Safety and Efficacy of Botulinum Toxin A Injection in Patients With Painful Artificial Knee Joint

Condition(s) targeted: Arthroplasty, Replacement, Knee

Intervention: Botulinum toxin A (Drug); Normal Saline (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Minneapolis Veterans Affairs Medical Center

Official(s) and/or principal investigator(s):
Jasvinder Singh, MBBS, MPH, Principal Investigator, Affiliation: Minneapolis Veterans Affairs Medical Center

Overall contact:
Jasvinder Singh, MBBS, MPH, Phone: 612-467-4190, Email: jasvinder.singh@va.gov

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 our 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. We 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. We 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. 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.

Official title: Botulinum Toxin A for Painful Prosthetic Knee: Randomized, Controlled Study

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

Change in Pain Severity on 0-10 Numeric Rating Scale

Change in Pain Severity on 0-10 cm VAS

Change in Pain Severity on WOMAC Pain Subscale (0-100)

Secondary outcome:

Patient global assessment of response to treatment.

Physician global assessment of response to treatment

Improvement in Physical Function subscale of the WOMAC and WOMAC total

Qualitative assessment of pain relief

Time to Onset of Pain Relief and duration of pain relief

Change in joint function as measured by active and passive range of motion, time for 50-feet walk 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

QOL: generic health status measure, the SF-36 and specific health status measures, the WOMAC

Clinical assessment of joint erythema, warmth, swelling and tenderness

Manual muscle strength testing of flexion and extension.

Clinically important change in pain (at least a 2-point or 30% decrease in pain severity on 0-10 Numeric rating scale (NRS)) at 2-mo follow-up (FU) visit

Minimal Clinically Important Improvement (MCII) on WOMAC physical function subscale

Baseline Serum and Joint Fluid Cytokine Levels

Change in Serum and Joint Fluid Cytokine Levels

Detailed description: 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) change in pain severity (on 0-10 NRS) 2 months after IA injection; Secondary outcomes that will be assessed at each follow-up (FU) visit include: (1) clinically meaningful pain relief (≥2-point or ≥30% decrease in pain severity on 0-10 NRS) 2 months after IA injection; (2) or (2) Minimal Clinically Important Improvement on Western Ontario MacMaster Arthritis Index (WOMAC) function subscale 2 months after IA injection; (3) amount of pain relief; (4) patient and physician global assessment of response; (5) QOL assessed by WOMAC and Short-form 36 (SF-36) scores; (6) change in function by Timed Stands Test (TST) and Timed-up-and-go (TUG) tests. 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. Multiple analysis of variance and 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 with last observation carried forward for missing data.

Minimum age: N/A. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Jasvinder Singh, MBBS, MPH, Phone: 612-467-4190, Email: jasvinder.singh@va.gov

Minneapolis VA Medical Center, Minneapolis, Minnesota 55417, United States; Recruiting
Jasvinder Singh, MBBS, MPH, Phone: 612-467-4190, Email: jasvinder.singh@va.gov
Ruth Brady, BS, Phone: 612-467-4190
Jasvinder Singh, MBBS, MPH, Principal Investigator
Maren Mahowald, MD, Sub-Investigator
Richard Schmidt, MD, Sub-Investigator
Edward Santos, MD, Sub-Investigator
Terrence Gioe, MD, Sub-Investigator
Hollis Krug, MD, Sub-Investigator

Minneapolis VA Medical Center, Minneapolis, Minnesota 55417, United States; Recruiting
Jasvinder Singh, MBBS, MPH, Phone: 612-467-4190, Email: jasvinder.singh@va.gov
Anthony Kouba, MPH, Phone: 612-467-2720, Email: anthony.kouba@va.gov
Jasvinder Singh, MBBS, MPH, Principal Investigator
Maren Mahowald, MD, Sub-Investigator
Richard Schmidt, MD, Sub-Investigator
Edward Santos, MD, Sub-Investigator
Terrence Gioe, MD, Sub-Investigator
Hollis Krug, MD, Sub-Investigator

Starting date: July 2006
Ending date: October 2008
Last updated: September 19, 2007