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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03505021




Registration number
NCT03505021
Ethics application status
Date submitted
16/04/2018
Date registered
20/04/2018
Date last updated
11/05/2022

Titles & IDs
Public title
Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
Scientific title
Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
Secondary ID [1] 0 0
3119002
Universal Trial Number (UTN)
Trial acronym
REFALS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amyotrophic Lateral Sclerosis 0 0
Condition category
Condition code
Neurological 0 0 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Levosimendan
Treatment: Drugs - Placebo for levosimendan

Experimental: Levosimendan - Levosimendan 1 mg capsules for oral administration, once to twice a day. The total duration of treatment 48 weeks

Placebo Comparator: Placebo for levosimendan - Placebo capsule for oral administration, once to twice a day. The total duration of treatment 48 weeks.


Treatment: Drugs: Levosimendan
Levosimendan 1 mg capsule for oral administration

Treatment: Drugs: Placebo for levosimendan
Placebo capsule for oral administration
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Supine Slow Vital Capacity (SVC)
Timepoint [1] 0 0
The change from baseline at 12 weeks
Secondary outcome [1] 0 0
Combined Assessment of Function and Survival Through 48 Weeks
Timepoint [1] 0 0
Mean rank at 48 weeks
Secondary outcome [2] 0 0
Time to Respiratory Event Through 48 Weeks
Timepoint [2] 0 0
Time to event through 48 weeks
Secondary outcome [3] 0 0
Change From the Baseline in Clinical Global Impression CGI at 48 Weeks
Timepoint [3] 0 0
The change from baseline at 48 weeks
Secondary outcome [4] 0 0
Change From Baseline in Respiratory Function of ALSFRS-R at 48 Weeks
Timepoint [4] 0 0
Slope of decline at 48 weeks
Secondary outcome [5] 0 0
Supine Borg Category Ratio 10 Scale at 12 Weeks
Timepoint [5] 0 0
Change from baseline at 12 weeks

Eligibility
Key inclusion criteria
- Written or verbal informed consent (IC) for participation in the study

- Male or female subjects with diagnosis of laboratory supported probable, probable or
definite ALS according to El Escorial revised criteria. Full electromyogram (EMG)
report available consistent with ALS (but not necessarily fulfilling the
electrodiagnostic criteria for ALS) from an experienced neurophysiologist

- Able to swallow study treatment capsules, and in the opinion of the investigator, is
expected to continue to do so during the study

- Sitting SVC between 60-90% of the predicted value for age, height and sex at screening
visit

- 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 and/or edaravone. If using riluzole (any daily dose
up to 100 mg), the dose must have been stable for at least 4 weeks before the
screening visit and should not be changed during the study. If using edaravone, the
treatment should have been started at least 4 weeks before the screening visit (at
least one 28-day treatment cycle as indicated) and should not be changed during the
study. If not on riluzole and/or edaravone, the respective treatments should not be
started during the study
Minimum age
18 Years
Maximum age
120 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Subject in whom other causes of neuromuscular weakness have not been excluded

- Subject with a 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 the present phase III study or earlier study with oral levosimendan
in ALS patients (LEVALS)

- 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. If the
HR is > 100 bpm in the first recording, then the second recording must be done after
another 5 min rest to confirm HR > 100 bpm

- 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
21/06/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
23/07/2020
Sample size
Target
Accrual to date
Final
496
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Brain and Mind Centre - Camperdown
Recruitment hospital [2] 0 0
Royal Brisbane and Women's Hospital - Brisbane
Recruitment hospital [3] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [4] 0 0
Calvary Health Care Bethlehem - Caulfield South
Recruitment hospital [5] 0 0
Perron Institute for Neurological and Translational Science - Murdoch
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
4029 - Brisbane
Recruitment postcode(s) [3] 0 0
5042 - Bedford Park
Recruitment postcode(s) [4] 0 0
3162 - Caulfield South
Recruitment postcode(s) [5] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
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California
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Colorado
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Connecticut
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District of Columbia
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Florida
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Georgia
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Illinois
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Kentucky
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Maryland
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Massachusetts
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Michigan
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Minnesota
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Missouri
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Nebraska
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Tyrol
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Turku
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Hessen
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Mecklenburg-western-pommerania
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Niedersachsen
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Nordrhein-westfalen
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Sachsen
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Pavia
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Roma
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Torino
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Vizcaya
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Karlstad
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England
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Liverpool

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Orion Corporation, Orion Pharma
Address
Country

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03505021
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Merja Mäkitalo, CSD
Address 0 0
Orion Corporation, Orion Pharma
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries