This was a double-blind, randomized, placebo-controlled, single-dose escalation safety study consisting of 4 dosing cohorts. Each cohort was to consist of 8 treated participants, with treatment allocation in a 3:1 active to placebo ratio.
The study was conducted at three sites in the US; 2 sites in Boston, Massachusetts and one in Chapel Hill, North Carolina. The local Human Research Ethics Committee at each site approved the study and all participants provided written informed consent. The study was prospectively registered with the NIH Clinical Trials Registry NCT00456157.
To be eligible for study participation, a patient had to meet all of the following criteria:
1. Ambulatory persons with OA of the knee with symptoms for at least 6 months and pain on the majority of days in the last 30 days. In participants with bilateral knee OA, the more symptomatic knee was the index knee.
2. Age > 40 years
3. A minimal score of >8 and <16 out of 20 for the WOMAC pain subscale in the index knee at the screening visit after a 2 day NSAID/analgesic washout period. Participants could take acetaminophen up to 1.0 gram every 6 hours.
4. Radiographic evidence on PA and lateral standing, flexed x-rays of at least one osteophyte.
1. Concurrent medical or arthritic conditions that could interfere with evaluation of the index knee joint, including fibromyalgia.
2. Participant has received arthroscopic or open surgery to the index joint within 6 months of study start.
3. Corticosteroid, hyaluronic acid or other intraarticular injection within 3 months of study start.
4. Use of chondroitin and/or glucosamine within 4 weeks of study start.
5. History of Reiter's syndrome, rheumatoid arthritis, psoriatic arthritis, ankylosing
spondylitis, lymphoma, arthritis associated with inflammatory bowel disease, sarcoidosis or amyloidosis.
6. Clinical signs and symptoms of active knee infection or crystal disease.
7. Clinically significant cardiac disease.
8. Have an increased predisposition for the development of infections.
9. History of malignancy, with the exception of resected basal cell carcinoma, squamous cell carcinoma of the skin, or resected cervical atypia or carcinoma in situ.
10. More significant pain from the back or the hip than the knee.
11. Skin breakdown at the knee where the injection would take place.
12. Planned knee replacement during the study period.
13. For participants undergoing MRI, the presence of contraindications to having an MRI at the specific imaging facility.
14. For participants undergoing MRI, the presence of chronic renal failure defined by a calculated Creatinine Clearance (CrCl) of < 60 mL/min using the Cockcroft-Gault estimate for GFR as follows: CrCl = (140-age [yrs]) × weight [kg]/serum creatinine [mg/dL] × 72 with female gender adjustment (CrCl female = CrCl × 0.85).
15. For participants undergoing MRI, known allergy to gadolinium contrast material.
16. Having known or clinically suspected infection with human immunodeficiency virus (HIV), hepatitis C or B viruses.
17. Having participated within 30 days or will participate concurrently in another investigational drug or vaccine study.
18. Has a history of drug or alcohol dependence in the past 3 years.
19. Known sensitivity to lidocaine or BMP-7.
20. Female with reproductive capability.
21. Prior use of a bone morphogenetic protein.
Participants who met all of the inclusion criteria and none of the exclusion criteria were randomized into the first cohort of 8 participants to receive either 1.0 mL lactose (placebo) (2 participants) or 1.0 mL containing 0.03 mg of BMP-7(6 participants) intraarticularly in an outpatient setting on Day 1. Dose selection was based upon preclinical studies in animals. After an observation period of at least 1 hour, participants were released and contacted via telephone on Day 2 to query for adverse events (AEs) and concomitant medications. Additional follow-up visits were on Days 7, 14, 28, 56, 84 and 168. We did not see participants on Day 2 however all participants were seen by a physician who performed the physical examination at each of the listed visits. After the first and subsequent cohorts of 8 participants each completed through Day 28, the data were reviewed by the Safety Committee (an independent monitor, Principal Investigators from each site and the Study Sponsor) and when deemed appropriate, the next cohort of 8 participants was treated with the next highest dose of BMP-7. The pre-planned dose escalation was 0.03, 0.1, 0.3 and 1.0 mg BMP-7 intra-articularly. Each cohort was randomized in a 3:1 treatment-to-lactose (placebo) ratio.
Randomization to lactose (placebo) or study drug was handled by a call-in randomization process. The investigational pharmacist was unblinded to study drug assignment. Preparation of study drug and lactose (placebo) occurred in the pharmacies which were then transported to the treatment area in 3-mL syringes that appeared identical regardless of whether they contained OP-1 or lactose (placebo).
Test product, dose and mode of administration
Active Treatment: Recombinant Human BMP-7 (bone morphogenetic protein -7) was supplied as a lyophilized cake in 6-mL vials containing 1 mg. Reconstitution with 1.0 mL sterile water for injection (WFI) resulted in a solution containing 1 mg/mL BMP-7 in 5% lactose (weight/volume). BMP-7 was diluted as needed per dose cohort in 5% lactose.
Lactose (placebo) Control: The lactose (placebo) was provided in a 6-mL vial containing a sterile lyophilized cake of lactose. It was reconstituted with sterile WFI to produce a dosage of 5% lactose in 1.0 mL.
Administration: Given under direct ultrasound or fluoroscopic guidance to ensure injection into the knee joint.
Handling and preparation of BMP-7 drug product and lactose (placebo) were carried out by institution staff in such a way as to maintain study blinding, except that the study pharmacist was unblinded to each participant's study treatment. The institutional pharmacists at each site had access to a code list identifying whether the participant received BMP-7 or lactose (placebo). The pharmacist did not disclose this information to any study personnel. BMP-7 was provided in a single dose 6-mL vial containing a sterile, lyophilized cake of BMP-7.
The participant, study site personnel (other than the research pharmacist), and Stryker Biotech study staff were all blinded to the treatment assignments.
When a minimum of 4 weeks had elapsed since the last participant of the current cohort had been treated, all safety data were collected and reviewed by the safety committee.
Only after the current dose level had been judged to be safe were participants enrolled into the next cohort and dose escalation occurred.
Study sites paid particular heed to the development of any of the following:
• Any evidence of ectopic bone formation not normally associated with OA.
• New or worsening erythema, inflammation and/or joint swelling of the index knee in the first 14 days (2 weeks) following study drug injection.
• The development of an inflammatory infusion in the index knee with WBC > 3,000/mm3 and greater than 30% polymorphonuclear leukocytes.
• Any serious adverse event thought to be at least possibly related to study drug
During the screening period lasting 1 to 28 days, participants provided medical and arthritis history, including the WOMAC questionnaire [19
], the KOOS survey[20
], SF-36 [21
] and VAS global assessments. The WOMAC is a disease specific measure that includes pain (5 items) and physical function (17 items) subscales that are assessed on a 5-point Likert scale for each. The OARSI Standing Committee for Clinical Trials Response Criteria Initiative had developed two sets of responder criteria to present the results of changes after treatment in three symptomatic domains (pain, function, and patient's global assessment) as a single variable for clinical trials with response defined by both a relative and an absolute change [22
At each visit concomitant medications were recorded, physical examination performed, samples obtained for urinalysis, hematology, chemistry, immunology and serum and plasma banked for biomarker testing. ECG, bilateral knee x-rays was obtained on all participants and an MRI of the index knee in selected participants was done.
At each of the study visits, the following clinical laboratory evaluations were performed:
• Hematology: WBC count, RBC count, hemoglobin, hematocrit, platelet count, WBC differential count.
• Coagulation: PT, aPTT, INR
• Clinical chemistry: Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), bicarbonate, bilirubin (total), calcium, phosphorus, chloride, creatinine, glucose, potassium, sodium, total protein, urea (BUN), uric acid.
• Urinalysis: Color, appearance, specific gravity, pH, protein, glucose, ketones, blood, microscopic examination (RBC, WBC, casts, crystals).
At each visit, patient samples were screened for anti-BMP 7 IgM and IgG antibodies. Anti- BMP 7 neutralizing activity was determined only in samples positive for anti- BMP 7 binding antibodies.
Blood samples for serum were obtained just prior to injection, immediately post-injection, 1 hour post-injection and at the 7 day visit to assess BMP 7 drug levels.
Participants were asked to maintain their usual dose of NSAIDs and/or analgesic during the course of the trial, except during the 48 hour period preceding KOOS, SF-36 and patient global assessment evaluations (Acetominophen was permitted during this 48 hour window).
PA and lateral views of the index knee were taken serially in follow-up at Days 28, 84 and 168. At the screening visit, bilateral x-rays were done to determine presence of osteophytes, to determine study eligibility. Follow-up x-rays were performed on the index knee only. X-rays were performed in the 3 recruiting centres and sent for central reading to a musculoskeletal radiologist with osteoarthritis expertise.
Participants enrolled at the Boston sites also had an MRI acquired to assess gadolinium enhanced MRI of their treated knee for dGEMRIC. MRI results were exploratory and given concerns over sample size, adequate powering and also the fact that we did not find anything (either favourable or adverse) these are not further presented due to space limitations.
The primary objective of this study was to determine the safety and tolerability including laboratory assessments, immunogenicity data and radiographic assessments. All participants receiving any part of at least one injection of BMP-7 or lactose (placebo) were evaluated for safety. The safety analyses included evaluation of the incidence of treatment emergent adverse events by preferred term and body system. Laboratory measures were compared with their corresponding normal ranges, and the incidence of abnormally high and of abnormally low laboratory values was calculated for each relevant protocol-specified laboratory test. Fixed flexion PA and lateral x-rays of the index knee for assessment of joint space narrowing, osteophyte changes and ectopic bone formation were performed. As this was primarily a safety study no formal a-priori power calculation was conducted for secondary endpoints of efficacy.
Secondary objectives were to determine the proportion of participants with a 20%, 50%, and 70% improvement in the WOMAC pain and function subscales at 4, 8, 12, and 24 weeks. Other secondary outcomes included the change from baseline to 4, 8, 12, and 24 weeks for the OARSI responder criteria. As this was a Phase 1 study, descriptive statistics (average, standard deviations, minimum, maximum, proportions, and confidence intervals) were used to report study data and no formal statistical techniques have been applied to the data.