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.
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