PROTEIN MISFOLDING, AMYOTROPHIC LATERAL SCLEROSIS AND GUANABENZ: A PHASE II RCT WITH FUTILITY DESIGN

INTERVENTION: Product Name: GUANABENZ ACETATO Product Code: GUANA2015 Pharmaceutical Form: Tablet INN or Proposed INN: GUANABENZ CAS Number: 23256‐50‐0 Current Sponsor code: GUANA2015 Other descriptive name: GUANABENZ Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 8‐ Product Name: RILUZOLO Pharmaceutical Form: Tablet INN or Proposed INN: RILUZOLO CAS Number: 1744‐22‐5 Current Sponsor code: RILU2015 Other descriptive name: RILUZOLO Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ CONDITION: Amiotrophic Lateral Sclerosis ; MedDRA version: 19.1 Level: PT Classification code 10028003 Term: Motor neurone disease System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: To investigate the effect of guanabenz as add‐on treatment compared to riluzole alone in reducing the proportion of patients progressed to higher stages of disease over 6 months in sporadic (SALS) or familial ALS (FALS) patients. Primary end point(s): Proportion of patients progressed to higher stages of disease at 6 months (measured by the ALS‐MITOS system) by at least 35% in the guanabenz arm compared to their baseline stage and to the placebo arm (null hypothesis in the futility design). Secondary Objective: To assess safety and tolerability related to alpha2agonist activity of guanabenz. To explore serum biomarkers of ALS progression (creatinine, albumin tau, pNfH, TDP43, cystatin C, fetuin A, transthyretin, and CD14/S100ß and pNfH/C3) in guanabenz and riluzole alone arms at baseline and study end. In patients giving consent the biomarkers will be explored also in the cerebrospinal fluid. Timepoint(s) of evaluation of this end point: 6 months SECONDARY OUTCOME: Secondary end point(s): 3) Difference in at least one serum and/or CSF biomarker of neurodegeneration (creatinine, albumin, tau, pNfH, TDP43, cystatin C, fetuin A, transthyretin, and CD14/S100ß and pNfH/C3 assayed by ELISA and Western blot) comparing baseline and study end between guanabenz and placebo arm. Timepoint(s) of evaluation of this end point: At baseline and at the end of the study INCLUSION CRITERIA: 1) Diagnosis of, probable, probable laboratory supported or definite sporadic (SALS) or familiar (FALS) ALS according to the revised El Escorial criteria; 2) age >18 yrs; 3) onset =18 months before randomization; 4) sVC =70% in spinal onset; 5) riluzole 100 mg/day or no riluzole; 6) written informed consent Are the trial subjects under 18? no Number of subjects for this age range: 1 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 166 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 42