Efficacy of Amniotic Suspension Allograft in Patients with Osteoarthritis of the Knee

This study is being conducted to evaluate the efficacy and safety of ASA compared to placebo in the management of osteoarthritis (OA) symptoms of the knee.

This is a prospective, multicenter, randomized, double-blind, placebo-controlled Phase 3 study of ASA in patients with OA of the knee. Initially, 474 subjects are planned for inclusion in this study using a group sequential design with two interim analyses and a final analysis. Sample size re-estimation is planned at the second interim analysis. Based on conditional power, the maximum sample size may be increased to up to 700 patients. Patients will be randomly assigned in a 1:1 ratio to receive a single intra-articular (IA) injection of 2 mL of ASA (plus 2 mL of normal saline) or 4 mL of normal saline.

Patients will be screened after informed consent is obtained. Eligible patients will be randomized to receive a single IA injection on Day 1. They will have serial assessments of knee pain, function, and symptoms scores, as well as safety assessments for up to 52 weeks after administration of the study drug.

The planned sequence and maximum duration of the study periods will be as follows:

* Screening: 2 weeks
* Treatment: 1 day
* Follow-up: 52 weeks

The maximum treatment duration for each patient is 1 day.

The maximum study duration for each patient is 54 weeks.

Efficacy will be assessed via Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responder rates.

Safety will be assessed via monitoring of adverse events (AEs), safety laboratory testing, vital signs, physical examination, and concomitant medication use.

An independent data monitoring committee (DMC) with a defined charter will review study data and make preliminary decisions relative to interim analyses.

The assessments that are used in this study are standard, and are generally recognized as reliable, accurate, and relevant.

No pediatric patients will be included as OA of the knee is an age-related disorder and rarely occurs in patients under the age of 18 years. The sponsor plans to submit a waiver for studies in all pediatric age subgroups.

Eligibility Criteria:
Inclusion Criteria:

1. Males or females 18 years of age or older
2. Diagnosis of OA of the knee by a combination of clinical and radiographic findings
3. OA of the knee with Kellgren and Lawrence radiographic classification (Grade 2-4 inclusive) confirmed by posterior-anterior, weight-bearing, fixed flexion radiography with 10° caudal beam angulation. A specially designed positioning frame will be used to standardize the positioning for image acquisition.
4. Patients who have failed to adequately respond for at least 6 months to at least 2 OA therapies that include conservative, non-pharmacological therapy and simple analgesics (e.g., acetaminophen); nonsteroidal anti-inflammatory drugs (NSAIDS); avoidance of activities that cause joint pain; exercise; weight loss; physical therapy; and removal of excess fluid from the knee
5. Overall pain score over the previous 7 days of 11 or more on the WOMAC Pain scale.
6. Body mass index (BMI) \< 40 kg/m²
7. If female, must be postmenopausal (for at least 2 years), surgically sterilized (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), sexually abstinent, or willing and able to use 2 methods of contraception from Day 1 through 12 months after treatment
8. Males who are not surgically sterile (vasectomy) for at least 6 months prior to screening must confirm their willingness to use adequate methods of contraception from Day 1 through 12 months after treatment
9. Willing to agree not to use illicit drugs during the study, and to have illicit drug testing at screening and at later time points, if illicit drug use is suspected during the study
10. Able to comply with study requirements and complete the full sequence of protocol-related procedures and evaluations, including post-hospitalization, out-patient, and follow-up visits
11. Able to understand and provide written informed consent

Exclusion Criteria:

1. Use of pain medication (including NSAIDs and cannabidiol \[CBD\] oil) less than 15 days before treatment (acetaminophen allowed)
2. Regular use of anticoagulants
3. Symptoms of locking, intermittent block to range of motion, or loose body sensation that could indicate meniscal displacement or an IA loose body
4. Corticosteroid injection into the index knee within 3 months prior to screening
5. Viscosupplement (e.g., hyaluronic acid \[HA\]) injection, platelet-rich plasma injection, bone marrow aspirate (BMA) or bone marrow aspiration concentrate (BMAC), placental-derived tissue/cells, adipose tissue, or any other autologous or allogeneic product into the index knee within 6 months prior to screening
6. Patients with known hypersensitivity reactions to ASA or any of its constituents (e.g., HA, dimethyl sulfoxide \[DMSO\])
7. Knee surgery on the index knee within 12 months prior to screening and/or planned knee surgery during the study
8. Knee surgery on the contralateral knee within 6 months prior to screening and/or planned knee surgery during the study
9. Acute index knee trauma within 3 months prior to screening
10. Knee effusion requiring aspiration of the index or contralateral knee within 3 months prior to screening
11. Contralateral knee pain ≥ 4 on the WOMAC Pain scale on most days during the past week.
12. Current therapy with any immunosuppressive therapy, including corticosteroids (\> 5 mg/day of prednisone)
13. Clinically significant findings on the screening laboratory tests or physical examination that are not specific to OA of the knee and may interfere with study conduct or interpretation of data or increase patient risk
14. Clinically significant intercurrent illness, medical condition, non-knee pain, or medical history (including neurological or mental illness, human immunodeficiency virus, fibromyalgia, complex regional pain syndrome, or any active infection, including hepatitis B or C) that could jeopardize the patient safety, limit participation, or compromise interpretation of data derived from the patient
15. Active alcohol or substance use disorder, or any other reason that would make it unlikely for the patient to comply with study procedures
16. Females who are pregnant (positive pregnancy test at screening or prior to treatment) or lactating
17. Participation in another clinical trial within the 30 days (or 5 half-lives of the investigational compound, whichever is longer) before screening