ROCK-ALS: Inhibition of Rho Kinase (ROCK) With Fasudil as Disease-modifying Treatment for ALS

Sponsor

University Medical Center Goettingen (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03792490

Collaborator

(none)

120

Enrollment

Locations

Arms

52.3

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder and therapeutic options are limited. The rho kinase (ROCK) inhibitor Fasudil was shown to be neuroprotective, induced axonal regeneration and improved survival and behavioral outcome in models of ALS and other neurodegenerative diseases. The aim of this phase IIa, multi-center and double-blind study is to analyze the safety, tolerability and efficacy of fasudil in two different doses compared to placebo in approximately 16 trial sites in Germany, France and Switzerland. Intravenous application of fasudil will be performed in 80 patients and placebo in 40 patients two times daily for 20 treatment days. The hypothesis is that fasudil is safe and well-tolerated and its application will significantly improve the clinical outcome in patients with ALS.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Fasudil Drug: Placebo	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Inhibition of Rho Kinase (ROCK) With Fasudil as Disease-modifying Treatment for ALS

Actual Study Start Date :

Feb 20, 2019

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fasudil 30 mg Fasudil (Fasudil hydrochloride hydrate IV solution) Dosage form: intravenous, application over 45 minutes Dosage: 30 mg/ day Frequency: 2 x 15 mg Duration of treatment: 20 days	Drug: Fasudil Fasudil hydrochloride hydrate IV solution
Experimental: Fasudil 60 mg Fasudil (Fasudil hydrochloride hydrate IV solution) Dosage form: intravenous, application over 45 minutes Dosage: 60 mg/ day Frequency: 2 x 30 mg Duration of treatment: 20 days	Drug: Fasudil Fasudil hydrochloride hydrate IV solution
Placebo Comparator: Placebo Sodium chloride (NaCl) 0.9% Dosage form: intravenous, application over 45 minutes Dosage: 100 ml Frequency: 2 x Duration of treatment: 20 days Do2 x 1 ml, NaCl 0.9%	Drug: Placebo Placebo to Fasudil hydrochloride hydrate, NaCl 0,9%

Arm

Intervention/Treatment

Experimental: Fasudil 30 mg

Fasudil (Fasudil hydrochloride hydrate IV solution) Dosage form: intravenous, application over 45 minutes Dosage: 30 mg/ day Frequency: 2 x 15 mg Duration of treatment: 20 days

Drug: Fasudil

Fasudil hydrochloride hydrate IV solution

Experimental: Fasudil 60 mg

Fasudil (Fasudil hydrochloride hydrate IV solution) Dosage form: intravenous, application over 45 minutes Dosage: 60 mg/ day Frequency: 2 x 30 mg Duration of treatment: 20 days

Drug: Fasudil

Fasudil hydrochloride hydrate IV solution

Placebo Comparator: Placebo

Sodium chloride (NaCl) 0.9% Dosage form: intravenous, application over 45 minutes Dosage: 100 ml Frequency: 2 x Duration of treatment: 20 days Do2 x 1 ml, NaCl 0.9%

Drug: Placebo

Placebo to Fasudil hydrochloride hydrate, NaCl 0,9%

Outcome Measures

Primary Outcome Measures

Safety (proportion of patients without treatment-related serious adverse events (SAE) up to day 180) and tolerability (proportion of patients without significant drug intolerance during the treatment period) [From baseline (day 1) to last follow-up (day 180 ± 5)]
Primary endpoint is the proportion of patients without significant drug intolerance during the treatment period (tolerability) and the proportion of patients without treatment-related serious adverse events (SAE) up to day 180 (safety).

Secondary Outcome Measures

Survival time [From baseline (day 1) to end of treatment (day 26 to 30), second follow-up (day 90 ± 4), last follow-up (day 180 ± 5)]
ALS Functional Rating Scale (ALSFRS-R) [From baseline (day 1) to end of treatment (day 26 to 30), second follow-up (day 90 ± 4), last follow-up (day 180 ± 5)]
Amyotrophic lateral sclerosis functional rating scale - revised (ALSFRS-R): a scale to determine different aspects of functionality in patients with ALS, minimum 0 points, maximum 48 points, derived from a questionnaire with 12 questions, each of which can yield up to 4 points, higher score indicates better functionality
ALS Assessment Questionnaire (ALSAQ-5) [From baseline (day 1) to end of treatment (day 26 to 30), second follow-up (day 90 ± 4), last follow-up (day 180 ± 5)]
Amyotrophic lateral sclerosis assessment questionnaire (ALSAQ-5): a patient self-report five-item scale to determine the health status and quality of life in patients with ALS, higher scores show worse quality of life
Edinburgh Cognitive and Behavioral ALS Screen (ECAS) [From baseline (day 1) to end of treatment (day 26 to 30), second follow-up (day 90 ± 4), last follow-up (day 180 ± 5)]
Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS): a scale to determine the cognitive function of patients with ALS, minimum 0 points, maximum 136 points, higher scores show better cognitive performance
Motor Unit Number Index (MUNIX) [From baseline (day 1) to end of treatment (day 26 to 30), second follow-up (day 90 ± 4), last follow-up (day 180 ± 5)]
Motor Unit Number Index (MUNIX): a neurophysiological method based on surface EMG recordings to estimate the number of motor units, higher scores indicate a higher number of motor units
slow Vital capacity (VC) [From baseline (day 1) to end of treatment (day 26 to 30), second follow-up (day 90 ± 4), last follow-up (day 180 ± 5)]
Safety (proportion of patients without treatment-related serious adverse events (SAE) up to end of treatment (day 26 to 30)) and tolerability (proportion of patients without significant drug intolerance during the treatment period) [From baseline (day 1) to end of treatment (day 26 to 30)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Probable (clinically or laboratory) or definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria
Disease duration more than 6 months and less than 24 months (inclusive). Disease onset defined as date of first muscle weakness, excluding fasciculations and cramps
Vital capacity more than 65% of normal (slow vital capacity; best of three measurements)
Age: ≥ 18 years
Patients have to be treated with Riluzole (2 x 50mg/d), must be stable for at least four weeks before randomization
Patients who have started on Edaravone therapy shall continue Edaravone treatment. Edaravone treatment must not be discontinued for reasons of trial participation.
Women of childbearing age 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 such as 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 good clinical practice (GCP)
Patients have to have a valid health insurance, when recruited in a center in France

Exclusion Criteria:

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
Tracheostomy or continuous assisted ventilation of any type during the preceding three months before randomization or a significant pulmonary disorder not attributed to ALS, which may complicate the evaluation of respiratory function, intermittent non-invasive ventilation is permitted,
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, magnetic resonance (MR)- or x-ray-based cranial imaging not older than 24 months must confirm absence of bleeding, aneurysms or Moyamoya.
Gastrostomy
Any medical condition known to have an association with motor neuron dysfunction or involving neuromuscular weakness or another neurodegenerative disease, e.g. Parkinson's disease (PD) or Alzheimer's disease (AD), which might confound or obscure the diagnosis of ALS
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 aspartate transaminase (ASAT) and/or alanine aminotransferase (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 Modification of Diet in Renal Disease (MDRD) 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 study drug
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
Prisoners or subjects who are involuntary incarcerated
Patients subject to legal protection measures

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Centre Hospitalier Universitaire Marseille	Marseille	France
2	Centre Hospitalier Universitaire Montpellier	Montpellier	France
3	Centre Hospitalier Universitaire Nice	Nice	France
4	Centre Hospitalier Universitaire Tours	Tours	France
5	Charité Universitätsmedizin Berlin	Berlin	Germany
6	Universitätsklinikum Carl Gustav Carus Dresden	Dresden	Germany
7	University Medical Center Göttingen	Göttingen	Germany	37075
8	Universitätsklinikum Halle (Saale)	Halle (Saale)	Germany
9	Medizinische Hochschule Hannover	Hannover	Germany
10	Universitätsklinikum Jena	Jena	Germany
11	Universitätsklinikum Leipzig	Leipzig	Germany
12	Klinikum rechts der Isar der Technischen Universität München	München	Germany
13	Universitätsklinikum Ulm	Ulm	Germany
14	University of Würzburg	Würzburg	Germany
15	Kantonsspital St. Gallen	Saint Gallen	Switzerland