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

"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.

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