Safety and Efficacy of Botulinum Toxin A Injection in Patients With Painful Artificial Knee Arthroplasty (TKA)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 sub-scales 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.

Official Title
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Botulinum Toxin A for Painful Total Knee Arthroplasty (TKA): Randomized, Controlled, Triple-blind Study

Conditions
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Knee Pain

Intervention / Treatment
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* Drug: Botulinum toxin A
* Drug: Normal Saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, 18 years of age or older. Written informed consent and written authorization for use or release of health and research study information have been obtained. Subject has chronic Prosthetic knee joint pain for more than 3 months. Subject has pain 6 or greater on a 10 point Numerical Pain Rating scale Ability to follow study instructions and likely to complete all required visits. Negative urine pregnancy test on the day of treatment prior to the administration of study medication (for females of childbearing potential). (if applicable) Negative infectious etiology workup (joint aspiration, serological parameters such as Erythrocyte Sedimentation Rate (ESR) or C-reactive protein (CRP) and clinical examination). Patients who were considered not to be candidates for Prosthetic knee joint revision surgery and have failed traditional treatments including oral pain medications, as determined by referring orthopedic surgeon Exclusion Criteria: Use of aminoglycoside antibiotics, curare-like agents, or other agents that might interfere with neuromuscular function. Any medical condition that may put the subject at increased risk with exposure to BOTOX ®including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or known disorders of neuromuscular function Females who are pregnant, breast-feeding, or planning a pregnancy during the study or who think that they may be pregnant at the start of the study, or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study. Know allergy or sensitivity to any of the components in the study medication. History of recent or ongoing alcohol or drug abuse. Known, uncontrolled systemic disease. Concurrent participation in another research study Any condition or situation that, in the investigator's opinion, may put the subject at significant risk, confound the study results, or interfere significantly with the subject's participation in the study. Patients whose pain is rated as less than 6 on a 10 point Numerical Pain Rating scale at the screening visit
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>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<br>* 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit<br>* Other names: Botox;|
| Placebo Comparator: B<br>Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit | Drug: Normal Saline<br>* Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit<br>* Other names: saline control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Clinically Meaningful Improvement in Pain Severity (0-10 cm; Higher Score on Pain Scale is Worse) | 2-point reduction in pain Visual Analog Scale (VAS) from baseline to the 2-month follow-up visit, which is considered clinically meaningful Change in Pain Severity; Pain Severity on VAS ranges from 0 (no pain) to 10 (maximum pain) | 2-month post-injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Pain VAS (0-10) | VAS pain score at 2-month post-injection; Pain Severity on VAS ranges from 0 (no pain) to 10 (maximum pain) with higher score indicating worse pain | 2-months post-injection | 
| Physician Global Assessment of Response to Treatment | Physician global assessed on an ordinal scale with very much improved category as the outcome of interest (compared to all other categories of global assessment as reference category) | 2-month (primary end-point) | 
| Physical Function Subscale of the WOMAC at 2-months | Physical Function subscale score of the WOMAC at 2-months on a 0 (best physical function) to 100 (worst physical function), with higher score indicating worse physical function | 2-month | 
| WOMAC Stiffness (0-100) | WOMAC stiffness subscale score on 0-100 scale at 2-month follow-up visit with scores ranging 0 (no joint stiffness) to 100 (worst joint stiffness), with higher score indicating worse joint stiffness | 2-months | 
| Timed Up-and-go (TUG) Test | Time to get up from a chair, walk 3 meters turn back and sit in the chair in seconds at the 2-month visit (higher number is worse, i.e., taking a longer time to complete the task is worse) | 2-month | 
| QOL: SF-36 Score Physical Functioning Scale, a Generic Health Status Measure | Short Form (SF)-36 physical functioning subscale on 0-100, at 2-month FU visit, as a generic health status measure, with a score ranging from 0 (worst physical functioning) to 100 (best physical functioning), with higher score indicating better physical functioning (higher number is better) | 2-month | 
| Number of Participants With Occurrence of Joint Erythema, Warmth, Swelling or Tenderness | Occurence of any of the above clinical features (erythema, warmth, swelling or tenderness) as a new finding compared to the absence of the same feature at baseline | Upto 6 months | 
| Manual Muscle Strength Testing of Knee Flexion and Extension | Occurence of decrease in strength of knee flexion or extension at any of the follow-up visits, as measured by the Manual muscle strength testing (MMT) with scores ranging 0-5; 0 indicates None: No visible or palpable contraction; 1 indicates Trace: Visible or palpable contraction with no motion; 2 indicates Poor: Full range of motion (ROM) gravity eliminated; 3 indicates Fair: Full ROM against gravity; 4 indicates Good: Full ROM against gravity, moderate resistance; and 5 indicates Normal: Full ROM against gravity, maximal resistance | Upto 6-months | 
| McGill Affective Dimension | McGill Affective Dimension Score on 0-12 scale at 2-months (higher number is worse) | 2-month | 
| Change in Serum Cytokine (Interleukin 7) Levels at 2-month Post-injection | The change in serum interleukin 7 was defined as the difference between the follow-up (2-month) and the baseline value of serum interleukin 7. We compared the mean change in serum interleukin 7 levels between the WOMAC pain responders vs. the WOMAC pain non-responders. | Baseline to 2-months | 
| McGill Sensory Pain Score | McGill Sensory pain score on 0-33 at 2-month FU visit (higher score is worse) | 2-month | 
| Change in Serum Cytokine (Interleukin 10) Levels at 2-month Post-injection | The change in serum interleukin 10 was defined as the difference between the follow-up (2-month) and the baseline value of serum interleukin 10. We compared the mean change in serum interleukin 10 levels between the WOMAC pain responders vs. the WOMAC pain non-responders. | Baseline to 2-months | 
| Change in Serum Cytokine (Interleukin 12 p70) Levels at 2-month Post-injection | The change in serum interleukin 12 p70 was defined as the difference between the follow-up (2-month) and the baseline value of serum interleukin 12 p70. We compared the mean change in serum interleukin 12 p70 levels between the WOMAC pain responders vs. the WOMAC pain non-responders. | Baseline to 2-months | 
| Change in Serum Cytokine (Eotaxin) Levels at 2-month Post-injection | The change in serum Eotaxin was defined as the difference between the follow-up (2-month) and the baseline value of serum Eotaxin. We compared the mean change in serum Eotaxin levels between the WOMAC pain responders vs. the WOMAC pain non-responders. | Baseline to 2-months | 
| Change in Serum Cytokine (Interferon Gamma) Levels at 2-month Post-injection | The change in serum Interferon Gamma was defined as the difference between the follow-up (2-month) and the baseline value of serum Interferon Gamma. We compared the mean change in serum Interferon Gamma levels between the WOMAC pain responders vs. the WOMAC pain non-responders. | Baseline to 2-months | 
| Change in Serum Cytokine (Tumor Necrosis Factor Alpha) Levels at 2-month Post-injection | The change in serum tumor necrosis factor alpha was defined as the difference between the follow-up (2-month) and the baseline value of serum tumor necrosis factor alpha. We compared the mean change in serum tumor necrosis factor alpha levels between the WOMAC pain responders vs. the WOMAC pain non-responders. | Baseline to 2-months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Painful Knee Arthroplasty, Botulinum Toxin A, Randomized Controlled Trial, Pain and Function