Osteoarthritis of the Knee, Inflammation, and the Effect of Adalimumab (OKINADA)

This is a Canadian randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the clinical efficacy and safety of adalimumab versus placebo when used to treat subjects with a diagnosis of osteoarthritis of the knee, and with clinical features of inflammation, whose pain persists despite receiving maximum tolerated doses of conventional therapy.

This is a Canadian randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the clinical efficacy and safety of adalimumab versus placebo when used to treat subjects with a diagnosis of osteoarthritis of the knee, and with clinical features of inflammation, whose pain persists despite receiving maximum tolerated doses of conventional therapy. A total of 100 subjects will be entered into the study.

Subjects will be randomized (1:1) at baseline to receive either adalimumab 40 mg every other week or placebo for 16 weeks. The study drug will be self-administered via subcutaneous injection. Efficacy will be assessed at week 16 while the safety of the study drug will be monitored throughout the study. At week 16 all subjects will begin to receive open label adalimumab 40 mg every other week.

Eligibility Criteria:
Inclusion Criteria:

1. ≥ 40 years of age
2. If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or is of childbearing potential and practicing methods of birth control.
3. If female and of childbearing potential, serum pregnancy results must be negative at Screening
4. Has a diagnosis of Osteoarthritis (OA) of the index knee according to American College of Rheumatology (ACR) criteria, including radiological evidence of OA (Kellgren-Lawrence grades 2 or 3).
5. Subject has had knee pain for at least 1 month prior to the Screening Visit.
6. Subject has had knee pain that has persisted despite conventional treatment, defined as any one of the following medications taken for at least 1 month in the past:

   * acetaminophen (2- 4 grams per day)
   * therapeutic dose range of an NSAID
   * acetaminophen/codeine combination (i.e. Tylenol No. 2, 3, 4) taken at least 3 times daily.
7. Has a pain score of ≥ 4 (0-10 NRS) in the index (more symptomatic) knee at Screening and Baseline.
8. If the subject is taking Analgesic/NSAIDs, then the Analgesic/NSAIDs has been stable for 14 days prior to the Baseline visit.
9. Has clinical evidence of a knee effusion in the index (more symptomatic) knee at Screening and Baseline.
10. Able and willing to self-administer SC injections or has available qualified person(s) to administer SC injections.
11. Has voluntarily signed and dated an approved informed consent form prior to any study-specific procedures.

Exclusion Criteria:

1. Has a history of an allergic reaction or significant sensitivity to constituents of adalimumab.
2. Has other bone and articular diseases (antecedents and/or current signs) such as chondrocalcinosis, Paget's disease of the ipsilateral limb to the target knee, rheumatoid arthritis, aseptic osteonecrosis, gout, septic arthritis, ochronosis, acromegaly, haemochromatosis, Wilson's disease, osteochondromatosis, seronegative spondylo-arthropathy, mixed connective tissue disease, collagen vascular disease, psoriasis, inflammatory bowel disease.
3. Subject has a BMI over 40.
4. Planned/anticipated surgery of the index knee during the study period.
5. Already scheduled for any surgery during the time of the study or within 70 days after the end of treatment.
6. Prior arthroscopic or open surgery of the index knee within 12 months of Baseline.
7. Has a history of cancer or lymphoproliferative disease other than: Successfully and completely treated cervical dysplasia, with no recurrence within the last five years, Basal or Squamous Cell Carcinoma that has been adequately treated or excised.
8. Has had prior treatment with intravenous (IV) immunoglobulin or any investigational agent within 30 days or 5 half-lives of the agent from Baseline, whichever is longer.
9. History of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease (e.g. multiple sclerosis).
10. History of uncontrolled diabetes, unstable ischemic heart disease, active congestive heart failure, New York Heart Association (NHYA) III, IV, inflammatory bowel disease, active peptic ulcer disease, recent stroke (within 12 weeks of Screening), or any other condition, which in the opinion of the investigator, would put the patient at risk by participating in the study.
11. Has concurrent local or systemic infection that would preclude the use of adalimumab.
12. Has had a persistent or severe infection(s) requiring hospitalization or treatment with IV antibiotics within 30 days, or oral antibiotics within 14 days, prior to Baseline.
13. History of active tuberculosis or listeriosis, or other infections suggestive of significant or profound immunosuppression, such as Pneumocystis carinii, aspergillosis or other systemic protozoal or fungal infections.
14. Has latent TB (positive purified protein derivative (PPD) skin test, two-step PPD when applicable, and chest X-ray indicative of TB) or has other risk factors for the activation of latent TB, e.g. previous exposure to TB, and has not initiated TB prophylaxis prior to the first adalimumab treatment.
15. Will be excluded if the Chest x-ray is found to have changes indicative of old healed tuberculous lesion (e.g. calcified nodule, fibrotic scar, apical or basilar pleural thickening etc.).
16. Has a positive serology for Hepatitis B or Hepatitis C that indicates active infection.
17. Has a history of positive HIV status.
18. Currently taking or likely to begin anti-retroviral therapy at any time during the course of the study.
19. Female subject is pregnant or breast-feeding.
20. Has a history of clinically significant drug or alcohol abuse in the last year, prior to Screening.
21. Subject, in the opinion of the principal investigator, is unlikely to comply with the study protocol or is unsuitable for any other reason.

Treatment-Related Exclusion Criteria

1. Subject has received intra-articular injections of steroid and/or hyaluronate compounds into the index knee within 12 weeks prior to Baseline.
2. Subjects using injectable corticosteroids for any medical condition (intra-articular/soft tissue injections are allowed, but not in the target knee).
3. Subjects using indomethacin or oral steroids.
4. Subjects taking glucosamine and/or chondroitin at screening must discontinue or remain on a stable dose, unmodified if at all possible for the entire duration of the study.
5. If treatment for osteoarthritis (NSAID) or osteoporosis (bisphosphonates, selective estrogen receptor modulators) is necessary, it will have to be continued, unmodified if at all possible for the entire duration of the study. If the subject does not wish to continue them during the study, they must be stopped 14 days prior to the Baseline visit.
6. Subjects who have used compounds containing non-approved agents for arthritis or agents claiming to possess disease/structure-modifying properties in the 14 days prior to the Baseline visit (see exception above).
7. Subjects who require acetaminophen at daily doses \> 4000 mg (4 g) on a regular basis.
8. Subjects who are taking lithium carbonate, phenytoin or anticoagulants (with the exception of aspirin up to a maximum daily dose of 325 mg).
9. Subjects who use calcitonin.
10. Subjects who use immunosuppressive drugs. Subjects that are using methotrexate or hydroxychloroquine must withdraw treatment 1 month prior to baseline, to be eligible to enter the study.
11. Topical analgesics and NSAID's cannot be used on the target knee within the 48 hours before each study visit.
12. No new physical modalities of treatment can be introduced and subject must maintain normal activity during the study.