Treatment Of Knee Osteoarthritis With Intra-Articular Infliximab

This is an unbalanced randomized, double-blind pilot study of Infliximab (100 mg), placebo
(100 mg) and Methylprednisolone acetate (80 mg). A total of 16 subjects will be randomized; 8
subjects will be randomized to receive infliximab, 4 subjects will be randomized to receive
placebo and 4 additional subjects will be randomized to receive Methylprednisolone acetate.
Subjects will be seen at screening, day 0, day 14, day 28 and day 56. After study drug
injection at day 0, patients will return for follow-up visits at approximately 2 weeks, 1 and
2 months in order to obtain clinical endpoint measures for a total of 10 weeks. Outcome
measures include blood tests, MRI, ultrasound, synovial lining tissue biopsy questionnaires
and adverse events.

Inclusion Criteria:

1. Adults ≥ age 35 but ≤ age 85.

2. Painful knees for 3-60 months.

3. VAS joint pain score greater than 30 mm (scale 0-100)

4. Knee radiograph showing minimal to moderate change (early OA).

5. No NSAID therapy for at least one week.

6. Have the capacity to understand and sign an informed consent form.

7. Gender: Male or female

8. Women must be postmenopausal (no menstrual period for a minimum of 1 year) or
surgically sterilized and have a negative serum pregnancy test on entry in the study.
Men must agree to use adequate birth control during the study for 6 months after the
infusion of study agent.

9. Men and women of childbearing potential must use adequate birth control measures
(e.g., abstinence, oral contraceptives, intrauterine device, barrier method with
spermicide, implantable or injectable contraceptives or surgical sterilization) for
the duration of the study and should continue such precautions for 6 months after
receiving the last infusion.

10. The screening laboratory test results must meet the following criteria

1. WBC (white blood cell count): >3.5/uL

2. Hemoglobin: > 10 gm/dl

3. Platelets: > 100,000/ul

4. Serum Creatinine: < 1.8

5. SGPT (ALT - alanine aminotransferase) <3 times ULN

6. UA (urinalysis) with microscopic exam: WNL

7. Negative tests for HbsAg or hepatitis C Ab

8. PT/PTT: WNL

11. Are considered eligible according to the following TB screening criteria:

1. Have no history of latent or active TB prior to screening. An exception is made
for subjects who have a history of latent TB (defined for the purposes of this
study as having had a positive result from either the tuberculin skin test or the
QuantiFERON-TB Gold test prior to screening) and documentation of having
completed an adequate treatment regimen for latent TB within 3 years prior to the
first administration of study agent under this protocol. Adequate treatment for
latent TB is defined according to local country guidelines for immunocompromised
patients. If no local guidelines for immunocompromised patients exist, US
guidelines must be followed. It is the responsibility of the investigator to
verify the adequacy of previous anti-TB treatment and provide appropriate
documentation.

2. Have no signs or symptoms suggestive of active TB upon medical history and/or
physical examination.

3. Have had no recent close contact with a person with active TB or, if there has
been such contact, will be referred to a physician specializing in TB to undergo
additional evaluation and, if warranted, receive appropriate treatment for latent
TB prior to or simultaneously with the first administration of study agent.

4. Within 1 month prior to the first administration of study agent, either have
negative diagnostic TB test results (defined as both a negative tuberculin skin
test and a negative QuantiFERON-TB Gold test, as outlined in Attachment 3 and
Attachment 4, respectively), or have a newly identified positive diagnostic TB
test result (defined as either a positive tuberculin skin test or a positive
QuantiFERON-TB Gold test) during screening in which active TB has been ruled out
and for which appropriate treatment for latent TB has been initiated either prior
to or simultaneously with the first administration of study agent. The tuberculin
skin test and QuantiFERON-TB Gold test are not required at screening for subjects
with a history of latent TB and documentation of having completed adequate
treatment as described in Inclusion Criterion 12a. Furthermore, these subjects
are not required to initiate additional treatment for latent TB.

5. Have a chest radiograph (both posterior-anterior and lateral views), taken within
3 months prior to the first administration of study agent and read by a qualified
radiologist, with no evidence of current active TB or old inactive TB.

Exclusion Criteria:

1. Moderate to Severe OA, as determined by severe joint space narrowing (Kellgren grade
IV) (7) in medial and lateral compartments

2. Insulin-dependent diabetes mellitus.

3. Systemic inflammatory illness, e.g. rheumatoid arthritis.

4. Intra-articular injections within 3 months.

5. Prior treatment with infliximab or other anti-TNF drug.

6. Acute injury to knees (< 2 weeks)

7. Women who are pregnant, nursing, or planning pregnancy within 6 months after the last
infusion (this includes father's who plan on fathering a child within 6 months after
their last infusion).

8. Have had any previous treatment with monoclonal antibodies or antibody fragments.

9. History of receiving human/murine recombinant products or a known allergy to murine
products. A known allergy to murine product is definitely an exclusion criterion

10. Documentation of a positive test for hepatitis B surface antigen or hepatitis C.

11. Have a history of alcohol or substance abuse within the preceding 6 months that, in
the opinion of the investigator, may increase the risks associated with study
participation or study agent administration, or may interfere with interpretation of
results.

12. Have a known history of serious infections (e.g., hepatitis, pneumonia, or
pyelonephritis) in the previous 3 months.

13. Have or have had an opportunistic infection (e.g., herpes zoster [shingles],
cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or mycobacteria
other than TB) within 6 months prior to screening

14. Currently receiving Coumadin, Ticlid, Plavix, or heparin/heparin analog within 7 days
prior to synovial biopsy.

15. Currently receiving aspirin within 7 days prior to synovial biopsy.

16. Have a chest radiograph at screening that shows evidence of malignancy or infection.

17. Have a history of lymphoproliferative disease, including lymphoma or signs suggestive
of possible lymphoproliferative disease such as lymphadenopathy of unusual size or
location (e.g., nodes in the posterior triangle of the neck, infraclavicular,
epitrochlear, or periaortic area), or splenomegaly.

18. Currently have any known malignancy or have a history of malignancy within the
previous 5 years, with the exception of basal cell or squamous cell carcinoma of the
skin that has been fully excised with no evidence of recurrence as well as carcinoma
in situ of the cervix.

19. Have current signs or symptoms of severe, progressive or uncontrolled renal, hepatic,
hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, or cerebral
disease.

20. Are unable or unwilling to undergo multiple venipunctures because of poor tolerability
or lack of easy access.

21. Use of any investigational drug within 30 days prior to screening or within 5
half-lives of the investigational agent, whichever is longer.

22. Presence of a transplanted solid organ (with the exception of a corneal transplant > 3
months prior to screening).

23. Have a concomitant diagnosis or history of congestive heart failure Grade III-IV.

24. Have had a nontuberculous mycobacterial infection or opportunistic infection (e.g.,
cytomegalovirus, Pneumocystis carinii, and aspergillosis) within 6 months prior to
screening.