Efficacy and Safety of ELIXCYTE Intra-articular Injection in Subject With Knee Osteoarthritis

This is a Phase III, double-blinded, placebo-controlled, multicenter study to investigate the efficacy and safety of a new study intervention, ELIXCYTE, compared to placebo (normal saline) in subjects with knee osteoarthritis. The primary hypothesis of the study is to demonstrate that ELIXCYTE is superior to placebo (saline) in improving knee pain on the target knee from baseline.

During the study, each participant will receive either ELIXCYTE (study intervention) or placebo (normal saline) intra-articular injection once on the target knee after eligibility criteria check. The target knee will be assessed by X-ray, MRI and subject self-evaluation knee questionnaires (WOMAC, KSS and KOOS) in the following visits. Other safety assessments, including lab test, physical examination, vital sign, medical/medication history and adverse events will also be collected throughout the study.

This Phase III study is a prospective, double-blind, parallel, multicenter, 2-arm study to evaluate the efficacy and safety of intra-articular ELIXCYTE injection compared to placebo in subjects with knee OA. All the subjects will be enrolled in Taiwan. Subjects aged 40 to 80 years with knee OA will be enrolled in the study. Approximately 165 eligible subjects will be randomized to receive either ELIXCYTE, or placebo in a 2:1 ratio.

The target population will be composed of subjects with unilateral or bilateral knee OA. For subjects with bilateral OA knees, only the knee with more severe symptoms will be selected as the target knee, while the non-target knee can continue the regular local treatment for ethical consideration. If the severities of the OA symptoms will be the same for both knees, the knee with more pain should be selected based on the WOMAC pain score. Eligible subjects will be randomized into one of the study groups (ELIXCYTE, or placebo in a 2:1 ratio).

The study consists of 9 visits and the duration per subject will be approximately 50 weeks (14 days of screening period, a treatment visit on Day 1, and 48 weeks of evaluation period). Unscheduled visit(s) may be arranged when deem necessary by the investigator.

In addition, if ELIXCYTE provided medical benefits with no safety issues to ELIXCYTE group at the end of week 48, subjects assigned to placebo group will be offered a treatment with ELIXCYTE under an extension study after study unblinding.

Eligibility Criteria:
Inclusion Criteria:

A subject is eligible for the study if all of the following apply:

1. Either gender, aged 40 to 80
2. With unilateral/bilateral knee OA of Kellgren-Lawrence grading II-III (determined by American College of Rheumatology criteria of knee OA).
3. WOMAC pain score of 7 - 17 in the target knee even if treated with chronic doses of NSAID.
4. Has received conventional therapies for knee OA (e.g., analgesic administration or physical therapy) for more than 3 months but the symptoms have not relieved.
5. Unwilling or not suitable to undergo knee surgery (including total knee replacement and knee arthroplasty).
6. Understands and has signed the informed consent form.
7. With adequate hematological indices:

   * White blood cell (WBC) ≥ 3,000/mm3
   * Platelet count ≥ 80,000/μL
8. With adequate coagulation indices: Prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) ≤ 1.5 times the upper limit of the normal range (ULN).
9. With adequate liver function where serum total bilirubin ≤ 1.5 times ULN, aspartate aminotransferase (AST) ≤ 3 times ULN, and alanine aminotransferase (ALT) ≤ 3 times ULN.
10. Has an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2, calculated by the Modification of Diet in Renal Disease (MDRD) equation.

Exclusion Criteria:

Any subject meeting any of the exclusion criteria will be excluded from study participation.

1. With previous surgery of articular fracture, ligament reconstruction, meniscal reconstruction, and knee arthroplasty on the target knee joint.
2. With any IA intervention of the target knee within 3 months prior to screening (e.g. steroid, anesthetic). But, sodium hyaluronate by IA intervention of the target knee within 6 months prior to screening.
3. Administered systemic anti-inflammatory drugs (e.g. non-steroidal anti-inflammatory drug or steroid) or topical anti-inflammatory drugs on the target knee within 7 days prior to screening. A subject requiring routine use of low-dose Aspirin for preventing thrombosis (≤ 100 mg/day) will not be excluded from this study.
4. Administered local immunosuppressive agent, local anti-inflammatory drug, local steroid, local analgesics, over-the-counter medications contain analgesics, herbal, homeopathic, or naturopathic remedies for knee OA within 2 weeks prior to screening.
5. Has participated in other investigational studies within 4 weeks prior to screening.
6. Administered monoamine oxidase inhibitor, selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitors, benzodiazepine, or tricyclic antidepressants within 4 weeks prior to screening.
7. With joint diseases expect knee OA that is considered not eligible to enter the study by the investigator.
8. Systemic diseases that may affect joints, including but not limited to inflammatory joint diseases, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.
9. Known or suspected infection around the target knee joint.
10. Has serious medical conditions or ongoing disease (e.g. concomitant illness such as cardiovascular (e.g. New York Heart Association grade III or IV), hepatic (e.g. Child-Pugh Class C), psychiatric condition, alcoholism, drug abuse), medical history, physical findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely affect the safety of the subject.
11. With any evidence of malignant disease with a life expectancy less than 1 year.
12. With a known history of human immunodeficiency virus (HIV) infection.
13. With a known history of alcohol abuse.
14. With a known history of opioid dependent.
15. Known or suspected hypersensitivity to any ingredients of the investigational product (ELIXCYTE) or contrast medium for magnetic resonance imaging (MRI).
16. Body mass index (BMI) ≥ 35 kg/m2
17. Judged to be not applicable to this study by investigator such as the difficulty of follow-up observation.
18. Has claustrophobia and/or cannot take MRI test.
19. Has any existing active/inactive implanted medical devices, such as a cardiac pacemaker, cochlear, intracranial vascular clips, or neurostimulator, etc.
20. Has any existing metallic intraocular foreign body.
21. Female subject of childbearing potential who:

    * Is lactating; or
    * Has positive pregnancy test result at eligibility checking; or
    * Refuses to adopt at least one form of birth control from signing informed consent to the end of the study.
22. Male subject with female spouse/partner who is of childbearing potential refuses to adopt at least one form of birth control from signing informed consent to the end of the study.
23. Known allergy to acetaminophen and tramadol.
24. Has any abnormal radiographic evidence of target knee, such as excessive malalignment, other arthropathies, or systemic metabolic bone disease, etc.
25. Known any contraindication to IA intervention of the target knee, such as skin infection of injection site, coagulopathy, or routine use of anticoagulant, etc.

For exclusion criteria #21 and #22, acceptable forms of birth control include:

* Established use of oral, injected, or implanted hormonal methods of contraception.
* Placement of an intrauterine device (IUD) or intrauterine system (IUS).
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps).