Trial Outcomes & Findings for Study of Intra-articular Injections vs Placebo in Patients With Pain From Osteoarthritis of the Knee (NCT NCT01887678)

Last Updated: 2018-04-02

Results Overview

Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess pain, scores from WOMAC Section A, items 1 to 5 are averaged to yield the Pain Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. A two-sided test of equality of the study drug (Traumeel®-Zeel®) and Placebo at level 0.05 was computed using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and the corresponding Baseline value of the primary efficacy variable as a covariate. The test decision was based on the (two-sided) p-value for the corresponding test of no treatment difference.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

287 participants

Primary outcome timeframe

from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)

Results posted on

2018-04-02

Participant Flow

A total of 28 investigational sites in the United States (US) entered at least one patient into the study database, 24 sites randomized at least one patient, 4 sites had Lead-In screening failures only.

In total, 287 patients were enrolled into the study, 55 of them were Lead-In screening failures and therefore were not included.

Participant milestones

Participant milestones
Measure	Co-administered Traumeel® and Zeel® Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Overall Study STARTED	119	113
Overall Study COMPLETED	102	85
Overall Study NOT COMPLETED	17	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Co-administered Traumeel® and Zeel® Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Overall Study Adverse Event	4	6
Overall Study Exceeded rescue medication dosage	4	5
Overall Study Withdrawal of consent	3	4
Overall Study Lost to Follow-up	4	2
Overall Study Deterioration of clinical condition	0	4
Overall Study Lack of Efficacy	1	2
Overall Study Non-compliance	0	3
Overall Study Specified	1	2

Baseline Characteristics

Study of Intra-articular Injections vs Placebo in Patients With Pain From Osteoarthritis of the Knee

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Co-administered Traumeel® and Zeel® n=119 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=113 Participants At baseline, patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Total n=232 Participants Total of all reporting groups
Age, Continuous	60.7 years STANDARD_DEVIATION 9.11 • n=5 Participants	59.7 years STANDARD_DEVIATION 8.68 • n=7 Participants	60.2 years STANDARD_DEVIATION 8.90 • n=5 Participants
Sex: Female, Male Female	43 Participants n=5 Participants	46 Participants n=7 Participants	89 Participants n=5 Participants
Sex: Female, Male Male	76 Participants n=5 Participants	67 Participants n=7 Participants	143 Participants n=5 Participants
Region of Enrollment United States	119 participants n=5 Participants	113 participants n=7 Participants	232 participants n=5 Participants

PRIMARY outcome

Timeframe: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)

Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS	-32.0 units on a scale Standard Deviation 26.88	-25.5 units on a scale Standard Deviation 24.08

SECONDARY outcome

Timeframe: from Baseline to post-Baseline visits except End of Study Visit (up to day 105)

Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess pain, scores from WOMAC Section A, items 1 to 5 are averaged to yield the Pain Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in pain subscore were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 8±1	-15.8 units on a scale Standard Deviation 18.65	-13.6 units on a scale Standard Deviation 19.11
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 15±1	-24.4 units on a scale Standard Deviation 24.31	-18.5 units on a scale Standard Deviation 20.02
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 43±3	-26.8 units on a scale Standard Deviation 26.12	-21.5 units on a scale Standard Deviation 21.62
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 29±3	-29.7 units on a scale Standard Deviation 26.65	-22.4 units on a scale Standard Deviation 22.33
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 57±3	-30.4 units on a scale Standard Deviation 26.69	-22.7 units on a scale Standard Deviation 23.37
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 71±3	-31.0 units on a scale Standard Deviation 26.23	-23.3 units on a scale Standard Deviation 24.38
Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS Day 85±3	-31.1 units on a scale Standard Deviation 26.63	24.7 units on a scale Standard Deviation 24.57

SECONDARY outcome

Timeframe: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)

Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess stiffness, scores from WOMAC Section B, items 6 to 7 are averaged to yield the Stiffness Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in stiffness score were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS	-34.1 units on a scale Standard Deviation 28.16	-28.2 units on a scale Standard Deviation 25.73

SECONDARY outcome

Timeframe: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)

Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess physical function, scores from WOMAC Section C, items 8 to 24 are averaged to yield the Physical Function Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in Physical Function subscore were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=110 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS	-31.1 units on a scale Standard Deviation 27.38	-26.9 units on a scale Standard Deviation 24.40

SECONDARY outcome

Timeframe: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)

Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. A total WOMAC score was computed by averaging all 24 possible responses. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in total WOMAC score were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=110 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Total WOMAC Score (All Subscales) Recorded on 100 mm VAS	-31.5 units on a scale Standard Deviation 26.94	-26.7 units on a scale Standard Deviation 24.14

SECONDARY outcome

Timeframe: from Baseline (Day 1, predose)

Patients made an overall Global Assessment of the knee osteoarthritis with the assessment stages "Very good", "Good", "Fair", "Poor" and "Very poor".

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Patient Global Assessment (PGA) Very Good	1 participants	0 participants
Patient Global Assessment (PGA) Good	6 participants	7 participants
Patient Global Assessment (PGA) Fair	62 participants	59 participants
Patient Global Assessment (PGA) Poor	39 participants	43 participants
Patient Global Assessment (PGA) Very Poor	8 participants	2 participants
Patient Global Assessment (PGA) Missing	1 participants	0 participants

SECONDARY outcome

Timeframe: End of Study Visit (up to Day 119)

Patients made an overall Global Assessment of the knee osteoarthritis with the assessment stages "Very good", "Good", "Fair", "Poor" and "Very poor".

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Patient Global Assessment (PGA) Very Good	30 participants	22 participants
Patient Global Assessment (PGA) Good	49 participants	39 participants
Patient Global Assessment (PGA) Fair	31 participants	38 participants
Patient Global Assessment (PGA) Poor	6 participants	11 participants
Patient Global Assessment (PGA) Very Poor	1 participants	1 participants
Patient Global Assessment (PGA) Missing	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline (Day 1, predose)

Study Physicians made an overall Global Assessment of the knee osteoarthritis with the assessment stages "Very good", "Good", "Fair", "Poor" and "Very poor".

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Physician Global Assessment (PhGA) Very Good	0 participants	0 participants
Physician Global Assessment (PhGA) Good	7 participants	7 participants
Physician Global Assessment (PhGA) Fair	73 participants	77 participants
Physician Global Assessment (PhGA) Poor	34 participants	27 participants
Physician Global Assessment (PhGA) Very Poor	3 participants	0 participants
Physician Global Assessment (PhGA) Missing	0 participants	0 participants

SECONDARY outcome

Timeframe: End of Study Visit (up to Day 119)

Study Physicians made an overall Global Assessment of the knee osteoarthritis with the assessment stages "Very good", "Good", "Fair", "Poor" and "Very poor".

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Physician Global Assessment (PhGA) Very Good	28 participants	20 participants
Physician Global Assessment (PhGA) Good	51 participants	38 participants
Physician Global Assessment (PhGA) Fair	34 participants	47 participants
Physician Global Assessment (PhGA) Poor	4 participants	4 participants
Physician Global Assessment (PhGA) Very Poor	0 participants	2 participants
Physician Global Assessment (PhGA) Missing	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline (Day 1, predose) to post-Baseline visits (up to day 119)

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 8±1	-26.5 units on a scale Standard Deviation 22.39	-21.1 units on a scale Standard Deviation 22.09
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 15±1	-37.4 units on a scale Standard Deviation 23.80	-26.5 units on a scale Standard Deviation 21.97
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 29±3	-38.1 units on a scale Standard Deviation 25.37	-30.7 units on a scale Standard Deviation 24.14
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 43±3	-42.3 units on a scale Standard Deviation 25.13	-32.9 units on a scale Standard Deviation 24.45
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 57±3	-43.0 units on a scale Standard Deviation 25.04	-33.6 units on a scale Standard Deviation 25.32
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 71±3	-42.6 units on a scale Standard Deviation 25.31	-35.1 units on a scale Standard Deviation 23.69
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 85±3	-41.3 units on a scale Standard Deviation 27.29	-35.0 units on a scale Standard Deviation 24.38
Pain Immediately Following the 50-foot Walk (100 mm VAS) Day 119±3	-42.3 units on a scale Standard Deviation 26.33	-36.7 units on a scale Standard Deviation 24.53

SECONDARY outcome

Timeframe: Baseline (Day 1, predose) to post-Baseline visits (up to day 119)

Changes in time to walk 50 feet (seconds)

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Time to Walking (50-foot Walk Test) Day 8±1	-2.8 seconds Standard Deviation 7.38	-2.5 seconds Standard Deviation 5.91
Time to Walking (50-foot Walk Test) Day 15±1	-3.0 seconds Standard Deviation 7.25	-2.7 seconds Standard Deviation 6.90
Time to Walking (50-foot Walk Test) Day 29±3	-3.7 seconds Standard Deviation 8.28	-3.5 seconds Standard Deviation 7.94
Time to Walking (50-foot Walk Test) Day 43±3	-4.4 seconds Standard Deviation 9.23	-3.9 seconds Standard Deviation 8.05
Time to Walking (50-foot Walk Test) Day 57±3	-4.1 seconds Standard Deviation 8.24	-3.7 seconds Standard Deviation 9.02
Time to Walking (50-foot Walk Test) Day 71±3	-4.6 seconds Standard Deviation 9.59	-4.3 seconds Standard Deviation 9.63
Time to Walking (50-foot Walk Test) Day 85±3	-4.6 seconds Standard Deviation 9.84	-4.9 seconds Standard Deviation 10.26
Time to Walking (50-foot Walk Test) Day 119±3	-4.8 seconds Standard Deviation 9.66	-4.6 seconds Standard Deviation 10.24

SECONDARY outcome

Timeframe: Statistically derived

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Time to 50% Pain Relief (Study Population Measure Statistically Derived) After 2nd Injection	22 days Interval 15.0 to 35.0	34 days Interval 22.0 to 54.0
Time to 50% Pain Relief (Study Population Measure Statistically Derived) After 1st Injection	15 days Interval 15.0 to 22.0	22 days Interval 15.0 to 23.0
Time to 50% Pain Relief (Study Population Measure Statistically Derived) After 3rd Injection	29 days Interval 22.0 to 37.0	50 days Interval 36.0 to 64.0

SECONDARY outcome

Timeframe: Statistically derived

Changes of the target (treated) knee pain following a 50 feet walk self-assessed by the patients on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. The time to 100% pain relief were statistical exercises and were analyzed for each individual patient from their self-assessment, however, the prevalence of 100% pain relief did not support an estimate for the median time. The number of patients who reached 100% pain relief is reported and the log rank test for difference in time to 100% pain relief was calculated for each injection.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Patients Achieving 100% Pain Relief After 1st Injection	26 participants	12 participants
Patients Achieving 100% Pain Relief After 2nd Injection	25 participants	12 participants
Patients Achieving 100% Pain Relief After 3rd Injection	26 participants	11 participants

SECONDARY outcome

Timeframe: Statistically derived

Time to and use of rescue medication (acetaminophen up to 3000 mg per day for breakthrough pain) as reported by the patients. Patients who used any rescue medication during the study.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived) - Patients Use	82 participants	72 participants

SECONDARY outcome

Timeframe: Statistically derived

Time to and use of rescue medication (acetaminophen up to 3000 mg per day for breakthrough pain) (study population measure statistically derived). Total number of tablets taken as reported by patient.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=117 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=111 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived). Tablets Taken.	49.0 Tablets Standard Deviation 64.64	55.8 Tablets Standard Deviation 59.71

OTHER_PRE_SPECIFIED outcome

Timeframe: Start of Lead-In period until individual study end, up to 16 weeks.

Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. MedDRA Version 16.0 terminology

Total number of patients affected.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=119 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=113 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Serious Adverse Events Total number of patients affected	2 participants	1 participants
Serious Adverse Events Bradycardia and Hyperglycaemia	1 participants	0 participants
Serious Adverse Events Haematemesis	1 participants	0 participants
Serious Adverse Events Transient ischemic attack	0 participants	1 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119)

Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. 8 patients without any injection (not randomized) reported 12 adverse events

Total number of patients affected.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=119 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=113 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Each Adverse Event (AE)	64 participants	43 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: during the treatment period and follow up period (Days 11 to 119)

Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. MedDRA Version 16.0 terminology. Adverse events during treatment (treatment-emergent) in 5% or more of total study patients

Total number of patients affected.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=119 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=113 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Incidence of Treatment Emergent Adverse Events (TEAEs) Total Number of Patients affected	64 participants	43 participants
Incidence of Treatment Emergent Adverse Events (TEAEs) Musculoskeletal and connective tissue disorders	26 participants	14 participants
Incidence of Treatment Emergent Adverse Events (TEAEs) Infections and infestations	12 participants	10 participants
Incidence of Treatment Emergent Adverse Events (TEAEs) Nervous system disorders	14 participants	8 participants
Incidence of Treatment Emergent Adverse Events (TEAEs) Skin and subcutaneous tissue disorders	14 participants	9 participants
Incidence of Treatment Emergent Adverse Events (TEAEs) General disorders and administration site conditio	11 participants	8 participants
Incidence of Treatment Emergent Adverse Events (TEAEs) Injury, poisoning and procedural complications	6 participants	6 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: All visits (Days 1 up to 119)

Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. Medical Dictionary for Regulatory Activities (MedDRA) Version 16.0 terminology.

Total number of patients affected.

Outcome measures

Outcome measures
Measure	Co-administered Traumeel® and Zeel® n=119 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=113 Participants Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Proportion of Patients Who Discontinued Due to an AE Pain in extremity	0 participants	1 participants
Proportion of Patients Who Discontinued Due to an AE Total number of patients affected	3 participants	4 participants
Proportion of Patients Who Discontinued Due to an AE Injection site joint pain	1 participants	1 participants
Proportion of Patients Who Discontinued Due to an AE Injection site vesicles	1 participants	0 participants
Proportion of Patients Who Discontinued Due to an AE Haemarthrosis	1 participants	0 participants
Proportion of Patients Who Discontinued Due to an AE Muscle tightness	0 participants	1 participants
Proportion of Patients Who Discontinued Due to an AE Nephrolithiasis	0 participants	1 participants
Proportion of Patients Who Discontinued Due to an AE Rash maculopapular	0 participants	1 participants

Adverse Events

Co-administered Traumeel® and Zeel®

Serious events: 2 serious events

Other events: 64 other events

Deaths: 0 deaths

Placebo Injectable Solution

Serious events: 1 serious events

Other events: 43 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Co-administered Traumeel® and Zeel® n=119 participants at risk Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.	Placebo Injectable Solution n=113 participants at risk At baseline, patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15.
Cardiac disorders Bradycardia	0.84% 1/119 • Number of events 1 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo	0.00% 0/113 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo
Metabolism and nutrition disorders Hyperglycemia	0.84% 1/119 • Number of events 1 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo	0.00% 0/113 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo
Gastrointestinal disorders Haematemesis	0.84% 1/119 • Number of events 1 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo	0.00% 0/113 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo
Nervous system disorders Transient Ischemic Attack	0.00% 0/119 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo	0.88% 1/113 • Number of events 1 • Study Duration, 9 Months. The safety analysis included 232 randomized patients receiving at least one injection. 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo

Other adverse events

Additional Information

Christine Frank, PhD, Global Clinical Project Manager

Biologische Heilmittel Heel GmbH

Phone: +49 7221 501 3188

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Investigator agreements in place restricting the PI from independently publishing the study results.
Publication restrictions are in place

Restriction type: OTHER