Efficacy and Safety Study of Botulinum Toxin Type A Against Placebo to Treat Abnormal Contraction or Twitch of the Eyelid

• Sponsor: Merz Pharmaceuticals GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01896895
• Collaborator: (none)
• Enrollment: 61
• Locations: 11
• Arms: 3
• Duration (Months): 36
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase 3 study will serve to collect efficacy and safety data of two different doses of NT 201 in subjects suffering from Bilateral Blepharospasm (BEB) who are BTX treatment-naïve.

In this study, BTX treatment-naïve subjects are defined as those who have not received BTX treatment within the last 12 months for the treatment of BEB. This definition aims to avoid bias by comparison of treatment effects in the subject's assessments. Furthermore, this study will substantiate the existing efficacy and safety database for the indication BEB.

Condition or Disease	Intervention/Treatment	Phase
Bilateral Blepharospasm (BEB)	Drug: IncobulinumtoxinA (Xeomin), 25 Units; Drug: IncobotulinumtoxinA (Xeomin), 12.5 Units; Drug: Placebo; Drug: IncobotulinumtoxinA (Xeomin), 35 Units	Phase 3

Detailed Description

Subjects to receive one injection with NT 201 or placebo at baseline of the placebo-controlled first cycle. Thereafter, all subjects entering the Open-Label Extension Period (OLEX) to receive a second injection of NT 201 (second injection cycle).

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Prospective, Double-blind, Placebo-controlled, Randomized, Parallel-group, Multi-center Study With an Open-label Extension Period to Investigate the Efficacy and Safety of Two Different Doses of NT 201 in Botulinum Toxin Treatment-naïve Subjects With Blepharospasm
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IncobotulinumtoxinA (Xeomin) 25U per eye Main Period: one injection session, 25 Units per eye. Open-Label Extension: one injection session, up to 35 Units per eye. Mode of administration: intramuscular injection.	Drug: IncobulinumtoxinA (Xeomin), 25 Units; IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Main Period: 25 Units per eye.; Other Names: NT 201 Xeomin Botulinum toxin type A (150 kiloDalton), free from complexing proteins ; Drug: IncobotulinumtoxinA (Xeomin), 35 Units; IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Open-Label Extension: up to 35 Units per eye.; Other Names: NT 201 Xeomin Botulinum toxin type A (150 kiloDalton), free from complexing proteins
Experimental: IncobotulinumtoxinA (Xeomin) 12.5U per eye Main Period: one injection session, 12.5 Units per eye. Open-Label Extension Period: one injection session, up to 35 Units per eye. Mode of administration: intramuscular injection.	Drug: IncobotulinumtoxinA (Xeomin), 12.5 Units; IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Main Period: 12.5 Units per eye.; Other Names: NT 201 Xeomin Botulinum toxin type A (150 kiloDalton), free from complexing proteins ; Drug: IncobotulinumtoxinA (Xeomin), 35 Units; IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Open-Label Extension: up to 35 Units per eye.; Other Names: NT 201 Xeomin Botulinum toxin type A (150 kiloDalton), free from complexing proteins
Placebo Comparator: Placebo Main Period: Placebo to IncobotulinumtoxinA (Xeomin)(12.5 or 25U/eye), one injection session. Open-Label Extension: IncobotulinumtoxinA (Xeomin), one injection session, up to 35 Units per eye. Mode of administration: intramuscular injection.	Drug: Placebo; Main Period: Placebo to IncobotulinumtoxinA (Xeomin), powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).; Drug: IncobotulinumtoxinA (Xeomin), 35 Units; IncobotulinumtoxinA (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). Open-Label Extension: up to 35 Units per eye.; Other Names: NT 201 Xeomin Botulinum toxin type A (150 kiloDalton), free from complexing proteins

Outcome Measures

Primary Outcome Measures

1. Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4) [Baseline, Day 43 (Visit 4)]

   JRS severity subscore was used to classify individual symptoms of blepharospasm and to determine therapeutic efficacy. JRS severity subscore ranges from 0 to 4, where 0: None; 1: increased blinking present with external stimuli; 2: Mild but spontaneous eyelid fluttering, definitely noticeable, possibly embarrassing, but not functionally disabling, 3: Moderate, very noticeable spasm of eyelids only, mildly incapacitating, 4: Severe, incapacitating spasm of eyelids and possibly other facial muscles. Values represent least square (LS) mean differences between baseline and visit 4 resulting from analysis of covariance (ANCOVA) with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates and missings replaced using the last observation carried forward (LOCF) method. Negative values denote improvement, while positive values denote deterioration vs. baseline.

Secondary Outcome Measures

1. Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4) [Baseline, Day 43 (Visit 4)]

   BSDI is a scale for assessment of impairment of specific activities of daily living caused by blepharospasm. BSDI consists of six items (driving a vehicle; reading; watching TV; shopping; getting about on foot (walking); doing everyday activities), each ranging from 0 (=no impairment) to 4 (=no longer possible due to illness). The BSDI total score is a mean score for non-missing items ranging from 0 to 4. It is calculated by adding scores of all applicable and answered items, and dividing the resulting sum by the number of items answered. Outcome values represent LS mean differences between baseline and visit 4 (visit 4 value minus baseline value) resulting from ANCOVA with treatment group, pooled site, gender as fixed factors and baseline BSDI total score, age as covariates. Missings were replaced by the LOCF method. Negative values denote an improvement, while positive values denote deterioration vs. baseline.

2. Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141) [Baseline, Final Visit (Day 43-Day 141)]

   PEGR scale is a descriptive subjective 9-point response self-rating scale ranging from "complete abolishment of signs and symptoms" (value=+4) down to "very marked worsening" (value=-4). Outcome values represent least square means at visit 4 resulting from an ANCOVA with treatment group, pooled site, gender as fixed factors and age as covariates. Missing were set to a zero effect (value=0). Positive values denote an improvement, while negative values denote deterioration.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female out-patients age ≥ 18 and ≤ 80 years.

• A clinical diagnosis of bilateral BEB characterized by spontaneous, spasmodic, intermittent or persistent involuntary contractions of orbicular oculi muscles.

• A need for injection of BTX defined as a Jankovic Rating Scale [JRS] severity subscore ≥ 2.

• Treatment-naïve subject defined as at least 12 months without BTX of any serotype for the treatment of BEB before administration of IP.

Exclusion Criteria:

• Subject with any previous unsuccessful treatment with BTX of any serotype for the treatment of BEB.

• Atypical variant of BEB (e.g., apraxia of the eyelid opening) caused by inhibition of levator palpebrae muscle.

• Neuroleptic-induced blepharospasm.

• Myotomy or denervation surgery in the affected muscles (e.g., peripheral denervation, spinal cord stimulation) and surgery in the upper face.

• Generalized disorders of muscles activity (e.g., myasthenia gravis in particular ocularis, Lambert-Eaton-Syndrome, amyotrophic lateral sclerosis) or any other significant neuromuscular dysfunction which might interfere with the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Merz Investigational Site #030002	Athens		Greece	11521
2	Merz Investigational Site #030001	Athens		Greece	11526
3	Merz Investigational Site #060007	Georgetown	Penang	Malaysia	10990
4	Merz Investigational Site #060004	Kota Kinabalu	Sabah	Malaysia	88586
5	Merz Investigational Site #060006	Kuala Lumpur		Malaysia	50586
6	Merz Investigational Site #060002	Kuala Lumpur		Malaysia	56000
7	Merz Investigational Site #060003	Selangor		Malaysia	43000
8	Merz Investigational Site #094001	Colombo		Sri Lanka	07
9	Merz Investigational Site #094005	Colombo		Sri Lanka	10350
10	Merz Investigational Site #094006	Kurunegala		Sri Lanka	60000
11	Merz Investigational Site #094002	Nugegoda		Sri Lanka	10250

Sponsors and Collaborators

• Merz Pharmaceuticals GmbH

Investigators

• Study Director: Merz Medical Expert, Merz Pharmaceuticals GmbH

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merz Pharmaceuticals GmbH
• ClinicalTrials.gov Identifier: NCT01896895
• Other Study ID Numbers: MRZ60201_3074_1; 2012-004821-26
• First Posted: Jul 11, 2013
• Last Update Posted: Mar 1, 2018
• Last Verified: Jan 1, 2018

• Additional relevant MeSH terms: Blepharospasm; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; incobotulinumtoxinA

Study Results

Participant Flow

Pre-assignment Detail	A total of 68 participants were screened, 61 were enrolled and treated of which 55 completed the double-blind main period (MP). 39 participants from the double-blind MP entered the Open label Extension (OLEX) period and completed the study.

Arm/Group Title	Double-blind MP: Placebo	Double-blind MP: IncobotulinumtoxinA 25 Units	Double-blind MP: IncobotulinumtoxinA 50 Units	OLEX: IncobotulinumtoxinA 70 Units
Arm/Group Description	Participants received 1.0 milliliter (mL) placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received up to 1.4 mL of incobotulinumtoxinA containing up to 70 units per injection session (35 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the OLEX Period.
Period Title: Double-blind MP
STARTED	20	22	19	0
COMPLETED	19	20	16	0
NOT COMPLETED	1	2	3	0
Period Title: Double-blind MP
STARTED	0	0	0	39
COMPLETED	0	0	0	39
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Double-blind MP: Placebo	Double-blind MP: IncobotulinumtoxinA 25 Units	Double-blind MP: IncobotulinumtoxinA 50 Units	Total
Arm/Group Description	Participants received 1.0 mL placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Total of all reporting groups
Overall Participants	20	22	19	61
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	17 85%	13 59.1%	14 73.7%	44 72.1%
>=65 years	3 15%	9 40.9%	5 26.3%	17 27.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.4 (12.01)	55.8 (15.70)	53.5 (13.82)	55.0 (13.79)
Sex: Female, Male (Count of Participants)
Female	12 60%	11 50%	13 68.4%	36 59%
Male	8 40%	11 50%	6 31.6%	25 41%
Region of Enrollment (participants) [Number]
Greece	4 20%	6 27.3%	4 21.1%	14 23%
Sri Lanka	10 50%	10 45.5%	10 52.6%	30 49.2%
Malaysia	6 30%	6 27.3%	5 26.3%	17 27.9%

Outcome Measures

1. Primary Outcome

Title	Double-blind MP: Change From Baseline in JRS Severity Subscore at Day 43 (Visit 4)
Description	JRS severity subscore was used to classify individual symptoms of blepharospasm and to determine therapeutic efficacy. JRS severity subscore ranges from 0 to 4, where 0: None; 1: increased blinking present with external stimuli; 2: Mild but spontaneous eyelid fluttering, definitely noticeable, possibly embarrassing, but not functionally disabling, 3: Moderate, very noticeable spasm of eyelids only, mildly incapacitating, 4: Severe, incapacitating spasm of eyelids and possibly other facial muscles. Values represent least square (LS) mean differences between baseline and visit 4 resulting from analysis of covariance (ANCOVA) with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates and missings replaced using the last observation carried forward (LOCF) method. Negative values denote improvement, while positive values denote deterioration vs. baseline.
Time Frame	Baseline, Day 43 (Visit 4)

Outcome Measure Data

Analysis Population Description

FAS was subset of participants in the SES of the double-blind MP for whom at least a baseline value of the JRS severity subscore was available.

Arm/Group Title	Double-blind MP: Placebo	Double-blind MP: IncobotulinumtoxinA 25 Units	Double-blind MP: IncobotulinumtoxinA 50 Units
Arm/Group Description	Participants received 1.0 mL placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.
Measure Participants	20	22	19
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.6	-1.0	-1.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind MP: Placebo, Double-blind MP: IncobotulinumtoxinA 50 Units
	Comments	The difference in change of JRS severity subscore between treatment groups was analyzed by an ANCOVA according to a hierarchical test procedure. First step of hierarchy is hypothesis of superiority of 50 unit dose group NT 201 compared to placebo. This was tested confirmatory (α=0.05, 2-sided) by an ANCOVA with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates based on LS means comparison. Missing values were imputed by LOCF.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.0004
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -1.9 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-blind MP: Placebo, Double-blind MP: IncobotulinumtoxinA 25 Units
	Comments	The difference in change of JRS severity subscore between treatment groups was analyzed by an ANCOVA according to a hierarchical test procedure. Second step of hierarchy is hypothesis of superiority of 25 unit dose group NT 201 compared to placebo. This was tested confirmatory (α=0.05, 2-sided) by an ANCOVA with treatment group, pooled site, and gender as fixed factors and baseline JRS severity subscore and age as covariates based on LS means comparison. Missing values were imputed by LOCF.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.1452
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.1 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at Day 43 (Visit 4)
Description	BSDI is a scale for assessment of impairment of specific activities of daily living caused by blepharospasm. BSDI consists of six items (driving a vehicle; reading; watching TV; shopping; getting about on foot (walking); doing everyday activities), each ranging from 0 (=no impairment) to 4 (=no longer possible due to illness). The BSDI total score is a mean score for non-missing items ranging from 0 to 4. It is calculated by adding scores of all applicable and answered items, and dividing the resulting sum by the number of items answered. Outcome values represent LS mean differences between baseline and visit 4 (visit 4 value minus baseline value) resulting from ANCOVA with treatment group, pooled site, gender as fixed factors and baseline BSDI total score, age as covariates. Missings were replaced by the LOCF method. Negative values denote an improvement, while positive values denote deterioration vs. baseline.
Time Frame	Baseline, Day 43 (Visit 4)

Outcome Measure Data

Analysis Population Description

FAS was subset of participants in the SES of the double-blind MP for whom at least a baseline value of the JRS severity subscore was available.

Arm/Group Title	Double-blind MP: Placebo	Double-blind MP: IncobotulinumtoxinA 25 Units	Double-blind MP: IncobotulinumtoxinA 50 Units
Arm/Group Description	Participants received 1.0 mL placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.
Measure Participants	20	22	19
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.4	-0.5	-0.7

3. Secondary Outcome

Title	Double-blind MP: Patient Evaluation of Global Response (PEGR) at Final Visit (Day 43-Day 141)
Description	PEGR scale is a descriptive subjective 9-point response self-rating scale ranging from "complete abolishment of signs and symptoms" (value=+4) down to "very marked worsening" (value=-4). Outcome values represent least square means at visit 4 resulting from an ANCOVA with treatment group, pooled site, gender as fixed factors and age as covariates. Missing were set to a zero effect (value=0). Positive values denote an improvement, while negative values denote deterioration.
Time Frame	Baseline, Final Visit (Day 43-Day 141)

Outcome Measure Data

Analysis Population Description

FAS was subset of participants in the SES of the double-blind MP for whom at least a baseline value of the JRS severity subscore was available.

Arm/Group Title	Double-blind MP: Placebo	Double-blind MP: IncobotulinumtoxinA 25 Units	Double-blind MP: IncobotulinumtoxinA 50 Units
Arm/Group Description	Participants received 1.0 mL placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.	Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.
Measure Participants	20	22	19
Least Squares Mean (95% Confidence Interval) [score on a scale]	1.3	1.8	2.2

Adverse Events

Time Frame	Double-blind MP: From the time point of first injection up to final visit (Day 43 to 141); OLEX Period: From the time point of first injection up to end of study visit (Day 43 to 141)
Adverse Event Reporting Description	Adverse events were collected systematically at each visit by the investigator.
Arm/Group Title	Double-blind MP: Placebo		Double-blind MP: IncobotulinumtoxinA 25 Units		Double-blind MP: IncobotulinumtoxinA 50 Units		OLEX: IncobotulinumtoxinA 70 Units
Arm/Group Description	Participants received 1.0 mL placebo matched to the volume of incobotulinumtoxinA doses per injection session via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.		Participants received 1.0 mL of incobotulinumtoxinA containing 25 units per injection session (12.5 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.		Participants received 1.0 mL of incobotulinumtoxinA containing 50 units per injection session (25 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the double-blind MP.		Participants received up to 1.4 mL of incobotulinumtoxinA containing up to 70 units per injection session (35 units per eye) via intramuscular injections into orbicular oculi muscles on Day 1 in the OLEX Period.
All Cause Mortality
	Double-blind MP: Placebo		Double-blind MP: IncobotulinumtoxinA 25 Units		Double-blind MP: IncobotulinumtoxinA 50 Units		OLEX: IncobotulinumtoxinA 70 Units
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/22 (0%)		0/19 (0%)		0/39 (0%)
Serious Adverse Events
	Double-blind MP: Placebo		Double-blind MP: IncobotulinumtoxinA 25 Units		Double-blind MP: IncobotulinumtoxinA 50 Units		OLEX: IncobotulinumtoxinA 70 Units
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		2/22 (9.1%)		1/19 (5.3%)		0/39 (0%)
Cardiac disorders
Acute myocardial infarction	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Atrioventricular block complete	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Endocrine disorders
Goitre	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Other (Not Including Serious) Adverse Events
	Double-blind MP: Placebo		Double-blind MP: IncobotulinumtoxinA 25 Units		Double-blind MP: IncobotulinumtoxinA 50 Units		OLEX: IncobotulinumtoxinA 70 Units
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/20 (30%)		7/22 (31.8%)		7/19 (36.8%)		4/39 (10.3%)
Eye disorders
Eyelid ptosis	0/20 (0%)	0	2/22 (9.1%)	2	3/19 (15.8%)	3	2/39 (5.1%)	2
Blepharospasm	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Eye irritation	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Eye pruritus	1/20 (5%)	1	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Eye swelling	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Eyelid disorder	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Eyelid function disorder	1/20 (5%)	1	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Ocular hyperaemia	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Vision blurred	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Blepharitis	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Dry eye	2/20 (10%)	2	0/22 (0%)	0	0/19 (0%)	0	2/39 (5.1%)	2
Periorbital oedema	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Gastritis	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
General disorders
Injection site erythema	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Injection site swelling	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Pyrexia	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Hepatic steatosis	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Infections and infestations
Rhinitis	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Upper respiratory tract infection	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Investigations
Blood creatine increased	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Metabolism and nutrition disorders
Dyslipidaemia	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)	1	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Muscular weakness	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Pain in extremity	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Nervous system disorders
Hypoaesthesia	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Headache	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Skin and subcutaneous tissue disorders
Eczema	0/20 (0%)	0	0/22 (0%)	0	1/19 (5.3%)	1	0/39 (0%)	0
Pruritus	0/20 (0%)	0	1/22 (4.5%)	1	0/19 (0%)	0	0/39 (0%)	0
Pruritus generalised	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0
Rash	1/20 (5%)	1	0/22 (0%)	0	0/19 (0%)	0	0/39 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Publication of study information usually requires agreement with the sponsor. In case of justified doubts by the sponsor, the INVESTIGATOR will consider these doubts in the publication as long as the scientific neutrality is not affected.