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] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064124 |
E.1.2 | Term | Cervical dystonia |
E.1.2 | System Organ Class | 100000004859 |
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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 multiple continuous treatments of DAXI for injection
- To assess immunogenicity to BoNTA and RTP004 after multiple treatments of DAXI for injection |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the long-term efficacy of multiple continuous treatments of DAXI for injection
- To establish the inter-treatment time interval or duration of effect
- To evaluate changes in symptom burden, daily activities, and psychosocial functioning after multiple continuous treatments of DAXI for injection |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adults, 18 to 80 years of age
2. Meets diagnostic criteria for isolated CD (idiopathic; dystonic symptoms localized to the head, neck, shoulder areas) with at least moderate severity at Baseline (Day 1), defined as a TWSTRS-total score of at least 20, with at least 15 on the TWSTRS-Severity subscale, at least 3 on the TWSTRS-Disability subscale, and at least 1 on the TWSTRS-Pain subscale (minimum TWSTRS subscale criteria applicable only to subjects not previously enrolled in Study Protocol 1720302)
3. Subjects who were previously enrolled in Study Protocol 1720302, who completed the study, including:
a) Those with no reduction or have an increase from baseline in the average TWSTRS-total score at Weeks 4 and 6 (i.e., improvement or worsened disease status), and the investigator agreed that there was a need for retreatment based on the subject’s symptoms and neurologic examination findings
b) Those who benefited from study treatment and complete follow-up study visits up to the time point of when their TWSTRS-total score reached/exceeded their target TWSTRS score
c) Those who benefit from study treatment but subsequently experienced significant recurrence of CD symptoms (e.g., pain) during the study before their TWSTRS-total score reached their target TWSTRS score and requested retreatment, which the investigator determined was warranted due
based on the subject’s symptoms and neurologic examination findings
d) Those who completed study visits up to Week 36 and their TWSTRS-total score never reached their target TWSTRS score and they never requested another treatment. The investigator determined that these subjects can be followed in the OLS until their TWSTRS-total score is the same or higher than their target TWSTRS score or until they request retreatment, which the investigator determined is clinically indicated
4. De novo subjects (not previously enrolled in Study Protocol 1720302):
a) Naïve to BoNT treatment
b) BoNT treatment-experienced; if previously treated with BoNTA, the subject must have demonstrated a clinically meaningful response to the last BoNTA treatment based on the clinical judgment of the investigator
5. Written informed consent including authorization to release health information |
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E.4 | Principal exclusion criteria |
1. Cervical dystonia attributable to an underlying etiology, (e.g., traumatic torticollis or tardive torticollis)
2. Predominant retrocollis or anterocollis CD
3. Significant dystonia in other body areas, or is currently being treated with BoNT for dystonia in areas other than those associated with isolated CD
4. Severe dysphagia (Grade 3 or 4 on the Dysphagia Severity Scale) at Screening or Baseline (prior to study treatment)
5. Any neuromuscular neurological conditions that may place the subject at increased risk of morbidity with exposure to BoNT, including peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis and motor neuropathy, and neuromuscular junctional disorders such as Lambert-Eaton syndrome and myasthenia gravis)
6. Previous treatment with any BoNT product, except investigational daxibotulinumtoxinA, for any condition within the 16 weeks prior to Screening (applicable only to de novo subjects)
7. Botulinum neurotoxin treatment-experienced subjects who have historically required <100 U of Botox or its equivalent to effectively treat their CD symptom (applicable only to de novo subjects)
8. Botulinum neurotoxin treatment-experienced subjects who had suboptimal or no treatment response to the most recent BoNTA injection for CD, as determined by the investigator, or history of primary or secondary non-response to BoNTA injections, known to have neutralizing antibodies to BoNTA, or have a history of botulinum toxin type B (rimabotulinumtoxinB [Myobloc/Neurobloc]) injection for CD due to nonresponse or suboptimal response to BoNTA (applicable only to de novo subjects)
9. Use of deep brain stimulation, or intrathecal baclofen for dystonia
10. Subjects on oral medications for focal dystonia (e.g., anticholinergics, muscle relaxants, benzodiazepines, dopamine depleter) or neuroleptics for psychiatric conditions (e.g., risperidone, olanzapine, clozapine, quetiapine), who have not been stable on their regimen for at least 4 weeks prior to Screening
11. Neurological abnormalities in the neck other than CD
12. Previous neck surgery, phenol injection to the neck muscles, myotomy or denervation surgery in the neck/shoulder region (e.g., peripheral denervation, spinal cord stimulation)
13. Profound atrophy of cervical musculature, or cervical contractures or cervical spinal deformity leading to marked limitation on passive range of motion
14. Use of aminoglycoside antibiotics, polymyxins, lincosamides (e.g., clindamycin), or other agents that might interfere with neuromuscular transmission (e.g., curare-like drugs, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride) within 14 days prior to Screening
15. Women of child bearing potential (WOCBP), who have a positive pregnancy test at Screening, or do not agree to use an effective method of birth control during the course of the study
16. Female, who is pregnant or nursing (lactating)
17. Screening 12-lead ECG with exclusionary conduction criteria of corrected QT interval (using Fridericia's correction formula): QTcF interval > 450 msec (males) or > 470 msec (females), heart block (i.e., second degree AV block Mobitz Type 2, third degree AV block or complete heart block), or ventricular tachycardia
18. History of severe (stage 3) chronic obstructive pulmonary disease, or unstable pulmonary disease within 30 days prior to Screening
19. History of chronic or recurrent hypokalemia, or serum potassium < 2.5 mEq/L or mmol/L on chemistry at Screening
20. History of congestive heart failure (New York Heart Association Class III or IV), Torsade de Pointe (TdP), and/or Long QT Syndrome
21. Participants in an investigational drug or device study within the last 30 days prior to Screening except for Revance study protocol 1720302.
22. Active skin infections at the injection sites which would put the subject at increased risk of morbidity with BoNT injections
23. Presence of any blood coagulation disorder, or on anticoagulation treatment with international normalized ratio (INR) > 3.5
24. Any acute illnesses or medical conditions including cognitive impairment (e.g., dementia), significant psychiatric illnesses (e.g., major depressive or bipolar disorder) or symptoms (e.g., suicidal ideation, psychosis) that are not stable, and in the investigator’s opinion, could put the subject at increased risk of morbidity, confound the study results, or interfere significantly with the subject’s participation in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
- The dose- and cycle-specific incidence of drug-related AEs
- The dose- and cycle-specific incidence of study drug discontinuation due to drug-related AEs
- The dose and cycle-specific incidence of treatment-emergent immunogenicity |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
It will be assessed at weeks 4 and 6 |
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E.5.2 | Secondary end point(s) |
• Inter-treatment time interval or duration of effect
• The dose- and cycle-specific average of the change in the TWSTRS-total score at Weeks 4 and 6 of each treatment cycle
• Percentage of subjects with at least “moderate” (a 2-point) improvement on CGIC at Week 4 or Week 6 of the treatment cycle
• Percentage of subjects with at least “moderate” (a 2-point) improvement on PGIC at Week 4 or Week 6 of the treatment cycle
• Changes in quality of life measures based on the CDIP-58
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
It will be assessed at Week 6. |
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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 | No |
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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 36 |
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 |
Austria |
Canada |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
United Kingdom |
United States |
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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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The end of study is defined as LVLS or procedure (EU and non EU). |
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 1 |