E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028335 |
E.1.2 | Term | Muscle spasticity |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048970 |
E.1.2 | Term | Arm spasticity |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the long-term safety of repeated doses of BOTOX for the treatment of pediatric upper limb spasticity. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Rollover patients:
• Eligible patients who successfully completed Allergan Study 191622-101 without major protocol deviations (eg, noncompliance to protocol-required procedures) and who, in the investigator’s clinical judgment, did not experience an adverse event that may indicate an unacceptable safety risk for additional BOTOX treatments
• Stable medical condition in the investigator’s opinion
• Written informed consent has been obtained from parent/legally authorized representative
• Written minor assent has been obtained in accordance with local laws and institutional review board (IRB)/independent ethics committee (IEC) requirements
• Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg, Written Authorization for Use and Release of Health and Research Study Information for United States [US] sites and written Data Protection consent for European Union [EU] sites)
• Negative urine pregnancy test at day 1 visit (for females of childbearing potential, defined as females post menarche)
De novo patients:
• Male or female, 2 to 16 years and 11 months of age (prior to 17th birthday) at the day 1 visit
• Minimum weight of 10 kg at the screening and day 1visits
• Upper limb monoplegic, hemiplegic, or triplegic spasticity (spasticity confirmed by Hypertonia Assessment Tool [HAT]) with single-arm sparing (only 1 arm requiring botulinum toxin treatment for spasticity during the study) resulting from cerebral palsy, or post-stroke with onset prior to age 2 and at least 12 months prior to the day 1 visit
• Patient’s spasticity meets at least one of the conditions below at the screening and day 1 visits:
a) Elbow flexor tone of 2 or greater as measured by the Modified Ashworth Scale – Bohannon (MAS-B) AND elbow flexor muscle contracture of no more than 30 degrees, and/or
b) Wrist flexor tone of 2 or greater as measured by the MAS-B AND at least neutral position for wrist with fingers at maximum extension
Gross Motor Function Classification System – Expanded and Revised (GMFCS-E&R) level I to IV at the screening visit
• Manual Ability Classification System (MACS) level I to IV at the screening visit
• Patients who are on anti-spastic medications or muscle relaxants (eg, oral baclofen, tizanidine, dantrolene, scopolamine [oral or patch], vigabatrin, or benzodiazepine therapy) must be on a stable dose
and regimen for at least 30 days prior to the day 1 visit
• Patients who are on anti-epileptic medications must be on a stable dose and regimen for at least 30 days prior to the day 1 visit
• Written informed consent has been obtained from parent/legally authorized representative
• Written minor assent has been obtained in accordance with local laws and IRB/IEC requirements
• Written documentation has been obtained in accordance with the relevant country and local privacy requirements, where applicable (eg, Written Authorization for Use and Release of Health and Research Study Information for US sites and written Data Protection consent for EU sites)
• Negative urine pregnancy test at the screening and day 1 visits (for females of childbearing potential, defined as females post menarche) |
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E.4 | Principal exclusion criteria |
• Any uncontrolled clinically significant medical condition other than the condition under study
• Any medical condition that may put the patient at increased risk with exposure to Botulinum Toxin Type A Purified Neurotoxin Complex, including diagnosed muscular dystrophy (eg, Duchenne’s muscular dystrophy), myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, mitochondrial disease, or any other significant disease that might interfere with neuromuscular function
• Fixed contracture of the principal muscle group (elbow or wrist) for the study limb
• Uncontrolled epilepsy defined as more than 1 generalized seizure per month within 3 months prior to the day 1 visit or history of prolonged seizures or repetitive seizure activity requiring administration of a rescue benzodiazepine (oral, rectal, etc) more than once a month, seizures lasting more than 10 minutes, status epilepticus, or epilepsy with autonomic involvement within 9 months prior to the day 1 visit
• Patients with presence or history of aspiration pneumonia, recurrent lower respiratory tract infections, uncontrolled asthma, or compromised respiratory function within 12 months prior to the day 1 visit that may indicate a vulnerable respiratory state per investigator’s clinical judgment
• Patients with presence or history (within 12 months prior to the day 1 visit) of aspiration or a condition(s) that, in the investigator’s opinion, may put the patient at an increased risk for aspiration (eg, significant drooling, chronic dysphagia [difficulty swallowing] requiring changes in diet, or clinically significant gastroesophageal reflux disease)
• Patients previously exposed to botulinum toxin therapy of any serotype who have a history of allergy or sensitivity to the toxin or its components or other significant adverse experiences that, in the investigator’s opinion, may put the patient at an unacceptable risk
• Botulinum toxin therapy of any serotype for any condition within 3 months prior to the day 1 visit (de novo patients only)
• History of treatment with phenol or alcohol block in the study upper limb within 6 months prior to the day 1 visit (de novo patients only) or planned treatment with phenol or alcohol block in the study upper limb during the study
• History of or planned treatment during the study with selective dorsal rhizotomy or deep brain stimulation
• History of surgical intervention of the study upper limb within 12 months prior to the day 1 visit (de novo patients only) or planned surgical intervention of any limb(s) during the study
• Females who are pregnant, nursing, or planning a pregnancy during the study
• Females of childbearing potential (defined as females post menarche) not using reliable means of contraception (see Section 4.5.1.1 for acceptable contraceptive methods) |
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E.5 End points |
E.5.1 | Primary end point(s) |
No primary efficacy variable is identified. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Grade change from baseline in MAS-B at each follow-up visit.
• CGI by Physician at each follow-up visit.
• The difference between slow (R2) and fast (R1) range of motion in degree (R2 - R1) on the MTS of elbow and wrist muscle groups in the study upper limb, the individual R1 and R2, and the respective changes from baseline at each follow-up visit.
• Faces Pain Scale-Revised (for patients who are 4 years and older at day 1 and reported pain [score > 0] at the day 1 visit).
• GAS by Physician (for rollover patients only) based on 2 functional goals (1 active and 1 passive) defined in Study 191622-101. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Evaluations at every visit. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Germany |
Hungary |
Italy |
Korea, Republic of |
Poland |
Russian Federation |
Turkey |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |