E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic tic disorders and Tourette syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Persistent neurobehavioural (=relationship between the action of the nervous system and behavior) disorders (chronic tic disorders and Tourette syndrome) |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10043835 |
E.1.2 | Term | Tic disorders |
E.1.2 | System Organ Class | 100000004873 |
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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 | 10018269 |
E.1.2 | Term | Gilles de la Tourette syndrome |
E.1.2 | System Organ Class | 100000004850 |
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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 demonstrate that treatment with the cannabis extract nabiximols is superior to placebo in reducing tics and comorbidities in patients with Tourette syndrome and chronic tic disorders |
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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 |
1. Chronic tic disorder or Tourette syndrome according to DSM-5 2. Age ≥18 years 3. YGTSS-TTS > 14 for patients with Tourette syndrome or YGTSS-TTS > 10 for patients with chronic motor or vocal tics only (= CTD) 4. CGI-S ≥ 4 5. Medication (and stimulation parameters for deep brain stimulation) for tics and comorbidities must be on a stable dose for at least 30 days before entering the study and patient must consent to maintain the stable dose during the study 6. Signed written informed consent and willingness to comply with treatment and follow-up procedures 7. Patients capable of understanding the investigational nature, potential risks and benefits of the clinical trial 8. Prevention of pregnancy: Women without childbearing potential defined as follows: • at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy or • hysterectomy or uterine agenesis or • ≥ 50 years and in postmenopausal state ≥ 1 year or • < 50 years and in postmenopausal state ≥ 1 year with urine FSH > 40 IU/l and urine oestrogen < 30 ng/l or a negative oestrogen test or Women of childbearing potential with a negative urine ß-HCG pregnancy test at screening who agree to meet one of the following criteria from the time of screening, during the study and for a period of three months following the last administration of study medication: • correct use of contraception methods. The following are acceptable: hormonal contraceptives (combined oral contraceptives, oestrogen-free pills with desogestrel, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), intrauterine device (IUS) • true abstinence (periodic abstinence and withdrawal are not acceptable methods of contraception) • sexual relationship only with female partners and/or sterile male partners or Males who are not surgically sterile and who are sexually active with female partner(s) of childbearing potential must agree to correct use of one of the following contraception methods from the time of screening, during the study and for a period of three months following the last administration of study medication: hormonal contraceptives (combined oral contraceptives, oestrogen-free pills with desogestrel, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), intrauterine device (IUS) |
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E.4 | Principal exclusion criteria |
1. One of the following conditions when unstable or in need of an initial adjustment for a therapy: Comorbid OCD, ADHD, depression, and anxiety disorder 2. Ongoing behavioural treatment for tics 3. History of schizophrenia, psychotic, severe personality, or pervasive developmental disorder 4. Patient has a history of suicidal ideation with intent to act or a plan to act in the 12 months preceding the Screening Visit 5. Current clinical diagnosis of substance abuse or dependence and compulsive disorder 6. Secondary tic disorders and other significant neurological disorders that, in the opinion of the investigator, might interfere with the patient’s participation in the study, poses added risk for the patient, or confounds the assessment of patient safety 7. Severe cardiovascular diseases, hepatitis C, or other severe hepatic and renal disorders by history that, in the opinion of the investigator, might interfere with the patient’s participation in the study, poses added risk for the patient, or confounds the assessment of patient safety 8. Any medical condition based on medical history, physical examination, and vital sign measurements that, in the opinion of the Investigator, might interfere with the patient’s participation in the study, poses added risk for the patient, or confounds the assessment of patient safety 9. Use of cannabis or CBM in the 30-day period prior to study entry and/or positive THC urine test 10. Positive urine pregnancy test 11. Pregnancy or lactation period 12. The subject has received any investigational medication or used any investigational device within 30 days prior to the first dose of study medication or is actively participating in any investigational drug or device study, or is scheduled to receive an investigational drug or to use an investigational device during the course of the study 13. Known or suspected hypersensitivity to any of the active substances or any excipients of the investigational medicinal product |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint: Response to treatment according to YGTSS-TTS, defined as a reduction in YGTSS-TTS of at least 30% (compared to baseline) after 9 weeks of stable treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 9 weeks of stable treatment |
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E.5.2 | Secondary end point(s) |
Key secondary endpoint: fitness to drive after 9 weeks of stable treatment as a binary criterion according to the Vienna Test System (a patient is fit to drive if none of the following tests has a percent rank below 16: Reaction time and choice reaction (RT), Stress Behavior capacity (DT-Auslastung), Stress Behavious performance quantity (DT_Mengenleistung), Concentration (COG), and Perceptual speed (ATAVT)).
Further secondary endpoints: individual fitness to drive scores (RT, DT-Auslastung, DT-Mengenleistung, COG, ATAVT) after 9 weeks of stable treatment, YGTSS-TTS as a continuous endpoint (change from baseline) after 9 weeks of stable treatment. YGTSS-TTS as a binary responder criterion as well as a continuous endpoint after 4 weeks stable treatment and 1 month after end of treatment. The following efficacy endpoints will be assessed after 4 and 9 weeks stable treatment and 1 month after end of treatment: Yale Global Tic Severity Scale-Global Score (YGTSS-GS), modified Rush Video-Based Tic Rating Scale (MRVS), Clinical Global Impression–Improvement Score (CGI-I), Clinical Global Impression–Severity Score (CGI-S), Adult Tic Questionnaire (ATQ), Tourette syndrome-quality of life scale (GTS-QoL), Pre-monitory Urge for Tics Scale (PUTS), Beck Depression Inventory-II (BDI-II), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Conners' Adult ADHD Rating Scale (CAARS), Beck Anxiety Inventory (BAI), Pittsburgh Sleep Quality Index (PSQI), Skala Impulsives-Verhalten-8 (I-8), 12-item short-form Health Survey (SF-12), and Rage attacks questionnaire for adults (RAQ).
Assessment of safety: (Serious) adverse events (AEs/SAEs), blood pressure, and pulse at each visit. An independent Data Monitoring Committee (DMC) will be established. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary endpoints: after 9 weeks of stable treatment
Further secondary endpoints: after 9 weeks of stable treatment; after 4 weeks stable treatment and 1 month after end of treatment; after 4 and 9 weeks stable treatment and 1 month after end of treatment, respectively
Assessment of safety: continuously at each 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 | 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 | 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 | 2 |
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 | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | |
E.8.9.1 | In the Member State concerned days | |