Osteoarthritis of the Knee
Conditions
Keywords
Mild to moderate osteoarthritis of the knee
Brief summary
The purpose of this study is to determine if an anti-inflammatory drug, called infliximab, will reduce inflammation in the synovial lining in patients with an early stage of osteoarthritis of the knee. It will also help determine if the study medication decreases the accumulation of synovial fluid and prevents cartilage breakdown.
Detailed description
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.
Interventions
DRUGInfliximab
the study drug will be injected into the joint through a needle
DRUGPlacebo
the placebo will be injected into the joint through a needle
DRUGStandard of Care: Methylprednisolone acetate
Methylprednisolone acetate will be injected into the joint through a needle
Sponsors
Centocor, Inc.
Herbert Lindsley, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Cellular Infiltrates From Day 0 to Day 28 | Day 0 to Day 28 | Cellular infiltration scored 0 to 3 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Joint Effusions From Day 0 to Day 56 Target Knee | Change from Day 0 to Day 56 | Outcome calculated based on Physician observation of joint swelling from 0-3. A score of 0 = no effusion,1 = positive bulge, 2 = moderate effusion, 3 = tense effusion. The outcome represents the change in means between the two time points. |
| Change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Score Target Knee | Change from Day 0 to Day 56 | The WOMAC questionnaire is used to evaluate the condition of patients with osteoarthritis. Patients answer questions based on how they are feeling. The questionnaire has a total of 24 questions which deal with pain, stiffness and physical function. Participants are asked to respond to how difficult it is for them to do/complete an activity. There is a total possible score of 96. A score of 0 equals no difficulty completing any of the 24 activities. A score of 96 would indicate extreme difficulty with all activities. |
| Change in Levels of Serum IL-6 | Change from Day 0 to Day 56 | — |
| Change in Serum CRP Day 0 to Day 56 | Day 0 to Day 56 | Serum measure of systemic inflammation |
| Change in Serum SAA Levels Day 0 to Day 56 | Day 0 to Day 56 | Serum Amyloid A |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Infliximab Investigational (Infliximab) - 100mg The study drug will be injected into the joint through a needle | 8 |
| Salt Water Placebo (Salt Water) - 10 ml Placebo solution will be injected into the joint through a needle | 4 |
| Methylprednisolone Acetate Methylprednisolone Acetate (Standard of Care: MPA) - Standard of Care: MPA 80mg injected into the joint through a needle | 4 |
| Total | 16 |
Baseline characteristics
| Characteristic | Infliximab | Salt Water | Methylprednisolone Acetate | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 4 Participants | 4 Participants | 15 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Number | 0 Number | 0 Number | 0 Number |
| Race/Ethnicity, Customized Asian | 0 Number | 0 Number | 0 Number | 0 Number |
| Race/Ethnicity, Customized Black or African American | 3 Number | 1 Number | 1 Number | 5 Number |
| Race/Ethnicity, Customized More than one race | 0 Number | 0 Number | 0 Number | 0 Number |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Number | 0 Number | 0 Number | 0 Number |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Number | 0 Number | 0 Number | 0 Number |
| Race/Ethnicity, Customized White | 5 Number | 3 Number | 3 Number | 11 Number |
| Region of Enrollment United States | 8 participants | 4 participants | 4 participants | 16 participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 8 | 1 / 4 | 2 / 4 |
| serious Total, serious adverse events | 0 / 8 | 0 / 4 | 0 / 4 |
Outcome results
Primary
Change in Cellular Infiltrates From Day 0 to Day 28
Cellular infiltration scored 0 to 3
Time frame: Day 0 to Day 28
Population: In the MPA arm, one subject was excluded from the analysis because their biopsy sample was of insufficient quantity to be processed in the lab.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Infliximab | Change in Cellular Infiltrates From Day 0 to Day 28 | Increased cellularity | 4 Participants |
| Infliximab | Change in Cellular Infiltrates From Day 0 to Day 28 | Decreased cellularity | 2 Participants |
| Infliximab | Change in Cellular Infiltrates From Day 0 to Day 28 | Unchanged cellularity | 2 Participants |
| Salt Water | Change in Cellular Infiltrates From Day 0 to Day 28 | Increased cellularity | 2 Participants |
| Salt Water | Change in Cellular Infiltrates From Day 0 to Day 28 | Decreased cellularity | 0 Participants |
| Salt Water | Change in Cellular Infiltrates From Day 0 to Day 28 | Unchanged cellularity | 2 Participants |
| Methylprednisolone Acetate | Change in Cellular Infiltrates From Day 0 to Day 28 | Decreased cellularity | 2 Participants |
| Methylprednisolone Acetate | Change in Cellular Infiltrates From Day 0 to Day 28 | Unchanged cellularity | 1 Participants |
| Methylprednisolone Acetate | Change in Cellular Infiltrates From Day 0 to Day 28 | Increased cellularity | 0 Participants |
Secondary
Change in Joint Effusions From Day 0 to Day 56 Target Knee
Outcome calculated based on Physician observation of joint swelling from 0-3. A score of 0 = no effusion,1 = positive bulge, 2 = moderate effusion, 3 = tense effusion. The outcome represents the change in means between the two time points.
Time frame: Change from Day 0 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change in Joint Effusions From Day 0 to Day 56 Target Knee | 0.3 units on a scale | Standard Deviation 0.5 |
| Salt Water | Change in Joint Effusions From Day 0 to Day 56 Target Knee | 0.0 units on a scale | Standard Deviation 0 |
| Methylprednisolone Acetate | Change in Joint Effusions From Day 0 to Day 56 Target Knee | 0.0 units on a scale | Standard Deviation 0 |
Secondary
Change in Levels of Serum IL-6
Time frame: Change from Day 0 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change in Levels of Serum IL-6 | -0.4 pg/ml | Standard Deviation 2 |
| Salt Water | Change in Levels of Serum IL-6 | 8.1 pg/ml | Standard Deviation 13 |
| Methylprednisolone Acetate | Change in Levels of Serum IL-6 | 5.5 pg/ml | Standard Deviation 9.5 |
Secondary
Change in Serum CRP Day 0 to Day 56
Serum measure of systemic inflammation
Time frame: Day 0 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change in Serum CRP Day 0 to Day 56 | -0.18 mg/dl | Standard Deviation 0.37 |
| Salt Water | Change in Serum CRP Day 0 to Day 56 | -0.15 mg/dl | Standard Deviation 0.3 |
| Methylprednisolone Acetate | Change in Serum CRP Day 0 to Day 56 | 0.08 mg/dl | Standard Deviation 0.81 |
Secondary
Change in Serum SAA Levels Day 0 to Day 56
Serum Amyloid A
Time frame: Day 0 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change in Serum SAA Levels Day 0 to Day 56 | -1.0 ug/ml | Standard Deviation 2256 |
| Salt Water | Change in Serum SAA Levels Day 0 to Day 56 | -715.6 ug/ml | Standard Deviation 1043 |
| Methylprednisolone Acetate | Change in Serum SAA Levels Day 0 to Day 56 | -1580.2 ug/ml | Standard Deviation 4819 |
Secondary
Change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Score Target Knee
The WOMAC questionnaire is used to evaluate the condition of patients with osteoarthritis. Patients answer questions based on how they are feeling. The questionnaire has a total of 24 questions which deal with pain, stiffness and physical function. Participants are asked to respond to how difficult it is for them to do/complete an activity. There is a total possible score of 96. A score of 0 equals no difficulty completing any of the 24 activities. A score of 96 would indicate extreme difficulty with all activities.
Time frame: Change from Day 0 to Day 56
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab | Change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Score Target Knee | -25.9 units on a scale | Standard Deviation 18.1 |
| Salt Water | Change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Score Target Knee | -9.3 units on a scale | Standard Deviation 27.2 |
| Methylprednisolone Acetate | Change in the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Score Target Knee | 2.0 units on a scale | Standard Deviation 5.8 |