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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-004821-26 | EudraCT Number |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IncobotulinumtoxinA (Xeomin) 25U per eye | Experimental | 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. |
|
| IncobotulinumtoxinA (Xeomin) 12.5U per eye | Experimental | 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. |
|
| Placebo | Placebo Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| IncobulinumtoxinA (Xeomin), 25 Units | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline, Day 43 (Visit 4) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Merz Medical Expert | Merz Pharmaceuticals GmbH | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Merz Investigational Site #030002 | Athens | 11521 | Greece | |||
| Merz Investigational Site #030001 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34384301 | Derived | 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. | |
| 33211907 | Derived |
Not provided
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Double-blind MP: Placebo | 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. |
| FG001 | Double-blind MP: IncobotulinumtoxinA 25 Units |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Double-blind MP |
|
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|
|
| IncobotulinumtoxinA (Xeomin), 12.5 Units | Drug | 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. |
|
|
| Placebo | Drug | Main Period: Placebo to IncobotulinumtoxinA (Xeomin), powder for solution for injection, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl). |
|
| IncobotulinumtoxinA (Xeomin), 35 Units | Drug | 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. |
|
|
| Baseline, Day 43 (Visit 4) |
| 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. | Baseline, Final Visit (Day 43-Day 141) |
| Athens |
| 11526 |
| Greece |
| Merz Investigational Site #060007 | George Town | Pulau Pinang | 10990 | Malaysia |
| Merz Investigational Site #060004 | Kota Kinabalu | Sabah | 88586 | Malaysia |
| Merz Investigational Site #060006 | Kuala Lumpur | 50586 | Malaysia |
| Merz Investigational Site #060002 | Kuala Lumpur | 56000 | Malaysia |
| Merz Investigational Site #060003 | Kuala Selangor | 43000 | Malaysia |
| Merz Investigational Site #094001 | Colombo | 07 | Sri Lanka |
| Merz Investigational Site #094005 | Colombo | 10350 | Sri Lanka |
| Merz Investigational Site #094006 | Kurunegala | 60000 | Sri Lanka |
| Merz Investigational Site #094002 | Nugegoda | 10250 | Sri Lanka |
| 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. |
| 32779096 | Derived | 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. |
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. |
| FG002 | Double-blind MP: IncobotulinumtoxinA 50 Units | 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. |
| FG003 | OLEX: IncobotulinumtoxinA 70 Units | 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
|
| OLEX Period |
|
Full analysis set (FAS) was subset of participants in the safety evaluation set (SES) of the double-blind MP for whom at least a baseline value of the Jankovic Rating Scale (JRS) severity subscore was available.
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| ID | Title | Description |
|---|---|---|
| BG000 | Double-blind MP: Placebo | 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. |
| BG001 | Double-blind MP: IncobotulinumtoxinA 25 Units | 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. |
| BG002 | Double-blind MP: IncobotulinumtoxinA 50 Units | 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. |
| BG003 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Day 43 (Visit 4) |
|
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|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Day 43 (Visit 4) |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | score on a scale | Baseline, Final Visit (Day 43-Day 141) |
|
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 events were collected systematically at each visit by the investigator.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Double-blind MP: Placebo | 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. | 0 | 20 | 0 | 20 | 6 | 20 |
| EG001 | Double-blind MP: IncobotulinumtoxinA 25 Units | 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. | 0 | 22 | 2 | 22 | 7 | 22 |
| EG002 | Double-blind MP: IncobotulinumtoxinA 50 Units | 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. | 0 | 19 | 1 | 19 | 7 | 19 |
| EG003 | OLEX: IncobotulinumtoxinA 70 Units | 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. | 0 | 39 | 0 | 39 | 4 | 39 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute myocardial infarction | Cardiac disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Atrioventricular block complete | Cardiac disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Goitre | Endocrine disorders | MedDRA (19.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Blood creatine increased | Investigations | MedDRA (19.0) | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Hypoaesthesia | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eyelid ptosis | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Blepharospasm | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eye irritation | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eye pruritus | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eye swelling | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eyelid disorder | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eyelid function disorder | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Ocular hyperaemia | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Vision blurred | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Blepharitis | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Dry eye | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Periorbital oedema | Eye disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Injection site erythema | General disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Injection site swelling | General disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Abdominal pain | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Gastritis | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Cholelithiasis | Hepatobiliary disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Hepatic steatosis | Hepatobiliary disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Eczema | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Dyslipidaemia | Metabolism and nutrition disorders | MedDRA (19.0) | Systematic Assessment |
| |
| Rhinitis | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
|
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Public Disclosure Manager | Merz Pharmaceuticals GmbH | +49 69 1503 1 | clinicaltrials@merz.de |
| ID | Term |
|---|---|
| C545476 | incobotulinumtoxinA |
| D019274 | Botulinum Toxins, Type A |
| ID | Term |
|---|---|
| D001905 | Botulinum Toxins |
| D008666 | Metalloendopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D045726 | Metalloproteases |
| D001426 | Bacterial Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001427 | Bacterial Toxins |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |
Not provided
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| Between 18 and 65 years |
|
| >=65 years |
|
| Male |
|
| Sri Lanka |
|
| Malaysia |
|
| 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. | ANCOVA | =0.1452 | LS mean difference | -0.5 | 2-Sided | 95 | -1.1 | 0.2 | Superiority |
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. |
| OG002 | Double-blind MP: IncobotulinumtoxinA 50 Units | 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. |
|
|
| Double-blind MP: IncobotulinumtoxinA 50 Units |
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. |
|
|