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Trial registered on ANZCTR


Registration number
ACTRN12621001667808
Ethics application status
Approved
Date submitted
14/08/2021
Date registered
3/12/2021
Date last updated
23/05/2022
Date data sharing statement initially provided
3/12/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
An Initial Study for the Use of a New Cold Energy System (BXT-786) to Provide Pain Relief Through A Regional Block for Subjects with unrelieved pain related to severe osteoarthritis of the knee.
Scientific title
A Pilot, Non-Randomized, Open Label Study of a Novel Device and its Delivery System (BXT Focused Cold Therapy), Providing Cold Energy Regional Anesthetic Block for Knee Pain Management
Secondary ID [1] 305027 0
BXT-786-TKA-01
Universal Trial Number (UTN)
U1111-1268-6055
Trial acronym
N/A
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
knee pain 323197 0
knee replacement 323991 0
Osteoarthritis (severe knee) 326423 0
Condition category
Condition code
Anaesthesiology 320779 320779 0 0
Pain management
Surgery 321495 321495 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eligible subjects will receive a genicular block (a standard of care procedure that impactis the knee region) utilizing the BXT-786 coolant and delivery system. The research block will be performed by a qualified anesthesiologist. The intervention is a single procedure consisting of three injections. Each injection dose is 20mL of Coolant. The Investigational product consists of a three component system: The BXT-786 coolant (located within the syringe); the BXT-786 syringe; and the BTX-786 dock (which processes the coolant within the syringe in preparation of each injection). The investigators have all agreed to a standard procedure for the genicular block and will confirm this with documentation within the research record. The singular research genicular block will typically occur within the clinic/ procedure room. Subjects 1-8 (of 16 total) will have a tourniquet (like blood pressure cuff) and ice pack applied prior to procedure.
Procedure:
The procedure itself will take approximately twenty minutes, however, with the pre-cooling of injection sites, and post procedure examination, the visit will last approximately 2 hours.
The proposed sequence of injections is superomedial, superolateral, and inferomedial.
Investigators will agree to observe the following principles:
1. Prior to procedure, all subjects should have completed an informed consent form and all screening procedures. However, should the anesthesiologist’s pre-procedure review note a significant change from screening assessment of the subject, they may deem that the procedure is not in the best interest of the subject and may withdraw them from participation. The subject will not complete enrollment and will be considered a screen failure.
2. Place BXT-786 Syringes into a regular freezer at -22 to -18°C for (minimum) 12 hours prior to injection
3. Instruct patient to change into hospital gown (may remain in clothing if target area is easily accessible)
4. Move patient to procedure room and position on exam table
5. Place patient in supine position with index knee flexed 10-45°
6. Apply a pneumatic, single cuff tourniquet to the mid-thigh – do not inflate. Note: this step is EXCLUDED for subjects 9-16.
7. Prep skin of target area with room temperature 10%(povidone-iodine) betadine
8. Place sterile towel over knee and position ice pack(s) over injection sites, by folding each pack in half and securing with medical tape, for approximately 20 minutes. Use ice pack provided by the Sponsor only. Note: this step is EXCLUDED for subjects 9-16.
9. Remove ice pack(s) and reapply 10% (povidone-iodine) butadiene to the skin of the target area.
10. Anesthetize the skin and soft tissues (within region of each injection site) with 1-2mL of 1% lidocaine
11.Identify the anatomical landmarks of the superomedial, superolateral, and inferomedial genicular nerves of the index knee under ultrasound or fluoroscopic imaging. The following instructions can be utilized for fluoroscopic imaging:
• Superomedial Genicular Nerve
1. AP Fluoroscopic View: Needle positioned 1-2cm medial to femoral shaft – confluence of medial femoral shaft and medial epicondyle. Needle advanced until it touches the bone.
2. Lateral Fluoroscopic View: Needle repositioned so tip is positioned half-way across the diameter of the femoral shaft, withdrawn 4mm superficial to periosteum.
• Superolateral Genicular Nerve
1. AP Fluoroscopic View: Needle positioned 1-2cm lateral to femoral shaft – confluence of lateral femoral shaft and lateral epicondyle. Needle advanced until it touches the bone.
2. Lateral Fluoroscopic View: Needle repositioned so tip is positioned half-way across the diameter of the femoral shaft, withdrawn 4mm superficial to periosteum.
• Inferomedial Genicular Nerve
1. AP Fluoroscopic View: Needle is positioned 2-3cm medial and 3-4cm inferior to tibial shaft – confluence of medial tibial shaft and tibial flare. Needle advanced until it touches the bone.
2. Lateral Fluoroscopic View: Needle repositioned so tip is positioned at the mid-point of the diameter of tibial shaft and withdrawn 4mm superficial to periosteum.
12. Physician to position three 17-gauge, 50-mm, regular bevel needles at the appropriate locations. Note: Use injection needles provided by the Sponsor.
13. Remove stylets from needles and check for blood (if applicable)
14. Inflate tourniquet 50-100mmHg above patient’s systolic blood pressure. Note: this step is EXCLUDED for subjects 9-16.
15. Assistant of physician to retrieve one BXT-786 Syringe from freezer and place into BXT-786 Dock. Note: it is important to immediately transfer Syringe from freezer to Dock – do not leave the Syringe sitting out.
16. BXT-786 Dock will prepare Syringe for approximately 1-2 minutes; wait for blinking green light to indicate that Syringe is ready for injection. Note: it is important to immediately inject Focused Cold Therapy once Syringe has completed preparation.
17. Assistant of physician to remove Syringe from Dock
18. Physician to connect Syringe to needle positioned for superomedial genicular nerve of the index knee
19. Physician to administer 20mL of BXT Focused Cold Therapy into extra-neural space of the superomedial genicular nerve. Do not rub or massage knee once injection has been administered in order to keep Coolant within target area. Discard Syringe and needle. Note: it is important to immediately inject Coolant into patient without delay after removal from the Dock.
20. Repeat steps 14-18 for superolateral genicular nerve
21. Repeat steps 14-18 for inferomedial genicular nerve
22. Deflate and remove tourniquet. Note: this step is EXCLUDED for subjects 11-15.
23. Assistant of physician to remove physician’s outer pair of gloves
24. Place adhesive bandages over injection sites
25. Move patient to recovery area for 5-15 minutes – Assistant/physician to aid patient with mobilization; may require wheelchair
26. During recovery period, physician to perform anesthesia exam, which includes motor, sensory, and vascular evaluations. Allow patient to ask questions, print post-op instructions and follow-up schedule for patient to take home
27. Discharge patient if medically stable and able to ambulate--if patient requires assistance with mobility, provide as per standard of care at institution.
Intervention code [1] 321423 0
Treatment: Devices
Comparator / control treatment
There is no control group. However, there will be a comparison between subjects 1-8 (receiving pre-cooling and tourniquet in conjunction with injection), and subjects 9-16 (injection alone). The only difference in the study between the groups is listed below.

--Prior to cleaning injection sites, apply a pneumatic, single cuff tourniquet to the mid-thigh – do not inflate. Note: this step is EXCLUDED for subjects 9-16.
--Prep skin of target area with room temperature 10% (povidone-iodine) betadine
--Place sterile towel over knee and position ice pack(s) over injection sites for approximately 20 minutes. Use ice pack provided by the Sponsor only. Note: this step is EXCLUDED for subjects 9-16.
--Remove ice pack(s) and reapply 10% (povidone-iodine) butadiene to the skin of the target area.
--anesthetize the skin and soft tissues (within region of each injection site) with 1-2mL of 1% lidocaine
--Inflate tourniquet 50-100mmHg above patient’s systolic blood pressure. Note: this step is EXCLUDED for subjects 9-16.
--After injections are complete, deflate and remove tourniquet. Note: this step is EXCLUDED for subjects 9-16
Control group
Active

Outcomes
Primary outcome [1] 328595 0
Safety and tolerability of the BXT-786 system for genicular nerve block. (composite outcome).
The following are assessments utilized to evaluate any impact on sensory, motor, vascular, or systemic impact:
--physical examination
--height and weight
--clinical laboratory testing: Chemistry: BUN, Calcium, Chloride, Creatinine, Creatinine to BUN ratio, Bicarbonate (HCO3), Potassium, Sodium, albumin, ALT, ALP, AST, Total bilirubin, and Total protein. Hematology: Hematocrit, Hemoglobin, Platelets, RBC, WBC (with Differentials); Urinalysis: Color, Appearance, Specific Gravity, pH, Protein, Blood, Ketone, Urobilinogen, Glucose, Bilirubin, Leukocyte esterase, Nitrite,
--pregnancy testing
--Pain Scale Assessment (NRS scale)
--Timed Up and Go test (TUG)
--Brief Pain Inventory
--investigator sensory, motor, and vascular exam
--Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact
--Assessment for any Adverse Events (during on-site or remote visits)
Timepoint [1] 328595 0
Safety assessments will occur throughout the subject's study participation. Baseline assessments will be made prior to intervention. Ongoing assessments occur post intervention (post intervention on day of procedure) and at Day 1-6; Weeks 1-10; and a final evaluation at week 12 post intervention. Specifically for each assessment times are listed below:
--physical examination: at screening visit and final visit.
--height and weight: at screening
--clinical laboratory testing: at screening visit and final visit.
--pregnancy testing: at screening (there would be no impact to pregnancy after this point)
--Pain Scale Assessment (NRS scale): at screening; all visits; and 3 times daily within subject diary
--Timed Up and Go test (TUG): at screening; will be performed twice on day of diagnostic block – one TUG test before diagnostic block and one TUG test after diagnostic block; and will then be daily from three days prior to diagnostic block until end of study.
--Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study.
--investigator sensory, motor, and vascular exam: at screening, day of research procedure; post procedure day one; week one; and final visit.
--Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact
--Assessment for any Adverse Events: ongoing review during on-site or remote visits
Secondary outcome [1] 399575 0
Identify time of onset / duration of BXT-786 block (this is a composite secondary outcome and reflects the range of the duration of the device treatment). Time-to-onset will be determined and defined as a 20% reduction in NRS pain scores reported in subject diaries. Similarly, block resolution will be defined and determined by a consistent increase in pain symptoms, sustained over 1 week, as reported in subject diaries. These timepoints used to assess onset and duration are captured through some of the already defined safety assessments:
--Pain Scale Assessment (NRS scale): at screening; all visits; and 3 times daily within subject diary
--Timed Up and Go test (TUG): at screening; will be performed twice on day of diagnostic block – one TUG test before diagnostic block and one TUG test after diagnostic block; and will then be daily from three days prior to diagnostic block until end of study.
--Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study.
--Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact. The diaries will be completed at screening/day of diagnostic block, and then will be daily beginning 3 days prior to research block.
Timepoint [1] 399575 0
The time of onset and resolution of the BXT-786 block will be measured from day of intervention through resolution of block. These assessments will be made Day of intervention, Post-procedure days 1-6; and week 1-10. The timepoints for each assessment used in the calculation fo these outcomes are:
--Pain Scale Assessment (NRS scale): at screening; all visits; and 3 times daily within subject diary
--Timed Up and Go test (TUG): at screening; will be performed twice on day of diagnostic block – one TUG test before diagnostic block and one TUG test after diagnostic block; and will then be daily from three days prior to diagnostic block until end of study.
--Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study.
--Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact. The diaries will be completed at screening/day of diagnostic block, and then will be daily beginning 3 days prior to research block.
Secondary outcome [2] 401964 0
Affirming/monitoring preservation of motor function as measured by activities of daily living (ADLs). This outcome will be assessed through previously stated safety measurements: --physical examination: at screening visit and final visit. --Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study. --Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact. The diaries will be completed at screening/day of diagnostic block, and then will be daily beginning 3 days prior to research block.
Timepoint [2] 401964 0
The frequency of the assessments for affirming/monitoring preservation of activities of daily living (ADLs) is as listed below:
--physical examination: at screening visit and final visit.
--Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study.
--Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact. The diaries will be completed at screening/day of diagnostic block, and then will be daily beginning 3 days prior to research block.
Secondary outcome [3] 401969 0
Assessing evidence of sensory blockade along genicular nerve distribution. This will be assessed through the Anesthesiologist assessments (sensory, vascular, and motor). These will be assess through the following assessments:
--Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study.
--investigator sensory, motor, and vascular exam: at screening, day of research procedure; post procedure day one; week one; and final visit.
--Subject Diaries (3 times daily. review of pain/meds/activity/any bladder-bowel impact. The diaries will be completed at screening/day of diagnostic block, and then will be daily beginning 3 days prior to research block.
Timepoint [3] 401969 0
The frequency of the assessments for assessing evidence of sensory blockade along genicular nerve distribution is as follows:
--Brief Pain Inventory: at screening, day of procedure, and then weekly until end of study.
--investigator sensory, motor, and vascular exam: at screening, day of research procedure; post procedure day one; week one; and final visit.

Eligibility
Key inclusion criteria
Subjects meeting ALL of the following criteria will be considered eligible for clinical trial entry:
1. Age 21 to 70 of any gender
2. Average baseline pain intensity >/= 4 on Numeric Rating Scale (NRS), despite current treatment
3. A decrease of >50% from highest NRS score with diagnostic genicular nerve block
4. Meets criteria for primary, unilateral total knee arthroplasty (TKA):
• Criteria 1: Severe osteoarthritis of the knee (K-L stage 3 or 4) on plain x-rays AND
• Criteria 2: Failed conservative treatments (NSAID, acetaminophen, physical therapy, cortisone injections)
3. Willing/able to understand informed consent form, provide written informed consent, and able to complete outcome measures
• Subjects should have access to device/equipment with internet capabilities, in order to participate in telehealth visits
Minimum age
21 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Subjects meeting ANY of the following criteria will NOT be considered eligible for clinical trial entry:
1. Known allergy to any component of BXT-786 (glycerol and/or phosphate buffered saline)
2. History of cryoglobulinemia
3. History of paroxysmal cold hemoglobinuria
4. History of cold urticaria
5. History of Raynaud’s disease
6. Open and/or infected wounds at or near treatment site
7. History of significant renal or hepatic insufficiency
8. History of vascular surgery involving femoral vessels on the injection side
9. History of surgical procedures to affected limb that, in the opinion of the Investigator, impact the integrity of the genicular nerves
10. History of arrhythmia or seizures
11. History of low blood pressure or uncontrolled high blood pressure
12. Currently on anticoagulants or antibiotics
13. Active infection
14. Currently taking >40mg of morphine equivalent daily oral dose
15. Severe psychiatric or neurological disease that prevents subject from reporting pain assessment
16. History of local tumor-related disease
17. Pre-existing lower limb neurology that, in the opinion of the Investigator, impairs assessment of safety and/or pain
18. History of systemic inflammatory conditions such as rheumatoid arthritis
19. Previous recipient of cryoneurolysis, thermal or pulsed radiofrequency ablation, or phenol injection for the knee
20. Use of hyaluronic acid, prolotherapy, autologous blood, or platelet rich plasma injections within the previous 30 days
21. Injection of corticosteroid within the previous 3 months
22. Difficulty comprehending health status/pain questionnaires
23. Subjects who may not be able to cooperate with post-injection follow-ups/regimen
24. A history of medical conditions that would hamper block or be exacerbated by block (i.e. medical conditions requiring blood thinners; poorly managed diabetes/diabetic neuropathy; alcohol or drug addiction, COPD; etc.)
25. Known contraindication to use of a regional block
26. Pregnant/breastfeeding persons
27. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the subject or the quality of study data
28. Participation in any clinical study of an investigational product within 30 days prior to enrollment and through completion of study participation
29. No scheduled surgeries until all study visits are completed (3 months)


Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Subjects 1-8 will receive the block (injection) with a tourniquet to the leg (blood pressure cuff) and ice pack prior to procedure. Subjects 9-16 will receive the block without the addition of tourniquet or ice pack.
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Safety endpoints analysis will be performed as part of the primary endpoint analysis. Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages will be provided per treatment group of subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing premature discontinuation.

Device safety will be assessed and tabulated according to the following parameters:
• Assessment of sensory blockade identified through subject diaries
• Monitoring for preservation of motor function of the lower limb
• Monitoring for preservation of activities of daily living (ADLs)
• Monitoring for severe or progressive inflammation, redness, swelling, discharge, bruising, or discoloration at the injection site
• Monitoring for severe or progressive pain at the injection site
• Monitoring vitals, and watching for fever, chills, nausea, or vomiting
• Monitoring for bowel or bladder dysfunction (i.e. inability to pass stool or urinate, or difficulty controlling either)
• Monitoring for severe discomfort, pain, or loss of blood circulation associated with tourniquet use
• Assessment of capillary refill
• Clinical laboratory testing
• Adverse event (AE) query (reported, elicited, and observed)

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/06/2022
Actual
Date of last participant enrolment
Anticipated
1/12/2022
Actual
Date of last data collection
Anticipated
1/03/2023
Actual
Sample size
Target
16
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 20988 0
Frankston Pain Management - Frankston
Recruitment postcode(s) [1] 35819 0
3199 - Frankston

Funding & Sponsors
Funding source category [1] 309415 0
Commercial sector/Industry
Name [1] 309415 0
Brixton Biosciences Inc.
Country [1] 309415 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Brixton Biosciences Pty Ltd
Address
Brixton Biosciences Pty Ltd
Studio 4, 9 Mogo Place
Billinudgel NSW 2483
Country
Australia
Secondary sponsor category [1] 310385 0
None
Name [1] 310385 0
N/A
Address [1] 310385 0
N/A
Country [1] 310385 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309218 0
St. Vincent's Hospital-Melbourne HREC
Ethics committee address [1] 309218 0
Ethics committee country [1] 309218 0
Australia
Date submitted for ethics approval [1] 309218 0
04/04/2022
Approval date [1] 309218 0
17/05/2022
Ethics approval number [1] 309218 0
HREC D 065/22; Project ID number 85750

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113382 0
Dr Murray Taverner
Address 113382 0
Frankston Pain Management
Suite 7, 20 Clarendon Street
Frankston VIC. 3199
Country 113382 0
Australia
Phone 113382 0
+61 3 9770 0522
Fax 113382 0
N/A
Email 113382 0
[email protected]
Contact person for public queries
Name 113383 0
Lori T. Gilmartin
Address 113383 0
Brixton Biosciences
1 Mifflin Place, Suite 320
Cambridge, MA. 02138
Country 113383 0
United States of America
Phone 113383 0
+1 781 4131643
Fax 113383 0
+1 866 3608031
Email 113383 0
[email protected]
Contact person for scientific queries
Name 113384 0
Anh L. Ngo
Address 113384 0
Brixton Biosciences
1 Mifflin Place, Suite 320
Cambridge, MA. 02138
Country 113384 0
United States of America
Phone 113384 0
+1 702 3508080
Fax 113384 0
N/A
Email 113384 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a first in human subject study that is designed for initial review of safety.


What supporting documents are/will be available?

No Supporting Document Provided



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