Safety and Efficacy of Botulinum Toxin A Injection in Patients With Painful Artificial Knee Joint
Primary Total Knee joint replacement surgery is highly successful surgery for relieving pain and improving function in patients with disabling arthritis. Unfortunately, like all biomedical devices, prosthesis failure is a complication of knee replacement surgery that leads to disabling pain, stiffness and loss of function. Approximately 1% of the knee replacements fail every year leading to a 20% failure rate over 20 years. The common causes of failure of prosthetic joint are infection, loosening, trauma or wear of the prosthesis. Currently, a revision surgery is the best option for long term pain relief (analgesics or other pain medications are options but are of limited benefit). Surgery may not be feasible in patients due to advancing age, other medical conditions and surgical/technical difficulties or patient's choice. In addition, the results from revision surgery are not as good as the initial knee joint surgery. Therefore, there is a great need for a novel, targeted therapy that provides an option to patients who are unfit, unable, or unwilling to undergo surgery.
In the investigators' recent pilot study, a single injection of Botulinum toxin A (Botox) in painful natural knee, ankle and shoulder joints of patients with various types of arthritis led to significant and durable improvement in pain and function and was safe to use. The investigators propose this 6-month study to compare pain relief, improvement of function and safety of an injection of Botulinum toxin compared to placebo in patients with a painful prosthetic knee joint. Both patients and investigators will be blinded to the treatment assignment to a patient until the study is completed. The investigators will assess the amount and duration of pain relief, improvement in function and short term safety of Botulinum toxin using standard validated measures. Patients will be evaluated at baseline, 2 weeks, 1-, 2-, 3-, 4- and 6-months after a single injection of either placebo or BoNT/A in the hip or knee prosthesis. The six-month follow-up is to assess the duration of meaningful pain relief. If successful, this will offer a new treatment option for patients with a chronically painful knee prosthetic joint, provide more insight into the origin and cause of pain in prosthetic joints and direct future investigations in new directions.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Botulinum Toxin A for Painful Prosthetic Knee: Randomized, Controlled, Triple-blind Study|
- proportion with clinically meaningful Change in Pain Severity (0-10) [ Time Frame: 2-month ] [ Designated as safety issue: No ]
- Patient global assessment of response to treatment [ Time Frame: 2-month and at all efficacy time-points ] [ Designated as safety issue: No ]
- Physician global assessment of response to treatment [ Time Frame: 2-month and at all efficacy time-points ] [ Designated as safety issue: No ]
- Improvement in Physical Function subscale of the WOMAC and WOMAC total [ Time Frame: 2-month and at all efficacy time-points ] [ Designated as safety issue: No ]
- Time to Onset of Pain Relief and duration of pain relief [ Time Frame: Upto 6-month data ] [ Designated as safety issue: No ]
- Change in joint function as measured by active and passive range of motion, and Time to perform sit to stand 10 times without using arms to push up (Timed Stands Test) and Timed up-and-go (TUG) tests [ Time Frame: 2-month and at all efficacy time-points ] [ Designated as safety issue: No ]
- QOL: SF-36 scores, a generic health status measure [ Time Frame: 2-month and at all efficacy time-points ] [ Designated as safety issue: No ]
- Clinical assessment of joint erythema, warmth, swelling and tenderness [ Time Frame: Upto 6 months ] [ Designated as safety issue: Yes ]
- Manual muscle strength testing of flexion and extension. [ Time Frame: Upto 6-months ] [ Designated as safety issue: Yes ]
- Proportion with Minimal Clinically Important Improvement (MCII) on VAS pain, WOMAC pain, physical function, stiffness subscales and total scores [ Time Frame: 2-month and at all efficacy time-points ] [ Designated as safety issue: No ]
- correlation of Baseline Serum and Joint Fluid Cytokine Levels with baseline pain and function [ Time Frame: Baseline values ] [ Designated as safety issue: No ]
- Correlation of Change in Serum and Joint Fluid Cytokine Levels with improvement in pain and function [ Time Frame: Baseline to 2-3 months and to the time of maximum pain relief ] [ Designated as safety issue: No ]
- McGill Sensory pain, affective pain and total score [ Time Frame: 2-month (primary end-point) and all efficacy time-points ] [ Designated as safety issue: No ]
|Study Start Date:||July 2006|
|Study Completion Date:||January 2009|
|Primary Completion Date:||January 2009 (Final data collection date for primary outcome measure)|
Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit
Drug: Botulinum toxin A
100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit
Other Name: Botox
Placebo Comparator: B
Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Drug: Normal Saline
Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Other Name: saline control
"This 6-month randomized, placebo-controlled, double blind trial will compare a single intra-articular (IA) injection of 100 units of Botulinum Toxin A (BoNT/A) to placebo for improvement in pain, function and quality of life (QOL), and safety in patients with painful total knee arthroplasty (TKA). Patients will be recruited at the Minneapolis VA Medical Center. Patients will be eligible if they are over age 18, have TKA, have pain ≥6/10 on 0-10 numeric rating scale (NRS) and are not candidates for revision surgery.
The primary outcome is: (1) proportion with clinically meaningful change in pain severity (on 0-10 scale) 2 months after IA injection. The choice of 2-month for primary end-point is based on previous observations from open-label case series in painful TKA. Secondary outcomes will be assessed at each efficacy follow-up (FU) visit. The duration of the trial is 6-months to capture the duration of pain relief. Based on other trials of Botulinum toxin, we expect the peak effect between 2-8 weeks and expect the effect to wear off between 2-4 months. Therefore, for all analyses except duration of pain relief, the efficacy time-points (2 wk, 4 wk, 2 month) and possibly 3- or 4-month (depending on duration of pain relief) will be used. Secondary outcomes include: (1) clinically meaningful pain relief (≥2-point or ≥30% decrease) in pain severity (0-10 scale); (2) change in pain severity at 2 months and at all efficacy time-points; (3) percent with Minimal Clinically Important Improvement on Western Ontario MacMaster Arthritis Index (WOMAC) pain and function subscales at 2 months and at all efficacy time-points; (4) amount and duration of pain relief; (5) patient and physician global assessment of response at 2 months and at all efficacy time-points; (6) QOL assessed by WOMAC and Short-form 36 (SF-36) scores at 2 months and at all efficacy time-points; (7) change in function by Timed Stands Test (TST) and Timed-up-and-go (TUG) tests at 2 months and at all efficacy time-points; (8) change in dose of analgesics during the study. We will determine time to onset of and duration of pain relief and time to improvement in function. Safety will be assessed by structured interview form for adverse effects, sensory and manual muscle strength testing, and index joint examination for swelling, erythema and tenderness.
At visit #1, after informed consent and screening for inclusion/exclusion criteria, patients will undergo: index joint X-ray, laboratory tests; history, physical examination, index joint pain history, comorbidity and medication history; patient pain assessments, WOMAC and SF-36; and blinded index joint, neurological examination, TST and TUG tests. 50 patients will be randomized to receive either IA BoNT/A 100 units or sterile saline in the index joint. FU phone interviews at 2 and 4-weeks will include pain assessments, WOMAC, patients' global assessment and adverse effects. Interim visits at 2, 3 and 4-months will be identical to visit #1, but will also include patients' and physicians' global assessment and there will be no joint injection. End of study visit at 6 months will be identical to interim visits with the addition of index joint X-ray and laboratory tests.
Main analyses will include patients with unilateral TKAs. Sensitivity analyses will be done by including patients with bilateral knees, accounting for correlatedness of observations. Multiple analysis of variance, mixed model regression analyses and/or generalized estimating equations will be used for analysis of continuous and categorical outcomes respectively. Chi-square tests will be used to compare frequency of adverse events. Analysis will be intention-to-treat.
|United States, Minnesota|
|Minneapolis VA Medical Center|
|Minneapolis, Minnesota, United States, 55417|
|Principal Investigator:||Jasvinder Singh, MBBS, MPH||Minneapolis Veterans Affairs Medical Center|