A Phase 1 Study of Intraoperative Administration of CA-008 for the Correction of Hallux Valgus Deformity

This is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, sequential-group Phase 1 study. The study will be conducted utilizing a cohort design, with sequential groups of 8 subjects. Within each dose cohort, 6 subjects will be randomized to active, and 2 will be randomized to placebo.

This is a single-center, randomized, double-blind, placebo-controlled, single ascending dose, sequential-group Phase 1 study.

The study will be conducted utilizing a cohort design, with sequential groups of 8 subjects. Within each dose cohort, 6 subjects will be randomized to active, and 2 will be randomized to placebo. Placebo patients from each cohort were pooled for analysis. The initial cohort will receive the lowest planned dose of CA-008, and sequential cohorts will receive escalating doses of CA-008 in a fixed volume of administration. There will be at least a 6-day period between cohorts, in order to ensure a minimum of 3 days to review safety data from the last subject in a cohort and to allow the meeting of the Data Monitoring Committee (DMC) to review the safety data from the entire cohort prior to a making decision for dose escalation. Dose escalation rules will be protocol defined.

Subjects will be undergoing unilateral transpositional first metatarsal osteotomy for the correction of hallux valgus deformity (bunionectomy). In accordance with standard of care, subjects will receive regional anesthesia (MAYO block) with 0.5% bupivacaine. Prior to wound closure, 10 mL of study drug will be injected into the soft tissues and periosteum of the surgical site.

After the surgery, subjects will be monitored for 48 hours at the trial site. Safety and efficacy evaluations will be performed as described herein. Subjects will be required to meet certain pre-specified criteria prior to discharge.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female aged 18 - 65 years old, inclusive.
2. Planning to undergo a primary unilateral first metatarsal bunionectomy repair, without collateral procedures.
3. Be American Society of Anesthesiology (ASA) physical Class 1 or 2.
4. In good health and capable of undergoing a bunionectomy under regional anesthesia.
5. No additional planned surgeries other than a bunionectomy during the course of the study.
6. Male subjects must be either sterile (surgically or biologically), or commit to an acceptable method of birth control while participating in the study.
7. Female subjects are eligible only if all of the following apply:

   1. Not pregnant (female subject of child bearing potential must have a negative serum pregnancy tests at screening and negative urine pregnancy test before surgery);
   2. Not lactating;
   3. Not planning to become pregnant during the study;
   4. Be surgically sterile; or at least two years post-menopausal; or have a monogamous partner who is surgically sterile; or is practicing double-barrier contraception; or practicing abstinence (must agree to use double-barrier contraception in the event of sexual activity); or using an insertable, injectable, transdermal, or combination oral contraceptive approved by the FDA for greater than 2 months prior to screening visits and commits to the use of an acceptable form of birth control for the duration of the study and for 30 days from completion of the study.
8. Have a body mass index ≤ 35 kg/m2.
9. Willing and able to sign the informed consent form (ICF) approved by the Institutional Review Board (IRB).
10. Willing and able to complete the study procedures and pain scales, and to communicate meaningfully in English with study personnel.

Exclusion Criteria:

1. Subjects with a history of hypertension, cardiovascular disease and a history of cerebrovascular events.
2. Subjects with concurrent painful conditions that may require analgesic treatment during the study period, or, in the opinion of the Investigator, may confound post-operative pain assessments.
3. Have been receiving or have received chronic opioid therapy defined as greater than 15 morphine equivalents units per day for greater than 3 out of 7 days per week over a one-month period within 12 months of study treatment initiation.
4. Have a known allergy or intolerance to the following medications or related substances: capsaicin, chili peppers, propofol, bupivacaine, benzodiazepines, midazolam, oxycodone, or ondansetron.
5. Have a clinically significant abnormal clinical laboratory test value according to the judgment of the investigator.
6. Have, as determined by the investigator or the study's medical monitor, a history or clinical manifestations of significant renal, hepatic, cardiovascular, metabolic, neurologic, psychiatric, or other condition that would preclude participation in the study.
7. Use concurrent therapy that could interfere with the evaluation of efficacy or safety, such as any drugs which, in the investigator's opinion, may exert significant analgesic properties or act synergistically with CA-008.
8. Use of disallowed pain medications within 2 days prior to Day 1 (NSAIDs, COX-2 inhibitors, tramadol, ketamine, clonidine, gabapentin, pregabalin, or cannabinoids).
9. Use of central nervous system (CNS) active drugs such as benzodiazepines, tricyclic antidepressants, SNRIs, or SSRIs for pain within seven days prior to Day 1. These drugs are permitted for non-pain indications if the dose has been stable for at least 30 days prior to Day 1 and is planned to remain stable throughout the study. The use of lorazepam and other sleep medications, except those containing analgesic properties, is permitted.
10. Have evidence of a clinically significant 12-lead ECG abnormality according to the judgment of the investigator, including QTcF \>450 for men and \>470 for women.
11. Use of dietary supplements or over-the-counter (OTC) medications containing significant amounts of capsaicin within 1 day prior to Day 1, and throughout the hospitalization period.
12. Subjects with active cutaneous disease, or other disease, at the anticipated site of surgery.
13. History of peripheral vascular disease, sickle cell disease, vascular grafts, or vasospastic disorders.
14. Use of parenteral or oral corticosteroid(s) within 14 days prior to Day 1.
15. Known bleeding disorder or is taking agents affecting coagulation preoperatively. Deep venous thrombosis (DVT) prophylaxis of the surgeon's choice is permitted postoperatively.
16. A medical condition that in the investigator's opinion could adversely impact the subject's participation or safety, conduct of the study, or interfere with the pain assessments.
17. Diabetes mellitus.
18. Use of antihypertensive agent or diabetic regimen at a dose that has not been stable for at least 30 days, or which is not expected to remain stable throughout the study.
19. Use of digoxin, warfarin (see exception below), lithium, theophylline preparations, aminoglycosides, and all antiarrhythmics except beta-blockers, and use of anticonvulsants except benzodiazepines within 7 days prior to Day 1 and throughout the study. (Use of warfarin is allowed, at the investigator's discretion, for DVT prophylaxis after the surgery).
20. History of illicit drug use, or prescription medicine or alcohol abuse (regularly drinks \> 4 units of alcohol per day; 8 oz. beer, 3 oz. wine, 1 oz. spirits) within the past 2 years, in the opinion of the Investigator.
21. Have positive results on the alcohol breath test indicative of alcohol abuse or urine drug screen indicative of illicit drug use (unless results can be explained by a current prescription or acceptable over-the-counter medication at screening as determined by the investigator) at screening, and/or prior to surgery.
22. Stable medication regimen for at least 14 days prior to the scheduled bunionectomy procedure, within 5 half-lives of the specific prior medication (or, if half-life is not known, within 48 hours) before dosing with study medication.
23. Participated in another clinical trial or used an investigational product within 30 days or five half-lives (whichever is longer) prior to the planned bunionectomy surgery, or is scheduled to receive an investigational product other than CA-008 while participating in the study.
24. Previously participated in a clinical study with CA-008 or capsaicin.
25. Subjects with peripheral neuropathies which would potentially confound the planned neurosensory testing.
26. Any past or current medical condition that in opinion of investigator, puts subject at undue safety risk for surgical complications or for use of the investigational product.
27. Subjects who donated blood or plasma within the 30 days prior to screening.