 IA injection will be 
administered using standard aseptic techniques.  
e. Controlled cooling will be reapplied for a minimum of 30 minutes, and up to 
90 minutes, as needed, after CNTX-4975-05 injection, depending on the subject’s 
comfort. The cooling may be discontinued after a minimum of 30 minutes after 
IA CNTX-4975-05 injection, if the subject has a pain level that is acceptable for 
the subject and investigator (0-4 scale: none, mild, moderate, moderately severe, 
and severe). 


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2. Gel Pack Cooling Group 
a. Gel pack cooling applied for 40 minutes to the knee using the gel pack over a 
stockinette or light-weight pants. This may be outside of the exam room, but at 
the investigator’s discretion, may be done in the exam room. If done outside the 
exam room, subject may be moved to the exam room ± 5 minutes of the 
40-minute cooling (with gel pack remaining on the knee). 
b. Inject IA the full 15 mL 2% lidocaine (without epinephrine) into the knee joint 
using appropriate aseptic techniques.  
c. Gel pack cooling is applied for 10 minutes to the knee using the gel pack over a 
stockinette or light-weight pants. 
d. The gel pack will then be removed, and CNTX-4975-05 IA injection will be 
administered using appropriate aseptic techniques.  
e. Gel pack cooling will be reapplied for a minimum of 10 minutes, and up to 
90 minutes, as needed, after CNTX-4975-05 injection, depending on the subject’s 
comfort. The cooling may be discontinued after a minimum of 10 minutes after 
IA CNTX-4975-05 injection. If the subject has a pain level that is acceptable for 
the subject and investigator (0-4 scale: none, mild, moderate, moderately severe 
and severe). 
3. Shortened Gel Pack Cooling Group  
a. Gel pack cooling applied for 30 minutes to the knee using the gel pack over a 
stockinette or light-weight pants. This may be outside of the exam room, but at 
the investigator’s discretion, may be done in the exam room. If done outside the 
exam room, subject may be moved to the exam room ± 5 minutes of the 
30-minute cooling (with gel pack remaining on the knee). 
b. Inject IA the full 15 mL 2% lidocaine (without epinephrine) into the knee joint 
using appropriate aseptic techniques. 
c. Gel pack cooling is applied for 5 minutes to the knee using the gel pack over a 
stockinette or light-weight pants. 
d. The gel pack will then be removed, and CNTX-4975-05 IA injection will be 
administered using appropriate aseptic techniques.  
e. Gel pack cooling may be reapplied for up to 90 minutes, as needed, after 
CNTX-4975-05 injection, depending on the subject’s comfort. The subject may 
remain in the exam room, or be moved to a more comfortable area with the gel 
pack. The gel pack may be discontinued after IA CNTX-4975-05 injection if the 
subject has a pain level that is acceptable for the subject and investigator 
(0-4 scale: none, mild, moderate, moderately severe and severe). 
4. Single Needle Injection Gel Pack Cooling Group-2% IA Lidocaine 
a. Gel pack cooling applied for 45 minutes to the knee using the gel pack over a 
stockinette or light-weight pants. This may be outside of the exam room, but at 
the investigator’s discretion, may be done in the exam room. If done outside the 
exam room, subject may be moved to the exam room ± 5 minutes of the 4--minute 
cooling (with gel pack remaining on the knee).   


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b. Inject IA the full 15 mL 2% lidocaine (without epinephrine) into the knee joint 
using appropriate aseptic techniques.   
c. After the 2% lidocaine IA injection, CNTX-4975-05 IA injection, using the same 
needle, will be injected into the knee joint using appropriate aseptic techniques 
after 3 minutes of the 2% lidocaine (without epinephrine).  
d. Gel pack cooling may be reapplied for up to 90 minutes, as needed, after 
CNTX-4975-05 injection, depending on the subject’s comfort. The subject may 
remain in the exam room, or be moved to a more comfortable area with the gel 
pack. The gel pack may be discontinued after a minimum of 10 minutes after IA 
CNTX-4975-05 injection if the subject has a pain level that is acceptable for the 
subject and investigator (0-4 scale: none, mild, moderate, moderately severe and 
severe). 
5. Single Needle Injection Gel Pack Cooling Group-1% IA Lidocaine 
a. Gel pack cooling applied for 45 minutes to the knee using the gel pack over a 
stockinette or light-weight pants. This may be outside of the exam room, but at 
the investigator’s discretion, may be done in the exam room. If done outside the 
exam room, subject may be moved to the exam room ± 5 minutes of the 
40-minute cooling (with gel pack remaining on the knee).   
b. Inject IA the full 15 mL 1% lidocaine (without epinephrine) into the knee joint 
using appropriate aseptic techniques.   
c. After the 1% lidocaine IA injection, CNTX-4975-05 IA injection, using the same 
needle, will be injected into the knee joint using appropriate aseptic techniques 
after 3 minutes of the 1% lidocaine (without epinephrine).  
d. Gel pack cooling may be reapplied for up to 90 minutes, as needed, after 
CNTX-4975-05 injection, depending on the subject’s comfort. The subject may 
remain in the exam room, or be moved to a more comfortable area with the gel 
pack. The gel pack may be discontinued after IA CNTX-4975-05 injection if the 
subject has a pain level that is acceptable for the subject and investigator 
(0-4 scale: none, mild, moderate, moderately severe and severe). 
9.3.3 Injection of CNTX-4975-05 
It is recommended that the CNTX-4975-05 injection be administered using ultrasound-guided 
needle placement, but is not required. If imaging-guided injection is not used, then confirmation 
of location of the needle within the index knee joint must be verified by aspirating joint fluid. If 
no joint fluid is aspirated, CNTX-4975-05 should not be injected. If there is a substantial effusion 
within the knee joint, the effusion should be aspirated, when possible, such that the estimated 
remaining joint fluid in the knee is approximately 5-10 mL. Record the amount of joint fluid 
aspirated.  
Subjects should not take a hot bath or shower, or expose the injected knee(s) to external heat, 
within 12 hours after the injection.  




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stiffness, and baseline pain. In addition, the safety profile of CNTX-4975 was similar to that of 
placebo throughout the 24-week study. 
9.8 
Dose Adjustment Criteria 
Dose adjustment is not allowed in this study. 
9.9 
Selection of Timing of Dose for Each Subject 
All subjects will receive a single clinical or ultrasound-guided IA injection of CNTX-4975-05 into 
the index knee (and the contralateral knee, if applicable) at the study site under the surveillance of 
appropriate study personnel on Study Day 1 (Treatment Day 1). If applicable, injection of the 
contralateral knee will occur 1 week later. 
9.10 Drug Accountability 
The site pharmacist must maintain adequate records showing the receipt, dispensing, return, or 
other disposition of the IP including the date, quantity, batch or code number, and identification 
of subjects (subject number) who received the IP. The site pharmacist will not supply the IP to any 
person except those named as the investigator or sub-investigators, designated study personnel, 
and subjects in this study. The site pharmacist will not dispense the IP from any study sites other 
than those listed. Investigational product(s) may not be relabeled or reassigned for use by other 
subjects. If any of the IP is not dispensed, is lost, stolen, spilled, unusable, or is received in a 
damaged container, this information must be documented and reported to Centrexion Therapeutics 
Corp. and appropriate regulatory agencies, as required. 
Upon completion of the study, the IP (partly used, unused, and empty packaging) must be left in 
the original packaging and returned to the sponsor or designee for destruction. 
9.11 Treatment Compliance 
All injections at the study site should be under the surveillance of appropriate study personnel. 
Injection procedure details will be recorded in the subject’s eCRF.  
All concomitant medications used (including over the counter [OTC] medications) will be 
recorded in the source document and on the appropriate eCRF. 
9.12 Permitted and Prohibited Therapies 
All concomitant medications used (including OTC medications) will be recorded in the source 
document and on the appropriate eCRF.  
9.12.1 Rescue Medication for OA Knee Pain  
Subjects may come into the study with a single analgesic of their choice for their OA knee pain.  
(prescription or OTC). The current pain medication is to be taken only for OA knee pain, not for 
another pain indication (such as knee pain in the knee with a PJR/TJR). This medication will be 
considered the subject’s “background” medication; for subjects having both knees injected with 
CNTX-4975, background medications are those used to treat either knee. From screening through 
the end of the study, subjects are not to change to a different background pain medication. Subjects 
are permitted to change their dosage of background medication and/or discontinue their 


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background medication. Any change in dose, change in dose frequency, or discontinuation of 
background medication should be entered into the paper diary and the eCRF.  
Subjects may take another analgesic as rescue medication for pain of the index knee as needed. 
The rescue medication is not allowed to be in the same drug class as the ongoing background 
medication. For example, subjects will not be allowed to take tramadol as a rescue medication if 
they are already taking an opioid, or an NSAID as rescue if they are already taking an NSAID. 
Data on the type of rescue and background medication, and the daily dose, will be reported daily 
by the subjects using a paper diary. Additional rescue medication details will be collected at study 
visits and follow-up telephone calls in the source documents and eCRF. 
Subjects should not take rescue medication for knee osteoarthritis pain, or for other pain, within 
24 hours prior to a clinic visit. 
Other analgesics may be taken for occasional pain, but should not be taken within 24 hours of a 
clinic visit; these are to be recorded as concomitant medications, not as rescue or background 
medication for knee osteoarthritis. 
9.12.2 Prohibited Therapies 
The following therapies are prohibited both prior to and during the study: 
• Injection of corticosteroids in the index knee from 90 days prior to Screening through 
study completion. 
• Current use of opioids for any condition other than for OA of the injected knees or 
PJR/TJR knees (maximum dose of 15 mg of hydrocodone [or equivalent] per day as 
background medication allowed at entry). 
• Regular use of anticoagulant blood thinners (except low-dose aspirin, Dabigatran 
150 mg qd, Enoxaparin 40 mg qd, Rivaroxaban 10 mg qd, or Apixaban 2.5 mg bid, 
which are allowed).  
• Use of an investigational medication within 30 days or 5 pharmacokinetic or 
pharmacodynamic half-lives (whichever is longer) prior to Screening or while 
participating in the study.  
• Physical/occupational/chiropractic therapy for the lower extremities or acupuncture for 
the lower extremities within 15 days of Screening, or need for such therapy during the 
course of the study. 
• Joint replacement surgery of the index knee at any time, or open surgery of the index 
knee in the past 24 months prior to Screening, or prior arthroscopic surgery of the index 
knee within 6 months of Screening. For subjects with bilateral knee OA who will receive 
an injection into both knees, joint replacement surgery of both knees at any time, or open 
surgery of the index knee in the past 24 months, is excluded. 
• Surgery, or other invasive procedures, or IA injections (other than CNTX-4975-05) 
while participating in the study. 
• Subjects should not take a hot bath or shower, or expose the injected knee(s) to external 
heat, within 12 hours after the injection.  


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The subject should be excluded from study participation if they have taken any medication prior to 
treatment that would indicate that the subject has a serious or unstable illness, is not in good general 
health, or has a condition that would contraindicate study participation. 
Subjects receiving excluded therapies will be ineligible for study enrollment. If subjects receive 
excluded therapies after enrollment, continuation in the study will be at the discretion of the 
sponsor/investigator/medical monitor. 
9.13 Treatment After End of Study 
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10 STUDY PROCEDURES 
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 2). 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. 
10.1 Study Visits 
10.1.1 Screening Visit, Day -14 to Day 1, Visit 1 
The subject must be screened within 14 days before enrollment into the study. The following 
procedures will be performed at screening. 
• Written informed consent 
• Confirmation of knee OA K-L grade (1 to 4) of the knee, based on radiographs 
• Confirmation of diagnosis of knee OA, based on ACR diagnostic criteria 
• Inclusion/exclusion criteria 
• Height and weight (BMI) 
• History of cancer 
• Knee pain with walking (during last 24 hours, assessed in the clinic using NPRS of 0-10) 
• Demographics 
• Medical history, including current OA medications (prescription and non-prescription 
medications) and treatment history (including noninvasive or previous invasive treatments) 
• HADS 
• FSS 
• Knee circumference 
• Complete physical examination 
• ECG 
• Clinical laboratory testing (fasting) 
• Urine drug screen 
• Urine pregnancy test 
• Vital signs  
• Issue paper diary to the subject with instructions on use and recording of background 
analgesic and rescue medication for index knee (or bilateral knee for subjects being treated 
for both knees) 


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10.1.2 Treatment, Day 1, Visit 2 
As 2 cases of severe allergic reactions have occurred in the entire CNTX-4975 program, a crash 
cart and personnel certified in advanced cardiac life support (ACLS) should be immediately 
available. See section 11.2.1 for details. 
The following procedures will be performed on Day 1. 
• Knee pain with walking (during last 24 hours, assessed in the clinic using NPRS of 0-10) 
• Partial physical examination 
• ECG 
• Urine drug screen 
• Urine pregnancy test 
• Vital signs (before and after injection of CNTX-4975-05). All subjects must be monitored 
for at least 30 minutes (or longer, as required by the protocol) after study drug injection to 
ensure that they do not have a hypersensitivity reaction/anaphylaxis. Vital signs (VS) are 
to be done standing and sitting within approximately 5 minutes before the injection of IP, 
and sitting-only vital signs within approximately 5, 15, and 30 minutes after the injection 
of IP. 
• Injection site assessment (erythema, edema) before injection and 1 and 2 hours after the 
injection 
• Review paper diary 
• Sensory testing 
• Subject assessment of procedure pain (using 0-4 scale)  
o at rest prior to pre-medication;  
o prior to IA lidocaine (without epinephrine);  
o at rest 10 minutes (±2 minutes) after IA lidocaine (without epinephrine);  
o at 30 minutes (±5 minutes) after IA injection of CNTX-4975-05; and  
o at rest at the 1-hour and 2-hour time points after IA injection of CNTX-4975-05 
(±10 minutes). 
• CNTX-4975-05 injection procedure, including lidocaine and cooling 
• KOOS 
• IS questionnaire 
• Joint replacement questionnaire 
• AEs 
• Review use of background, analgesic, rescue, and other concomitant medications and 
therapies 
• SS with treatment procedure 


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10.1.3 Day 3, Telephone Visit 3 
• Knee pain with walking (during last 24 hours, assessed using NPRS of 0-10) 
• Subject assessment of procedure pain (using 0-4 scale) 
• AEs 
• Review use of background, analgesic, rescue, and other concomitant medications and 
therapies 
• SS with treatment procedure 
10.1.4 Day 1 of Treatment 2 (Bilaterally Treated Subjects Only), Visit 4 
As 2 cases of severe allergic reactions have occurred in the entire CNTX-4975 program, a crash 
cart and personnel certified in advanced cardiac life support should be immediately available. See 
section 11.2.1 for details. 
The following procedures will be performed on Day 1 of Treatment 2 (bilaterally treated subjects 
only). 
• Knee pain with walking (during last 24 hours, assessed in the clinic using NPRS of 0-10) 
• Partial physical examination 
• Clinical laboratory testing 
• Urine pregnancy test 
• Vital signs (before and after injection of CNTX-4975-05). All subjects must be monitored 
for at least 30 minutes (or longer, as required by the protocol) after study drug injection to 
ensure that they do not have a hypersensitivity reaction/anaphylaxis. Vital signs (VS) are 
to be done standing and sitting within approximately 5 minutes before the injection of IP, 
and sitting-only vital signs within approximately 5, 15, and 30 minutes after the injection 
of IP. 
• Assessment of injection site on second knee (erythema, edema) before injection and 1 and 
2 hours after the injection 
• Review paper diary 
• Sensory testing 
• Subject assessment of procedure pain (using 0-4 scale)  
o at rest prior to pre-medication;  
o prior to IA lidocaine (without epinephrine);  
o at rest 10 minutes (±2 minutes) after IA lidocaine (without epinephrine);  
o at 30 minutes (±5 minutes) after IA injection of CNTX-4975-05; and  
o at rest at the 1-hour and 2-hour time points after IA injection of CNTX-4975-05 
(±10 minutes). 
• CNTX-4975-05 injection procedure, including lidocaine and cooling 


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• IS questionnaire 
• AEs 
• Review use of background, analgesic, rescue, and other concomitant medications and 
therapies 
• SS with treatment procedure 
10.1.5 Day 3 of Treatment 2 (Bilaterally Treated Subjects Only), Telephone Visit 5 
• Knee pain with walking (during last 24 hours, assessed using NPRS of 0-10) 
• Subject assessment of procedure pain (using 0-4 scale) 
• AEs 
• Review use of background, analgesic, rescue, and other concomitant medications and 
therapies 
• SS with treatment procedure 
10.1.6 Week 4 Follow-up, Visit 6 
• Knee pain with walking (during last 24 hours, assessed in the clinic using NPRS of 0-10) 
• Urine drug screen 
• Urine pregnancy test 
• Vital signs  
• Injection site assessment (erythema, edema)  
• Review paper diary 
• KOOS 
• SS with treatment procedure 
• SS with PJR/TJR (if applicable) 
• AEs 
• Review use of background, analgesic, rescue, and other concomitant medications and 
therapies 
10.1.7 Week 8, Visit 7 (or Early Termination) 
• Knee pain with walking (during last 24 hours, assessed in the clinic using NPRS of 0-10) 
• Complete physical examination 
• ECG 
• Clinical laboratory testing 
• Urine drug screen 


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• Urine pregnancy test 
• Vital signs  
• Sensory testing 
• Review and collect paper diary 
• KOOS 
• SS with study treatment 
• SS with PJR/TJR (if applicable) 
• Subject retreatment question 
• IS questionnaire 
• Joint replacement questionnaire 
• AEs 
• Review use of background, analgesic, rescue, and other concomitant medications and 
therapies 
10.2 Study Duration 
10.2.1 Overall Study Schedule 
The overall study duration is expected to be 13 months, with 10 months of active enrollment and 
about 3 months for screening and treatment follow-up. 
The planned sequence and maximum duration of the study periods will be as follows: 
1. Screening Period: up to 15 days 
2. Treatment Period (open-label): 1 day per knee treated, maximum 2 days 
3. Post-treatment Period: 8 weeks from the first CNTX-4975-05 IA injection 
The maximum treatment duration for each subject is 2 days. The maximum study duration for each 
subject is approximately 10 weeks. 
10.3 Assessments 
10.3.1 Efficacy 
10.3.1.1 Average Walking OA Knee Pain (NPRS) 
At each visit, subjects will assess their average daily index knee pain with walking during the 
previous 24 hours. Average daily OA knee pain with walking will be evaluated using a 0-10 NPRS 
(0=no pain and 10=worst possible pain). Subjects will rate each knee separately. 
10.3.1.2 Knee Injury and Osteoarthritis Outcome Score (KOOS) 
The KOOS was developed as an extension of the WOMAC Osteoarthritis Index with the purpose 
of evaluating short-term and long-term symptoms and function in subjects with knee injury and 
OA. The KOOS holds 5 separately scored subscales: pain, other symptoms, function in daily 


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living, function in sport and recreation, and knee-related QOL. The KOOS has been validated for 
several orthopedic interventions such as anterior cruciate ligament reconstruction, meniscectomy, 
and total knee replacement. In addition, the instrument has been used to evaluate physical therapy, 
nutritional supplementation, and glucosamine supplementation. The effect size is generally largest 
for the subscale QOL followed by the subscale Pain. The KOOS is a valid, reliable, and responsive 
self-administered instrument that can be used for short-term and long-term follow-up of several 
types of knee injury, including OA.  
10.3.1.3 Joint Replacement Questionnaire 
The investigator will judge the likelihood of the need for joint replacement surgery, based on 
KOOS subscales and subject satisfaction outcomes. 
The subject will judge the likelihood of the desire for joint replacement surgery, based on their 
personal response to treatment with CNTX-4975-05. 
10.3.1.4 Subject Satisfaction Questionnaire 
Subjects will be asked to rate their overall satisfaction with the treatment procedure. Subjects with 
a PJR/TJR will also compare their satisfaction with their PJR/TJR versus their CNTX-4975-05 
treatment. These will be rated using the following 7-point scale:  
 
1 – Completely dissatisfied  
 
2 – Mostly dissatisfied  
 
3 – Somewhat dissatisfied  
 
4 – Neither satisfied or dissatisfied  
 
5 – Somewhat satisfied  
 
6 – Mostly satisfied  
 
7 – Completely satisfied 
Subjects will also be asked whether they would undergo the study treatment again. 
10.3.1.5 Investigator Satisfaction Questionnaire 
The investigator will rate his or her satisfaction with the subject’s study treatment. 
The investigator will rate his or her satisfaction with the treatment procedure. 
10.3.1.6 Rescue Medication Use 
Subjects may take rescue medication for pain of the index knee as described in Section 9.12.1, 
except that they should not use rescue medication within 24 hours before a planned study visit. 
Data on the type of rescue medication and background analgesics for knee OA, and the daily dose, 
will be reported daily by the subject on a paper diary from Screening through Week 8/ET. 
Additional rescue medication details will be collected at study visits and follow-up telephone calls 
in the source documents and in the eCRF. 


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10.3.2 Clinical Pharmacology 
Not applicable for this study. 
10.3.3 Safety 
Safety will be assessed by injection site assessments (erythema and edema), assessment of 
procedure pain, AEs, physical examination findings, vital sign measurements, 12-lead ECG 
findings, clinical laboratory test results, and sensory testing. 
10.3.3.1 Laboratory Safety Assessments 
10.3.3.1.1 Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (Section 2). 
Hematology 
hemoglobin, hematocrit, red blood cell count, red blood cell indices, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, platelet count (or estimate), white blood cell count 
including differential 
Serum Chemistry 
albumin, total bilirubin, total protein, calcium, alkaline phosphatase, 
alanine aminotransferase, aspartate aminotransferase, blood urea 
nitrogen, 
creatinine, 
glucose, 
sodium, 
potassium, 
chloride, 
bicarbonate, lactate dehydrogenase, uric acid 
Coagulation Panel 
prothrombin time, partial thromboplastin time, fibrinogen 
Urinalysis 
pH, specific gravity, occult blood, leukocyte esterase, glucose, protein, 
ketones 
Urine Pregnancy Test 
Only for women of childbearing potential. A serum pregnancy test will 
be performed if the urine pregnancy test is positive. 
Urine Drug Screen 
amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, and tetrahydrocannabinol 
Other 
HgbA1c 
Knee Radiographs 
Radiographs of both knees using standard standing films or using the 
fixed flexion method. Scoring will use the Kellgren-Lawrence Grading 
Scale. 
Blood and urine samples for hematology, serum chemistry, and urinalysis will be sent to a central 
laboratory for analyses. Urine drug screens and urine pregnancy tests may be conducted at the 
study sites. 
10.3.3.1.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 


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both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
10.3.3.1.3 Evaluation of Laboratory Values 
The normal ranges of values for the laboratory assessments in this study will be provided by the 
responsible laboratory and submitted to Centrexion Therapeutics Corp. prior to the beginning of 
the study. They will be regarded as the reference ranges on which decisions will be made. 
If a laboratory value is out of the reference range, it is not necessarily clinically relevant. The 
investigator must evaluate the out-of-range values and record his or her assessment of the clinical 
relevance in the appropriate eCRF. 
All laboratory values that, in the investigator’s opinion, show clinically relevant or pathological 
changes during or after termination of the treatment have to be reported as AEs and followed as 
described in Section 11.2.6. 
All measurements described in this section are recognized standard methods. 
10.3.3.2 Clinical Examinations 
10.3.3.2.1 Vital Signs 
Vital signs measurements will be conducted according to the schedule of events, Section 2 and 
will include systolic and diastolic blood pressure, heart rate (HR) and respiratory rate (RR), and 
will be measured with the subject standing and also after the subject has been in a sitting position 
for 5 minutes. Temperature will also be measured at all office visits. 
10.3.3.2.2 Electrocardiogram 
A standard 12-lead ECG will be performed at rest, with the subject lying down for approximately 
5 minutes before the ECG is obtained. The ECG will be evaluated at the investigational site to 
determine the subject’s eligibility and to monitor safety during the trial. The principal investigator 
or qualified designee will review, sign, and date each ECG reading, noting whether or not any 
abnormal results are of clinical significance. The ECG will be repeated if any results are considered 
to be clinically significant. All ECG recordings will be identified with the subject number, initials, 
date, and time of the recording. 
10.3.3.2.3 Physical Examination 
Complete (excluding a genitourinary exam) or partial physical examinations will be conducted 
according to the schedule of events, Section 2. The investigator should assess periarticular 
tenderness and pain in the soft tissue of the injected knee(s) at each physical examination and 
record the results on the eCRF. At each physical examination, the investigator should also listen 
to the heart and lungs at a minimum and follow up any symptoms with a targeted physical exam, 
as appropriate. 
Height and weight will be measured at the Screening Visit. Knee circumference will be measured 
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The principal investigator or his or her appointed designee is primarily responsible for performing 
the physical examination. Whenever possible, the same individual should perform all physical 
examinations if feasible.  
10.3.3.2.4 Injection Site Assessment 
The injection site will be examined and assessed for erythema and edema (separately by an 
investigator using a categorical scale of none, mild, moderate, or severe) before each 
CNTX-4975-05 injection, after each injection at 1 and 2 hours post-dose, and at the Week 4 study 
visit. Significant bruising or other clinically significant injection site reactions (other than 
erythema or edema) will be recorded as AEs. 
10.3.3.2.5 Sensory Testing 
Sensory testing will be performed before each CNTX-4975-05 injection and at Week 8/ET. The 
following sensory tests will be performed bilaterally: 
• Position sense at the knee and great toe 
• Vibratory sense at the patella (measured via 128 Hz tuning fork) 
• Light touch assessed over the patella, the popliteal area, and the top of the foot 
• Pinprick sensibility tested at the top of the foot and over the patella 
Each of the above sensory tests will be graded using the following 5-point Likert Scale: 
Finding 
Score Definition 
Normal 
4 
Normal sensory function, sensory response as expected in a 
normal subject 
Mild Deficit 
3 
Defined as a possible, inconsistent deficit 
Moderate Deficit 
2 
Defined as a clear, consistent deficit 
Severe Deficit 
1 
Defined as a major impairment 
Absent Sensation 
0 
Defined as a complete loss of sensation 
 
The use of the 5-point Likert Scale (0-4) will be based on the clinician’s assessment. 
10.3.3.3 Assessment of Procedure Pain 
Procedure pain will be assessed by asking subjects to rate their index knee for pain (1) at rest prior 
to pre-medication; (2) prior to IA lidocaine (without epinephrine); (3) at rest 10 minutes 
(±2 minutes) after IA lidocaine (without epinephrine); (4) at 30 minutes (±5 minutes) after IA 
injection of CNTX-4975-05 and (5) at rest at the 1-hour and 2-hour time points after IA injection 
of CNTX-4975-05 (±10 minutes).  
Categorical scoring will be used: none, mild, moderate, moderately severe, or severe.  
 


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11 ADVERSE EVENTS 
11.1 Definitions 
11.1.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality of the disease or condition (worsening of a 
pre-existing condition is considered an AE). 
Events occurring in subjects treated with placebo or active comparator or during treatment-free 
periods of the study are also considered AEs. 
11.1.2 Unexpected Adverse Event 
An expected AE is one for which the nature or severity is consistent with the known AE profile of 
the product. For an investigational product, the known information is contained in the IB. For a 
marketed product, the known information is contained in the current package insert for the product. 
An unexpected adverse event (UAE) is one for which the specificity or severity is not consistent 
with the current IB. For example, hepatic necrosis would be unexpected (greater severity) if the 
IB only listed elevated hepatic enzymes or hepatitis. Likewise, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (greater specificity) if the IB only listed cerebral vascular 
accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be (a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and (b) hepatitis with a first occurrence of fulminant 
hepatitis (fulminant hepatitis would be unexpected). 
11.1.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose 
• results in death 
• is life-threatening 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe. 
• requires inpatient hospitalization or prolongation of existing hospitalization 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the test drug, 
or a hospital admission for a diagnostic evaluation of an AE, does not qualify the condition 


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or event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical 
background does not need to be considered an SAE. 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the IP 
during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject that has 
received an IP is not considered an SAE unless it is suspected that the IP(s) interacted with 
a contraceptive method and led to the pregnancy.  
• is an important medical event 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above.  
11.1.4 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including withdrawal of IP, dose reduction, or significant additional concomitant therapy. 
11.1.5 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of IP.  
11.2 Management of Adverse Events 
Adverse events will be collected from the time of signing the ICF through the Week 8/ET Visit. 
11.2.1 Adverse Event of Special Interest: Severe Allergic Reaction – Anaphylaxis/ 
Anaphylactoid Reaction 
Only study sites with crash carts or equivalent and ACLS-certified personnel immediately 
available are permitted to treat subjects with study drug. 
A case of laryngospasm was observed during a hip replacement operation after capsaicin was 
instilled into the surgical wound, requiring the subject to be intubated during the procedure.  
A case of severe allergic reaction was seen immediately after CNTX-4975-05 was injected into 
the knee of a subject in study CNTX-4975i-OA-303, with the subject complaining of dyspnea and 
tachycardia. Epinephrine 0.5 mg and IM solumedrol were given, and the subject recovered in 
minutes, with no subsequent adverse events. 
Anaphylactic Reaction  
An anaphylactic reaction is a rapid onset serious allergic reaction that has a variety of symptoms 
and outcomes, which can include death. An anaphylactic reaction typically has symptoms and 
signs starting over minutes to hours. Anaphylaxis causes more than one of the following: low 


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blood pressure, lightheadedness, shortness of breath, an itchy rash, throat or tongue swelling, and 
vomiting.  
Anaphylactoid reaction  
These reactions produce the same clinical signs and symptoms anaphylactic reactions, but are not 
IgE mediated, but instead occur through a direct non-immune-mediated release of mediators from 
basophils and/or mast cells or can manifest from direct complement activation. 
All subjects must be monitored for at least 30 minutes (or longer, as required by the protocol) after 
study drug injection to ensure that they do not have a hypersensitivity reaction/anaphylaxis. Vital 
signs (VS) are to be done pre-injection and 5 minutes after the injection, standing and sitting, and 
then vital signs must now be taken at 15 and 30 minutes (sitting only) after injection of study drug 
Any subject that meets the criteria for anaphylaxis or anaphylactoid reactions, as described in the 
paper by Sampson et al. (2006)13 (see Appendix C) following the first/prior injection is prohibited 
from being re-treated with study drug. 
Clinical Criteria for Diagnosing Anaphylaxis  
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, 
or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula), AND AT LEAST 
ONE OF THE FOLLOWING: 
a. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-
uvula) 
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) 
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
a. Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP∗ 
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person's baseline 
Source: Sampson et al. (2006) 
Abbreviations: PEF, Peak expiratory flow; BP, blood pressure. 
∗ Low systolic blood pressure for children is defined as less than 70 mmHg from 1 month to 1 year, less 
than (70 mmHg + [2 × age]) from 1 to 10 years, and less than 90 mmHg from 11 to 17 years. 
 
 


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In the event of an anaphylactic reaction or anaphylactoid event, institute treatment immediately, 
as outlined in Appendix C. Note also that a serum tryptase blood level must be obtained using the 
Vacutainer tube provided. 
All anaphylactic and anaphylactoid events (e.g. rash, dyspnea, gastrointestinal symptoms) must be 
recorded with the time that the events occurred and resolved, and treatments (e.g. epinephrine) 
should be recorded with their time of administration. 
11.2.2 Collection 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
11.2.3 Evaluation 
11.2.3.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as 
Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
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 subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity, 
whereas an SAE is an AE that meets serious criteria, as described in Section 11.1.3. 
11.2.3.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 11.1.3. 
11.2.3.3 Action(s) Taken 
Action(s) taken may consist of 
Dose 
increased 
An indication that a medication schedule was modified by addition; either by 
changing the frequency, strength or amount. 


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Dose not 
changed 
An indication that a medication schedule was maintained. 
Dose reduced 
An indication that a medication schedule was modified by subtraction, either 
by changing the frequency, strength or amount. 
Drug 
interrupted 
An indication that a medication schedule was modified by temporarily 
terminating a prescribed regimen of medication. 
Drug 
withdrawn 
An indication that a medication schedule was modified through termination of 
a prescribed regimen of medication. 
Not applicable Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
11.2.3.4 Outcome at the Time of Last Observation 
• The outcome at the time of last observation will be classified as 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 
• Unknown 
*Only select fatal as an outcome when the AE results in death. If more than one AE is possibly 
related to the subject’s death, the outcome of death should be indicated for each such AE. Although 
“fatal” is usually an event outcome, events such as sudden death or unexplained death should be 
reported as SAEs. 
11.2.3.5 Adverse Event Relationship to Investigational Product 
The investigator must make an assessment of each AE’s relationship to the IP. The categories for 
classifying the investigator’s opinion of the relationship are listed below. 
Not related 
An AE with sufficient evidence to accept that there is no causal relationship 
to IP administration (e.g., no temporal relationship to drug administration, 
because the drug was administered after onset of event; investigation shows 
that the drug was not administered; another cause was proven). 
Unlikely 
related 
An AE, including laboratory test abnormality, with a temporal relationship to 
IP administration that makes a causal relationship improbable, and in which 
other drugs, events or underlying disease provide plausible explanations. 
Possibly related An AE with a reasonable time sequence to administration of the IP, but which 
could also be explained by concurrent disease or other drugs or events. 
Information on drug withdrawal may be lacking or unclear. 


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Related 
An AE occurring in a plausible time relationship to IP administration and 
which cannot be explained by a concurrent disease or other drugs or events. 
The response to withdrawal of the drug (dechallenge) is clinically reasonable. 
11.2.4 Documentation 
All AEs occurring within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 11.2.) 
• AE name or term 
• When the AE first occurred (start date and time) 
• When the AE stopped (stop date and time or an indication of “ongoing”) 
• Severity of the AE 
• Seriousness (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP(s) 
11.2.5 Treatment of Adverse Events 
Adverse events that occur during the study will be treated, if necessary, by established standards 
of care. The decision about whether the subject may continue in the study will be made by the 
sponsor after consultation with the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, the investigator must decide whether to stop the 
subject’s involvement in the study and/or treat the subject. Special procedures may be 
recommended for the specific IP, such as the collection of a serum sample for determining blood 
concentrations of IP, specific tapering procedures, or treatment regimens, as appropriate. 
11.2.6 Follow-up 
Any AE will be followed to a satisfactory resolution, until it becomes stable, or until it can be 
explained by another known cause(s) (i.e., concurrent condition or medication) and clinical 
judgment indicates that further evaluation is not warranted. Potentially related AEs that are 
ongoing at the Week 8 clinic visit will be followed until they are stable, resolved, or no longer 
clinically significant, in the opinion of the investigator, or until 4 weeks after the study is 
completed. All findings relevant to the final outcome of an AE must be reported in the subject’s 
medical record and recorded on the eCRF page.  




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reports, autopsy reports) is provided to the designated individual(s) as soon as it is 
available. 
• Specific information may be requested by the 
 Pharmacovigilance 
Department using a follow-up request form.  
• The investigator is required to comply with applicable regulations (including local laws 
and guidances) regarding the notification of his or her health authorities, IRB/ IEC, 
principal and coordinating investigators, study investigators, and institutions. The detailed 
reporting duties and division of responsibilities between the sponsor and 
 
will be provided in a separate document (see CNTX-4975i-OA-303 Safety Management 
Plan). Each investigator is obligated to learn about the reporting requirements for 
investigators in his or her country. The study monitor may be able to assist with this.  
11.2.7.2 Non-serious Adverse Events 
Non-serious AEs will be recorded in the eCRF and reported by 
 to Centrexion 
Therapeutics Corp. 
11.3 Special Considerations 
11.3.1 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice adequate birth control and on the importance of avoiding pregnancy during study 
participation. Women should be instructed to contact the investigator or study staff immediately if 
pregnancy occurs or is suspected. 
Pregnancy testing will be conducted prior to administration of CNTX-4975-05 on every woman 
of childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be a Screening failure. 
A woman who becomes pregnant within 2 days of treatment with CNTX-4975-05 will be 
immediately discontinued from study participation. The investigator must report the pregnancy as 
if it were an SAE within 24 hours of learning of the pregnancy, to 
 
Pharmacovigilance using the Pregnancy Data Collection Form via the same fax number and/or 
email address as for SAE reporting. The investigator should contact the designated individual(s) 
who receive SAE notification and record information related to the pregnancy on an SAE and AE 
form (entering the event temporarily as non-serious on both forms) provided by the sponsor or its 
designee. 
Early Termination Visit assessments are required as soon as possible after learning of the 
pregnancy. The investigator is also responsible for following the pregnancy until delivery or 
termination. These findings must be reported on the SAE and AE form and forwarded to the 
designated individual(s). The event meets the SAE criterion only if it results in a spontaneous 
abortion or a congenital anomaly. 
11.3.2 Overdose 
The maximal dose of CNTX-4975-05 should not be exceeded during the study. 


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Overdose that occurs during the study will be treated and documented as an AE/UAE/SAE if it 
fulfills the criteria. If the overdose does not result in an AE, it should be reported in written form 
to the designated individual(s) who receive SAE notification. The information contained therein 
should include study site identification, reporter identification, subject identification, IP, dose, 
action taken, and any comments. 


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12 DATA SAFETY MONITORING BOARD 
A Data Safety Monitoring Board will not be used in this study.  


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13 STATISTICS 
The statistical analysis was developed to meet the requirements of the US FDA and the European 
Medicines Agency. 
13.1 Study Endpoints 
13.1.1 Primary Efficacy Endpoint 
The primary endpoint is assessment of the CNTX-4975-05 treatment regimens, with the Breg 
Cooling Control Group as the standard, using a combination of 3 assessments of the index knee: 
1) pain 30 minutes after CNTX-4975-05 injection (using the 0-4 scale of none, mild, moderate, 
moderately severe, and severe); 2) subject satisfaction with the treatment regimen; and 3) 
investigator satisfaction with the treatment regimen.  
13.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
• Assessment of the primary combined outcome using the contralateral knee for the subjects 
who received bilateral injections and the index knee for all other subjects 
• Assessment of the primary combined outcome for each subject type 
• Assessment of the primary combined outcome, using the contralateral knee for the subjects 
who received bilateral injections 
• Percent of Outcome Measures in Rheumatology-Osteoarthritis Research Society 
International (OMERACT-OARSI) responders at Week 8 for subjects with a single 
CNTX-4975-05 joint injection (index knee, moderate to severe pain index knee, pain not 
>3 for contralateral knee) 
• Percent of OMERACT-OARSI responders at Week 8 for subjects with bilateral knee 
injections of CNTX-4975-05 (index knee, moderate to severe pain index knee, both knees 
meeting OMERACT-OARSI responder criteria) 
• Percent of OMERACT-OARSI responders at Week 8 for subjects with a single 
CNTX-4975-05 joint injection (population with index knee, moderate to severe pain index 
knee, non-index knee with PJR/TJR) 
• For each of the 3 types of subjects, the absolute change; the number of subjects who have 
≥30%, ≥50%, ≥70%, or ≥90% improvement area under the curve; and landmark analysis 
on the 5 subscales of the KOOS through Week 8 using the average of both knees: 
o Pain 
o Other symptoms 
o Activities of daily living 
o Sports and recreation 
o QOL 


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• Assess the SS of treatment with CNTX-4975-05 IA injection for each of the 3 types of 
subjects, and all subjects in the trial 
• For subjects with a PJR/TJR, assess their satisfaction with the CNTX-4975-05 IA injection 
versus their satisfaction with their knee with a PJR/TJR 
13.1.3 Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include:  
• Likelihood of the need for joint replacement surgery, based on KOOS subscales and SS 
outcomes, from Baseline through Week 8 
• SS with the treatment of the index knee through Week 8 of the trial (7-point Likert Scale 
where 1=completely dissatisfied and 7=completely satisfied) 
• The effect of subject characteristics (including K-L grade, sex, BMI, age, 
unilateral/bilateral knee OA, bilateral knee OA treatment, and history of contralateral 
PJR/TJR) on the analgesic efficacy of CNTX-4975-05, using the KOOS subscales at each 
study visit through Week 8 
• Frequency of use of background analgesic medication for pain in the injected knee(s) 
throughout the study period. 
• Assessment of the mean of the individual outcome measures, using the average of both 
knees for the subjects who received bilateral knee injections 
13.1.4 Safety Endpoints 
Safety endpoints include: 
• AEs  
• Vital signs 
• Clinical laboratory evaluations (hematology, chemistry, and urinalysis) 
• 12-lead ECGs 
• Physical examination (including the presence or absence of an effusion in the index knee, 
periarticular pain/tenderness) 
• Concomitant medications and therapies 
• Degree of procedure pain (not recorded as AEs) 
• Local physical findings after injection of the index knee  
• Injection site assessment of erythema and edema 
• Sensory testing 
13.2 Sample Size Determination 
Approximately 850 subjects will be treated with CNTX-4975-05. This sample size was chosen 
based on the need to fulfill safety requirements for regulatory review. 


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13.3 Analysis Populations 
The following analysis populations are planned for this study: The following analysis populations 
are planned for this study:  
• Safety: all subjects who receive any amount of planned CNTX-4975-05.  
• Intent-to-Treat (ITT): all enrolled subjects.  
Membership in the analysis populations will be determined prior to database lock. 
13.4 Statistical Analyses 
This section presents a summary of the planned statistical analyses. A statistical analysis plan that 
describes the details of the analyses to be conducted will be written prior to database lock.  
Unless otherwise indicated, all testing of statistical significance will be two-sided, and a difference 
resulting in a p value of ≤0.05 will be considered statistically significant. To control for the overall 
type I error rate, hierarchical testing based on fixed sequence procedure will be used. If statistical 
significance is declared for the primary analysis, formal hypothesis testing will be done for the 
secondary endpoints until a non-significant result is reached. All other p values from secondary 
and exploratory endpoints, after a non-significant p value is reached, will be considered nominal. 
For analyses involving study site, if the number of subjects per site is small, sites may be pooled 
for analysis, or omitted from statistical models. The final determination will be made prior to 
database lock.  
Summary statistics will be provided for the variables described below. For continuous variables, 
these statistics will typically include the number of subjects, mean, standard deviation (SD), 
median, minimum, and maximum. For categorical variables, these statistics will typically include 
the number and percentage of subjects in each category. 
13.4.1 Study Subjects and Demographics 
13.4.1.1 Disposition and Withdrawals 
The numbers of subjects treated, completing, and withdrawing, along with reasons for withdrawal, 
will be tabulated overall, by subject type, and by injection procedure. The number of subjects in 
each analysis population will be reported. 
13.4.1.2 Protocol Deviations 
Protocol deviations will be identified and summarized or listed as appropriate. 
13.4.1.3 Demographics and Other Baseline Characteristics 
These analyses will be conducted for all analysis populations.  
Demographic variables will include age, sex/gender, height, and weight. Information on race and 
ethnicity will be collected for any eventual analysis of differences in response to CNTX-4975-05, 
in accordance with local regulatory requirements. Baseline subject characteristics will include 
medical history, including confirmation of OA diagnosis and time since diagnosis, and physical 
examination findings.  


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Prior and concomitant medications will be summarized, by the number and percentage of subjects 
taking each medication, classified using World Health Organization Drug Dictionary Anatomical 
Therapeutic Chemical classes and preferred terms. 
13.4.2 Exposure and Compliance 
All subjects will receive up to 1 CNTX-4975-05 injection in each knee, at the study site under the 
surveillance of appropriate study personnel and, therefore, no compliance will be calculated. 
Injection procedure details and CNTX-4975-05 batch or lot number(s) will be recorded in the 
subject’s eCRF/electronic data capture (EDC) system and summarized or listed as appropriate. 
13.4.3 Efficacy Analyses 
Efficacy variables will be summarized and analyzed using the ITT population, unless otherwise 
specified.  
13.4.3.1 Primary Analysis 
The primary analysis will compare each experimental treatment regimen to the Breg Cooling 
Control Group using an equally-weighted, combined score calculated from the following 3 
measures: 1) pain 30 minutes after CNTX-4975-05 injection (using the 0-4 scale of none, mild, 
moderate, moderately severe, and severe), 2) SS with the treatment regimen; and 3) IS with the 
treatment regimen, all assessed on the index knee. Ratios of the mean values of test/control will 
have 95% confidence intervals constructed for each treatment regimen versus the Breg Cooling 
Control Group. For a treatment regimen to be considered clinically acceptable, it must be no more 
than 30% worse than the Breg Cooling Control Group and the lower limit of the 95% confidence 
interval for the treatment regimen must be greater than 0.7. This analysis will be performed on the 
ITT population.  
For analysis, satisfaction scores (SS and IS) and 30 minute pain after CNTX-4975-05 injection 
will be transformed to equivalent scales, and 30 minute pain after CNTX-4975-05 injection will 
be reverse-scored so that higher scores represent lower pain, in order to have the 3 components on 
the same scale before they are combined by summing the 3 scores for a composite score. A 
sensitivity analysis will be performed that creates a composite score using the original scales (with 
the pain scores still reverse-scored to ensure the direction of the effect remains the same), using 
the ITT population.  
All other continuous secondary and exploratory efficacy endpoints will be summarized using 
descriptive statistics by subject type, experimental treatment regimen, and week/visit, as 
appropriate, and analyzed using a mixed-model repeated measures (MMRM) analysis or by 
analysis of covariance, as appropriate. Categorical endpoints will be compared between treatments 
using Pearson’s chi-square or Fisher’s exact test, as appropriate.  
Safety analyses will be conducted using data from the safety population. 
13.4.3.2 Secondary and Exploratory Analyses 
Secondary and exploratory analyses will include analysis of the combined score by subject type, 
OMERACT-OARSI responders, KOOS subscale (including AUCs), and SS. 


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All continuous secondary and exploratory efficacy endpoints will be summarized using descriptive 
statistics by week/visit, as appropriate, and analyzed using an MMRM analysis or by analysis of 
covariance, as appropriate. Categorical endpoints will use Pearson’s chi-square or Fisher’s exact 
test, as appropriate. P values from exploratory endpoints will be considered nominal and no 
adjustments for multiplicity will be made. 
13.4.4 Safety and Tolerability Analyses 
Safety analyses will be conducted using data from the safety population (as defined in 
Section 13.3). Safety variables include injection site assessments (erythema and edema), 
assessment of procedure pain, AEs, physical examination findings, vital sign measurements, 
12-lead ECG findings, clinical laboratory test results, and sensory testing. No formal inferential 
analyses will be conducted for safety variables unless otherwise noted. 
13.4.4.1 Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 
16.0 or higher.  
Treatment-emergent AEs are defined as: 
• AEs with onset at the time of or following the start of treatment with CNTX-4975-05 
through the Week 8/ET Visit  
The number and percentage of subjects with AEs will be displayed for each injection procedure 
by system organ class and preferred term. Summaries of AEs by severity and relationship to 
CNTX-4975-05 will also be provided. Serious AEs and AEs resulting in discontinuation of 
CNTX-4975-05 will be summarized separately in a similar manner. Subject listings of AEs, SAEs 
and AEs causing discontinuation of CNTX-4975-05 will be produced. 
13.4.4.2 Clinical Laboratory Evaluations 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual (absolute) values 
and changes from Baseline values will be presented for clinical laboratory values at each time 
point. 
The number of subjects with clinical laboratory values categorized as below, within, or above 
normal ranges, will be tabulated showing change from Baseline (shift tables) for each clinical 
laboratory analyte by study visit. Pre- and post-treatment values will also be presented with 
analysis summary of mean changes from Baseline.  
Laboratory values that are outside the normal range will also be flagged in the data listings, along 
with corresponding normal ranges. Any out-of-range values that are identified by the investigator 
as being clinically significant will be reported as AEs. 
13.4.4.3 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for systolic blood pressure, diastolic blood pressure, HR, 
and RR. 


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13.4.4.4 Electrocardiograms 
The number and percentage of subjects with normal and abnormal ECG findings will be 
summarized at each time point. A comparison of QT results will be presented. Summary statistics 
for Baseline values at Screening and at study visits according to the schedule of events will be 
displayed for QT and the QT interval corrected for HR (QTc) calculated using Bazett’s and 
Fridericia’s QT correction methods. In addition, the number and percent of subjects who 
experienced a change >30 ms or a change >60 ms will be presented. 
Descriptive summaries (mean, SD, median, minimum, and maximum) will be presented for ECG 
measures of PR interval, QRS interval, QT interval, QTc interval (both correction methods), and 
HR for each injection procedure at each time point. 
13.4.4.5 Physical Examination Findings 
The number and percentage of subjects with normal and abnormal findings in the complete 
physical examination will be displayed. 
13.4.4.6 Injection Site Assessment 
The number and percentage of subjects with erythema and edema findings separately categorized 
as none, mild, moderate, or severe will be summarized at each time point.  
13.4.4.7 Sensory Testing 
The number and percentage of subjects with each sensory assessment categorized from normal to 
absent, using a 5-point Likert Scale, where 0=absent sensation and 4=normal sensation, will be 
summarized at each time point.  
13.4.4.8 Procedure Pain 
The number and percentage of subjects with each pain assessment categorized as none, mild, 
moderate, moderately severe, or severe will be summarized at each time point. These pain 
assessments are also a component of the efficacy endpoints. 
13.4.5 Interim Analyses 
To ensure that the benefit/risk ratio continues to be appropriate for the OA knee indication, interim 
analyses for a focused review of safety and efficacy may be performed when approximately 20%, 
50%, and/or 75% of subjects have completed the trial. The output for the interim analyses will be 
consistent with the currently planned final analyses. 


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14 STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
14.1 Sponsor and Investigator Responsibilities 
14.1.1 Sponsor Responsibilities 
The sponsor is obligated to conduct the study in accordance with strict ethical principles 
(Section 15). The sponsor reserves the right to withdraw a subject from the study, to terminate 
participation of a study site at any time (Section 14.7), and/or to discontinue the study. 
Centrexion Therapeutics Corp. agrees to provide the investigator with sufficient material and 
support to permit the investigator to conduct the study according to the study protocol. 
14.1.2 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.1), the investigator indicates that he/she has 
carefully read the protocol, fully understands the requirements, and agrees to conduct the study in 
accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities, including the April 1996 International Council 
for Harmonisation (ICH) Guidance for Industry E6 Good Clinical Practice (GCP), and in 
agreement with the 2013 version of the Declaration of Helsinki. While delegation of certain 
aspects of the study to subinvestigators and study coordinators is appropriate, the investigator will 
remain personally accountable for closely overseeing the study and for ensuring compliance with 
the protocol and all applicable regulations and guidelines. The investigator is responsible for 
maintaining a list of all persons that have been delegated study-related responsibilities 
(e.g., subinvestigators and study coordinators) and their specific study-related duties. 
Investigators should ensure that all persons who have been delegated study-related responsibilities 
are adequately qualified and informed about the protocol, IPs, and their specific duties within the 
context of the study. Investigators are responsible for providing Centrexion Therapeutics Corp. 
with documentation of the qualifications, GCP training, and research experience for themselves 
and their staff as required by the sponsor and the relevant governing authorities. 
To ensure compliance with the guidelines, the study may be audited by an independent person. 
The investigator agrees, by written consent to this protocol, to cooperate fully with compliance 
checks by allowing access to all study documentation by authorized individuals. 
14.2 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from the sponsor or its designee that the study can be initiated at the study site. The study site will 
not be authorized for study initiation until: 
1. The study site has received the appropriate IRB/IEC approval for the protocol and the 
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2. All GCP documents have been submitted to and approved by the sponsor or its designee. 
3. The study site has a Clinical Trial Agreement in place. 
4. Study site personnel, including the investigator, have participated in a study initiation 
meeting. 
14.3 Screen Failures 
Subjects who fail inclusion and/or exclusion criteria may be rescreened for the study. Subjects may 
only be rescreened once 30 days or more after the original Screening Visit. If a subject is eligible 
to enter the study after having previously failed screening, the subject will be assigned a new 
subject identification number. 
14.4 Study Documents 
All documentation and material provided by Centrexion Therapeutics Corp. for this study are to 
be retained in a secure location and treated as confidential material. 
14.4.1 Investigator’s Regulatory Documents 
The regulatory documents are listed in the Study Manual. 
The regulatory documents must be received from the investigator and reviewed and approved by 
Centrexion Therapeutics Corp. or its designee before the study site can initiate the study and before 
Centrexion Therapeutics Corp. will authorize shipment of CNTX-4975-05 to the study site. Copies 
of the investigator’s regulatory documents must be retained at the study site in a secure location. 
Additional documents, including a copy of the protocol and applicable amendment(s), the 
CNTX-4975-05 IB, eCRF completion guidelines, copies of regulatory references, copies of 
IRB/IEC correspondence, and CNTX-4975-05 accountability records should also be retained as 
part of the investigator’s regulatory documents. It is the investigator’s responsibility to ensure that 
copies of all required regulatory documents are organized, current, and available for inspection. 
14.4.2 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. The sponsor or its designee will provide the necessary training on the use of the 
specific eCRF system used during the study to ensure that the study information is captured 
accurately and appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the eCRF/EDC system 
according to the completion guidelines provided by the sponsor or its designee. 
The eCRFs must be signed by the investigator or a subinvestigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 


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14.4.3 Source Documents 
Information recorded in the eCRF/EDC system should be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 
instruments, memoranda, and pharmacy dispensing records. 
Clinical laboratory data required by the protocol will be electronically transferred from the 
central/local laboratory to the sponsor or its designee. A paper copy of the laboratory results will 
be provided to the study site and should be retained with each subject’s source data 
14.5 Data Quality Control 
Centrexion Therapeutics Corp. and its designees will perform quality control checks on this 
clinical study. 
14.5.1 Monitoring Procedures 
Centrexion Therapeutics Corp. and/or its designee will conduct site visits to monitor the study and 
ensure compliance with the protocol, GCP, and applicable regulations and guidelines. The 
assigned clinical research associate(s) (CRAs) will visit the investigator and study site at periodic 
intervals and maintain periodic communication. The investigator agrees to allow the CRA(s) and 
other authorized Centrexion Therapeutics Corp. personnel access. The CRA(s) will maintain 
current personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the investigator and staff. While 
on site, the CRA(s) will review 
• regulatory documents, directly comparing entries in the eCRF/EDC system with the source 
documents 
• consenting procedures 
• AE procedures 
• storage and accountability of CNTX-4975-05 and study materials 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting eCRF are described in the study manual. As representatives of the sponsor, CRAs are 
responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.1), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Centrexion Therapeutics Corp. or designee auditors or inspectors from regulatory 
agencies to review records and to assist the inspectors in their duties, if requested.  
14.5.2 Data Management 
Centrexion Therapeutics Corp. or designee will be responsible for activities associated with the 
data management of this study. The standard procedures for handling and processing records will 
be followed per GCP and 
 standard operating procedures (SOPs). A 
comprehensive data management plan (DMP) will be developed including a data management 


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overview, description of database contents, annotated eCRF, pre-entry review list, self-evident 
correction conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the study manual. 
14.5.3 Quality Assurance/Audit 
This study will be subject to audit by Centrexion Therapeutics Corp. or its designee. Audits may 
be undertaken to check compliance with GCP guidelines, and can include: 
• site audits 
• Trial Master File audits 
• database audits 
• document audits (e.g., protocol and/or clinical study report) 
Centrexion Therapeutics Corp. or its designee may conduct additional audits on a selection of 
study sites, requiring access to subject notes, study documentation, and facilities or laboratories 
used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Centrexion Therapeutics Corp. immediately.  
14.6 Study Termination 
The study may be terminated at the discretion of Centrexion Therapeutics Corp. at any time and 
for any reason. 
14.7 Study Site Closure 
At the end of the study, all study sites will be closed. Centrexion Therapeutics Corp. may terminate 
participation of a study site at any time. Examples of conditions that may require premature 
termination of a study site include, but are not limited to, the following: 
• Noncompliance with the protocol and/or applicable regulations and guidelines 
• Inadequate subject enrollment 
14.7.1 Record Retention 
The investigator shall retain and preserve 1 copy of all data generated in the course of the study, 
specifically including, but not limited to, those defined by GCP as essential until: 


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• At least 2 years after the last marketing authorization for CNTX-4975 has been approved 
or the sponsor has discontinued its research with CNTX-4975, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
CNTX-4975 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her intent to 
destroy all such material. The sponsor shall have 30 days to respond to the investigator’s notice, 
and the sponsor shall have a further opportunity to retain such materials at the sponsor’s expense. 
14.8 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Centrexion Therapeutics Corp. The protocol amendment must be 
signed by the investigator and approved by the IRB/IEC before it may be implemented. Protocol 
amendments will be filed with the appropriate regulatory agency(ies) having jurisdiction over the 
conduct of the study. 
14.9 Use of Information and Publication 
All information concerning CNTX-4975, Centrexion Therapeutics Corp.’s operations, patent 
applications, formulae, manufacturing processes, basic scientific data, and formulation 
information supplied by Centrexion Therapeutics Corp. or its designee to the investigator and not 
previously published, is considered confidential and remains the sole property of Centrexion 
Therapeutics Corp. Case report forms also remain the property of Centrexion Therapeutics Corp. 
The investigator agrees to use this information for purposes of study execution through finalization 
and will not use it for other purposes without the written consent of the sponsor. 
The information developed in this study will be used by Centrexion Therapeutics Corp. in 
connection with the continued development of CNTX-4975 and thus may be disclosed as required 
to other clinical investigators or government regulatory agencies. 
The information generated by this study is the property of Centrexion Therapeutics Corp. 
Publication or other public presentation of CNTX-4975 data resulting from this study requires 
prior review and written approval of Centrexion Therapeutics Corp. Abstracts, manuscripts, and 
presentation materials should be provided to Centrexion Therapeutics Corp. for review and 
approval at least 30 days prior to the relevant submission deadline. Data from individual study 
sites must not be published separately. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until Centrexion Therapeutics Corp. has reviewed and 
commented on such a presentation or manuscript for publication. 


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15 ETHICAL AND LEGAL CONSIDERATIONS 
15.1 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry E6 
GCP (including archiving of essential study documents), the 2013 version of the Declaration of 
Helsinki, the applicable regulations of the country(ies) in which the study is conducted, and with 
the Commission Directives 2001/20/EC and 2005/28/EC. 
See Appendix B for regulation and guidelines. 
15.2 Subject Information and Informed Consent 
A properly constituted, valid IRB/IEC must review and approve the protocol, the investigator’s 
informed consent document, and related subject information and recruitment materials before the 
start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
15.3 Approval by Institutional Review Board 
For Investigational New Drug studies, the minimum standards of conduct and requirements for 
informed consent are defined in the FDA regulations. 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be provided by the investigator to the sponsor’s monitor before 
shipment of investigational drug supplies, and will include the date of the committee’s approval 
and the chairperson’s signature. This written approval must consist of a completed IRB/IEC 
approval form or written documentation from the IRB/IEC containing the same information. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure not part of routine care for the subject’s condition. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Written approval from 
the IRB/IEC, or a designee, must be received by Centrexion Therapeutics Corp. before 
implementation. This written approval will consist of a completed IRB/IEC approval form or 
written documentation from the IRB/IEC containing the same information. 
15.4 Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and the sponsor. 


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16 REFERENCES 
1. Mamlin, L. A., C. A. Melfi, M. L. Parchman, B. Gutierrez, D. I. Allen, B. P. Katz, R. S. 
Dittus, D. A. Heck and D. A. Freund (1998). "Management of osteoarthritis of the knee by 
primary care physicians." Arch Fam Med 7(6): 563-567.
2. Caborn, D., J. Rush, W. Lanzer, D. Parenti, C. Murray and G. Synvisc 901 Study (2004). 
"A randomized, single-blind comparison of the efficacy and tolerability of hylan G-F 20 
and triamcinolone hexacetonide in patients with osteoarthritis of the knee." J Rheumatol 
31(2): 333-343.
3. Centrexion Therapeutics (2015). Investigational Drug Brochure, CNTX-4975 (PEG
300-capsaicin) for Injection. Baltimore, MD 21202, United States, Centrexion 
Corporation.
4. Caterina, M. J. and D. Julius (2001). "The vanilloid receptor: a molecular gateway to the 
pain pathway." Annu Rev Neurosci 24: 487-517.
5. Brederson, J. D., P. R. Kym and A. Szallasi (2013). "Targeting TRP channels for pain 
relief." Eur J Pharmacol 716(1-3): 61-76.
6. Simone, D. A., M. Nolano, T. Johnson, G. Wendelschafer-Crabb and W. R. Kennedy 
(1998). "Intradermal injection of capsaicin in humans produces degeneration and 
subsequent reinnervation of epidermal nerve fibers: correlation with sensory function." J 
Neurosci 18(21): 8947-8959.
7. Baranidharan, G., S. Das and A. Bhaskar (2013). "A review of the high-concentration 
capsaicin patch and experience in its use in the management of neuropathic pain." Ther 
Adv Neurol Disord 6(5): 287-297.
8. Acorda Therapeutics, I. (2009). QUTENZA® (capsaicin) 8% patch Full Prescribing 
Information. Ardsley, NY 10502, USA, Acorda Therapeutics, Inc.
9. Altman, R. D. and Gold, G. E (2007). “Atlas of individual radiographic features in 
osteoarthritis, revised.” Osteoarthritis and Cartilage 15: A1-A56.
10. Hunter, D.J., Altman, R.D., Cicuttini, F., Crema, M.D., Duryea, J. Eckstein, F., Guermazi, 
A., et al (2015). “OARSI Clinical Trials Recommendations: Knee imaging in clinical trials 
in osteoarthritis.” Osteoarthritis and Cartilage 23: 698-715.
11. Herdman, M., C. Gudex, A. Lloyd, M. Janssen, P. Kind, D. Parkin, G. Bonsel and X. Badia 
(2011). "Development and preliminary testing of the new five-level version of EQ-5D 
(EQ-5D-5L)." Qual Life Res 20(10): 1727-1736.
12. Obradovic, M., A. Lal and H. Liedgens (2013). "Validity and responsiveness of 
EuroQol-5 dimension (EQ-5D) versus Short Form-6 dimension (SF-6D) questionnaire 
in chronic pain." Health Qual Life Outcomes 11: 110.
13. Sampson H.A., Muñoz-Furlong A., Campbell R.L., et al. (2006). "Second symposium on 
the definition and management of anaphylaxis: summary report--Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium." 
J Allergy Clin Immunol 117(2): 391-397. 


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17 ATTACHMENTS 


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17.1 Investigator’s Agreement 
PROTOCOL 
NUMBER: 
CNTX-4975i-OA-303 
PROTOCOL TITLE: 
An Open-label, 8-Week Study to Compare the Comfort and Ease of 
Use of Five Different Treatment Regimens for CNTX-4975-05 
Intra-articular Injection in Subjects with Chronic, Moderate-to-Severe 
Osteoarthritis Knee Pain 
VERSION: 
Version 3.0, 13 June 2019 
I have read this protocol and agree to conduct this clinical trial as outlined herein. I will ensure 
that all subinvestigators and other study staff members have read and understand all aspects of this 
protocol. I agree to cooperate fully with Centrexion Therapeutics Corp. and 
 
during the study. I will adhere to all FDA, ICH, and other applicable regulations and guidelines 
regarding clinical trials on an IP during and after study completion. 
Principal Investigator: 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 


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18 APPENDICES 
A. Study Specific Requirements 
B. Regulations and Good Clinical Practice Guidelines 
 


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A. Study Specific Requirements 
Examples of the patient-reported outcome scales that will be used during this study are attached to 
this appendix. The following is an index:  
• American College of Rheumatology (ACR) diagnostic criteria 
• Hospital Anxiety and Depression Scale (HADS) 
• Fibromyalgia Symptom Scale Score (FSS) 
• Knee Injury and Osteoarthritis Outcome Score (KOOS) 
• Subject satisfaction questionnaire 
• Investigator satisfaction questionnaire 
• Joint replacement questionnaire 


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B. Regulations and Good Clinical Practice Guidelines 
1. Regulations 
Refer to the following US Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
2. Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_G
uideline.pdf 
 
 


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C. Severe Allergic Reaction – Anaphylaxis/ Anaphylactoid Reaction
1.
2. Sampson et al. (2006)






Appendix A 
Definitions: 
Anaphylactic Reaction 
Is a rapid onset serious allergic reaction that has a variety of symptoms, and outcomes, 
which can include death. An anaphylactic reaction typically has symptoms and signs 
starting over minutes to hours. Anaphylaxis causes more than one of the following: low 
blood pressure, lightheadedness, shortness of breath, an itchy rash, throat or tongue 
swelling, and vomiting.  
 
Anaphylactoid reaction 
These reactions produce the same clinical signs and symptoms anaphylactic reactions, but 
are not IgE mediated, but instead occur through a direct non-immune-mediated release of 
mediators from basophils and/or mast cells or can manifest from direct complement 
activation. 
 
Clinical Criteria for Diagnosing Anaphylaxis  
Criteria for anaphylaxis, Table 1 (Sampson HA, et al, J Allergy Clin Immunol 
2006;117(2):391-97 is appended to this letter). 
 
 
 
 


Typical Items Found in Adult Crash Carts 
The list is for demonstration purposes only, as crash carts will differ on medical vs. surgical 
facilities, or across hospitals, and certainly across countries. The key to an adequate crash 
cart are solutions and drapes for sterility, methods to deliver IV fluids, vasopressor agents, 
epinephrine (adrenaline), cardiac arrythmia treatments, vacutainers (for tryptase: e.g. 6 
mL dark blue-top [trace element, no additive]), cardiac defibrillator and means of 
maintaining an airway (oxygen valve bag mask, endotracheal tubes; oxygen available): 
below is the ACLS partial list  
• Alcohol swabs, amiodarone 150 mg/3ml vial, atropine 1mg/10 ml syringe, 
sodium bicarbonate 50mEq/50 ml syringe, calcium chloride 1gm/10 ml syringe, 
sodium chloride 0.9% 10 ml vial Inj. 20 ml vial, Dextrose 50% 0.5 mg/ml 50 ml 
syringe, Dopamine 400 mg/250 ml IV bag, Epinephrine 1 mg/10 ml (1:10,000) 
syringe, sterile water, lidocaine 100 mg 5ml syringes, lidocaine 2 gm/250 ml IV 
bag, povidone-iodine swabstick, vasopressin 20 units/ml 1 ml vial 
• Endotracheal tubes of various sizes, nasopharyngeal and perhaps 
oropharyngeal airways, laryngoscope handle and blades of different sizes, a 
flashlight with extra batteries, a syringe of sufficient size to inflate the cuff on -
an endotracheal tube, stylets, bite block, tongue depressors 
• V Start Kit (or similar CPR kit), angio-catheters 14 Ga and/or 16 Ga, 
disinfectants (chloraprep, Betadine, povidone-iodine), Luer lock syringes of 
various sizes, tourniquet tubing, Insyte autoguards of various sizes, Vacutainers 
• ECG electrodes, sterile gloves of various sizes, sutures of various sizes and 
materials, suction supplies, salem pump (double-lumen nasogastric tube for 
aspiration of stomach contents), cricothyroidotomy kit, adult cut down pack, 
Yankauer suction, drapes to create a sterile field, Suction Cath Kit 14 Fr & 18 Fr,  
• ECG / cardiac defibrillator  
 
Guidelines for treatment of Anaphylaxis 
As all sites must have ACLS or equivalent training, and appropriate equipment, this 
overview of treatment is at a high level. 
• Rapid assessment and maintenance of airway, breathing and circulation 
• Epinephrine (adrenaline) 0.01mg/kg – 0.5 mg maximum dose intramuscularly every 
5-15 minutes, as needed. 
• High flow oxygen through endotracheal tube or rebreather mask for respiratory 
symptoms or hypoxia 
o Inhaled beta-2 agonists (e.g. albuterol) for bronchospasm 
• With signs of hypoperfusion, position subject in a recumbent position with legs 
elevated, except for when there is vomiting or shortness of breadth 
• Subjects hypotensive despite epinephrine should have fluid resuscitation 
• If epinephrine and fluid resuscitation are not adequate for maintaining blood 
pressure, then vasopressors can be implemented (e.g. noradrenaline 
[noradrenaline], vasopressin) 
• Observation for a period of time must occur as a return of signs and symptoms 
may recur as epinephrine (adrenaline) blood concentrations decrease, or the 
subject has a biphasic reaction. 


Second symposium on the deﬁnition and
management of anaphylaxis: Summary
report—Second National Institute of Allergy
and Infectious Disease/Food Allergy and
Anaphylaxis Network symposium
Hugh A. Sampson, MD,a Anne Mun˜ oz-Furlong, BA,b Ronna L. Campbell, MD, PhD,c
N. Franklin Adkinson, Jr, MD,d S. Allan Bock, MD,e Amy Branum, MSPH,f Simon G. A.
Brown, MBBS, PhD,g Carlos A. Camargo, Jr, MD,h Rita Cydulka, MD, MS,i Stephen J.
Galli, MD,j Jane Gidudu, MD, MPH,k Rebecca S. Gruchalla, MD,l Allen D. Harlor, Jr,
MD,m David L. Hepner, MD,n Lawrence M. Lewis, MD,o Phillip L. Lieberman, MD,p Dean
D. Metcalfe, MD,q Robert O’Connor, MD,r Antonella Muraro, MD, PhD,s Amanda
Rudman, BA,q Cara Schmitt, MS,b Debra Scherrer, BA,b F. Estelle R. Simons, MD,t
Stephen Thomas, MD, MPH,u Joseph P. Wood, MD,v and Wyatt W. Decker, MDc
New York, NY, Fairfax, Va, Rochester, Minn, Baltimore, Hyattsville, and Bethesda, Md, Boulder and
Denver, Colo, Fremantle, Australia, Boston, Mass, Cleveland, Ohio, Stanford, Calif, Lilbum, Ga,
Dallas, Tex, Eugene, Ore, St Louis, Mo, Cordova, Tenn, Padua, Italy, Winnipeg, Manitoba, Canada,
and Scottsdale, Ariz
There is no universal agreement on the deﬁnition of anaphylaxis
or the criteria for diagnosis. In July 2005, the National Institute
of Allergy and Infectious Disease and Food Allergy and
Anaphylaxis Network convened a second meeting on
anaphylaxis, which included representatives from 16 different
organizations or government bodies, including representatives
from North America, Europe, and Australia, to continue
working toward a universally accepted deﬁnition of
anaphylaxis, establish clinical criteria that would accurately
identify cases of anaphylaxis with high precision, further
review the evidence on the most appropriate management
of anaphylaxis, and outline the research needs in this area.
(J Allergy Clin Immunol 2006;117:391-7.)
Key words: Anaphylaxis, IgE mediated hypersensitivity, anaphylac
toid, epinephrine
Even though anaphylaxis was ﬁrst described around
100 years ago and is one of the most alarming disorders
encountered in medicine, there is no universal agreement
on its deﬁnition or criteria for diagnosis. Furthermore, this
lack of speciﬁc criteria for diagnosing anaphylaxis has
greatly hampered research into the epidemiology, patho
physiology, and management of this disorder; led to
confusion on the part of ﬁrst responders, emergency
personnel, primary care physicians, and patients; and
resulted in a failure to diagnose and treat anaphylaxis in a
consistent manner.1-3
In an attempt to resolve these problems, the National
Institute of Allergy and Infectious Disease (NIAID) and
the Food Allergy and Anaphylaxis Network (FAAN)
convened a meeting in April 2004 to address these
deﬁciencies.4 This 2 day symposium brought together
experts and representatives from 13 professional, govern
mental, and lay organizations to address the issue of
deﬁning and managing anaphylaxis. Organizations repre
sented included the American Academy of Allergy,
Asthma and Immunology; the American Academy of
Emergency Physicians; the American Academy of Family
Physicians; the American Academy of Pediatrics; the
American College of Allergy, Asthma and Immunology;
the American College of Emergency Physicians; the
From athe Mount Sinai School of Medicine, New York; bthe Food Allergy &
Anaphylaxis Network, Fairfax; cthe Mayo Clinic, Rochester; dthe Johns
Hopkins University School of Medicine, Baltimore;
erepresenting the
Food Allergy & Anaphylaxis Network, Boulder; fthe National Center for
Health Statistics, Hyattsville;
gFremantle Hospital, Fremantle, WA,
Australia; hMassachusetts General Hospital, Boston; ithe Case Western
Reserve
University
School
of
Medicine,
Cleveland;
jthe
Stanford
University School of Medicine, Stanford; krepresenting the Centers for
Disease Control and Prevention, Lilburn;
lthe University of Texas
Southwestern
Medical
Center, Dallas;
mrepresenting
the
American
Academy of Pediatrics, Eugene; nrepresenting the American Society of
Anesthesiologists, Boston;
orepresenting the Society for Academic
Emergency Medicine, St. Louis; prepresenting the American College of
Allergy, Asthma and Immunology, Cordova; qthe National Institute of
Allergy and Infectious Diseases, the National Institutes of Health,
Bethesda;
rrepresenting the National Association of EMS Physicians,
Baltimore;
sthe University of Padua, Padua, Italy;
trepresenting the
American Academy of Allergy, Asthma and Immunology, Winnepeg,
MB,
Canada;
urepresenting
the
American
College
of
Emergency
Physicians,
Boston;
and
vrepresenting
the
American
Academy
of
Emergency Medicine, Scottsdale.
Received for publication December 7, 2005; accepted for publication
December 8, 2005.
Reprint requests: Hugh A. Sampson, MD, Division of Pediatric Allergy and
Immunology, Mount Sinai Hospital, One Gustave L. Levy Pl, Box 1198,
New York, NY 10029-6574. E-mail: hugh.sampson@mssm.edu.
0091-6749/$32.00
 2006 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2005.12.1303
391
Food allergy, dermatologic
diseases, and anaphylaxis


Abbreviations used
FAAN: Food Allergy and Anaphylaxis Network
NIAID: National Institute of Allergy and Infectious Disease
American Society of Anesthesiologists; the Centers for
Disease Control and Prevention; the Food Allergy
Initiative; the International Life Sciences Institute; the
National Association of EMS Physicians; the Society for
Academic Emergency Medicine; and the US Food and
Drug Administration. Clinical criteria were proposed that
emphasized the need for heightened suspicion of anaphy
laxis in patients with a previous history of allergic reac
tions to a speciﬁc allergen and a known exposure, as well
as in patients in whom there is no known history of allergic
reactions.
Recently, the Joint Task Force of the American
Academy of Allergy, Asthma and Immunology and the
American College of Allergy, Asthma and Immunology
published an updated practice parameter on the diagnosis
and management of anaphylaxis.5 In this report the Task
Force deﬁned anaphylaxis as ‘‘as a condition caused by
an IgE mediated reaction’’ and noted that such reactions
‘‘are often life threatening and almost always unantici
pated.’’ The purpose of the practice parameter was to
provide ‘‘the practicing physician with an evidence based
approach to the diagnosis and management of anaphy
lactic reactions.’’ In July 2005, the NIAID and FAAN
convened a second meeting, which included representa
tives from the previous organizations and the European
Academy of Allergy and Clinical Immunology, the Aus
tralasian Society of Clinical Immunology and Allergy,
and the Australasian College for Emergency Medicine,
to begin the process of facilitating an international agree
ment. The purpose of this second NIAID/FAAN Sympo
sium was to continue working toward a universally
accepted deﬁnition of anaphylaxis, establish clinical crit
eria that would accurately identify cases of anaphylaxis
with high precision, further review the evidence on the
most appropriate management of anaphylaxis, and outline
the research needs in this area.
DEFINITION OF ANAPHYLAXIS AND
CRITERIA FOR DIAGNOSIS
Anaphylaxis is a severe, potentially fatal, systemic
allergic reaction that occurs suddenly after contact with
an allergy causing substance. Participants at the sympo
sium agreed that a brief, broad deﬁnition of anaphylaxis
that reﬂected its course and potential severity would be
most useful to both the medical and lay community and
recommended the following: ‘‘Anaphylaxis is a serious
allergic reaction that is rapid in onset and may cause death.’’
To identify individuals experiencing such a reaction,
criteria proposed at the ﬁrst symposium were revised,4 as
outlined in Table I. Participants at the second symposium
agreed that the diagnostic criteria must provide the
emergency responder or treating physician with a rela
tively simple and rapid means to make the diagnosis of
anaphylaxis. It was acknowledged that no criteria will
provide 100% sensitivity and speciﬁcity, but it was be
lieved that the criteria proposed are likely to capture
more than 95% of cases of anaphylaxis. Because the ma
jority of anaphylactic reactions include skin symptoms,5-10
which are noted in more than 80% of cases when care
fully assessed, it was judged that at least 80% of anaphy
lactic reactions should be identiﬁed by criterion 1, even
when the allergic status of the patient and potential cause
of the reaction might be unknown. However, cutaneous
symptoms might be absent in up to 20% of anaphylactic
reactions in children with food allergy or insect sting al
lergy.11-13 Consequently, in patients with a known allergic
history and possible exposure, criterion 2 would provide
ample evidence that an anaphylactic reaction was occur
ring. Gastrointestinal symptoms were included as a perti
nent target response because they have been associated
with severe outcomes in various anaphylactic reactions.9
Finally, criterion 3 should identify the rare patients who
experience an acute hypotensive episode after exposure
to a known allergen, as described by Pumphrey and
Stanworth.14 Although participants believed that these cri
teria should accurately identify anaphylactic reactions in
more than 95% of cases, it was agreed that these criteria
need to be subjected to a prospective multicenter clinical
survey to establish their utility and determine whether
there is need for further reﬁnement.
MANAGEMENT OF ANAPHYLAXIS
As with the treatment of any critically ill patient, the
treatment of anaphylaxis begins with a rapid assessment
and maintenance of airway, breathing, and circulation.
When a patient fulﬁlls any of the 3 criteria of anaphylaxis
outlined above, the patient should receive epinephrine
immediately
because
epinephrine
is
the
treatment
of choice in anaphylaxis. There undoubtedly will be
patients who present with symptoms not yet fulﬁlling
the criteria of anaphylaxis yet in whom it would be
appropriate to initiate therapy with epinephrine, such as a
patient with a history of near fatal anaphylaxis to peanut
who ingested peanut and within minutes is experiencing
urticaria and generalized ﬂushing. Subsequent interven
tions are determined on the basis of the clinical course and
response to epinephrine. In general, participants at the
Second NIAID/FAAN Anaphylaxis Symposium support
the therapeutic approach outlined in recently published
guidelines.5 A summary of these guidelines is provided
below, along with a more detailed discussion of the recom
mended route of parenteral epinephrine, positioning
during treatment of anaphylaxis, and suggested observa
tion periods after treatment of an anaphylactic episode.
Epinephrine
Epinephrine is the treatment of choice for anaphylaxis.5
Aqueous epinephrine, 0.01 mg/kg (maximum dose,
J ALLERGY CLIN IMMUNOL
FEBRUARY 2006
392 Sampson et al
Food allergy, dermatologic
diseases, and anaphylaxis


0.5 mg) administered intramuscularly every 5 to 15 minutes
as necessary, is the recommended dosage for controlling
symptoms and maintaining blood pressure.15,16 The
5 minute interval between injections can be liberalized
to permit more frequent injections if deemed necessary
by the clinician.
Intramuscularversussubcutaneousepinephrine. A study
in children not experiencing anaphylaxis demonstrated
more rapid absorption and higher plasma epinephrine levels
when epinephrine was administered intramuscularly in the
anterior lateral thigh with an autoinjector when compared
with values after subcutaneous administration.17 Similarly,
in adults not experiencing anaphylaxis, peak plasma epi
nephrine concentrations were attained more quickly and
were higher after intramuscular epinephrine was injected
into the thigh than after epinephrine was injected intramus
cularly or subcutaneously into the upper arm (deltoid).18
Similar results were obtained with both an ampule of epi
nephrine or a spring loaded (eg, EpiPen [Dey, Napa,
Calif]) automatic epinephrine device.17,18 Epinephrine in
jected intramuscularly into the deltoid or subcutaneously
over the deltoid did not result in a signiﬁcant increase of
plasma epinephrine levels over endogenous epinephrine
levels.It shouldbenoted that studies of the route of injection
have not been performed in patients experiencing anaphy
laxis. On the basis of this evidence, the participants of the
NIAID/FAAN Symposium concluded that intramuscular
administration of injectable epinephrine in the anterior lat
eral thigh is preferred over subcutaneous injection. How
ever, as noted below, intravenous epinephrine might be
preferred in some cases if an intravenous line is in place
(eg, during surgery).
Intravenous epinephrine. Intravenous epinephrine is an
option for patients with severe hypotension or cardiac
arrest unresponsive to intramuscular doses of epinephrine
and ﬂuid resuscitation. Although there is no precisely
established dosage or regimen for intravenous epinephrine
in anaphylaxis, 5 to 10 mg intravenous bolus (0.2 mg/kg)
doses for hypotension and 0.1 to 0.5 mg administered
intravenously in the presence of cardiovascular collapse
have been suggested.19 A recent single center trial de
scribed successful initial management with intravenous
epinephrine infusions for anaphylaxis with hypotension,
suggesting that this might be a viable strategy.10,20
Detailed procedures for the preparation and administra
tion of epinephrine infusions have been published.5 It is
important to recognize the potential for lethal arrhythmias
when administering intravenous epinephrine, and there
fore continuous cardiac monitoring is recommended.
Continuous low dose epinephrine infusions might repre
sent the safest and most effective form of intravenous de
livery because the dose can be titrated to the desired effect
and can avoid the potential for accidental administration of
large boluses of epinephrine.
Oxygen and adrenergic agonists
High ﬂow oxygen (through a nonrebreather mask or
endotracheal tube) should be administered to patients ex
periencing respiratory symptoms or hypoxemia. Those who
are hemodynamically unstable might beneﬁt from oxygen
as well. Inhaled b2 agonists, such as albuterol, might be
useful for bronchospasm refractory to epinephrine.5
Positioning of the patient
Patients in anaphylactic shock (ie, those with anaphy
laxis and signs of critical organ hypoperfusion) should be
placed in a recumbent position with the lower extremities
elevated unless precluded by shortness of breath or
vomiting. These recommendations are based on evidence
that passive leg raise can increase stroke volume and
cardiac output by shifting ﬂuid centrally in patients in
shock.21 Furthermore, observations of victims of fatal
anaphylactic shock suggest that postural changes, such as
moving to a more upright position or being prevented
from taking a supine posture, might have contributed to
the fatal outcome.22
Fluid resuscitation
Patients who remain hypotensive despite epinephrine
should have aggressive ﬂuid resuscitation. Large volumes
TABLE I. Clinical criteria for diagnosing anaphylaxis
Anaphylaxis is highly likely when any one of the following 3 criteria are fulﬁlled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or
ﬂushing, swollen lips tongue uvula)
AND AT LEAST ONE OF THE FOLLOWING
a. Respiratory compromise (eg, dyspnea, wheeze bronchospasm, stridor, reduced PEF, hypoxemia)
b. Reduced BP or associated symptoms of end organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
a. Involvement of the skin mucosal tissue (eg, generalized hives, itch ﬂush, swollen lips tongue uvula)
b. Respiratory compromise (eg, dyspnea, wheeze bronchospasm, stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several hours):
a. Infants and children: low systolic BP (age speciﬁc) or greater than 30% decrease in systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
PEF, Peak expiratory ﬂow; BP, blood pressure.
*Low systolic blood pressure for children is deﬁned as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg 1 [2 3 age]) from 1 to 10 years,
and less than 90 mm Hg from 11 to 17 years.
J ALLERGY CLIN IMMUNOL
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Sampson et al 393
Food allergy, dermatologic
diseases, and anaphylaxis


of crystalloid might be needed in the ﬁrst 5 to 10 minutes;
in severe reactions with hypotension, up to 35% of the
blood volume might extravasate in the ﬁrst 10 minutes,
and vasodilatation can cause pooling, with even more
reduction in the effective blood volume and thus distrib
utive shock.23 The volume given must be tailored to the
clinical situation; persistent hypotension requires a more
aggressive approach with multiple ﬂuid boluses (10 20
mL/kg under pressure), including colloid, as well as crys
talloid, whereas a largely respiratory reaction or one that
responds promptly to initial treatment requires less aggres
sive ﬂuid management.
Vasopressors
Potent vasopressors, such as noradrenaline, vasopres
sin, or metaraminol, might be required to overcome
vasodilatation if epinephrine and ﬂuid resuscitation have
failed to maintain a systolic blood pressure of greater than
90 mm Hg.20 Recent case reports and animal studies have
demonstrated that vasopressin is useful when treating
hemorrhagic and septic shock. The effect of vasopressin
on systemic anaphylaxis has not been investigated, except
in clinical case reports. Vasopressin increases blood pres
sure because of vasoconstriction through the V1 receptor.24
H1- and H2-antihistamines
Antihistamines (H1 and H2 antagonists) are slower in
onset of action than epinephrine, have little effect on blood
pressure, and should be considered a second line treat
ment for anaphylaxis. Antihistamines are useful for the
symptomatic treatment of urticaria angioedema and pru
ritus. Diphenhydramine, administered intravenously or
intramuscularly (or orally for mild symptoms), can be
given at 25 to 50 mg for adults and 1 mg/kg (up to 50
mg) for children. Treatment with a combination of H1
and H2 antagonists has been reported to be more effective
in attenuating the cutaneous manifestations of anaphylaxis
than treatment with H1 antagonists alone.25,26 Ranitidine
and cimetidine have been most studied, but no controlled
studies have demonstrated superiority of one H2 antagonist
over another.
Corticosteroids
The effectiveness of corticosteroids in anaphylaxis has
never been determined in placebo controlled trials.
However, their usefulness in other allergic diseases has
led to their incorporation into anaphylaxis management.
Because the onset of action is slow, steroids are not useful
in the acute management stage. It has been suggested that
their use might prevent a protracted or biphasic reaction,
although there is no evidence to prove this.11,27 If given,
the dosing of intravenous corticosteroids should be equiv
alent to 1.0 to 2.0 mg/kg per dose of methylprednisolone
every 6 hours. Oral administration of prednisone, 1.0
mg/kg, up to 50 mg might be sufﬁcient for milder attacks.
Glucagon for persistent hypotension in
patients taking b-blockers
Although there are no epidemiologic studies that dem
onstrate increased frequency of anaphylaxis in patients
receiving b blockers, there are multiple reported cases of
increased severity or treatment refractory anaphylaxis in
these patients.28 Theoretically, there are multiple mecha
nisms by which b blockade could blunt the response to
epinephrine. If administration of epinephrine in these
patients is ineffective, administration of glucagon can be
attempted. Glucagon is thought to reverse refractory hypo
tension and bronchospasm by activating adenylate cyclase
independent of the b receptor; however, the occurrence
and importance of this mechanism of action in anaphy
laxis is unproved. The recommended dosage for glucagon
is 1 to 5 mg (20 30 mg/kg [maximum dose, 1 mg] in
children) administered intravenously over 5 minutes and
followed by an infusion (5 15 mg/min) titrated to clinical
response. Airway protection must be ensured because
glucagon frequently causes emesis.
Observation
After the treatment of an anaphylactic reaction, an
observation period should be considered for all patients
because the reaction might recur as the effect of epineph
rine wears off (intramuscular epinephrine results in in
creased serum levels for an hour or more) and because of
the risk of a biphasic reaction. The occurrence of biphasic
reactions has been established in the literature and appears
to occur in 1% to 20% of anaphylactic reactions (as
depicted in Table II).8,11,27,29-34 In a study evaluating
patients with fatal or near fatal food reactions, approxi
mately 20% of patients experienced a biphasic reaction,
indicating that biphasic reactions might be more likely
in patients who present initially with severe symptoms.11
The reported time intervals between the initial reaction
TABLE II. Biphasic reactions
Study
Frequency of biphasic
reactions
No. of biphasic
reactions/total no. of
patients in study
Time from
initial to biphasic
reaction (h)
Brazil and MacNamara33
18%
6/34
4.5 29.5
Douglas et al31
6%
6/103
1 72
Lee and Greenes34
6%
6/105
5.6 47.6
Starks and Sullivan29
20%
5/25
1 8
Brady et al32
3%
2/67
24 28
Smit et al8
5%
15/282
1 23
Adapted from Smit et al.8
J ALLERGY CLIN IMMUNOL
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394 Sampson et al
Food allergy, dermatologic
diseases, and anaphylaxis


and the onset of the second phase ranged from 1 to 72
hours.11,27,30-34 Unfortunately, no reliable clinical predic
tors have been identiﬁed to enable the identiﬁcation of
patients at increased risk of a biphasic reaction, although
some studies have suggested that patients requiring higher
doses of epinephrine to control initial symptoms or de
layed administration of epinephrine might be associated
with increased risk of a biphasic reaction.11,15,33,34
Generally, the same organ systems are involved in the
initial and secondary reaction. However, in the study
by Smit et al,8 3 patients with initially stable vital signs
returned with abnormal vital signs (2 with hypotension
and 1 with dyspnea and decreased oxygen saturation).
On the basis of the evidence to date, the participants
attending the NIAID/FAAN Symposium recommended
that observation periods be individualized on the basis
of the severity of the initial reaction, reliability of the
patient, and access to care. A reasonable length of time
to consider observing the postanaphylactic patient is 4 to
6 hours in most patients, with prolonged observation times
or hospital admission for patients with severe or refractory
symptoms. More caution should be used in patients with
reactive airway disease because most fatalities associated
with anaphylaxis occur in these patients.
Outpatient follow-up and management
Patients who have experienced anaphylaxis from ex
posures that might be encountered in nonmedical settings
should carry self injectable epinephrine for use if anaphy
laxis develops.5,11 As noted above, there has been no uni
versally accepted deﬁnition of anaphylaxis. Therefore the
clinical criteria suggested above might be helpful in deter
mining who should be prescribed self injectable epineph
rine. Until there are universally accepted criteria for the
diagnosis of anaphylaxis, the indications for the pres
cription of self injectable epinephrine will continue to be
problematic. Currently, there is a consensus that patients
experiencing respiratory or cardiovascular symptoms after
exposure to a known allergen in the community should
receive self injectable epinephrine. Beyond this consen
sus, it is unclear who should be given a prescription for
self injectable epinephrine. However, limiting prescrip
tions of self injectable epinephrine to this criteria in
patients with peanut and other nut allergy, for example,
would fail to cover up to 80% of patients experiencing a
fatal anaphylactic reaction.35 Patients who are prescribed
self injectable epinephrine should also have an emergency
action plan detailing its use and the follow up manage
ment. The complexities of prescribing self injectable
epinephrine and providing an accompanying emergency
action plan have been described recently by Sicherer and
Simons,36 and the ethical dilemmas have been discussed
by Hu et al.37
Before discharge from an emergency facility, all
patients experiencing an anaphylactic reaction should
receive information about how to avoid the precipitating
allergen (if known). Other issues to consider include
alerting patients about national organizations providing
important information and educational materials (eg, the
Food Allergy and Anaphylaxis Network, www.foodallergy.
org), as well as being advised to obtain prompt follow up
with an allergist and notify their primary care physician.
At present, these 3 steps (ie, self injectable epinephrine
prescription, patient education, and follow up evaluation)
are infrequently performed in North American emergency
departments.38,39 Because emergency departments are the
treatment setting for most anaphylaxis visits,1 this repre
sents an important and as yet untapped opportunity to
improve patient care.
RESEARCH NEEDS
The investigation of anaphylaxis has been impeded
by the lack of universally accepted diagnostic criteria and
the absence of reliable laboratory biomarkers to conﬁrm
the clinical impression. This in turn has thwarted efforts
to ascertain the incidence and outcome of anaphylaxis in
various populations, to determine the most effective forms
of therapy, to identify patients at risk for life threatening
anaphylaxis, and to elucidate the basic immunologic and
pathogenic mechanisms responsible for the variable
course of anaphylaxis in different individuals. A multi
center prospective study of the diagnostic criteria pro
posed herein is needed to determine whether they allow
the clinician and investigator to identify accurately pa
tients with anaphylaxis regardless of cause. Assuming that
these criteria prove to be adequately sensitive and speciﬁc
for diagnosing anaphylaxis, studies determining the inci
dence, cause, clinical features, natural course, and out
come of anaphylaxis are needed to provide the clinician
with evidence based features of this disorder that will
enable more effective prevention and therapeutic inter
ventions. Clinical trials can be facilitated by the formation
of an anaphylaxis consortium.
It was believed that the measurement of certain mast
cell derived mediators, such as histamine and tryptase,
would provide conﬁrmatory evidence of an anaphylactic
reaction. However, in a series of 97 patients presenting to
an emergency department and given diagnoses of ana
phylaxis, only 42% were found to have increased plasma
histamine levels, and 21% were determined to have
increased plasma tryptase levels.26 One small study dem
onstrated that serial estimations of plasma tryptase levels
might improve sensitivity (36% to 73%).40 Sensitive and
speciﬁc biomarkers of anaphylaxis and evolving anaphy
laxis are needed that will establish the presence of the
disorder when sufﬁcient historical information is not
available or symptoms are atypical. New proteomic ap
proaches, metabolomic approaches, or both might prove
useful in identifying relevant biomarkers. Biomarker
assays could be useful to conﬁrm the diagnosis when in
doubt, which can have important follow up implications.
If available at the bedside, they could even assist in the
identiﬁcation of patients at risk of persistent or delayed
phase reactions. However, given the emergency and ful
minant nature of this disease, such approaches are unlikely
to
be
useful
for
guiding
immediate
resuscitative
J ALLERGY CLIN IMMUNOL
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Sampson et al 395
Food allergy, dermatologic
diseases, and anaphylaxis


interventions. Laboratory trials can be facilitated by the
formation of an anaphylaxis registry with close collabora
tion between different centers and across specialties.
As outlined in the previous symposium,4 most anaphy
lactic reactions are due to IgE mediated hypersensitivity
reactions resulting from cross linking of allergen speciﬁc
IgE molecules on the surface of tissue mast cells and pos
sibly basophils. However, this mechanism alone does not
explain the severity of the allergic manifestations, the var
iability in target organ responses among individuals or
within the same individual, the differences in threshold
doses of allergen necessary to provoke anaphylactic re
sponses, the variable responses to therapy, the induction
of biphasic or protracted anaphylactic reactions, or the
eventual outcome of the reaction. A recent study sug
gested that the diversity of IgE allergenic epitope recog
nition might play a role in the severity of allergic
responses,41 but this represents a fraction of the potential
variables occurring between the time an allergen enters
the body and the end result of an anaphylactic reaction.
For example, it might be informative to perform genomic
and functional studies of polymorphisms or gain of func
tion mutations in various mediator, cytokine, and chemo
kine receptors; the Kit receptor; elements of intracellular
signaling pathways; or other factors that might inﬂuence
either the activation or function of the effector cells of
anaphylaxis or the responses of the structural cells in the
target organs affected in this disorder.
In addition, investigation is required into the patho
physiologic mechanisms and appropriate treatment of
reactions fulﬁlling the diagnostic criteria listed for
anaphylaxis but that do not involve an IgE mediated
mechanism, commonly referred to as anaphylactoid or
pseudoallergic reactions. Furthermore, studies have sug
gested a role for the nervous system in eliciting the full
symptom complex of anaphylaxis,42 and this is an area
that warrants further investigation. Well characterized an
imal models would clearly facilitate efforts to understand
the basic pathophysiology occurring during anaphylaxis;
to determine the interactions between various cell types;
to elucidate effects of mediators, cytokines, and chemo
kines released during an anaphylactic response; and to
delineate better therapeutic strategies. Recently, animal
models that appear reﬂective of anaphylaxis in human
subjects have been established in mice,43 dogs,44 and
pigs,45 but better models are needed.
During the NIAID/FAAN Symposium and in the
recently published practice parameter on anaphylaxis,5
therapeutic strategies for the management of anaphylaxis
were suggested largely on the basis of ‘‘clinical experi
ence.’’ In fact, there is a major need to evaluate the most
appropriate therapeutic measures and medications for
the treatment of anaphylaxis. Although virtually all au
thorities agree that epinephrine is the drug of choice for
the treatment of acute anaphylaxis, there are limited data
on the appropriate dose, timing, route, or frequency of
administration. H1 and H2 antihistamines, corticosteroids,
or both are commonly used in the treatment of anaphy
laxis, but there are virtually no data demonstrating their
functional role or effectiveness. Prospective controlled
trials to establish the appropriate dosing of these medica
tions and the role of other therapeutic interventions, such
as the optimal type and rate of ﬂuid replacement, and
the use of vasopressors, glucagon, nebulized albuterol or
epinephrine, leukotriene inhibitors, and cytokine antago
nists (eg, anti TNF) also are warranted. Ideally, therapeutic
measures could be studied in appropriate animal models be
fore initiating clinical trials. Before any clinical studies,
clinically useful severity scoring and outcome measure
ment tools need to be validated.
There is also a need for outcomes research in well
characterized patients. Little information is available
on the beneﬁts and risks of providing epinephrine auto
injectors, antihistamines, corticosteroids, and written
medical instructions to patients with food and insect
venom allergy and their caregivers (eg, parents and school,
day care, and restaurant personnel) and ﬁrst line emer
gency personnel. Studies of long term sequelae, adher
ence to follow up referral, subsequent reactions, and
quality of life in patients experiencing anaphylactic reac
tions also are lacking. As outcome data are becoming
available, evaluation of the most effective means of
disseminating information about the prevention and
management of anaphylaxis to patients, primary care
physicians, ﬁrst responders, and emergency department
personnel should help alleviate the tremendous disparities
in therapeutic approaches seen in the United States and
around the world.
A number of studies from around the world suggest that
anaphylactic reactions commonly occur both inside and
out of the hospital environment.46,47 In light of the general
increase in IgE dependent allergic disorders in the devel
oped world over the past several decades, there is an urgent
need to understand better the basic immunology and path
ophysiology of anaphylaxis and to optimize therapy on
the basis of well controlled clinical trials. In addition, the
characterization of clinical features and discovery of bio
markers that would identify patients at risk for anaphylaxis
or for biphasic or prolonged severe reactions would greatly
enhance the care of these patients, decrease patient and
family anxieties, and reduce the risk of unfavorable out
comes. The universal acceptance of speciﬁc clinical crite
ria to identify anaphylaxis, as proposed here, will facilitate
and expedite research in this critical area.
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Food allergy, dermatologic
diseases, and anaphylaxis