E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic upper limb spasticity caused by diverse etiologies |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028335 |
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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 |
The primary objective of the trial is to show non inferiority of an injection of NT 201 high volume dilution (20 U/ml) compared to an injection of NT 201 low-volume dilution (50 units/mL) in patients with upper limb spasticity in terms of responder analysis at week 4 for patients with an improvement (reduction) of at least 1 point from baseline visit in DAS for the principle therapeutic target. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of the trial are to compare the efficacy of two different solutions of NT 201(50 U/mL or 20 U/mL) in terms of: • Responder analysis over time for patients with an improvement (reduction) of at least 1 point from baseline visit in DAS for the principle therapeutic target • Change in Frenchay Arm Test from baseline over time • Change in Ashworth scale for each treated flexor muscle group and for treated forearm pronators from baseline over time • Change in Activity of Daily Living score (Barthel Index, selected items: eating, washing, toilet using, bathing/showering, dressing) from baseline over time • Change in investigator’s and patient’s global assessment of treatment response over time • Change in passive range of motion for wrist and elbow from baseline over time
As part of the safety evaluation during the trial the incidence of adverse events, vital signs, routine hematology and clinical chemistry values will be investigated. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Female or male patients ≥18 years -Stable upper limb spasticity of diverse etiology: ≥ 6 months after stroke, brain injury or spinal cord injury or multiple sclerosis with no relapse within 3 months prior to screening visit or cerebral palsy - Focal spasticity with ≥ 2 points on the Ashworth scale in the wrist flexors (incl. clinical pattern of flexed wrist) or wrist (incl. clinical pattern of flexed wrist) and elbow flexors (incl. clinical pattern of flexed elbow) - Disability Assessment Scale [DAS] score ≥ 2 for principle therapeutic target - For pre-treated patients only:source documentation of the most recent injection session with botulinum toxin and sufficient therapeutic response for flexed wrist or flexed wrist and elbow - For pre-treated patients only:Total dose of most recent injection with botulinum toxin must have been not more than of 400 units BOTOX® (1600 units Dysport® or 16.000 units Neurobloc® (type B)) for the affected flexors of wrist or affected flexors of wrist and elbow. For flexor carpi ulnaris, the maximal dose must have been not more than 50 units BOTOX® (200 units Dysport® or 2000 units Neurobloc®), for flexor carpi radialis, the maximal dose must have been not more than 60 units BOTOX® (240 units Dysport® or 2400 units Neurobloc®). - Negative blood pregnancy test before baseline for females of childbearing potential - Willingness of the patient to participate as documented by written informed consent |
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E.4 | Principal exclusion criteria |
- Bilateral upper limb paresis/paralysis - Previous treatment with botulinum toxin of any serotype during the last 4 months prior to screening - Planned concomitant treatment with botulinum toxin of any serotype and for any body region - Previous or planned treatment with phenol- or alcohol-injection in the target limb - Surgical treatment in the target limb for any indication within the 8 weeks prior to screening - Planned surgery in the target limb - Hypersensitivity to human serum albumin, sucrose, or botulinum toxin type A - Change in co-medication with centrally acting muscle relaxants (including benzodiazepines) within the 4 weeks prior to screening and/or co-medication with centrally acting muscle relaxants which dose cannot bekept constant during the trial - Antispastic medication with peripheral muscle relaxants (including dantrolene) within the 4 weeks prior to screening and during the trial - Change in antidepressive medication within the 8 weeks prior to screening visit and/or antidepressive medication which dose cannot be kept constant during the trial - Change in physical or occupational therapy regimens or in any other rehabilitation treatment of spasticity (including splinting) within the 4 weeks prior to screening and/or physical or occupational therapy or any other rehabilitation treatment of spasticity that cannot be kept constant during the trial - Treatment with intrathecal baclofen within 4 weeks prior to screening - Other non-authorized concomitant treatments - Concomitant rheumatic disease in the target limb, which in the opinion of the investigator would affect the therapeutic outcome of treatment with botulinum toxin - Fixed contracture, defined as severe restriction of the range of joint movement on passive stretch - Other muscle hypertonia (e.g., rigidity) - Current alcoholism or other drug abuse/dependence - Diagnosis of myasthenia gravis, Lambert-Eaton-Syndrome, amyotrophic lateral sclerosis, or any other significant neuromuscular disease which might interfere with the study - Severe or uncontrolled systemic disease (e.g., cardiac, renal, pulmonary, hepatic, or gastrointestinal), current malignancy, or anamnestic HIV infection - Clinically relevant pathological findings in laboratory parameters, indicating active disease of vital organs - Anticoagulation therapy which requires an INR value of > 2.5 - INR value > 2.5 on injection day - Severe atrophy of the target limb muscles - Infection in the area of the planned injection points - Nursing mothers or women of childbearing potential without reliable means of contraception (reliable contraception is hormonal contraception or intrauterine contraceptive device or combination of two barrier methods (e.g. condom or diaphragm plus spermicidal cream)) and women planning pregnancy during the course of the trial - Participant in a clinical study within the 4 weeks prior to screening - Previous randomization in this study - In the opinion of investigator the patient is unlikely to complete all study visits - Other contraindications which in the investigator’s opinion preclude participation in the study
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is the DAS response rate at week 4, defined as the proportion of patients with an improvement (reduction) of at least 1 point in DAS for the principle therapeutic target from baseline visit to week 4. Improvement of 1 point in DAS was previously considered to be clinically significant .(The aim of the study is to proof non-inferiority of the 20 units/mL dilution of NT 201 compared to the 50 units/mL dilution of NT 201 with respect to the primary endpoint in the sense of showing that the NT 201 20 units/mL dilution is (indirectly) superior to placebo.)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Yes |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Same IMP, two different dilutions (20u/ml vs 50u/ml) will be compared |
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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 | 28 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |