E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Amyotrophic Lateral Sclerosis |
|
E.1.1.1 | Medical condition in easily understood language |
Amyotrophic Lateral Sclerosis (ALS) / Motor Neurone Disease / Lou Gehrig's Disease |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to assess the efficacy of each drug versus placebo on overall survival, defined as death from any cause or respiratory insufficiency, in patients with ALS. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to assess: • the effect of each drug versus placebo on a combined assessment of survival and measures of daily functioning (ALS functional rating scale [ALSFRS-R]) • the effect of each drug versus placebo on ALSFRS-R • the effect of each drug versus placebo on respiratory function (SVC) • the effect of each drug versus placebo on plasma creatinine • the effect of each drug versus placebo on the time to reach advanced disease stages • the safety and tolerability of each drug administered orally to patients with ALS • the effect of each drug versus placebo on change in urinary P75EDC • the effect of each drug versus placebo on change in plasma neurofilament light and heavy chain • the effect of a drug versus placebo on change in plasma pharmacodynamic markers (e.g. HERV-K expression)
Lithium specific (UMC Utrecht only): To determine the value of the compound muscle action potential (CMAP) scan to monitor disease progression
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≥ 18 years at the time of screening. - Diagnosis of ALS according to the revised El Escorial criteria (possible, probable-laboratory supported, probable or definite). - Capable of providing informed consent and complying with trial procedures, including randomization to sub-studies. - ENCALS risk profile > -6.0 and < -2.0. - The use of riluzole will be permitted during the study. Subjects taking riluzole must be on a stable dose for at least 30 days prior to the baseline visit, or stopped taking riluzole at least 30 days prior to the baseline visit. - Women of childbearing potential must have a negative pregnancy test at baseline and be non-lactating. - Men must agree to practice contraception for the duration of the trial and for at least 3 months after last dose of study drug. - Men must not plan to father a child or to provide sperm for donation for the duration of the trial and 3 months after the last dose of study drug. - Women must not be able to become pregnant (e.g. post-menopausal***, surgically sterile or using effective birth control methods) for the duration of the study. Effective contraceptives are defined as having a failure rate of less than 1% per year when used consistently and correctly and, when applicable, in accordance with the product label, including: abstinence, hormonal contraception, intrauterine device in place for ≥ 3 months (Appendix 1). Women of childbearing potential must have a negative pregnancy test at baseline (i.e. treatment day 1), and be non-lactating. Women who are pregnant or are actively seeking to become pregnant, and women of reproductive potential who are not using effective contraceptives are excluded.
|
|
E.4 | Principal exclusion criteria |
For all subjects:
Safety Laboratory Criteria at baseline: o ALT ≥ 5 times upper limit of normal (ULN) o AST ≥ 3 times ULN o Bilirubin ≥ 1.5 times ULN o Estimated glomerular filtration rate (eGFR) < 50 mL / min based on Cystatin C, if not available eGFR can also be calculated based on creatinine clearance. o Platelet concentration of < 100 x109 per L o Absolute neutrophil count of < 1x109 per L o Haemoglobin < 100 g/L (<6.2 mmol/L) o Amylase & lipase ≥ 2 times ULN (suspected pancreatitis) o Lactate ≥ 2 times ULN (suspected lactate acidosis) Moderate to severe hepatic impairment according to Child-Pugh classification (Class B or higher; score ≥ 7). Child-Pugh classification is based on bilirubin, albumin, International Normalized Ratio (INR) and presence of encephalopathy or ascites. Participation in any other investigational drug trial or using investigational drug (within 30 days prior to screening). Hypothyroidism unresponsive to thyroid hormone supplementation. Subjects using non-invasive ventilation (NIV, ≥22 h per day) or having a tracheostomy. Subjects taking edaravone within 30 days prior to screening. Edaravone is approved by the FDA, but remains an investigational product in Europe and Australia. Clinically significant history of unstable or severe cardiac (e.g. congestive heart failure, coronary insufficiency and arrhythmias), oncological, hepatic or renal disease, neuromusculair diseases, significant pulmonary disorder or other medically significant illness. Drug or alcohol abuse. Unstable psychiatric illness defined as psychosis or untreated major depression within 90 days of the screening visit. This exclusion criterion is based on a prior psychiatric diagnosis that is unstable as determined by the subject’s treating Psychiatrist. Presence of frontotemporal dementia which prevents informed consent.
For Lithium carbonate: A potential subject who meets any of the following criteria will excluded from randomization to the Lithium carbonate sub-study:
- Patients heterozygous or homozygous for the A-allele of rs12608932 (UNC13A) - Known allergy or hypersensitivity to lithium, or its excipients, or to the components of the placebo. - Brain injury with posttraumatic epilepsy or neurologic deficit, excluding a concussion in the medical history. Brain infarction is an exclusion criteria, a transient ischemic attack is not. - Addison disease. - Patients with the following co-medication: antipsychotics, digoxin and calcium antagonists, carbamazepine, methyldopa, verapamil and diltiazem. - Brugada Syndrome or family history of Brugada Syndrome. - Plasma sodium <120 mmol/L |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival, defined as time to death from any cause or respiratory insufficiency (DRI; defined as tracheostomy or the use of non-invasive ventilation for ≥22 h per day for ≥10 consecutive days). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
For each sub-study, there is one pre-planned, event-driven, interim analysis when approximately 60% of the required events are available. If the trial cannot be terminated early, the trial continues until the required number of events is reached or until 24 months after the last enrolled patient, whichever occurs first. Patients are required to visit the clinic every 3 months for a maximum duration of 24 months. In case of the lithium sub-study, if treatment is futile, the trial can be stopped after an average of 28.0 months since first enrolled patient with an average sample size of 137 patients. In this scenario, the probability for individual patients to remain in the trial for 18 months or more is 11.3% and to complete 24 months of follow-up is 1.8%. |
|
E.5.2 | Secondary end point(s) |
Composite endpoint evaluating daily functioning and survival based on the joint model framework of survival and longitudinal ALSFRS-R total scores. Daily functioning, defined as mean change from baseline in ALSFRS-R total score. Respiratory function, defined as mean change from baseline in SVC (%predicted of normal according to the GLI-2012 reference standard). Quality of life, defined as change from baseline on the Visual Analogue Scale (single-item scale) and EQ-5D. Neuropsychological status, defined as change from baseline on the ECAS and ALS-FTD-Q. Clinical disease stage, defined as mean time spent in each stage of the King’s and ALS Milano-Torino staging systems. Change from baseline in laboratory parameters: Urinary P75ECD Neurofilament light and heavy chain Plasma creatinine Tolerability defined as time-to-discontinuation of assigned treatment since randomization. Safety based on the safety assessments including physical neurological examinations, clinical laboratory evaluations, vital signs and frequency of adverse events (AEs) or serious adverse events (SAEs). (S)AEs will be categorized according to the Common Terminology Criteria for Adverse Events and will be rated for severity and association with study drug. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints will be evaluated after the study is finished. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Sweden |
Netherlands |
Spain |
Belgium |
Ireland |
United Kingdom |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |