Efficacy, Tolerability and Safety of Azilect in Subjects With Progressive Supranuclear Palsy

Study Overview
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Brief Summary
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The purpose of this study is to determine whether rasagiline is effective in the treatment of Progressive Supranuclear Palsy (PSP), a rapidly progressing disease with a symptomatology similar to Parkinson's Disease. The major aim of this study is the limitation or halting of the process of neurodegeneration and influence postural instability.

Detailed Description
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Progressive Supranuclear Palsy (PSP) is a rapidly progressing disease with a median survival after onset of symptoms of 5.8 years.PSP is characterized by early falls, vertical ophthalmoparesis, akinetic-rigid features, prominent bulbar dysfunction and fronto-subcortical dementia. So far there is no treatment for the disease as the negative outcomes of the vast majority of studies make it impossible to set standards. As the majority of patients experience severe falls and vertigo already in the early phase of the disease, the drug of desire would be able to slow disease progression with a special focus on postural instability and exert neuroprotective effects. The monoamino oxidase inhibitor Rasagiline might be able to influence progression of PSP.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess the Efficacy, Safety and Tolerability of Rasagiline in Subjects With Progressive Supranuclear Palsy (Phase III)

Conditions
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Progressive Supranuclear Palsy

Intervention / Treatment
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* Drug: Rasagiline
* Drug: Sugar pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical signs of Progressive Supranuclear Palsy (PSP). Diagnosis will be made for patients with clinical probable PSP (Litvan et al., 1996). Patients will be included with PSP stage </= II (Golbe et al., 1997), at least with a PSPRS < 40 (Golbe et al., 2007) and according to the diagnostic criteria resumed after the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) trial (Bensimon et al., 2009) Patients, male or female, aged 50 to 80 years Subjects whose clinical condition at the time of enrolment does not or requires a low [</= 500 mg /day] stable dose of L-3,4-Dihydroxyphenylalanine (L-DOPA) for at least 2 weeks prior to study entry Capability and willingness to give written signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study Exclusion Criteria: No clinically probable PSP No written informed consent possible Age > 80 or < 50 years Dementia (Mini-Mental State Examination [MMSE] </= 24) Subjects with clinically significant psychiatric illness, including major depression Subjects who have taken any experimental drugs within 60 days prior to baseline Subjects who have used sympathomimetics (including over-the-counter remedies - nasal or oral), dextromethorphan, pethidine or St. John's wort within 7 days prior to baseline. Loss of postural reflexes (no independent walking possible, inability to stand unassisted, wheelchair-bound) Feeding tube / recommendation for a feeding tube Unintelligible speech History of brain disease (e.g. repeated strokes, cerebral tumour, hydrocephalus) 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) exposure Oculogyric crisis Early severe autonomic failure Systemic disorder affecting the brain Women who are not postmenopausal (e.g. one year without menstrual periods) or surgically sterilized. Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure Subjects who have used antidepressants, including selective serotonin re-uptake inhibitors, tricyclic and tetracyclic antidepressants (except amitriptyline <= 50 mg/day, trazodone < = 100 mg/day, citalopram < = 20 mg/ day, sertraline < = 100 mg/day and paroxetine < = 30 mg/day, escitalopram < = 10 mg/day) within 42 days prior to baseline Subjects who have used any drugs known to have been involved in a drug interaction via inhibition of hepatic Cytochrome P450 1A2 (CYP 1A2) within 30 days prior to baseline (cimetidine, ciprofloxacin, clarithromycin, enoxacin, erythromycin, fluvoxamine, isoniazide, nalidixic acid, norfloxacin, troleandomycin, zileuton) Subjects who have used Monoamine oxidase (MAO) inhibitors including reserpine and methyldopa within three months prior to baseline Anti-emetic or antipsychotic medication with central dopamine antagonist activity (except quetiapine fumarate) within six months prior to baseline Participation in a clinical trial within the last 30 days prior to study start Unstable antiparkinsonian medication within 30 days before baseline Previous use of Rasagiline or Selegiline Subjects who have a clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation (based on the investigator's judgment). Such conditions might include cardiovascular, vascular diseases, pulmonary, hepatic impairment (Child-Pugh score > 5), renal, or metabolic dis-eases or malignancies as determined by medical history, physical examination, laboratory tests, or ECG

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rasagiline<br> | Drug: Rasagiline<br>* tablet once daily 1 mg 1 year<br>* Other names: Azilect;|
| Placebo Comparator: Sugar pill<br> | Drug: Sugar pill<br>* tablet once daily one year<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the need for additional L-DOPA therapy or the need to increase the dose of L-DOPA during the trial | Since there is no established treatment regimen for Progressive Supranuclear Palsy (PSP) patients, the only well characterized medication is L-3,4-Dihydroxyphenylalanine (L-DOPA) therapy. Since this therapy may exert a small effect in PSP patients, begin with L-DOPA therapy or increase in L-DOPA therapy will be used in this trial as rescue medication. | 1 year | 
| Reduction of the reported deterioration using the PSP rating scale | To assess the efficacy of Rasagiline using the Progressive Supranuclear Palsy Rating Scale (PSPRS), aiming at a 33% reduction of the reported deterioration (Golbe et. al., 2007), i.e. a mean yearly increase of 6.5 instead of 9.7 points. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of gait disturbances and postural stability |  | 1 year | 
| Adverse Event (AE) incidence |  | 1 year | 
| Safety laboratory values (blood cell count, aspartate aminotransferase [AST], alanine aminotransferase [ALT], creatinine, Vitamin B12, folic acid, homocysteine and methylmalonic acid) |  | 1 year | 
| Vital signs |  | 1 year | 
| Number of subjects (%) who discontinue the study |  | 1 year | 
| Number of subjects (%) who discontinue the study due to AEs |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSP, Progressive Supranuclear Palsy, Rasagiline, Azilect, PROSPERA