The primary objective of this study is to confirm that levosimendan can significantly improve respiratory function measured by supine slow vital capacity (SVC) in amyotrophic lateral sclerosis (ALS) patients.The secondary objective is to confirm…
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Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy:
* The primary efficacy variable will be the change from baseline at 12 weeks in
SVC measured in supine position, SVC (supine). All SVC measurements prior to 12
weeks will be included in the statistical model. SVC is the maximum volume of
air that can be exhaled slowly after slow maximum inhalation.
* ALSFRS-R will be assessed. The variables derived will be the scores of the 12
separate items, the total scores of each subdomain and the total score of
ALSFRS-R.
* The *Time to respiratory event* composite endpoint will be used to validate
the changes seen in supine SVC. This variable consists of the following events:
- At least 1 point decrease in ALSFRS-R respiratory function score 10, 11 or 12
- Meeting *protocolised* criteria for NIV: supine SVC * 50% predicted
- Starting NIV (actual start or attempt to start NIV)
- Invasive mechanical ventilation by intubation or tracheostomy or death
Time to respiratory event will be reached whenever any of the 4 criteria listed
above has been first met.
* CGI is used to rate the severity of subjects* clinical condition. Clinical
condition is assessed by the subjects themselves with a visual analogue scale
(VAS).
* Perception on the intensity of dyspnoea will be assessed by Borg CR10 scale
in supine and sitting position.
* Daytime somnolence will be assessed by ESS.
* Sleep quality and disturbances will be assessed by PSQI.
* Health care and home care resource use will be assessed for possible later
use in pharmacoeconomic analysis.
* Other assessments: Subject*s status for NIV support, invasive mechanical
ventilation by intubation or tracheostomy and survival will be recorded at all
visits.
Secondary outcome
Pharmacokinetics (PK): Blood samples for the determination of levosimendan, its
metabolites OR-1855 and OR-1896 and riluzole concentrations in plasma will be
collected.
Biomarkers: Blood samples will be collected for exploratory biomarker analyses
which may give supportive data related to the disease state of the subjects.
Pharmacogenomics (PG): All subjects will provide a blood sample for
determination of subjects* acetylation status (NAT polymorphisms). The DNA of
subjects who have given a separate PG IC will be stored to allow possible
exploratory PG research to assess whether genetic polymorphisms relate to the
absorption, distribution, metabolism, excretion, pharmacodynamics or safety of
levosimendan.
Safety: Safety will be assessed by adverse events (AEs), vital signs, 12-lead
electrocardiograms (ECGs), physical examination, weight, laboratory tests and
by assessment of suicidality.
Background summary
see section 1.1 background in the protocol
Study objective
The primary objective of this study is to confirm that levosimendan can
significantly improve respiratory function measured by supine slow vital
capacity (SVC) in amyotrophic lateral sclerosis (ALS) patients.
The secondary objective is to confirm that levosimendan improves the
functionality of subjects, measured by Revised ALS Functional Rating Scale
(ALSFRS-R), Clinical Global Impression (CGI), Borg Category Ratio 10 (CR10)
scale on the intensity of dyspnea. Epworth Sleepiness scale (ESS) and
Pittsburgh Sleep Quality Index (PSQI). The latter two are sleep scales
assessing daytime somnolence and sleep quality, respectively. In addition, the
long-term tolerability and safety of levosimendan in ALS patients will be
evaluated, assessing up to 48 weeks of exposure.
Other objectives: For the purposes of potential later pharmacoeconomic
analysis, the use of specific health and home care resources and assistive
devices will be quantified. This will include both in and outpatient care, as
well as formal and informal home care.
Exploratory objectives: The plasma concentrations of levosimendan and the
metabolites OR-1855 and OR-1896 will be determined. In addition, a population
pharmacokinetic/pharmacodynamic (PK/PD) model between OR-1855 and OR-1896
exposure and efficacy related endpoints and heart rate (HR) will be explored.
Plasma concentrations of riluzole will also be determined. The effects of
levosimendan, OR-1855 and OR-1896 on plasma trough concentrations of riluzole
will be evaluated. The acetylation status will be determined for all subjects
to assess whether it affects the PD responses of levosimendan in patients with
ALS.
Study design
This is a randomised, double-blind, placebo-controlled, parallel-group,
multinational, multicentre study. The subjects will be allocated to 2 parallel
groups receiving either levosimendan 1-2 mg daily or placebo in 2:1 ratio.
There will be a screening visit, a baseline visit followed by visits at 2, 4,
8, 12, 24, 36 and 48 weeks, and telephone contacts during weeks 18, 30 and 42.
An end-of-study visit will take place 14-25 days after the last study treatment
administration for each subject. The total study duration for each subject will
be about 51-52 weeks including the end-of-study visit.
Intervention
Levosimendan 1 mg capsule/Placebo Levosimendan capsule
The daily doses of oral levosimendan will be 1-2 mg depending on the
tolerability (mainly judged by HR). The subjects will start with a 1 mg dose
(in the morning) for 2 weeks. Administration of placebo (1 or 2 capsules per
day) will be based on the same criteria as for levosimendan.
Study burden and risks
A: Medicine or other interactions
The patient needs to take the study drug approx. 1 hour before food intake,
since food may affect how the drug is take up by the body. Taking certain
other medicines together with levosimendan (ODM-109) may increase the chance of
unwanted effects. The risk will depend on how much of each medicine the
patient takes every day, and on how long the patient takes the medicines
together. If your study investigator instructs the patient to take these
medicines together on a regular basis, follow his or her directions carefully.
Report if you have taken any other medications during the study.
B: Side effects of the study medicinal product
The possible discomforts, side effects and risks related to levosimendan
(ODM-109) treatment are not all known, although some may be serious and may
require treatment or additional testing. This section describes how frequently
side effects occurred in subjects who were treated with levosimendan (ODM-109).
Very Common: Affects more than 1 user in 10:
* Mild-moderate headache lasting for about 2-3 days.
* Increased heart rate.
Common: Affects 1 to 10 users in 100
* Rapid or irregular beating of the heart.
* Slight decrease in red blood cell count which can lead to anemia, a condition
in which you don't have enough healthy red blood cells to carry adequate oxygen
to the body's tissues. Having anemia may make you feel tired and weak.
* Decrease in blood value of potassium. Potassium helps carry electrical
signals to cells in your body. It is critical to the proper functioning of
nerve and muscles cells, particularly heart muscle cells.
Previous studies with oral levosimendan (ODM-109) have not showed any signs of
more severe irregular heartbeats compared to placebo treatment. The patient
will still be carefully monitored in case you would experience rapid or
irregular beating of the heart, dizziness or loss of consciousness.
Because of possible drug reactions, the patient cannot enter this study if the
patient is allergic or sensitive to levosimendan (ODM-109). Serious allergic
reactions which could be life-threatening are rare, this could include swollen
face, lips, mouth and/or throat.
Other currently unknown risks and discomforts could appear. It is therefore
very important that any new health problem is quickly reported to the
investigator, regardless of whether or not the patient thinks it is to do with
the study.
See Appendix E of the ICF for Other Risks and discomforts
Orionintie 1A
Espoo FI-02200
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Orionintie 1A
Espoo FI-02200
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Listed location countries
Age
Inclusion criteria
Male or female subjects with diagnosis of ALS, disease duration from symptom
onset of 12-48 months, written or verbal informed consent (IC) obtained from
the subject. Age at least 18 years. 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. Able to perform supine SVC at screening and
baseline visits.
Subjects with or without riluzole. 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 not on riluzole,
the respective treatments should not be started during the study.
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.
Several renal impairment (creatinine clearance < 30 ml/min at screening),
creatinine > 170 *mol/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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-002754-36-NL |
| ClinicalTrials.gov | NCT03505021 |
| CCMO | NL64706.041.18 |