| 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 |
| Tourette Syndrome is a neurological disorder that is commonly characterized by childhood onset of motor and phonic/verbal tics. |
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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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10044127 |
| E.1.2 | Term | Tourette's syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic 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 |
The primary objective of this trial is to evaluate the safety and efficacy of the non ergot dopamine agonist pramipexole for the treatment of tics in children and adolescents (age 6-17 years inclusive) diagnosed with Tourette Disorder according to DSM-IV criteria.
The primary efficacy measure will be the Total Tic Score (TTS) of the YGTSS at 6 weeks.
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| E.2.2 | Secondary objectives of the trial |
Secondary efficacy measures:
YGTSS, total score; TTS of the YGTSS; CGI-I responder rate; CGI-S; PGI-I responder rate.
Safety measures:
Incidence of adverse events, proportion of withdrawals due to adverse events, vital signs, weight, ECG assessments as well as safety laboratory parameters.
The following additional assessments will be included to further assess the safety of study medication:
DuPaul ADHD rating scale IV; Child Depression Inventory-Short Version (CDI-S);
The Child Behavior Checklist (CBCL) for 6-18 year olds; The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS); Tanner Staging; MASC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients ages 6 years-17 years;
2. Written informed consent provided by the patient’s parent (or legal guardian) and assent provided by the patient consistent with ICH/GCP and Local Institutional Review Board requirements for children obtained prior to any study procedures being performed;
3. Ability and willingness to comply with study treatment regimen and to attend study assessments;
4. Diagnosed with Tourette’s Disorder as per the below DSM-IV criteria and with a score ≥22 on the Total Tic Score (TTS) of the YGTSS at baseline:
• Both multiple motor and one or more vocal tics have been present at some time during the illness, although not necessarily concurrently. (A tic is a sudden, rapid, recurrent, non-rhythmic, stereotyped motor movement or vocalization.)
• The tics occur many times a day (usually in bouts) nearly every day or intermittently throughout a period of more than 1 year, and during this period there was never a tic-free period of more than 3 consecutive months
• The onset is before age 18 years
• The disturbance is not due to the direct physiological effects of a substance (e.g., stimulants) or a general medical condition (e.g., Huntington’s disease or post-viral encephalitis)
• The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning
5. Diagnosis of Tourette’s Disorder when administering the Diagnostic Interview Schedule for Children (DISC-IV);
6. Women of childbearing potential must have a negative serum Beta-HCG pregnancy test at the Screening (Baseline) visit unless surgically sterile;
7. Either a de novo patient (not on current treatment for TS), or a patient who has been diagnosed with TS, but who the investigator feels, has not been adequately managed using current therapy, or has failed current therapy, whereby the patient may benefit in the use of pramipexole and, if on current therapy, can be safely discontinued from such therapy prior to enrollment into this study;
8. Women of childbearing potential must be using a medically accepted contraceptive method. Acceptable methods of birth control are limited to: Intra-Uterine Device (IUD), oral, implantable, injectable contraceptives and estrogen patch, double barrier
method (spermacide + diaphragm), or abstinence at the discretion of the investigator;
9. Having a body weight ≥20 kg. |
|
| E.4 | Principal exclusion criteria |
1. Any women of childbearing potential having a positive serum pregnancy test at screening;
2. Clinically significant renal disease or serum creatinine out of this range: 0.3-1.0 mg/dL for patients aged 6-12 years and 0.5-1.4 mg/dL for patients aged 13+ years;
3. Any of the following lab results at screening:
▪ Hemoglobin (Hgb) below lower limit of normal (LLN) which is determined to be clinically significant.
▪ Basal thyroid stimulating hormone (TSH), triiodothyronine (T3) or thyroxine (T4) clinically significantly (at the investigator’s discretion) out of normal range at screening (if not caused by substitution therapy according the investigator’s opinion).
▪ Patients with any clinically significant abnormalities in laboratory parameters at screening at the investigator’s discretion.
4. Other clinically significant metabolic-endocrine, hematological, gastrointestinal disease, pulmonary disease (such as severe asthma) in the opinion of the investigator which would preclude the patient from participating in this study;
5. History of schizophrenia or any psychotic disorder, history of mental disorders or any present Axis I psychiatric disorder according DSM IV (using the DISC-IV assessment interview) requiring any medical therapy except for TS, except for patients with a diagnosis of ADHD or OCD who are not on therapy;
6. History of/or clinical signs of epilepsy or seizures other than fever related seizures in early childhood;
7. History of/or clinical signs of any malignant neoplasm including suspicious undiagnosed skin lesion (which may be melanoma), melanoma, or a history of melanoma;
8. Any other conditions that in the opinion of the investigator would interfere with the evaluation of the results or constitute a health hazard for the patient;
9. Allergic response to pramipexole or the inactive ingredients in its tablet formulation;
10. Had previous treatment with dopamine agonists other than pramipexole within 14 days prior to baseline visit;
11. Had any other medical treatment for TS besides the study medication within 28 days prior to baseline visit (14 days for guanfacine and clonidine; 14 days for dopamine agonists; 14 days for L-Dopa);
12. Had withdrawal symptoms of any medication at screening or at the baseline visit;
13. Having a K BIT2 IQ score <70 at screening;
14. Having a CY-BOCS score >15 at baseline;
15. Patients who meet criteria for Restless Legs Syndrome and/or Periodic Limb Movement disorder;
16. Patients with a history of severe asthma or pulmonary complications. Patients with asthma that is well-controlled are not excluded;
17. Patients that have initiated psychotherapy for Tourette Syndrome, OCD or ADHD within 3 months prior to starting the trial;
18. Patients receiving psychological, cognitive and/or behavioral treatments greater than 3 months prior to starting the trial for Tourette Syndrome, OCD and/ or ADHD symptoms who will have changes in their treatment plan or treatment course during
the trial as well as those patients who will require the initiation of such treatments during the trial.
19. Concurrent participation in another clinical trial or any investigational therapy within thirty days prior to start of this study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline of the TTS of the YGTSS after 6 weeks of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after 6 weeks of treatment |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
YGTSS, total score, change from baseline at Week 1, 2, 3, 4 and 6.
TTS of the YGTSS at Week 1, 2, 3 and 4.
CGI-I responder rate (“much” and “very much improved”) at Weeks 1, 2, 3, 4 and 6.
CGI-S change from baseline to Weeks 1, 2, 3, 4 and 6.
PGI-I responder rate (“much” and “very much better”) at Weeks 1, 2, 3, 4 and 6.
Safety:
Incidence of adverse events, proportion of withdrawals due to adverse events, vital signs (blood pressure, orthostatic reaction and pulse rate), weight, ECG assessments as well as safety laboratory parameters, blood haematology and electrolyte assessments, serum chemistry and urine analyses at baseline and at the end of the treatment period.
DuPaul ADHD rating scale IV change from baseline at Week 6.
Child Depression Inventory-Short Version (CDI-S) change from baseline at Week 6.
The Child Behavior Checklist (CBCL) for 6-18 year olds change from baseline at Week 6.
The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) change from baseline at Weeks 1, 2, 3, 4 and 6. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA 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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| Last visit of the last patient undergoing the trial |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 15 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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