Treatment Combining Riluzole and IFB-088 in Bulbar Amyotrophic Lateral Sclerosis (TRIALS Protocol)

Inclusion Criteria:

1. Diagnosis of probable or definite ALS according to the revised El Escorial criteria [29], with bulbar onset of disease, familial or sporadic form,

2. Onset of symptoms ≤ 18 months prior to screening, as reported by the patient,

3. Adult males or females, aged at least 18 years old,

4. SVC > 60% of predicted value for age and sex,

5. ALSFRS-R score ≥ 36,

6. Treatment with riluzole 100 mg/day, at stable dose since at least one month and welltolerated,

7. Male or female patient of childbearing potential10 who agrees to use highlyeffective mechanical contraception methods (sexual abstinence, intrauterine device,bilateral tubal occlusion, vasectomised partner) throughout the study, and for 3months after the end of the treatment,

8. Patient who read, understood and signed the ICF,

9. Patient who is willing to adhere to the study visit schedule and is capable tounderstand and comply with protocol requirements.

Exclusion Criteria:

1. Known other significant neurological disease(s),

2. Serious illness(es) or medical condition(s) (e.g. unstable cardiac disease, cancer,hematologic disease, hepatitis or liver failure, renal failure) that is notstabilised or that could require hospitalisation and may jeopardise theparticipation in the study,

3. Abnormal renal function at screening defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2,

4. Abnormal liver function at screening defined as total bilirubin levels >1.5 ULN,and/or AST and/or ALT >3 ULN,

5. Neutropenia (ANC <1.5 x 109/L) at screening,

6. Other causes of neuromuscular weakness,

7. Non progressive or very rapidly progressing ALS (ALSFRS-R decline from disease onsetto randomisation ≤ 0.1 / month or ≥ 1.2 / month)11,

8. Non-invasive ventilation,

9. Tracheotomy,

10. Weight loss ≥ 10% compared to weight at symptoms onset as declared by the patient orBMI <18 kg/m2 at screening,

11. Dementia or other severe active psychiatric illness, including suicidal ideationassessed using the Columbia-Suicide Severity Rating Scale (C-SSRS),

12. Patient with a significant pulmonary disorder not attributed to ALS or who requiretreatments that might complicate the evaluation of the effect of ALS on respiratoryfunction,

13. Patient treated by edaravone for ALS,

14. Patient using unauthorised concomitant treatments, namely moderate or stronginhibitors or inducers of CYP1A2, strong inhibitors or inducers of CYP2D6 or 2C19and strong inhibitors of OCT2, as listed in Section 6.2. Combined oralcontraceptives containing ethinylestradiol are forbidden concomitant medications,

15. Smoker of > 10 cigarettes per day (e-cigarettes and nicotine patches are permitted),

16. Known hypersensitivity to any of the ingredients or excipients of the IMPs,

17. Pregnant, lactating women,

18. Patient who participated in another trial of investigational drug(s) within 30 daysprior to randomisation, or 5 half-lives of the previous investigational product,whichever is longer,

19. Patient who has forfeited their freedom by administrative or legal award, or who isunder guardianship or under limited judicial protection.