Trial Outcomes & Findings for Safety and Efficacy of Botulinum Toxin A Injection in Patients With Painful Artificial Knee Arthroplasty (TKA) (NCT NCT00403273)

NCT ID: NCT00403273

Last Updated: 2018-05-21

Results Overview

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)

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 54 participants
• Primary outcome timeframe: 2-month post-injection
• Results posted on: 2018-05-21

Participant Flow

Of the 194 TKAs (188 patients) screened, 60 TKAs (54 patients) were recruited in the 6-month study. Main analyses were performed only on 49 TKAs, after excluding bilateral TKAs, to meet the assumption of independence of observations.

No enrolled participants were excluded from analyses. Main analyses were done for Single TKA per patient, since 6 were bilateral TKAs; sensitivity analyses were done on all, regardless of unilateral or bilateral

Participant milestones

Measure	Intra-articular Botulinum Toxin Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Overall Study STARTED	25	29
Overall Study COMPLETED	22	25
Overall Study NOT COMPLETED	3	4

Reasons for withdrawal

Measure	Intra-articular Botulinum Toxin Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Overall Study Lost to Follow-up	3	2
Overall Study Physician Decision	0	1
Overall Study pt. wanted to have a surgical procedure	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Intra-articular Botulinum Toxin n=25 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=29 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit	Total n=54 Participants Total of all reporting groups
Age, Continuous	67 years STANDARD_DEVIATION 10 • n=5 Participants	67 years STANDARD_DEVIATION 12 • n=7 Participants	67 years STANDARD_DEVIATION 11 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	26 Participants n=7 Participants	46 Participants n=5 Participants
Race/Ethnicity, Customized caucasian	24 participants n=5 Participants	28 participants n=7 Participants	52 participants n=5 Participants
Race/Ethnicity, Customized Non-Caucasian	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants

PRIMARY outcome

Timeframe: 2-month post-injection

Population: all with follow-up data, allowing only single TKA per participant

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)

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Participants With Clinically Meaningful Improvement in Pain Severity (0-10 cm; Higher Score on Pain Scale is Worse)	15 participants	9 participants

SECONDARY outcome

Timeframe: 2-months post-injection

Population: patients providing pain VAS data at 2-month FU visit

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

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Mean Pain VAS (0-10)	4.4 units on pain VAS scale Standard Deviation 2.5	5.7 units on pain VAS scale Standard Deviation 2.9

SECONDARY outcome

Timeframe: 2-month (primary end-point)

Population: 2 patients did not have the outcome assessment; 1 lost to FU

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)

Outcome measures

Measure	Intra-articular Botulinum Toxin n=20 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Physician Global Assessment of Response to Treatment	6 participants	0 participants

SECONDARY outcome

Timeframe: 2-month

Population: people providing data 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

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Physical Function Subscale of the WOMAC at 2-months	48.5 units on a scale Standard Deviation 14.1	59.7 units on a scale Standard Deviation 17.4

SECONDARY outcome

Timeframe: 2-months

Population: patients providing the data

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

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
WOMAC Stiffness (0-100)	51.8 units on a scale Standard Deviation 19.1	60.4 units on a scale Standard Deviation 16.3

SECONDARY outcome

Timeframe: 2-month

Population: patients providing data

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)

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Timed Up-and-go (TUG) Test	17.2 seconds Standard Deviation 18.2	9.6 seconds Standard Deviation 13.8

SECONDARY outcome

Timeframe: 2-month

Population: patients providing data

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)

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
QOL: SF-36 Score Physical Functioning Scale, a Generic Health Status Measure	30.7 units on a scale Standard Deviation 21.8	23.6 units on a scale Standard Deviation 17.5

SECONDARY outcome

Timeframe: Upto 6 months

Population: patients providing data

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

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Number of Participants With Occurrence of Joint Erythema, Warmth, Swelling or Tenderness	0 participants	0 participants

SECONDARY outcome

Timeframe: Upto 6-months

Population: patients providing the data

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

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Manual Muscle Strength Testing of Knee Flexion and Extension	0 participants	0 participants

SECONDARY outcome

Timeframe: 2-month

Population: patients providing data

McGill Affective Dimension Score on 0-12 scale at 2-months (higher number is worse)

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
McGill Affective Dimension	3.8 units on a scale Standard Deviation 3.1	4.8 units on a scale Standard Deviation 3.4

SECONDARY outcome

Timeframe: Baseline to 2-months

Population: This protocol modification was made in the middle of the trial conduct, based on a suggestion on the K-12 application. Therefore, the total number of patients with these data is smaller than the total number of participants.

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.

Outcome measures

Measure	Intra-articular Botulinum Toxin n=12 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=23 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Change in Serum Cytokine (Interleukin 7) Levels at 2-month Post-injection	1.07 pg/ml Standard Deviation 1.17	0.08 pg/ml Standard Deviation 0.91

SECONDARY outcome

Timeframe: 2-month

Population: patients providing data

McGill Sensory pain score on 0-33 at 2-month FU visit (higher score is worse)

Outcome measures

Measure	Intra-articular Botulinum Toxin n=21 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
McGill Sensory Pain Score	14.5 units on a scale Standard Deviation 8	14.6 units on a scale Standard Deviation 7.5

SECONDARY outcome

Timeframe: Baseline to 2-months

Population: This protocol modification was made in the middle of the trial conduct, based on a suggestion on the K-12 application. Therefore, the total number of patients with these data is smaller than the total number of participants.

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.

Outcome measures

Measure	Intra-articular Botulinum Toxin n=12 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=23 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Change in Serum Cytokine (Interleukin 10) Levels at 2-month Post-injection	27.72 pg/ml Standard Deviation 21.56	8.51 pg/ml Standard Deviation 20.90

SECONDARY outcome

Timeframe: Baseline to 2-months

Population: This protocol modification was made in the middle of the trial conduct, based on a suggestion on the K-12 application. Therefore, the total number of patients with these data is smaller than the total number of participants.

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.

Outcome measures

Measure	Intra-articular Botulinum Toxin n=12 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=23 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Change in Serum Cytokine (Interleukin 12 p70) Levels at 2-month Post-injection	12.91 pg/ml Standard Deviation 9.60	3.36 pg/ml Standard Deviation 8.17

SECONDARY outcome

Timeframe: Baseline to 2-months

Population: This protocol modification was made in the middle of the trial conduct, based on a suggestion on the K-12 application. Therefore, the total number of patients with these data is smaller than the total number of participants.

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.

Outcome measures

Measure	Intra-articular Botulinum Toxin n=12 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=23 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Change in Serum Cytokine (Eotaxin) Levels at 2-month Post-injection	7.85 pg/ml Standard Deviation 12.28	-2.03 pg/ml Standard Deviation 13.92

SECONDARY outcome

Timeframe: Baseline to 2-months

Population: This protocol modification was made in the middle of the trial conduct, based on a suggestion on the K-12 application. Therefore, the total number of patients with these data is smaller than the total number of participants.

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.

Outcome measures

Measure	Intra-articular Botulinum Toxin n=12 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=23 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Change in Serum Cytokine (Interferon Gamma) Levels at 2-month Post-injection	15.61 pg/ml Standard Deviation 13.35	-1.24 pg/ml Standard Deviation 23.18

SECONDARY outcome

Timeframe: Baseline to 2-months

Population: This protocol modification was made in the middle of the trial conduct, based on a suggestion on the K-12 application. Therefore, the total number of patients with these data is smaller than the total number of participants.

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.

Outcome measures

Measure	Intra-articular Botulinum Toxin n=12 Participants Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=23 Participants Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Change in Serum Cytokine (Tumor Necrosis Factor Alpha) Levels at 2-month Post-injection	22.22 pg/ml Standard Deviation 24.65	4.46 pg/ml Standard Deviation 21.32

Adverse Events

Intra-articular Botulinum Toxin

Serious events: 3 serious events

Other events: 19 other events

Deaths: 0 deaths

Intra-articular Placebo

Serious events: 9 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Measure	Intra-articular Botulinum Toxin n=23 participants at risk Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 participants at risk Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Cardiac disorders Chest pain/new diagnosis of CAD	0.00% 0/23 • 6-months	11.5% 3/26 • Number of events 3 • 6-months
Cardiac disorders Supraventricular tachycardia	0.00% 0/23 • 6-months	3.8% 1/26 • Number of events 1 • 6-months
Cardiac disorders Subarachnoid hemorrhage	4.3% 1/23 • Number of events 1 • 6-months	0.00% 0/26 • 6-months
Musculoskeletal and connective tissue disorders Atypical chest pain	4.3% 1/23 • Number of events 1 • 6-months	0.00% 0/26 • 6-months
Immune system disorders Seafood allergy	4.3% 1/23 • Number of events 1 • 6-months	0.00% 0/26 • 6-months
Psychiatric disorders Depression	8.7% 2/23 • Number of events 2 • 6-months	0.00% 0/26 • 6-months
Musculoskeletal and connective tissue disorders Gouty arthritis	0.00% 0/23 • 6-months	3.8% 1/26 • Number of events 1 • 6-months
Infections and infestations Influenza	0.00% 0/23 • 6-months	3.8% 1/26 • Number of events 1 • 6-months
Infections and infestations Cellulitis and septic arthritis	0.00% 0/23 • 6-months	3.8% 1/26 • Number of events 1 • 6-months
Vascular disorders Deep vein thrombosis	0.00% 0/23 • 6-months	3.8% 1/26 • Number of events 1 • 6-months
Nervous system disorders Lethargy and decreased appetite	0.00% 0/23 • 6-months	3.8% 1/26 • Number of events 1 • 6-months

Other adverse events

Measure	Intra-articular Botulinum Toxin n=23 participants at risk Single Intra-articular Injection of 100 units of Botulinum toxin A in 5 cc of normal saline in the Painful TKA at screening visit	Intra-articular Placebo n=26 participants at risk Single Intra-articular Injection of 5 cc of normal saline in the Painful TKA at screening visit
Musculoskeletal and connective tissue disorders Accidental injury	34.8% 8/23 • Number of events 11 • 6-months	23.1% 6/26 • Number of events 7 • 6-months
Musculoskeletal and connective tissue disorders Pain in the study joint	26.1% 6/23 • Number of events 6 • 6-months	7.7% 2/26 • Number of events 2 • 6-months
Respiratory, thoracic and mediastinal disorders Upper respiratory infections	43.5% 10/23 • Number of events 10 • 6-months	38.5% 10/26 • Number of events 10 • 6-months
Surgical and medical procedures Surgical procedure	13.0% 3/23 • Number of events 3 • 6-months	19.2% 5/26 • Number of events 5 • 6-months

Additional Information

jasvinder singh

minneapolis VAMC

Phone: 205-504-9559

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place