Effect of Oral Levosimendan (ODM-109) on Respiratory Function in Patients with ALS (REFALS)

Study Purpose:

The purpose of the study is to evaluate safety and the effectiveness of levosimendan in preserving respiratory function in patients with amyotrophic lateral sclerosis (ALS).

Disease:

Amyotrophic Lateral Sclerosis (ALS), Familial ALS, Sporadic ALS

Study Type:

Interventional Trial

Study Category:

Drug Trial

Study Status:

Enrolling

Phase:

Phase III

Study Chair(s)/Principal Investigator(s):

Merit Cudkowicz, MD, Massachusetts General Hospital

Clinicaltrials.gov ID (11 digit #):

NCT03505021

Neals Affiliated?

Yes

Coordinating Center Contact Information

Massachusetts General Hospital
Merit E Cudkowicz, MD / .(JavaScript must be enabled to view this email address) / 617-726-2383
Merja Mäkitalo / .(JavaScript must be enabled to view this email address) / +358 10 426 7737
Boston, Massachusetts 02114 United States

Full Study Summary:

This study will evaluate whether prolonged oral levosimendan can preserve respiratory function more effectively than placebo, resulting in better patient functionality as measured by the ALSFRS-R scale. In this randomized, double-blind, placebo-controlled, parallel-group, multicenter study, subjects are allocated in a 2:1 ratio to receive either levosimendan (1 -2 mg daily) or placebo for 48 weeks. The primary endpoint is slow vital capacity (SVC) at 12 weeks, with the impact on patient function assessed through 48 weeks, adjusted for patient outcome, using ALSFRS-R (combined assessment of function and survival, CAFS). Other important efficacy measures include time to respiratory events, clinical global impression (CGI), assessment of dyspnea using the Borg scale and sleep scales (Pittsburgh sleep quality index and Epworth sleepiness scale). Patient safety is monitored using conventional methods including adverse events, safety laboratory tests, vital signs and 12-lead EKG. Following screening and baseline visits, patients attend the clinic at 2, 4, 8, 12, 24, 36 and 48 weeks, with telephone assessments conducted at weeks 18, 30 and 42. An end of study visit is performed 14-25 days after the last study treatment administration. The study will be monitored by an independent data and safety monitoring board. A long-term extension study will be available for patients completing the study.

Study Sponsor:

Orion Corporation, Orion Pharma

Participant Duration:

Total study duration for each subject will be 51-52 weeks, including the screening period, 48 weeks treatment and an end-of-study visit.

At screening, the visit length will be approximately 2 – 2.5hrs.

For visits 2, 3 and 8, the visit length will be approximately 3 – 5 hrs.

For visits 4 to 7, the visit length will be approximately 2 – 3hrs.

There will also be three telephone contacts made in-between sites visits that should not last longer than 30 minutes.

Depending on location of sites, the study participant may be required to travel.

Estimated Enrollment:

450

Estimated Study Start Date:

06/21/2018

Estimated Study Completion Date:

10/30/2020

Posting Last Modified Date:

01/22/2019

Date Study Added to alsconsortium.org:

07/06/2018

Eligibility Criteria

Gender:
Female, Male
Minimum Age:
18
Maximum Age:
N/A
Min Vital Capacity (% predicted normal):
60-90

Time since Symptom Onset:

Time since Diagnosis:

Can participants use Riluzole?
Yes

Inclusion criteria

Written or verbal informed consent (IC) for participation in the study
Diagnosis of laboratory supported probable, probable or definite ALS according to El Escorial revised criteria.
Able to swallow study treatment capsules, and in the opinion of the investigator, is expected to continue to do so during the study.
Disease duration from symptom onset (defined by first muscle weakness or dysarthria) 12-48 months at the time of visit 1 (baseline)
Able to perform supine SVC in an adequate and reliable way at screening and baseline visits as judged by the investigator.
Subjects with or without riluzole (up to 100mg/day, stable at least 4 weeks) and/or edaravone (at least one 28-day treatment cycle completed).

Exclusion criteria

Other causes of neuromuscular weakness not excluded.
Diagnosis of another neurodegenerative disease (e.g. Parkinson’s or Alzheimer’s disease).
Assisted ventilation of any type within 3 months before the screening visit or at screening.
Any use of a diaphragm pacing system (DPS) within 3 months before the screening visit.
Any form of stem cell or gene therapy for the treatment of ALS.
Known hypersensitivity to levosimendan.
Administration of levosimendan within 3 months before the screening visit or previous participation in oral levosimenan trial.
Any use of tirasemtiv or reldesemtiv within 1 month before the screening visit.
Participation in a clinical trial with any experimental treatment within 30 days or within 5 half-lives of that treatment (whichever is longer) before the screening visit.
Any botulinum toxin use within 3 months before the screening visit.
Recorded diagnosis or evidence of major psychiatric diagnosis, significant cognitive impairment or clinically evident dementia that may interfere with the patient’s ability to comply with study procedures.
Pulmonary illness (e.g. asthma or COPD) requiring regular treatment.
Haemodynamically significant uncorrected valve disease or hypertrophic cardiomyopathy or restrictive cardiomyopathy.
Any cardiovascular event (e.g. myocardial infarction, HF, arrhythmia or stroke) requiring hospitalisation within 3 months before the screening visit.
History of Torsades de Pointes (TdP) or diagnosed long QT-syndrome.
History of life-threatening ventricular arrhythmia, unless treated with reliable measures to prevent recurrence (e.g. with placement of implantable cardioverter defibrillator [ICD] or catheter ablation).
History of second or third degree atrioventricular (AV) block or sinus node disease at screening, if not treated with pacemaker.
HR repeatedly > 100 bpm in the 12-lead ECG after a 5-minute rest at screening.
Systolic blood pressure (SBP) < 90 mmHg at screening.
Potassium < 3.7 mmol/l or > 5.5 mmol/l at screening.
Severe renal impairment (creatinine clearance < 30 ml/min at screening), creatinine > 170 μmol/l at screening or on dialysis.
Blood haemoglobin < 10 g/dl at screening or blood donation or loss of significant amount of blood within 60 days before the screening visit.
Clinically significant hepatic impairment at the discretion of the investigator.
Body mass index (BMI) ≤ 18.5kg/m2 (BMI = weight/height2).
Women who are lactating or of reproductive age without a negative pregnancy test and without a commitment to using a highly effective method of contraception (e.g. oral hormonal contraceptives associated with inhibition of ovulation, intrauterine devices and long acting progestin agents), if sexually active during the study, and for 1 month after the last dose of the study treatment. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be reproductive and can be included.
Patient judged to be actively suicidal by the investigator during 3 months before the screening visit.
Patients with known history of human immunodeficiency virus (HIV) infection.
Any other clinically significant cardiovascular, gastrointestinal, hepatic, renal, neurological or psychiatric disorder or any other major concurrent illness that in the opinion of the investigator could interfere with the interpretation of the study results or constitute a health risk for the subject if he/she took part in the study.
Site Contact Information

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