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Lower Limb and Combined Lower Limb and Upper Limb Spasticity Due to Cerebral PalsyPhase 3NCT01905683

Long-term Open-label Study of Botulinumtoxin Type A to Treat Spasticity of Leg(s) or Leg(s) and Arm in Cerebral Palsy

A Phase 3 study testing IncobotulinumtoxinA (16-20 Units per kg body weight) in people with Lower Limb and Combined Lower Limb and Upper Limb Spasticity Due to Cerebral Palsy, run by Merz Pharmaceuticals GmbH at 43 sites in 12 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg(s) or of leg(s) and one arm are safe in treating children/adolescents (age 2-17 years) long-term with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy. Read more about this study

Who is it for?
Ages 2 to 17 years
What is being tested?
IncobotulinumtoxinA (16-20 Units per kg body weight)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
370 participants
Where
43 sitesin 12 countries
Study dates
Aug 2013to Jan 2017
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 2 to 17 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Main clinical inclusion criteria for completers of study MRZ6020130701:
  • Subject with lower limb [LL] spasticity who completed lead-in study MRZ60201_3070_1 in any of the three dose groups with duration of both injection cycles between 12 and 16 weeks.
  • Ashworth scale [AS] score ≥2 in plantar flexors (at least unilaterally). For subjects with an AS score of 1, the investigator has to decide on the clinical need for reinjection.
  • Clinical need for spasticity treatment with NT 201 according to the clinical judgment of the investigator for:
  • Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus and need for additional 8 U/kg BW NT 201 (maximum of 200 U) for treatment of clinical pattern flexed knee or adducted thigh (ipsilateral) or bilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus on each side.
  • No treatment of other clinical patterns is allowed.
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  • Main clinical inclusion criteria for subjects who did not participate in MRZ6020130701:
  • Female or male subject of 2 to 17 years age (inclusive).
  • Uni- or bilateral CP with clinical need for BoNT injection to treat limb spasticity.
  • AS score ≥ 2 in plantar flexors (at least unilaterally).
  • Clinical need according to the clinical judgment of the investigator in one out of four treatment combinations:
  • For LL(s) treatment only (Gross Motor Function Classification System [GMFCS] levels IV): Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus, and 8 U/kg BW NT 201 (maximum of 200 U) into flexed knee or adducted thigh or bilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into each pes equinus (AS score ≥ 2 on both sides).
  • For combined unilateral UL and unilateral LL, (GMFCS levels I-III): Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus, and 8 U/kg BW NT 201 (maximum of 200 U) into flexed knee or adducted thigh plus Unilateral treatment of UL spasticity with 4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.
  • For combined unilateral UL and unilateral LL (GMFCS level IV-V): Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum 200 U) into pes equinus, and 4 U/kg BW NT201 (maximum 100 U) into flexed knee or adducted thigh plus unilateral treatment of UL spasticity with 4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.
  • For combined unilateral UL and bilateral LL (GMFCS levels I-III): Bilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into each pes equinus (AS score ≥ 2 on both sides) plus unilateral treatment of UL spasticity with 4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.

Who cannot join

  • Exclusion Criteria for subjects who completed MRZ6020130701:
  • Infection and/or inflammation in the area of the planned injection points.
  • Pregnancy for female with history of menarche.
  • Clinically relevant pathological findings indicating active disease of vital organs.
  • Exclusion Criteria for subjects who did not participate in MRZ6020130701:
  • Fixed contracture defined as severe restriction of the range of joint movement on passive stretch in the target clinical pattern(s) or predominant forms of muscle hypertonia other than spasticity (e.g., dystonia) in the target limb(s).
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  • Surgery in the pes equinus on side(s) intended to treat with BoNT injections within 12 months prior to Screening Visit (V1), within the screening period or planned for the time of participation in this study.
  • Hip flexion requiring BoNT injection.
  • Limitation of hip abduction to less than 40° or pre-diagnosed migrational percentage greater than 30.
  • Vaccination within 2 weeks prior to Screening Visit (V1) and/or within the screening period.
  • Non-resolved fractures of the treated limb.
  • Ventilator dependency.
  • Severe neurological diagnosis and comorbidity outside the spectrum of cerebral palsy.
  • Pure dyskinetic CP or mixed CP with predominantly dyskinetic movements.
  • Treatment with BoNT (other than study drug in this study) for any body region within 14 weeks prior to Screening Visit (V1), within the screening period and/or intended to be administered during the study period.
  • Treatment with phenol or alcohol of any muscle within 6 months prior to Screening Visit (V1), within the screening period, and/or intended to be administered during the study period.
  • Treatment with
  • drugs acting as peripheral muscle relaxants
  • intrathecal baclofen, or
  • oral anticoagulants administered within 2 weeks prior to Screening Visit (V1), within the screening period, and/or intended to be administered during the study period.

Trial locations and contacts

43 sites in 12 countries.

43 sites in 12 countries

Poland7 sites

  • Merz Investigational Site #048089

    Bialystok, 15-274

  • Merz Investigational Site #048063

    Gdansk, 80-389

  • Merz Investigational Site #048059

    Krakow, 30-539

  • Merz Investigational Site #048084

    Lublin, 20-828

  • Merz Investigational Site #048072

    Luboń, 62-030

  • Merz Investigational Site #048075

    Sandomierz, 27-600

  • Merz Investigational Site #048061

    Warsaw, 02-315

Other trials in Poland

Russia6 sites

  • Merz Investigational Site #007014

    Kazan', 420097

  • Merz Investigational Site #007015

    Khabarovsk, 680038

  • Merz Investigational Site #007018

    Novosibirsk, 630091

  • Merz Investigational Site #007017

    Saint Petersburg, 194100

  • Merz Investigational Site #007013

    Smolensk, 214029

  • Merz Investigational Site #007019

    Stavropol, 355029

Other trials in Russia

Germany4 sites

  • Merz Investigational Site #049328

    Bochum, 44791

  • Merz Investigational Site #049327

    Munich, 80337

  • Merz Investigational Site #049329

    Münster, 48149

  • Merz Investigational Site #049326

    Vogtareuth, 83569

Other trials in Germany

Slovakia4 sites

  • Merz Investigational Site #421003

    Banská Bystrica, 97409

  • Merz Investigational Site #421008

    Bratislava, 82108

  • Merz Investigational Site #421006

    Krompachy, 05342

  • Merz Investigational Site #421004

    Levoča, 05401

Other trials in Slovakia

South Korea4 sites

  • Merz Investigational Site #082019

    Goyang, 410-773

  • Merz Investigational Site #082021

    Incheon, 400-711

  • Merz Investigational Site #082018

    Seongnam-si, 463-712

  • Merz Investigational Site #082020

    Seoul, 135-710

Other trials in South Korea

Ukraine4 sites

  • Merz Investigational Site #380001

    Dnipropetrovsk, 49027

  • Merz Investigational Site #380005

    Kharkiv, 61068

  • Merz Investigational Site #380002

    Kiev, 04209

  • Merz Investigational Site #380003

    Odesa, 65012

Other trials in Ukraine

Israel3 sites

  • Merz Investigational Site #972003

    Jerusalem, 91240

  • Merz Investigational Site #972001

    Tel Aviv, 6423906

  • Merz Investigational Site #972002

    Tel Aviv, 6423906

Other trials in Israel

Romania3 sites

  • Merz Investigational Site #040003

    Bucharest, 041408

  • Merz Investigational Site #040001

    Bucharest, 041914

  • Merz Investigational Site #040002

    Iași, 700309

Other trials in Romania

Turkey (Türkiye)3 sites

  • Merz Investigational Site #090005

    Elâzığ, 23119

  • Merz Investigational Site #090003

    Izmir, 35100

  • Merz Investigational Site #090002

    İzmit, 41380

Other trials in Turkey (Türkiye)

Czechia2 sites

  • Merz Investigational Site #420029

    Brno, 65691

  • Merz Investigational Site #420028

    Olomouc, 77520

Other trials in Czechia

Estonia2 sites

  • Merz Investigational Site #372001

    Tallinn, 13419

  • Merz Investigational Site #372002

    Tartu, 51014

Other trials in Estonia

Austria1 site

  • Merz Investigational Site #043036

    Vienna, 1100

Other trials in Austria

About this study

Official title: Open-label, Non-controlled, Multicenter Long-term Study to Investigate the Safety and Efficacy of Xeomin® (Incobotulinumtoxin A, NT 201) for the Treatment of Spasticity of the Lower Limb(s) or of Combined Spasticity of Upper and Lower Limb in Children and Adolescents (Age 2 - 17 Years) With Cerebral Palsy

The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg(s) or of leg(s) and one arm are safe in treating children/adolescents (age 2-17 years) long-term with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

Being tested
IncobotulinumtoxinA (16-20 Units per kg body weight)

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IncobotulinumtoxinA (16-20 Units per kg body weight)Drug

    Also called Xeomin, NT 201, Botulinum toxin type A (150 kiloDalton), free from complexing proteins

    Active ingredient: Clostridium Botulinum neurotoxin type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Total dose per injection cycle: up to 500 units; Mode of administration: intramuscular injection into spastic muscles.

Study groups in NCT01905683
Study groupRoleWhat they receive
16-20 Units per kg body weight incobotulinumtoxinAExperimentalNot described
Receives: Drug: IncobotulinumtoxinA (16-20 Units per kg body weight)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle

    TEAEs are events observed from the time point of first injection until end of study visit (Week 50-66). Values reported here refer to the number of participants affected.

    Measured: From the timepoint of first injection up to end of study visit (Week 50-66)

  2. Occurrence of Treatment Emergent Adverse Events of Special Interest (TEAESI) Overall and Per Injection Cycle

    TEAEs occurring after treatment that were thought to possibly indicate toxin spread throughout the trial conduct are defined as TEAESI. Values reported here refer to the number of participants affected.

    Measured: From the timepoint of first injection until end of study visit (Week 50-66)

  3. Occurrence of Treatment-emergent Serious Adverse Events (TESAEs) Overall and Per Injection Cycle

    TESAEs are events observed from the time point of first injection until end of study visit (Week 50-66). Values reported here refer to the number of participants affected.

    Measured: From the timepoint of first injection until end of study visit (Week 50-66)

Secondary outcomes (7)

  1. Investigator's Global Assessment of Tolerability at Day 99 (Week 14) of Each Injection Cycle

    The investigator's global assessment of tolerability was assessed on a 4-point ordinal scale where 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Results for Day 99 (Week 14) of 4th injection cycles were collected at the end of study visit.

    Measured: Day 99 (Week 14) of 1st, 2nd, 3rd and 4th injection cycle

  2. Changes in AS Score of Left and Right Plantar Flexors (PF) From Baseline to All Other Visits, From Day 1 of Each Injection Cycle to Day 29 (Week 4), Day 57 (Week 8, 1st Injection Cycle Only) and Day 99 (Week 14) of the Respective Injection Cycle

    The Ashworth Scale (AS) is a well-known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (= no increase in tone) to 4 (=limb rigid in flexion or extension). For participants with bilateral pes equinus, the body side for efficacy analysis that is, "primary body side" was decided by investigator at screening and was kept throughout the entire study. V3 = Week 4 of 1st Injection Cycle; V4 = Week 8 of 1st Injection Cycle; V5 = Day 1 of 2nd Injection Cycle; V6= Week 4 of 2nd Injection Cycle; V7 = Day 1 of 3rd Injection Cycle; V8 = Week 4 of 3rd Injection Cycle; V9 = Day 1 of 4th Injection Cycle; V10 = Week 4 of 4th Injection Cycle; V11= Week 14th of 4th Injection Cycle = end of study visit.

    Measured: Baseline (Day 1, Visit [V] 2) to all other visits (V3, V4, V5, V6, V7, V8, V9, V10, and V11); From Day 1 of Each Injection Cycle to Day 29 (Week 4), Day 57 (Week 8, 1st Injection Cycle only) and Day 99 (Week 14) of the respective Injection Cycle

  3. Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale (GICS) at Day 29 (Week 4) of Each Injection Cycle

    The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the participant (if feasible) and by parents'/caregiver (if applicable). GICS is 7-Point Likert Scale ranging from +3 (very much improved function) to -3 (very much worse function).

    Measured: Day 29 (Week 4) of 1st, 2nd, 3rd and 4th injection cycle

  4. Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of Left and Right PF at Day 29 (Week 4) of Each Injection Cycle

    The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the participant (if feasible) and by parents'/caregiver (if applicable). GICS is a 7-Point Likert Scale ranging from +3 (very much improved function) to -3 (very much worse function). For participants with bilateral pes equinus, the body side for efficacy analysis that is "primary body side" was decided by investigator at screening and was kept throughout the entire study.

    Measured: Day 29 (Week 4) of 1st, 2nd, 3rd and 4th injection cycle

  5. Changes in Modified Tardieu Scale (MTS) of Left and Right PF From Baseline to All Other Visits, From Day 1 of Each Injection Cycle (IC) to Day 29 (Week 4), Day 57 (Week 8, 1st IC Only) and Day 99 (Week 14) of the Respective Injection Cycle

    The MTS assesses spastic muscle tone by subtraction of two angles measured at different conditions of passive muscle stretch. R2 is the angle of passive range of motion with a passive movement at slow speed. R1 is the angle where a "catch-and-release" or clonus can be triggered at the fastest possible speed. Score values represent the measured (R2-R1) difference, that is, the dynamic tone component of the examined muscle(s). Decreases of (R2-R1) represent reductions in the dynamic component of spasticity, that is, improvement of dynamic muscle spasticity. V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5 = Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.

    Measured: Baseline (Day 1, Visit [V] 2) to all other visits (V3, V4, V5, V6, V7, V8, V9, V10, and V11); From Day 1 of Each IC to Day 29 (Week 4), Day 57 (Week 8, 1st IC cycle only) and Day 99 (Week 14) of the respective IC

  6. Change in Scores of Pain Intensity (From Participants) and Frequency (From Parent/Caregiver) From Baseline to All Visits, From Day 1 of Each IC to Day 29 (Week 4), Day 57 (Week 8, 1st IC Cycle Only) and Day 99 (Week 14) of Respective Injection

    The questionnaire on pain caused by Spasticity (QPS) is a participant-reported outcome for children and adolescents (2-17 years) with cerebral palsy on spasticity-related pain. Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with QPS. The QPS total score for pain intensity ranges from 0 ('No Hurt') to 10 ('Hurt Worst'). The QPS total score for the observed pain frequency ranges from 0 (Never) to 4 (Always). V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5= Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.

    Measured: Baseline (Day 1, Visit [V] 2) to all other visits (V3, V4, V5, V6, V7, V8, V9, V10, and V11); From Day 1 of Each IC to Day 29 (Week 4), Day 57 (Week 8, 1st IC cycle only) and Day 99 (Week 14) of the respective IC

  7. Changes in Gross Motor Function Measure (GMFM)-66 Score From Baseline to All Injection Visits and End of Study

    The GMFM-66 is a standardized observational 66-item instrument designed and validated to measure change in gross motor function over time in participants with cerebral palsy. Score values represent the total GMFM-66 score. Total GMFM scores range from 0 (worst) to 100 (best).

    Measured: Baseline to Day 1 of 2nd (V5), 3rd (V7), 4th (V9) IC and End of study (Week 44-68) (V11)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jul 2013 (estimated)
  2. Study startAug 2013
  3. Primary completionJan 2017
  4. Study completionJan 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
370 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01905683
Sponsor's protocol ID
MRZ60201_3071_1
Other IDs
2012-005055-17
Status last verified
Sep 2017
First submitted
18 Jul 2013
Last updated
27 Oct 2017
Data monitoring committee
Yes

Publications

  • Berweck S, Banach M, Gaebler-Spira D, Chambers HG, Schroeder AS, Geister TL, Althaus M, Hanschmann A, Vacchelli M, Bonfert MV, Heinen F, Dabrowski E. Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis. Toxins (Basel). 2022 Aug 25;14(9):585. doi: 10.3390/toxins14090585.

    PubMed 36136523

  • Kanovsky P, Heinen F, Schroeder AS, Chambers HG, Dabrowski E, Geister TL, Hanschmann A, Martinez-Torres FJ, Pulte I, Banach M, Gaebler-Spira D. Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy. J Pediatr Rehabil Med. 2022;15(1):113-127. doi: 10.3233/PRM-210041.

    PubMed 34957963

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing IncobotulinumtoxinA (16-20 Units per kg body weight) in people with Lower Limb and Combined Lower Limb and Upper Limb Spasticity Due to Cerebral Palsy, run by Merz Pharmaceuticals GmbH at 43 sites in 12 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 43 sites in Poland, Russia, Germany, Slovakia, South Korea and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle (time frame: From the timepoint of first injection up to end of study visit (Week 50-66)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01905683, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2017.

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