Safety, Tolerability and Symptomatic Efficacy of the ROCK-Inhibitor Fasudil in Patients With Parkinson's Disease

Study Overview
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Brief Summary
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The aim of this phase Ila trial is to provide evidence on safety, tolerability and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with early Parkinson's disease (PD). Fasudil has shown neuroprotective and pro-regenerative effects, modulated microglial activity and attenuated alpha-synuclein aggregation in PD models in vitro and in vivo. It has been licensed in Japan since 1995 for the treatment of vasospasms and has a beneficial safety profile arguing for its repurposing. Up to 15 trial centers in Germany will recruit patients. Blinded trial medication will be prepared and shipped by the University Pharmacy Leipzig. Fasudil in two dosages or placebo will be administered orally twice daily to 75 early PD patients for a total of 3 weeks. Safety, tolerability and symptomatic efficacy endpoints will be assessed up to 4 weeks after end of treatment. Its well-known safety profile and the lack of disease-modifying treatments for PD justifies its use in patients with early Parkinson's disease. ROCK-PD is a prerequisite for subsequent long-term clinical trials assessing disease-modification in PD in addition to symptomatic efficacy.

Official Title
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Safety, Tolerability and Symptomatic Efficacy of the ROCK-Inhibitor Fasudil in Patients With Parkinson's Disease (ROCK-PD)

Conditions
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Idiopathic Parkinson´s Disease

Intervention / Treatment
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* Drug: Fasudil hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of at least probable PD according to MDS criteria (Postuma et al. MovDis 2015) and Hoehn & Yahr stage 1 - 3 must be non-fluctuating (no wearing-off, no dyskinesia) and stable on symptomatic PD medication for at least 6 weeks age: 30 - 80 years Women of childbearing potential must be non-lactating and surgically sterile or using a highly effective method of birth control and have a negative pregnancy test. Acceptable methods of birth control with a low failure rate (i.e. less than 1% per year) when used consistently and correct are for example implants, injectables, combined oral contraceptives, hormonal intrauterine devices (IUDs), sexual abstinence or vasectomized partner Capable of thoroughly understanding all information given and giving full informed consent according to GCP Exclusion Criteria: Atypical, secondary Parkinsonian syndromes, PD mimics, or any other medical condition known to have an association with Parkinsonian syndromes, which might confound or obscure the diagnosis of PD Patients with a history of intracranial bleeding, known intracerebral aneurysms or Moyamoya disease, or positive family history for the above. If only family history positive, MR- or x-ray-based cranial imaging not older than 24 months must confirm absence of bleeding, aneurysms, or Moyamoya Presence of any concomitant life-threatening disease or impairment likely to interfere with functional assessment Patients with known arterial hypotension (resting blood pressure <90/60 mmHg) or previous hypotensive episodes or requiring treatment for increasing of blood pressure, such as fludrocortisone, midodrine, etilefrine, cafedrine, or theodrenaline Patients with an uncontrollable or unstable arterial hypertensive disease (resting blood pressure >180 mmHg systolic and/or >120 mmHg diastolic under current antihypertensive medication) Known pulmonary hypertension and any medication prescribed for treatment of pulmonary hypertension Confirmed hepatic insufficiency or abnormal liver function (stable ASAT and/or ALAT greater than 3 times the upper limit of the normal range) and determined to be non-transient through repeat testing Renal insufficiency with a glomerular filtration rate (GFR) <60 ml/min/1,73m² (calculated by MDRD equation or byCKD-EPI equation) and determined to be non-transient through repeat testing Major psychiatric disorder, significant cognitive impairment or clinically evident dementia precluding evaluation of symptoms Hypersensitivity to any component of the IMP Liable to be not cooperative or comply with the trial requirements (as assessed by the investigator), or unable to be reached in the case of emergency Pregnant or breast-feeding females or females with childbearing potential, if no adequate contraceptive measures are used Previous participation in another clinical study involving trial medication within the preceding 12 weeks or five terminal half times of the longest to be eliminated trial medications (whichever is longer) or previous participation in this trial

Ages Eligible for Study
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Minimum Age: 30 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intervention arm (low dose)<br>oral Fasudil solution 88 mg/day (2 x 44 mg) | Drug: Fasudil hydrochloride<br>* Duration of intervention per patient: 22 days; Application scheme: one dose on day 1, two doses on days 2 - 21, one dose on day 22.<br>* Other names: Fasudil hydrochloride (Fasudil);|
| Experimental: intervention arm (high dose)<br>oral Fasudil solution 44 mg/day (2 x 22 mg) | Drug: Fasudil hydrochloride<br>* Duration of intervention per patient: 22 days; Application scheme: one dose on day 1, two doses on days 2 - 21, one dose on day 22.<br>* Other names: Fasudil hydrochloride (Fasudil);|
| Placebo Comparator: Control intervention arm (placebo)<br>oral placebo solution 2x/day. | Drug: Placebo<br>* 0.05 ml Quinine dihydrochloride solution (from Quinina Labesfal) in screw flask supplemented with 30 ml Glucose 40% solution from miniplasco directly before use<br>* Other names: Quinine dihydrochloride solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined occurrence of intolerance and/or occurrence of self-reported and pre-defined treatment-related SAEs | Combined occurrence of intolerance (termination of treatment because of treatment-related AE) and/or occurrence of self-reported and pre-defined (laboratory, vital signs) treatment-related SAEs | from day 1 to day 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of intolerance | Occurrence of intolerance (termination of treatment because of treatment-related AE) | from day 1 to day 22 | 
| Occurrence of self-reported and pre-defined treatment-related SAEs | Occurrence of self-reported and pre-defined (laboratory, vital signs) treatment-related SAEs | from day 1 to day 22, and day 1 to day 50 | 
| Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) | the change of MDS-Unified PD Rating Scale (MDS-UPDRS) each part I to IV, min-max: 0-260, 0 indicating no disability and 260 indicating total disability, Part I: Nonmotor experiences of daily living: 13 items. Score range: 0-52; Part II: Motor experiences of daily living: 13 items. Score range: 0-52; Part III: Motor examination: 18 items. Score range: 0-132; Part IV: Motor complications: 6 items. Score range: 0-24; Each item has 0-4 ratings: 0 (normal), 1 (slight), 2 (mild), 3 (moderate), and 4 (severe). | part I and II from day 1 to day 22, and day 1 to day 50; time frame: part III and IV from day 1 to day 10, day 1 to day 22, and day 1 to day 50 | 
| MDS-Unified PD Rating Scale (MDS-UPDRS) score | the change of MDS-Unified PD Rating Scale (MDS-UPDRS) score part I to IV, min-max: 0-260, 0 indicating no disability and 260 indicating total disability, Part I: Nonmotor experiences of daily living: 13 items. Score range: 0-52; Part II: Motor experiences of daily living: 13 items. Score range: 0-52; Part III: Motor examination: 18 items. Score range: 0-132; Part IV: Motor complications: 6 items. Score range: 0-24; Each item has 0-4 ratings: 0 (normal), 1 (slight), 2 (mild), 3 (moderate), and 4 (severe). | from day 1 to day 22, and day 1 to day 50 | 
| Parkinson's Disease Questionnaire (PDQ-8) | the change of 8-item PD Quality of Life Scale (PDQ-8), min-max: 0-32, 0 no and 32 max | from day 1 to day 22, and day 1 to day 50 | 
| Non-Motor Symptom Questionnaire (NMSQuest) | the change of PD Non-Motor Symptom Questionnaire (NMSQuest), min-max: 0-30, 0 no and 30 max | from day 1 to day 10, day 1 to day 22, and day 1 to day 50 | 
| Montreal Cognitive Assessment (MoCA) | the change of Montreal Cognitive Assessment (MoCA), Montreal Cognitive Assessment MoCA: min-max: 0 (worse) -30 (better outcome) | from day 1 to day 22, and day 1 to day 50 | 
| Beck's Depression Inventory II (BDI-II) | the change of Becks depression inventory-II (BDI-II), min-max: 0-63, 0 no and 63 max | from day 1 to day 22, and day 1 to day 50 | 
| Clinician Global Impression of Improvement (CGI-I) and Patient Global Impression of Improvement (PGI-I) | CGI-I [clinician]: min-max: 1-7, min-max: 1 (better) -7 (worse outcome) PGI-I [patient]: min-max: 1-7, min-max: 1 (better) -7 (worse outcome) | at day 10, 22 and day 50 |