Trial Outcomes & Findings for Efficacy and Safety Study of Botulinum Toxin Type A Against Placebo to Treat Spasticity in the Leg After a Stroke (NCT NCT01464307)

Last Updated: 2016-11-07

Results Overview

The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

290 participants

Primary outcome timeframe

Baseline and Week 4

Results posted on

2016-11-07

Participant Flow

A total of 331 individuals suffering from post-stroke lower-limb spasticity were screened and 290 were included in study at 51 sites. One ineligible subject was randomized to placebo but withdrawn from study prior to first treatment with study medication. For purpose of study analysis overall number of subjects enrolled is therefore considered 289.

A total of 290 subjects were enrolled in study. One ineligible subject was randomized to placebo but withdrawn from study prior to first treatment with study medication. A total of 289 subjects were enrolled in main period. All of the 269 subjects who completed the main period of the study entered the open-label extension period.

Participant milestones

Participant milestones
Measure	IncobotulinumtoxinA (Xeomin) 400 Units IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9 percent (%) Sodium Chloride (NaCl), 400 units, total volume 8.0 milliliter (mL); Mode of administration: intramuscular injection. IncobotulinumtoxinA (400 Units): Open-Label Extension Period: All subjects receive three injection sessions of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Placebo Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Main Period STARTED	144	145
Main Period Treated	144	145
Main Period COMPLETED	129	140
Main Period NOT COMPLETED	15	5
Open-Label Extension Period STARTED	269	0
Open-Label Extension Period Treated	269	0
Open-Label Extension Period COMPLETED	218	0
Open-Label Extension Period NOT COMPLETED	51	0

Reasons for withdrawal

Reasons for withdrawal
Measure	IncobotulinumtoxinA (Xeomin) 400 Units IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9 percent (%) Sodium Chloride (NaCl), 400 units, total volume 8.0 milliliter (mL); Mode of administration: intramuscular injection. IncobotulinumtoxinA (400 Units): Open-Label Extension Period: All subjects receive three injection sessions of solution, prepared by reconstitution of powder with 0.9% NaCl, 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Placebo Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Main Period Death	0	1
Main Period Adverse Event	6	1
Main Period Lack of Efficacy	2	0
Main Period Withdrawal by Subject	5	2
Main Period Predefined discontinuation criteria	2	1
Open-Label Extension Period Adverse Event	15	0
Open-Label Extension Period Withdrawal by Subject	14	0
Open-Label Extension Period Lack of Efficacy	5	0
Open-Label Extension Period Death	1	0
Open-Label Extension Period Lost to Follow-up	1	0
Open-Label Extension Period Non-compliance	9	0
Open-Label Extension Period Predefined discontinuation criteria	6	0

Baseline Characteristics

Efficacy and Safety Study of Botulinum Toxin Type A Against Placebo to Treat Spasticity in the Leg After a Stroke

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Main Period: IncobotulinumtoxinA (Xeomin) 400 Units n=144 Participants IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Main Period: Placebo n=145 Participants Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection	Total n=289 Participants Total of all reporting groups
Age, Continuous	57.3 years STANDARD_DEVIATION 11.2 • n=93 Participants	57.0 years STANDARD_DEVIATION 13.0 • n=4 Participants	57.2 years STANDARD_DEVIATION 12.1 • n=27 Participants
Gender Female	40 Participants n=93 Participants	55 Participants n=4 Participants	95 Participants n=27 Participants
Gender Male	104 Participants n=93 Participants	90 Participants n=4 Participants	194 Participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline and Week 4

Population: The Full Analysis Set (FAS) included subjects in the Safety Evaluation Set (SES) of the main period for whom the primary efficacy variable was available, whereby SES is the subset of all subjects who were exposed to IP in the main period at least once.

Outcome measures

Outcome measures
Measure	IncobotulinumtoxinA (Xeomin) 400 Units n=144 Participants IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Placebo n=145 Participants Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 Baseline	2.8 Units on a scale Standard Deviation 0.7	2.8 Units on a scale Standard Deviation 0.7
Change From Baseline in Ashworth Scale (AS) for Plantar Flexors at Week 4 Change at Week 4	-0.4 Units on a scale Standard Deviation 0.7	-0.4 Units on a scale Standard Deviation 0.7

PRIMARY outcome

Timeframe: Baseline to Week 12

A 4-point Likert scale will be used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Investigator's Global Assessment of Efficacy at Week 12 will be a co-primary outcome measure to fulfill post marketing commitments for U.S. regulatory authorities only. Elsewhere, it will be a secondary outcome measure.

Outcome measures

Outcome measures
Measure	IncobotulinumtoxinA (Xeomin) 400 Units n=144 Participants IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Placebo n=145 Participants Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 Very good	3.5 Percentage of Participants	4.8 Percentage of Participants
Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 Good	28.5 Percentage of Participants	22.8 Percentage of Participants
Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 Moderate	22.2 Percentage of Participants	26.9 Percentage of Participants
Co-primary Variable: Investigator's Global Assessment of Efficacy at Week 12 Poor	45.8 Percentage of Participants	45.5 Percentage of Participants

SECONDARY outcome

Timeframe: Week 4, 8, and 12

Population: The FAS included subjects in SES of main period for whom primary efficacy variable was available, whereby SES is subset of all subjects who were exposed to IP in main period at least once. Here, "N"(Number of Participants Analyzed) and "n" signifies those participants who were evaluable for this outcome measure and at given time point respectively.

Response is defined as an improvement (reduction) of the plantar flexor Ashworth Score by at least one score point. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).

Outcome measures

Outcome measures
Measure	IncobotulinumtoxinA (Xeomin) 400 Units n=142 Participants IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Placebo n=144 Participants Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) Week 4 (n=142, 144)	37.3 Percentage of Participants	35.4 Percentage of Participants
Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) Week 8 (n=140, 142)	39.3 Percentage of Participants	33.8 Percentage of Participants
Response Rate for Plantar Flexors at All Post-Baseline Visits for Subjects With an Improvement (Reduction) of at Least 1 Point From Baseline in the Ashworth Scale (AS) Week 12 (n=135, 141)	20 Percentage of Participants	17 Percentage of Participants

SECONDARY outcome

Timeframe: Baseline, Week 4, 8, and 12

Outcome measures

Outcome measures
Measure	IncobotulinumtoxinA (Xeomin) 400 Units n=144 Participants IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Placebo n=145 Participants Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection
Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits Week 12 (n= 135, 141)	2.7 Units on a scale Standard Deviation 0.8	2.7 Units on a scale Standard Deviation 0.7
Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits Baseline (n=144, 145)	2.8 Units on a scale Standard Deviation 0.7	2.8 Units on a scale Standard Deviation 0.7
Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits Week 4 (n= 142, 144)	2.4 Units on a scale Standard Deviation 0.9	2.4 Units on a scale Standard Deviation 0.8
Ashworth Scale (AS) for Plantar Flexors at All Post-Baseline Visits Week 8 (n=140, 142)	2.4 Units on a scale Standard Deviation 0.9	2.5 Units on a scale Standard Deviation 0.7

Adverse Events

Main Period: IncobotulinumtoxinA (Xeomin) 400 Units

Serious events: 6 serious events

Other events: 13 other events

Deaths: 0 deaths

Main Period: Placebo

Serious events: 5 serious events

Other events: 13 other events

Deaths: 0 deaths

Open-Label Extension: IncobotulinumtoxinA (Xeomin) 400 Units

Serious events: 22 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Main Period: IncobotulinumtoxinA (Xeomin) 400 Units n=144 participants at risk IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Main period: One injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.	Main Period: Placebo n=145 participants at risk Placebo to incobotulinumtoxinA (Xeomin) powder for solution for injection. Placebo Comparator: Main period: one injection session of solution, prepared by reconstitution of powder with 0.9% NaCl, corresponding total placebo volume 8.0 mL; Mode of administration: intramuscular injection	Open-Label Extension: IncobotulinumtoxinA (Xeomin) 400 Units n=269 participants at risk IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA (400 Units): Open-Label Extension Period: All subjects receive three injection session of solution, prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400 units, total volume 8.0 mL; Mode of administration: intramuscular injection.
Musculoskeletal and connective tissue disorders Pain in extremity	4.9% 7/144 • Number of events 8 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	4.8% 7/145 • Number of events 9 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	3.7% 10/269 • Number of events 10 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
Nervous system disorders Headache	0.69% 1/144 • Number of events 1 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	2.1% 3/145 • Number of events 4 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	0.74% 2/269 • Number of events 2 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
Infections and infestations Nasopharyngitis	2.1% 3/144 • Number of events 3 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	0.69% 1/145 • Number of events 1 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	1.5% 4/269 • Number of events 5 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
Eye disorders Vision blurred	2.1% 3/144 • Number of events 4 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	0.00% 0/145 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	0.37% 1/269 • Number of events 2 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
Injury, poisoning and procedural complications Fall	0.00% 0/144 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	1.4% 2/145 • Number of events 3 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	4.1% 11/269 • Number of events 12 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
Investigations γ-glutamyltransferase increased	0.00% 0/144 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	0.00% 0/145 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	2.6% 7/269 • Number of events 7 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
General disorders Oedema peripheral	0.00% 0/144 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	2.1% 3/145 • Number of events 3 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	1.1% 3/269 • Number of events 3 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/144 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	0.00% 0/145 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.	2.2% 6/269 • Number of events 6 • From time point of first injection until 120 +/- 7 days after last administration of injection The investigator asked the subject for adverse events systematically at each visit.

Additional Information

Public Disclosure Manager

Merz Pharmaceuticals GmbH

Phone: +49 69 1503 1

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER