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 | 17.0 |
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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024132 |
E.1.2 | Term | Leg 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 safety and efficacy of a single treatment of 2 doses (4 U/kg and 8 U/kg) of BOTOX with standardized PT in pediatric patients with lower 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 |
• 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 1 visits • Monoplegic or hemiplegic patients with cerebral palsy who have dynamic muscle contracture (spasticity confirmed by Hypertonia Assessment Tool [HAT]) of the ankle plantar flexors associated with true equinus foot deformity as described by Rodda and Graham (2001; see Figure 1 in exclusion criteria). Equinovarus or equinovalgus deformities are acceptable. • MAS-B score ≥ 2 for the ankle plantar flexors and minimum range of dorsiflexion of 0 degrees of the ankle with knee fully extended in the study limb at screening and day 1 visits • Patients for whom study treatment in the 3 ankle plantar flexors (namely gastrocnemius, soleus, and tibialis posterior) of the study leg is appropriate • Gross Motor Function Classification System – Expanded and Revised (GMFCS-E&R) 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 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 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 one 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 ankle for the study limb - Patients with clinically significant spasticity of the knee flexors in the study limb that, in the investigator’s opinion, require BOTOX injection to the knee flexors during the study - Patients with the following gait patterns in the study limb: Type 1 “drop foot” or Type IV “equinus with jump knee, or pelvic rotation, hip flexed, adducted, or internal rotation” (see Figure 1) - Uncontrolled epilepsy defined as more than 1 generalized seizure in any month within the 3 months prior to the day 1 visit or history of any of the following within 9 months prior to the day 1 visit: 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. - Patients with presence or history of any of the following within 12 months prior to the day 1 visit that may indicate a vulnerable respiratory state per the investigator’s clinical judgment: aspiration pneumonia, recurrent lower respiratory tract infections, uncontrolled asthma, or compromised respiratory function - 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 6 months prior to the day 1 visit - Patients who are on an active intrathecal baclofen pump therapy within 7 days prior to the day 1 visit or plan to receive such therapy during the study - History of treatment with phenol or alcohol block in the study limb within 12 months prior to the day 1 visit or planned treatment with phenol or alcohol block in any limb(s) 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 lower leg (the knee and below of the study limb; except for tendon lengthening more than 12 months prior to the day 1 visit) or planned surgical intervention of any limb(s) during the study - Previous casting within 6 months prior to the day 1 visit or splinting with a dynamic splint (eg, Dynasplint® or UltraFlex®) within 3 months prior to the day 1 visit for spasticity of the study limb or the affected upper limb, or planned casting or splinting with a dynamic splint (eg, Dynasplint or UltraFlex) for spasticity of the study limb or affected upper limb 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) - Patients with a significant risk of suicide within the 12 months prior to screening, or since screening at the day 1 visit |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoints will be the average grade change from baseline to weeks 4 and 6 in MAS-B. The co-primary efficacy endpoints will be the average grade change from baseline to weeks 4 and 6 in MASB and the average CGI by Physician. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, week 4 and week 6. |
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E.5.2 | Secondary end point(s) |
CGI by Physician (for non-US FDA analyses) will be evaluated at weeks 2, 4, 6, 8, and 12. In addition to each timepoint, the average of the weeks 4 and 6 CGI by Physician will be analyzed. Functional goals, active and passive, using GAS by Physician will be evaluated separately relative to baseline at weeks 8 and 12. Secondary efficacy variables of MTS include the difference between slow (R2) and fast (R1) range of motion (R2 - R1) as well as respective change from baseline on the MTS for the ankle plantar flexors (with knee extended and knee flexed) at weeks 2, 4, 6, 8, and 12. Additionally changes from baseline for each R1 and R2 at each assessment point will be evaluated. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, weeks 2, 4, 6, 8, 12. |
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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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |
India |
Italy |
Korea, Republic of |
Poland |
Russian Federation |
Spain |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |