Download PDF

Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled, Single Dose Phase IIb Exploratory Study to Document the Clinical Effects and Safety of Intra-articular Injections of Lopain (MTX-071) in Patients With Chronic Osteoarthritic Knee Joint Pain (Part 1 and Part 3) With Exploratory Pharmacokinetics (Part 3) and of Higher Doses or Consecutive Administrations With Local Anesthetics With Exploratory Pharmacokinetics (Part 2)

Summary
EudraCT number	2018-000818-37
Trial protocol	AT SK HR
Global end of trial date	26 Jan 2023

Results information
Results version number	v1(current)
This version publication date	11 Feb 2024
First version publication date	11 Feb 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

MTX-071-P03

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Grünenthal GmbH

Sponsor organisation address

Zieglerstr. 6, Aachen, Germany, 52099

Public contact

Grünenthal Trial Information Desk, Grünenthal GmbH, +49 241 569 3223, Clinical-trials@grunenthal.com

Scientific contact

Grünenthal Trial Information Desk, Grünenthal GmbH, +49 241 569 3223, Clinical-trials@grunenthal.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Mar 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Jan 2023

Was the trial ended prematurely?

Main objective of the trial

Part 1, 2: To compare the pain reduction effects (absolute and relative) at 3 months and 6 months of intra articular (IA) injections of different dose levels of MTX-071 (Lopain) relative to placebo in subjects with chronic osteoarthritic knee joint pain Part 3: To compare the pain reduction effects (absolute and relative) at 3 months and 6 months of IA injections of different dose levels of MTX-071 (Lopain) relative to placebo in a narrowed subjects population having insufficient pain relief and being unsatisfied with optimized Standard of Care (including corticosteroids, hyaluronic acid, NSAIDs, opioids, non-pharmacological treatment).

Protection of trial subjects

The trial was conducted according to Good Clinical Practice guidelines, the ethical principles that have their origins in the Declaration of Helsinki, and the applicable local laws and regulations. The regulatory authority approved the trial as required by national regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Jun 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovakia: 54

Country: Number of subjects enrolled

Croatia: 14

Country: Number of subjects enrolled

Austria: 93

Worldwide total number of subjects

161

EEA total number of subjects

161

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

The study was conducted at 7 sites in 3 countries between 23 October 2018 and 26 Jan 2023.

Screening details

The study was conducted in 3 parts: Part 1, Part 2 and Part 3. A total of 161 subjects were enrolled and treated in the study.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Part 1 - MTX-071 Group 1

Arm description

Subjects received a single 5 millilitres (mL) IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 1 - MTX-071 Group 2

Arm description

Subjects received a single 5 mL IA injection of MTX-071 within 15 more minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 1 - Placebo

Arm description

Subjects received single IA injection of placebo matched to MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received IA injection of placebo matched to MTX-071 to the knee.

Part 2 - MTX-071 Group 1

Arm description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 2. "Consecutive" treatment required IA injection of investigational medicinal product within 1 minute after IA injection of ropivacaine.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 2 - MTX-071 Group 2

Arm description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 2 - MTX-071 Group 3

Arm description

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 2 - MTX-071 Group 4

Arm description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 2 - Placebo

Arm description

Subjects received single IA injection of placebo matched to MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received IA injection of placebo matched to MTX-071 to the knee.

Part 3 - MTX-071 Group 1

Arm description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 3 - MTX-071 Group 2

Arm description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Arm type

Experimental

Investigational medicinal product name

MTX-071

Investigational medicinal product code

RTX-GRT7039

Other name

Lopain

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received 5 mL MTX-071 IA injection to the knee.

Part 3 - Placebo

Arm description

Subjects received single IA injection of placebo matched to MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection

Routes of administration

Intraarticular use

Dosage and administration details

Subjects received IA injection of placebo matched to MTX-071 to the knee.

Number of subjects in period 1	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Started	24	23	20	11	5	10	7	7	18	18	18
Completed	22	20	18	9	5	9	5	6	16	17	17
Not completed	2	3	2	2	0	1	2	1	2	1	1
Consent withdrawn by subject	1	2	-	-	-	-	-	1	-	1	-
Adverse event	-	-	-	1	-	-	-	-	2	-	1
Serious adverse event	-	-	1	1	-	-	-	-	-	-	-
Lost to follow-up	1	1	-	-	-	1	-	-	-	-	-
Therapeutic procedure	-	-	-	-	-	-	1	-	-	-	-
Lack of efficacy	-	-	1	-	-	-	-	-	-	-	-
Protocol deviation	-	-	-	-	-	-	1	-	-	-	-

Baseline characteristics

Top of page

Reporting group title

Part 1 - MTX-071 Group 1

Reporting group description

Subjects received a single 5 millilitres (mL) IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 1 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 more minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 1 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 2 - MTX-071 Group 1

Reporting group description

Reporting group title

Part 2 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 2 - MTX-071 Group 3

Reporting group description

Reporting group title

Part 2 - MTX-071 Group 4

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 2 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 3 - MTX-071 Group 1

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group title

Part 3 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group title

Part 3 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo	Total
Number of subjects	24	23	20	11	5	10	7	7	18	18	18	161
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	60.7 ( 7.88 )	62.5 ( 6.95 )	62.2 ( 9.22 )	66.3 ( 9.48 )	64.2 ( 9.44 )	66.2 ( 9.47 )	61.0 ( 5.03 )	68.9 ( 7.17 )	63.2 ( 8.50 )	61.0 ( 7.96 )	64.1 ( 7.46 )	-
Gender categorical
Units: Subjects
Female	17	14	16	7	5	7	3	3	13	11	13	109
Male	7	9	4	4	0	3	4	4	5	7	5	52

End points

Top of page

Reporting group title

Part 1 - MTX-071 Group 1

Reporting group description

Subjects received a single 5 millilitres (mL) IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 1 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 more minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 1 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 2 - MTX-071 Group 1

Reporting group description

Reporting group title

Part 2 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 2 - MTX-071 Group 3

Reporting group description

Reporting group title

Part 2 - MTX-071 Group 4

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 2 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 3 - MTX-071 Group 1

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group title

Part 3 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group title

Part 3 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Primary: Absolute Reduction From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Top of page

End point title

Absolute Reduction From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6 ^[1]

End point description

Subjects were asked to document the severity of pain on motion and for pain on rest on individual VAS. The subject was asked to mark a position on two 100 millimetre (mm) (where 0 = no pain and 100 = maximum pain) horizontal lines that correspond to the intensity of the pain of the treated knee as an average of the last two days, respectively at rest and on motion. The absolute reduction of the VAS for pain on motion as average of the last two days will be evaluated as the absolute change, defined as: VAS score at post-baseline visit - VAS score at baseline visit. Analysis was performed on intent to treat (ITT) population which included all randomized subject who received study drug and had at least one efficacy assessment at Baseline and post-baseline. Here, 'n' = subjects with available data for each specified category.

End point type

Primary

End point timeframe

Baseline, Months 3 and 6

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint was descriptive in nature, no statistical analysis was reported.

End point values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	24	23	19	11	5	10	7	7	18	18	18
Units: millimetre
arithmetic mean (standard deviation)
Month 3 (n=23,19,18,10,5,10,7,5,18,18,18)	-37.43 ( 19.797 )	-36.68 ( 34.167 )	-17.00 ( 23.098 )	-39.75 ( 39.764 )	-40.20 ( 35.316 )	-30.25 ( 25.640 )	-34.14 ( 31.757 )	-8.50 ( 19.994 )	-22.33 ( 30.662 )	-33.39 ( 23.655 )	-31.11 ( 30.932 )
Month 6 (n=22,20,17,8,5,10,5,6,16,17,17)	-33.52 ( 22.894 )	-41.48 ( 32.576 )	-28.26 ( 25.029 )	-46.49 ( 29.164 )	-43.40 ( 34.883 )	-22.00 ( 26.491 )	-38.60 ( 29.905 )	-3.42 ( 19.371 )	-19.78 ( 30.001 )	-24.09 ( 27.583 )	-34.21 ( 29.226 )

No statistical analyses for this end point

Primary: Percent Change From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Top of page

End point title

Percent Change From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6 ^[2]

End point description

Subjects were asked to document the severity of pain on motion and for pain on rest on individual VAS. The subject was asked to mark a position on two 100 mm (where 0 = no pain and 100 = maximum pain) horizontal lines that correspond to the intensity of the pain of the treated knee as an average of the last two days, respectively at rest and on motion. The percentage change of the VAS for pain on motion as average of the last two days will be evaluated as the relative change, defined as: 100% x ([VAS score at post-baseline visit] - [VAS score at baseline visit])/ (VAS score at baseline visit). Analysis was performed on ITT population. Here, 'n' =subjects with available data for each specified category.

End point type

Primary

End point timeframe

Baseline, Month 3 and 6

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: As the endpoint was descriptive in nature, no statistical analysis was reported.

End point values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	24	23	19	11	5	10	7	7	18	18	18
Units: percent change
arithmetic mean (standard deviation)
Month 3 (n=23,19,18,10,5,10,7,5,18,18,18)	-56.57 ( 27.982 )	-49.71 ( 47.529 )	-28.97 ( 36.941 )	-49.45 ( 53.671 )	-54.56 ( 47.355 )	-56.13 ( 42.347 )	-51.04 ( 46.856 )	-19.18 ( 42.058 )	-31.16 ( 42.824 )	-45.98 ( 31.448 )	-46.94 ( 51.966 )
Month 6 (n=22,20,17,8,5,10,5,6,16,17,17)	-51.25 ( 37.599 )	-58.61 ( 47.182 )	-50.29 ( 42.821 )	-64.65 ( 37.866 )	-58.26 ( 43.402 )	-39.23 ( 43.903 )	-57.76 ( 43.448 )	-8.30 ( 40.908 )	-27.96 ( 42.305 )	-33.32 ( 43.098 )	-54.28 ( 44.301 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Greater Than or Equal to (>=) 50% and >= 70% Decrease From Baseline in VAS Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Top of page

End point title

Percentage of Subjects With Greater Than or Equal to (>=) 50% and >= 70% Decrease From Baseline in VAS Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

End point description

Subjects were asked to document the severity of pain on motion and for pain on rest on individual VAS. The subject was asked to mark a position on two 100 mm (where 0 = no pain and 100 = maximum pain) horizontal lines that correspond to the intensity of the pain of the treated knee as an average of the last two days, respectively at rest and on motion. Percentage of subjects with >= 50% and >= 70% reduction from Baseline in VAS scores for pain on motion at Months 3 and 6 are reported in this endpoint. Analysis was performed on ITT population. Here, 'n' = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Months 3 and 6

End point values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	24	23	19	11	5	10	7	7	18	18	18
Units: percentage of subjects
number (not applicable)
>= 50%: Month 3 (n=23,19,18,10,5,10,7,5,18,18,18)	60.9	52.6	33.3	60.0	60.0	60.0	57.1	40.0	55.6	38.9	55.6
>=50%: Month 6 (n=22,20,17,8,5,10,5,6,16,17,17)	63.6	65.0	52.9	75.0	60.0	50.0	60.0	16.7	31.3	41.2	52.9
>= 70%: Month 3 (n=23,19,18,10,5,10,7,5,18,18,18)	43.5	47.4	16.7	40.0	60.0	40.0	57.1	0	16.7	16.7	38.9
>=70%: Month 6 (n=22,20,17,8,5,10,5,6,16,17,17)	31.8	55.0	47.1	50.0	40.0	30.0	60.0	16.7	18.8	23.5	47.1

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 1 and 2

Top of page

End point title

Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 1 and 2 ^[3]

End point description

WOMAC is used to assess pain, stiffness, and physical function in subjects with hip and/or knee osteoarthritis (OA). It consists of 24 items divided into 3 subscales: Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing; Stiffness (2 items): after first waking and later in the day; Physical Function (17 items): stair use, rising from sitting, standing, bending, walking, getting in/out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in/out of bath, sitting, getting on / off toilet, heavy household duties, light household duties. Each item was scored on a 5-point Likert scale ranging 0 to 4 and the scores are summed for items in each subscale, with possible ranges as follows: pain score=0-20, stiffness score=0-8, physical function score=0-68. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. ITT population. Here, 'n' = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Month 3 and 6

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is reporting data for all applicable arms.

End point values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo
Number of subjects analysed	24	23	19	11	5	10	7	7
Units: percent change
arithmetic mean (standard deviation)
Month 3 (n=22,19,18,10,5,10,7,6)	-36.55 ( 30.189 )	-35.59 ( 45.713 )	-18.22 ( 48.508 )	-46.44 ( 37.723 )	-27.04 ( 34.262 )	-26.27 ( 64.208 )	-38.09 ( 32.723 )	-20.82 ( 27.887 )
Month 6 (n=22,19,17,8,5,10,5,6)	-40.84 ( 24.783 )	-42.44 ( 56.651 )	-28.63 ( 63.077 )	-44.88 ( 39.702 )	-29.30 ( 41.600 )	-21.22 ( 53.451 )	-42.48 ( 23.602 )	18.15 ( 55.757 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 3

Top of page

End point title

Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 3 ^[4]

End point description

WOMAC is used to assess pain, stiffness, and physical function in subjects with hip and/or knee OA. It consists of 24 items divided into 3 subscales: Pain (5 items): during walking, using stairs, in bed, sitting or lying, and standing; Stiffness (2 items): after first waking and later in the day; Physical Function (17 items): stair use, rising from sitting, standing, bending, walking, getting in/out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in/out of bath, sitting, getting on / off toilet, heavy household duties, light household duties. Each item was scored on a 11-point numeric rating scale ranging 0 to 10 and the scores are summed for items in each subscale, with possible ranges as follows: pain score = 0-50, stiffness score = 0-20, physical function score = 0-170. Higher scores on the WOMAC indicate worse pain, stiffness, and functional limitations. ITT population. Here, 'n' = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Months 3 and 6

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is reporting data for all applicable arms.

End point values	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	18	18	18
Units: percent change
arithmetic mean (standard deviation)
Month 3 (n=18,18,18)	-21.91 ( 33.203 )	-35.58 ( 39.477 )	-36.86 ( 49.661 )
Month 6 (n=16,17,17)	-22.74 ( 35.132 )	-16.47 ( 84.916 )	-42.24 ( 38.514 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Improvement in Patient Global Impression of Change (PGIC) Score at Day 8, Month 1, 3 and 6

Top of page

End point title

Percentage of Subjects With Improvement in Patient Global Impression of Change (PGIC) Score at Day 8, Month 1, 3 and 6 ^[5]

End point description

The questionnaire reflects a subject's belief about the efficacy of treatment. The PGIC is a 7-point scale (1-7) depicting a subject's rating of overall improvement. Subjects rate their change as 1 = "very much improved," 2 = "much improved," 3 = "minimally improved," 4 = "no change," 5 = "minimally worse," 6 = "much worse," or 7 = "very much worse." Lower values represent a better outcome. Analysis was performed on ITT population. Here, 'n' = subjects with available data for each specified category. Data for this endpoint was planned to be collected and reported for Part 3 only.

End point type

Secondary

End point timeframe

Day 8, Month 1, 3 and 6

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is reporting data for all applicable arms.

End point values	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	18	18	18
Units: percentage of subjects
number (not applicable)
Day 8	66.67	83.33	77.78
Month 1	61.11	83.33	72.22
Month 3	66.67	50.00	72.22
Month 6	56.25	64.71	82.35

No statistical analyses for this end point

Secondary: Change From Baseline in Patient Specific Functional Scale (PSFS) Total Score at Months 3 and 6

Top of page

End point title

Change From Baseline in Patient Specific Functional Scale (PSFS) Total Score at Months 3 and 6 ^[6]

End point description

PSFS is a three-item instrument, administered verbally, that is used to evaluate whether a health condition impacts a subject's ability to perform activities that are important to him/her. On the initial assessment, the subject is asked to identify "up to three important activities that you are unable to do or are having difficulty with as a result of your OA." Subject then provides a rating for each item, on an 11-point ordinal scale ranging from 0 ("unable to perform activity") to 10 ("able to perform activity at the same level as before the injury or problem"). During reassessments, the subject is prompted to re-rate the same three activities. The average of up to 3 specific activity scores was recorded, and the range of possible scores is 0 - 10. Total score = sum of activity scores/number of activities. Higher scores indicate less impairment. Analysis was performed on ITT population. Data for this endpoint was planned to be collected and reported for Part 3 only. Here, n = subjec

End point type

Secondary

End point timeframe

Baseline, Months 3 and 6

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is reporting data for all applicable arms.

End point values	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	18	18	18
Units: score on a scale
arithmetic mean (standard deviation)
Month 3 (n = 18, 18, 18)	1.11 ( 1.674 )	1.91 ( 1.427 )	1.23 ( 1.890 )
Month 6 (n = 16, 17, 17)	1.18 ( 1.603 )	1.60 ( 1.645 )	1.86 ( 2.378 )

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Top of page

End point title

Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

End point description

An Adverse Event (AE) was any untoward medical occurrence in a subject administered a pharmaceutical product and which did not necessarily had to have causal relationship with treatment. TEAEs were defined as AEs that occurred or worsened in severity between the first dose of the IMP until the end of follow up. A SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. Analysis was performed on all treated population.

End point type

Secondary

End point timeframe

From Baseline up to Month 6

End point values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	24	23	20	11	5	10	7	7	18	18	18
Units: subjects
Any TEAEs	15	18	15	10	3	8	6	6	16	17	14
Any TESAEs	2	3	1	2	0	0	0	0	1	1	3

No statistical analyses for this end point

Secondary: Maximal VAS Scores During Day 1

Top of page

End point title

Maximal VAS Scores During Day 1

End point description

A 100 mm VAS was used to assess the subject's current pain. The subject rated their current pain from 0 (no pain) to 100 (worst possible pain). A negative value indicates improvement in symptoms. Analysis was performed on ITT population. Here, 'subjects analyzed' = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

0 hour, 0.5 hour, 1.5 hour and 3 hour post-dose on Day 1

End point values	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Number of subjects analysed	24	23	19	11	5	10	7	4	18	18	18
Units: score on a scale
arithmetic mean (standard deviation)	61.29 ( 24.451 )	71.41 ( 24.644 )	28.86 ( 19.866 )	73.45 ( 24.407 )	81.80 ( 34.120 )	69.70 ( 21.756 )	77.86 ( 16.767 )	43.07 ( 26.276 )	22.28 ( 29.416 )	74.58 ( 19.177 )	36.47 ( 23.845 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From Baseline up to Month 6

Adverse event reporting additional description

Analysis was performed on all treated population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Part 1 - MTX-071 Group 1

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 1 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 more minute of pre-treatment with ropivacaine on Day 0 in Part 1.

Reporting group title

Part 1 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 on Day 0 in Part 1.

Reporting group title

Part 2 - MTX-071 Group 1

Reporting group description

Reporting group title

Part 2 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 2 - MTX-071 Group 3

Reporting group description

Reporting group title

Part 2 - MTX-071 Group 4

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 15 minute of pre-treatment with ropivacaine on Day 0 in Part 2.

Reporting group title

Part 2 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 on Day 0 in Part 2.

Reporting group title

Part 3 - MTX-071 Group 1

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group title

Part 3 - MTX-071 Group 2

Reporting group description

Subjects received a single 5 mL IA injection of MTX-071 within 1 minute of pre-treatment with ropivacaine on Day 0 in Part 3.

Reporting group title

Part 3 - Placebo

Reporting group description

Subjects received single IA injection of placebo matched to MTX-071 on Day 0 in Part 3.

Serious adverse events	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 24 (8.33%)	3 / 23 (13.04%)	1 / 20 (5.00%)	2 / 11 (18.18%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	1 / 18 (5.56%)	3 / 18 (16.67%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 24 (4.17%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Knee operation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Knee arthroplasty
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary arterial stent insertion
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Lumbar radiculopathy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Impaired healing
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis ulcerative
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Part 1 - MTX-071 Group 1	Part 1 - MTX-071 Group 2	Part 1 - Placebo	Part 2 - MTX-071 Group 1	Part 2 - MTX-071 Group 2	Part 2 - MTX-071 Group 3	Part 2 - MTX-071 Group 4	Part 2 - Placebo	Part 3 - MTX-071 Group 1	Part 3 - MTX-071 Group 2	Part 3 - Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 24 (62.50%)	18 / 23 (78.26%)	15 / 20 (75.00%)	10 / 11 (90.91%)	3 / 5 (60.00%)	8 / 10 (80.00%)	6 / 7 (85.71%)	6 / 7 (85.71%)	16 / 18 (88.89%)	17 / 18 (94.44%)	14 / 18 (77.78%)
Vascular disorders
Peripheral venous disease
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Blood pressure fluctuation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Blood pressure increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Hypertension
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Surgical and medical procedures
Paronychia drainage
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Postoperative wound complication
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 18 (0.00%)	2 / 18 (11.11%)	1 / 18 (5.56%)
occurrences all number	0	0	2	2	0	0	0	1	0	3	2
Injection site pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 18 (11.11%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	1
Application site joint warmth
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Asthenia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Body temperature increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Chills
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Discomfort
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Epistaxis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Inflammation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Injection site haematoma
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0
Injection site joint swelling
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Peripheral swelling
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Post-acute COVID-19 syndrome
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Pyrexia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Reproductive system and breast disorders
Menopausal symptoms
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Allergic sinusitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Bronchitis
subjects affected / exposed	0 / 24 (0.00%)	3 / 23 (13.04%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	3	0	0	0	0	0	0	0	0	1
Cough
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	2 / 20 (10.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	2 / 18 (11.11%)	1 / 18 (5.56%)
occurrences all number	0	1	3	0	0	0	0	0	0	2	1
Dyspnoea
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	1	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	2	1	0
Throat irritation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Psychiatric disorders
Depressed mood
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Insomnia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Restlessness
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	4	0	0	0
Sleep disorder
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Injury
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Multiple injuries
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Wound
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 18 (11.11%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	1
Contusion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1
Haematoma
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Rib fracture
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Scar pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Extrasystoles
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Tachycardia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	2 / 24 (8.33%)	6 / 23 (26.09%)	3 / 20 (15.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	4 / 7 (57.14%)	5 / 18 (27.78%)	4 / 18 (22.22%)	2 / 18 (11.11%)
occurrences all number	3	6	6	2	0	1	1	10	13	9	9
Dizziness
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0
Lumbar spinal stenosis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Stress
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 18 (11.11%)	1 / 18 (5.56%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	2	1	1
Sciatica
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	2 / 18 (11.11%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Anxiety
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0
Burning feet syndrome
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Lumbar radiculopathy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Peripheral nerve paresis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Polyneuropathy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Blood and lymphatic system disorders
White blood cell count increased
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0
Iron deficiency anaemia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Eye disorders
Cataract
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	2
Foreign body in eye
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Diabetic retinopathy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0
Eye disorder
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Maculopathy
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	0 / 24 (0.00%)	1 / 23 (4.35%)	2 / 20 (10.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	1	2	1	0	0	1	0	0	0	0
Toothache
subjects affected / exposed	0 / 24 (0.00%)	2 / 23 (8.70%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	2	1	0	0	0	1	0	0	1	0
Dental care
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Diarrhoea
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	3 / 18 (16.67%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	3	0
Procedural pain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Tooth extraction
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Vomiting
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	2 / 18 (11.11%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Abdominal pain upper
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Colitis ulcerative
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0
Diverticulitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Flatulence
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Pharyngeal paraesthesia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Hepatobiliary disorders
Liver disorder
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Feeling hot
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	2	1	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Rash
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Dermatitis allergic
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	0
Erythema nodosum
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Renal and urinary disorders
Bladder irritation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Cystitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Gallbladder disorder
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Endocrine disorders
Basedow's disease
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Blood glucose increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 24 (8.33%)	4 / 23 (17.39%)	5 / 20 (25.00%)	1 / 11 (9.09%)	2 / 5 (40.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 18 (11.11%)	3 / 18 (16.67%)	2 / 18 (11.11%)
occurrences all number	2	6	5	1	4	1	0	0	3	3	2
Osteoarthritis
subjects affected / exposed	2 / 24 (8.33%)	1 / 23 (4.35%)	2 / 20 (10.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 18 (5.56%)	1 / 18 (5.56%)	1 / 18 (5.56%)
occurrences all number	2	1	5	0	1	2	1	0	1	1	1
Pain in extremity
subjects affected / exposed	1 / 24 (4.17%)	2 / 23 (8.70%)	1 / 20 (5.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 18 (11.11%)	3 / 18 (16.67%)	1 / 18 (5.56%)
occurrences all number	1	2	1	0	0	0	1	0	4	7	1
Joint dislocation
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0
Knee arthroplasty
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Myalgia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Restless legs syndrome
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Joint effusion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	2 / 18 (11.11%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	1	2	1
Joint swelling
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	2 / 18 (11.11%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	3	0
Trigger finger
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1
Intervertebral disc protrusion
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Muscle strain
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Periarthritis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5
Rotator cuff syndrome
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Arthralgia (Knee pain)
subjects affected / exposed	4 / 24 (16.67%)	4 / 23 (17.39%)	5 / 20 (25.00%)	5 / 11 (45.45%)	1 / 5 (20.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 7 (14.29%)	5 / 18 (27.78%)	1 / 18 (5.56%)	1 / 18 (5.56%)
occurrences all number	5	4	8	7	1	1	0	1	5	1	1
Arthralgia (Gonalgia)
subjects affected / exposed	2 / 24 (8.33%)	0 / 23 (0.00%)	1 / 20 (5.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	4 / 10 (40.00%)	1 / 7 (14.29%)	1 / 7 (14.29%)	3 / 18 (16.67%)	1 / 18 (5.56%)	1 / 18 (5.56%)
occurrences all number	2	0	1	2	0	8	2	1	7	1	5
Arthralgia (Pain in knee)
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	2 / 18 (11.11%)	2 / 18 (11.11%)
occurrences all number	0	0	0	1	0	0	0	0	1	2	2
Arthralgia (Coxalgia)
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 18 (11.11%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	5	2	0
Arthralgia (Shoulder pain)
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 18 (11.11%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	1	0
Arthralgia (Arthralgia aggravated)
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Arthralgia (Pain in hip)
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Arthralgia (Pain in joint involving shoulder region)
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 24 (4.17%)	2 / 23 (8.70%)	3 / 20 (15.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 18 (5.56%)	4 / 18 (22.22%)	0 / 18 (0.00%)
occurrences all number	1	2	4	0	0	0	1	0	1	4	0
Influenza
subjects affected / exposed	2 / 24 (8.33%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	2 / 18 (11.11%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	3	0
Oral herpes
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	1 / 5 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1
Viral infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0
COVID-19
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 18 (5.56%)	5 / 18 (27.78%)	4 / 18 (22.22%)
occurrences all number	0	0	0	0	0	0	0	0	1	5	4
Herpes zoster
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1
Bone marrow oedema
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Coronavirus infection
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Tracheitis
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)	0 / 18 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	1 / 11 (9.09%)	0 / 5 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Hypercholesterolaemia
subjects affected / exposed	0 / 24 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)	0 / 11 (0.00%)	0 / 5 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 18 (0.00%)	0 / 18 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

22 Nov 2018

Following changes were made: • The trial was extended to trial sites in Croatia; In some parts of the protocol, the IMP was called “MTX-071”, which could have been interpreted as relating only to verum. To clarify, “MTX-071” was replaced by “MTX-071/placebo”; The time window for administration of IMP, which was already described in the information for the pharmacist, was added to the protocol; The determination of postmenopausal women was initially defined as “no menses for at least 24 months”; however, a follicle-stimulating hormone test was planned and mentioned in Section 8.3.10.7: laboratory assessments. The definition “postmenopausal as confirmed by follicle-stimulating hormone level” was added: contraceptive measures; Investigational medicinal product transport from the pharmacy to the trial sites was accepted in a ready-made syringe instead of the glass vial. This change was made upon advice from the participating pharmacists and investigators; A clarification was added to the randomisation numbers table indicating that it was just illustrating the principle and did not show the actual randomization numbers.

04 Feb 2019

Following changes were made: The trial was extended to trial sites in Austria and Croatia; A blinded interim analysis was planned with the first 3 subjects of each trial site (in total 9 subjects). As the number of trial sites had increased, the definition of the subjects to be analysed was changed to first 3 subjects of 3 trial sites; The time window for administration of premedication was aligned in different sections in the protocol.

12 Jul 2019

Following changes were done: The trial was extended to include administration of higher doses of RTX-GRT7039 (that had already been used in a Phase I trial) and a consecutive injection with a local anesthetic; The number of subjects to be included in Part 2 of the trial was added together with the planned treatment groups; An unblinded interim analysis (with no hold) of the efficacy (VAS) data of Part 1 was included to evaluate the evolution of the trial. The interim analysis was to take place after all subjects completed the 3-month VAS assessment; An option was added to perform the follow-up remotely.

19 Dec 2019

Following change was done: Voluntary blood sampling for pharmacokinetics at several timepoints on the day of injection was added for up to 7 subjects in Part 2.

13 Apr 2021

Following changes were done: The trial was extended with Part 3, to include an additional 60 subjects who were to receive RTX-GRT7039 or placebo consecutively with a local anesthetic; Two additional questionnaires (PGIC and PSFS) were added to investigate the effect of treatment on knee joint pain, compared to placebo; Subjects included in Part 3 of the trial were given the opportunity to receive a second injection with RTX-GRT7039 in case of recurring knee pain 6 months or 9 months after the first injection; The documentation of knee pain in the subject diary was changed to a weekly basis instead of a monthly basis; The documentation of knee pain at the trial site was updated to include the pain in the contra-lateral knee for at least 3 visits.

31 Aug 2021

Following changes were made: Voluntary blood sampling for pharmacokinetics at several timepoints on the day of injection was added for a minimum of 9 subjects in Part 3; The additional exploratory objectives and endpoints were updated to reflect the collection and analysis of blood samples for pharmacokinetics in Part 3.

30 Mar 2022

Following changes were made: The sponsor was changed from Mestex AG, Klosterberg 11, CH-4051 Basel, Switzerland to Grünenthal GmbH, 52099 Aachen, Germany; effective as of 01 Apr 2022. Associated changes to the author and key trial personnel were made; The IMP packaging and labeling information presented in the protocol were updated; The safety reporting procedure was adapted as Grünenthal Global Drug Safety prepared to takeover reporting to the competent authorities (safety reporting takeover took place on 28 Apr 2022) while the Safety Unit at QPS performed reporting to the ethics committee and investigators; The description of IMP handling in the protocol was updated with subsequent section renumbering.

18 Aug 2022

Following changes were made: The coordinating investigator was changed, and the respective details were updated: The medical monitor was changed, and the respective details were updated; The name and function on the sponsor signature page was changed.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Absolute Reduction From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Primary: Absolute Reduction From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Primary: Percent Change From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Primary: Percent Change From Baseline in the Visual Analog Scale (VAS) Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Secondary: Percentage of Subjects With Greater Than or Equal to (>=) 50% and >= 70% Decrease From Baseline in VAS Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Secondary: Percentage of Subjects With Greater Than or Equal to (>=) 50% and >= 70% Decrease From Baseline in VAS Scores for Pain on Motion in the Target Knee Joint at Months 3 and 6

Secondary: Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 1 and 2

Secondary: Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 1 and 2

Secondary: Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 3

Secondary: Percent Change From Baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Total Scores at Months 3 and 6: Part 3

Secondary: Percentage of Subjects With Improvement in Patient Global Impression of Change (PGIC) Score at Day 8, Month 1, 3 and 6

Secondary: Percentage of Subjects With Improvement in Patient Global Impression of Change (PGIC) Score at Day 8, Month 1, 3 and 6

Secondary: Change From Baseline in Patient Specific Functional Scale (PSFS) Total Score at Months 3 and 6

Secondary: Change From Baseline in Patient Specific Functional Scale (PSFS) Total Score at Months 3 and 6

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Secondary: Maximal VAS Scores During Day 1

Secondary: Maximal VAS Scores During Day 1

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA