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

Prospective, international, randomised, double-blind, placebo controlled, multicentre, parallel group study. Patients will be randomised in a 2:1 allocation ratio to receive either IFB-088 + riluzole 100 mg or placebo + riluzole 100 mg. This clinical trial is an exploratory study, designed to show a signal of efficacy of IFB-088 through ALSFRS-R, MITOS and King's College. Respiratory function will be followed through SVC. Biomarkers and quality of life will also be evaluated throughout the study.

Patients will be treated over a 6-month period. After a screening/consent visit, patients will undergo clinic visits at randomisation (V0), at 2 weeks (V1), and at months 1 (V2), 3 (V3) and 6 (V4). One week after V0, the patient will undergo urine analysis (dipstick)and blood sampling for measurement of creatinine

, as well as blood sampling for measurement of creatinine and calculation of eGFR at months 2, 4 and 5. At the V2 visit, in addition to other assessments, patients will undergo blood sampling for PK measurements and urine sampling for crystalluria examination. Blood and urine chemistry, as well as physical examination and vital signs assessment to assess safety will be performed at each visit for safety purpose and crystalluria examination will be repeated at the follow-up visit, performed one month ± one week after V4.


Eligibility Criteria:
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 well tolerated,
7. Male or female patient of childbearing potential10 who agrees to use highly effective mechanical contraception methods (sexual abstinence, intrauterine device, bilateral tubal occlusion, vasectomised partner) throughout the study, and for 3 months 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 to understand 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 not stabilised or that could require hospitalisation and may jeopardise the participation 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 onset to 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 or BMI \<18 kg/m2 at screening,
11. Dementia or other severe active psychiatric illness, including suicidal ideation assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS),
12. Patient with a significant pulmonary disorder not attributed to ALS or who require treatments that might complicate the evaluation of the effect of ALS on respiratory function,
13. Patient treated by edaravone for ALS,
14. Patient using unauthorised concomitant treatments, namely moderate or strong inhibitors or inducers of CYP1A2, strong inhibitors or inducers of CYP2D6 or 2C19 and strong inhibitors of OCT2, as listed in Section 6.2. Combined oral contraceptives 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 days prior 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 is under guardianship or under limited judicial protection.