E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
De novo Amyotrophic Lateral Sclerosis patients |
|
E.1.1.1 | Medical condition in easily understood language |
De novo Amyotrophic Lateral Sclerosis patients |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of the trial is to assess the efficacy of deferiprone compared to placebo in reducing the combined assessment of function and survival score |
|
E.2.2 | Secondary objectives of the trial |
To assess the efficacy of deferiprone compared to placebo on: - change in ALSFRS-R total score from baseline (randomization visit) to 12 months. - all-cause mortality or respiratory insufficient at 12 month. - disease progression on muscle strength, respiratory insufficiency, weight and quality of life. - reduction of iron overload in spinal cord, brainstem and the motor cortex. - reduction in excess oxidative stress and iron storage without alteration of iron metabolism - neuropshychological impact (behaviour). - To assess the efficacy of deferiprone compared to placebo according the status of the disease (probable or definite ALS according to the El Escrorial criteria) and the onset form (bulbar vs spinal) |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- MRI, 22-01-2018 V1 - Specifici biochemical screen; 22-01-2018 V1 -additional blood analysis 22-01-2018 V1 - cerebro spinal fluid analysis via lumbar puncture 22-01-2018 V1 |
|
E.3 | Principal inclusion criteria |
– Adults patients – Categorized as; possible, laboratory supported probable, probable, or definite ALS (revised El Escorial criteria) – Spinal and bulbar forms of ALS – Duration of the disease since the first symptoms of motor deficit or amyotrophy ≥ 7 months and ≤ 18 months (isolated cramps or fasciculation will not be considered). – A mild functional handicap score for ALSFRS-R ≥36 – An upright slow vital capacity ≥ 75% of the predicted value for age, height, and sex and an inspiratory pressure > 60 cm of H2O at screening (In case of a limit abnormal value, it will be recommended that patient re-assessment occurs three months later). – Able to swallow (required for oral treatment) – Patients covered by a social insurance – Written informed consent dated and signed prior to the beginning of any procedures related to the clinical trial
|
|
E.4 | Principal exclusion criteria |
– Patients with high frequency of comorbidity or vital risks that may reasonably impair life expectancy – Progressing axis I psychiatric disorders (psychosis, hallucinations, substance addiction, bipolar disorder, severe depression, suicidal ideation), in accordance with the Diagnostic and Statistical Manual of Mental Disorders. Before entry into the study, exclusion or stabilization of conditions must occur for patients suffering from mild or moderate depressive episodes (not in remission) or severe and uncontrolled anxiety. – Dementia according to the Diagnostic and Statistical Manual of Mental Disorders – If the patient is under riluzole, it has to be for at least 1 month (to rule out the principal risk of hepatitis) – Due to the risk of agranulocytosis (estimated at 2%) caused by the Investigational Medicinal Products (IMPs) and the unknown mechanism by which this agranulocytosis is induced, combining deferiprone with other medicinal products known to cause agranulocytosis (as described in the IB) will not be allowed. Such medicinal products include clozapine as well as some NSAIDs (e.g. Phenylbutazone or Metamizole), antithyroid agents, sulfonamide antibiotics or metothrexate. – Patients with agranulocytosis or with a history of agranulocytosis. – A history of relapsing neutropenia – Hypersensitivity to deferiprone – Patients with anaemia (regardless of latter aetiology) or a history of another haematological disease. Haemochromatosis is not an exclusion criterion if controlled. – Pregnant or breastfeeding women or women of childbearing potential not taking highly effective contraception. – Kidney or liver failure. – Inability to provide informed consent. – Participation in another drug study (Investigational medical product) within 1 month prior to inclusion in the study – Patients under trusteeship Exclusion criteria for the biomarker study and the ancillary study (i) MRI: • Subjects for whom MRI is contraindicated (e.g. metal objects in the body, severe claustrophobia, pacemaker, incompatible surgical material). (ii) Lumbar puncture: • Blood coagulation disorders, antiplatelet drugs or anticoagulants. • Intracranial hypertension. (iii) Contraindications to nitrous oxide (for painless lumbar puncture): • Ventilation with FiO2 >50%, emphysema or pneumothorax • Altered states of consciousness, non-cooperative patient (need to stop the nitrous oxide)
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy criterion: The primary endpoint is the CAFS score (Combined Assessment of Function and Survival: Cudkowicz et al., 2011; 2013; Berry et al., 2013), based on changes in amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) total scores and time to death from baseline (randomization visit) to 12 months.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The secondary criteria: 1. Change in ALS Functional Rating Scale-Revised (ALSFRS-R) total score from baseline (randomization visit) to 12 months 2. Time to death for all cause or respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 23 h per day for 14 consecutive days) from baseline until 12 month 3. Change in muscle strength measurements from baseline to 12 month determined by the overall mega-score for manual muscular testing. 4. Change in the slow vital capacity (reflecting the Respiratory insufficiency) (quantitative variable) 5. Change in weight from baseline to 12 months 6. Change in Quality of life assessed using the five-item form of the ALS assessment questionnaire (ALSAQ-5) from baseline to 12 months 7. Neuropsychological impact (subcortico-frontal cognition, frontal behaviour) (1 hour): -7.1 At 12 Month DSMIV criteria: dementia (yes/no) -7.2 At 12 Month Fronto-Temporal Dementia criteria (Rascovsky K et al 2011; Lamarre AK et al 2013) (yes/no) -7.3 Change in MOCA from baseline to 12 months (quantitative variable) -7.4 Change in Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) (Niven et al., 2015) (ALS specific: fluency, executive functions and social cognition, language and ALS Non-specific: memory, visuospatial functions) from baseline to 12 months (quantitative variables) - 8. Analysis of the CAFS score according to disease status (probable or definitive ALS).
Safety criteria will include: A biomarker analysis to assess the biomarker's potential surrogate value: • MRI: • Specific biochemical screen:
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | |
E.8.9.1 | In the Member State concerned months | 36 |
E.8.9.1 | In the Member State concerned days | |