Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome

Study Overview
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Brief Summary
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The primary objective of this open-label, flexible dose study is to assess the safety and efficacy of pramipexole over a 24-week period in children and adolescents (age 6-17 years inclusive) diagnosed with Tourette Syndrome according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria and who have completed either Study 248.641 (NCT 00681863) or 248.644 (NCT 00558467).

Official Title
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Open Label Extension Study With Pramipexole (PPX) in Children With Tourette Syndrome

Conditions
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Tourette Syndrome

Intervention / Treatment
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* Drug: pramipexole 0.125 mg BID
* Drug: pramipexole 0.0625 mg QD
* Drug: pramipexole 0.125 mg TID
* Drug: pramipexole 0.25 mg BID
* Drug: pramipexole 0.0625 mg BID


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Male or female patients aged 6-17 years at the time of enrollment into study 248.641 or 248.644 and who have completed study 248.641 or 248.644. Written informed consent provided by the patient's parent (or legal guardian) and assent provided by the patient consistent with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) and local Institutional Review Board (IRB) requirements for children obtained prior to any study procedures being performed. Ability and willingness to comply with study treatment regimen and to complete study assessments. Females of childbearing potential having a negative serum pregnancy test at Visit 1. Females of childbearing potential must be using a medically accepted contraceptive method throughout the study. Acceptable methods of birth control are limited to: Intra-Uterine Device (IUD), oral, implantable, injectable contraceptives or estrogen patch, double barrier method (spermicide + diaphragm), or abstinence at the discretion of the investigator Exclusion criteria Breastfeeding females. Development of any clinical condition in the preceding trial that in the investigator's opinion could be worsened by treatment with pramipexole. Clinically significant renal disease or serum creatinine out of this range: 0.3 1.0 mg/dL for patients aged 3-12 years and 0.5-1.4 mg/dL for patients aged 13+ years. 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 significant (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. Other clinically significant metabolic-endocrine, hematological, gastrointestinal disease, or pulmonary disease (such as severe asthma) in the opinion of the investigator that would preclude the patient from participating in this study. History or presence of schizophrenia or any psychotic disorder. History or presence of any psychiatric disorder requiring medical therapy with the exception for patients with a diagnosis of Tourette Syndrome (TS), Attention Deficit Hyperactivity Disorder (ADHD) or Obsessive Compulsive Disorder (OCD) who are not on therapy other than pramipexole. History or presence of clinical signs of epilepsy or seizures other than fever-related seizures in early childhood. History or presence of clinical signs of any malignant neoplasm including suspicious undiagnosed skin lesion (which may be melanoma), melanoma, or a history of melanoma. History of any other medical treatment for TS besides the study medication within 28 days prior to the baseline visit (14 days prior to baseline for guanfacine, 14 days prior to baseline for dopamine agonists, 14 days prior to baseline for L-Dopa, 35 days prior to baseline for fluoxetine). Patients receiving psychotherapy are excluded unless they started the treatment at least 3 months prior to starting the trial and no changes in treatment are planned for the duration of the study. Allergic response to pramipexole or the inactive ingredients in its tablet formulation. Non-compliance with study medication (defined as less than 80% or more than 120%) during the preceding Study 248.641 or 248.644. Concurrent participation in another clinical trial using any investigational drug since completion of the preceding Study 248.641 or 248.644. 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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: pramipexole 0.0625 mg BID (twice daily)<br>all patients to receive one tablet of pramipexole 0.0625 mg BID for first 4 weeks (flexible dosing for all other arms) | Drug: pramipexole 0.0625 mg BID<br>* 0.0625 mg BID given for first 4 wks of treatment<br>|
| Active Comparator: pramipexole 0.0625 mg QD (once daily)<br>patients to receive one tablet of pramipexole 0.0625 mg QD | Drug: pramipexole 0.0625 mg QD<br>* dose down titrated for those patients unable to tolerate the 0.0625 mg BID dosing<br>|
| Active Comparator: pramipexole 0.125 mg BID<br>patients to receive one tablet of pramipexole 0.125 mg BID | Drug: pramipexole 0.125 mg BID<br>* titrated dose for those patients whose symptoms were not controlled on the 0.0625 mg BID dose<br>|
| Active Comparator: pramipexole 0.125 mg TID (three times daily)<br>patients to receive one tablet of pramipexole 0.125 mg TID | Drug: pramipexole 0.125 mg TID<br>* titrated up for those patients whose symptoms were not adequately controlled on 0.125 mg BID dose<br>|
| Active Comparator: pramipexole 0.25 mg BID<br>patients to receive one tablet of pramipexole 0.25 mg BID | Drug: pramipexole 0.25 mg BID<br>* titrated for those patients whose symptoms were not adequately controlled on 0.125 mg TID dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Adverse Events Leading to Discontinuation of Trial Drug | Number of patients with Adverse Events leading to discontinuation of trial drug | 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and week 24 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 24 (end of treatment visit) | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 1 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 2 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 3 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and week 4 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 8 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 12 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 16 | 
| Mean Change From Baseline in Total Tic Score (TTS) of the Yale Global Tic Severity Scale | Total Tic Score is the sum of ten individual ratings of the impairment due to tics. Each scale ranges from 0 (None/Absent) to 5 (Severe) and total score ranges from 0 to 50. | baseline and Week 20 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 1 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 2 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 3 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 4 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 8 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 12 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 16 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 20 | 
| Mean Change From Baseline in Total Score of the Yale Global Tic Severity Scale | Total Score is a rating of the overall impairment due to motor and phonic tics. The scale ranges from 0 (None) to 50 (Severe). | baseline and Week 24 | 
| Clinical Global Impressions - Severity of Illness | Overall improvement during the last week compared to baseline ranging from 1 (very much improved), 2 (much improved), to 7 (very much worse). Responder has 'very much' or 'much' improvement. Non responder has less improvement than 'much' improvement. | week 24 | 
| Clinical Global Impressions - Severity of Illness, Categorized | Assessment of the overall severity of illness on a scale ranging from 1 (not at all ill) to 7 (among the most extremely ill patients). Overall improvement during the last week compared to baseline ranging from 1 (very much improved), 2 (much improved), to 7 (very much worse). Responder has 'very much' or 'much' improvement. Non responder has less improvement than 'much' improvement. | week 24 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 1 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 2 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 3 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 4 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 8 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 12 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 16 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 20 | 
| Clinical Global Impressions - Improvement | Assessment of the overall improvement during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much improved) to 7 (very much worse). | week 24 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 1 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 2 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 3 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 4 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 8 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 12 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 16 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 20 | 
| Patient Global Impression - Improvement | Assessment of the change of the patient's overall condition during the last week compared to the patient's condition at baseline on a scale ranging from 1 (very much better) to 7 (very much worse). A responder is defined as having a response of very much (1) or much better (2). | week 24 | 
| Frequency of Patients With Possible Clinically Significant Abnormalities for Laboratory Parameters | Frequency of patients with possible clinically significant abnormalities for laboratory parameters (blood hematology and electrolyte assessments, serum chemistry, including follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol for pubertal female patients, prolactin in all patients, testosterone in pubertal male patients, urine analysis) | Baseline and 24 weeks |