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

Primary Purpose

Bilateral Blepharospasm (BEB)

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
IncobulinumtoxinA (Xeomin), 25 Units
IncobotulinumtoxinA (Xeomin), 12.5 Units
Placebo
IncobotulinumtoxinA (Xeomin), 35 Units
Sponsored by
Merz Pharmaceuticals GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bilateral Blepharospasm (BEB)

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Merz Investigational Site #030002
  • Merz Investigational Site #030001
  • Merz Investigational Site #060007
  • Merz Investigational Site #060004
  • Merz Investigational Site #060006
  • Merz Investigational Site #060002
  • Merz Investigational Site #060003
  • Merz Investigational Site #094001
  • Merz Investigational Site #094005
  • Merz Investigational Site #094006
  • Merz Investigational Site #094002

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

IncobotulinumtoxinA (Xeomin) 25U per eye

IncobotulinumtoxinA (Xeomin) 12.5U per eye

Placebo

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Double-blind MP: Change From Baseline in JRS Severity Subscore at 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

Double-blind MP: Change From Baseline in Blepharospasm Disability Index (BSDI) at 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.
Double-blind MP: Patient Evaluation of Global Response (PEGR) at 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.

Full Information

First Posted
July 8, 2013
Last Updated
February 28, 2018
Sponsor
Merz Pharmaceuticals GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT01896895
Brief Title
Efficacy and Safety Study of Botulinum Toxin Type A Against Placebo to Treat Abnormal Contraction or Twitch of the Eyelid
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 Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
November 2013 (undefined)
Primary Completion Date
April 2016 (Actual)
Study Completion Date
November 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merz Pharmaceuticals GmbH

4. Oversight

Data Monitoring Committee
No

5. 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.
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bilateral Blepharospasm (BEB)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
61 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IncobotulinumtoxinA (Xeomin) 25U per eye
Arm Type
Experimental
Arm Description
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.
Arm Title
IncobotulinumtoxinA (Xeomin) 12.5U per eye
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
IncobulinumtoxinA (Xeomin), 25 Units
Other Intervention Name(s)
NT 201, Xeomin, Botulinum toxin type A (150 kiloDalton), free from complexing proteins
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
IncobotulinumtoxinA (Xeomin), 12.5 Units
Other Intervention Name(s)
NT 201, Xeomin, Botulinum toxin type A (150 kiloDalton), free from complexing proteins
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Main Period: Placebo to IncobotulinumtoxinA (Xeomin), powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl).
Intervention Type
Drug
Intervention Name(s)
IncobotulinumtoxinA (Xeomin), 35 Units
Other Intervention Name(s)
NT 201, Xeomin, Botulinum toxin type A (150 kiloDalton), free from complexing proteins
Intervention Description
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.
Primary Outcome Measure Information:
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)
Secondary Outcome Measure Information:
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)
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Merz Medical Expert
Organizational Affiliation
Merz Pharmaceuticals GmbH
Official's Role
Study Director
Facility Information:
Facility Name
Merz Investigational Site #030002
City
Athens
ZIP/Postal Code
11521
Country
Greece
Facility Name
Merz Investigational Site #030001
City
Athens
ZIP/Postal Code
11526
Country
Greece
Facility Name
Merz Investigational Site #060007
City
Georgetown
State/Province
Penang
ZIP/Postal Code
10990
Country
Malaysia
Facility Name
Merz Investigational Site #060004
City
Kota Kinabalu
State/Province
Sabah
ZIP/Postal Code
88586
Country
Malaysia
Facility Name
Merz Investigational Site #060006
City
Kuala Lumpur
ZIP/Postal Code
50586
Country
Malaysia
Facility Name
Merz Investigational Site #060002
City
Kuala Lumpur
ZIP/Postal Code
56000
Country
Malaysia
Facility Name
Merz Investigational Site #060003
City
Selangor
ZIP/Postal Code
43000
Country
Malaysia
Facility Name
Merz Investigational Site #094001
City
Colombo
ZIP/Postal Code
07
Country
Sri Lanka
Facility Name
Merz Investigational Site #094005
City
Colombo
ZIP/Postal Code
10350
Country
Sri Lanka
Facility Name
Merz Investigational Site #094006
City
Kurunegala
ZIP/Postal Code
60000
Country
Sri Lanka
Facility Name
Merz Investigational Site #094002
City
Nugegoda
ZIP/Postal Code
10250
Country
Sri Lanka

12. IPD Sharing Statement

Citations:
PubMed Identifier
34384301
Citation
Mitsikostas DD, Dekundy A, Hanschmann A, Althaus M, Scheschonka A, Pagan F, Jankovic J. Duration and onset of effect of incobotulinumtoxinA for the treatment of blepharospasm in botulinum toxin-naive subjects. Curr Med Res Opin. 2021 Oct;37(10):1761-1768. doi: 10.1080/03007995.2021.1965975. Epub 2021 Aug 24.
Results Reference
derived
PubMed Identifier
33211907
Citation
Duarte GS, Rodrigues FB, Marques RE, Castelao M, Ferreira J, Sampaio C, Moore AP, Costa J. Botulinum toxin type A therapy for blepharospasm. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD004900. doi: 10.1002/14651858.CD004900.pub3.
Results Reference
derived
PubMed Identifier
32779096
Citation
Mitsikostas DD, Dekundy A, Sternberg K, Althaus M, Pagan F. IncobotulinumtoxinA for the Treatment of Blepharospasm in Toxin-Naive Subjects: A Multi-Center, Double-Blind, Randomized, Placebo-Controlled Trial. Adv Ther. 2020 Oct;37(10):4249-4265. doi: 10.1007/s12325-020-01427-6. Epub 2020 Aug 10.
Results Reference
derived

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

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