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

Study Overview
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Brief Summary
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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.

Official Title
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A Double-blind, Placebo-controlled, Exploratory Randomised Clinical Trial to Assess the Safety and Efficacy of IFB-088 Plus Riluzole 100 mg vs Placebo Plus Riluzole 100 mg in Patients With Bulbar-onset Amyotrophic Lateral Sclerosis.

Conditions
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ALS, Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: IFB-088 50mg/day
* Drug: Placebo
* Drug: Riluzole 100mg/day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of probable or definite ALS according to the revised El Escorial criteria [29], with bulbar onset of disease, familial or sporadic form, Onset of symptoms ≤ 18 months prior to screening, as reported by the patient, Adult males or females, aged at least 18 years old, SVC > 60% of predicted value for age and sex, ALSFRS-R score ≥ 36, Treatment with riluzole 100 mg/day, at stable dose since at least one month and well tolerated, 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, Patient who read, understood and signed the ICF, Patient who is willing to adhere to the study visit schedule and is capable to understand and comply with protocol requirements. Exclusion Criteria: Known other significant neurological disease(s), 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, Abnormal renal function at screening defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, Abnormal liver function at screening defined as total bilirubin levels >1.5 ULN, and/or AST and/or ALT >3 ULN, Neutropenia (ANC <1.5 x 109/L) at screening, Other causes of neuromuscular weakness, Non progressive or very rapidly progressing ALS (ALSFRS-R decline from disease onset to randomisation ≤ 0.1 / month or ≥ 1.2 / month)11, Non-invasive ventilation, Tracheotomy, Weight loss ≥ 10% compared to weight at symptoms onset as declared by the patient or BMI <18 kg/m2 at screening, Dementia or other severe active psychiatric illness, including suicidal ideation assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), 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, Patient treated by edaravone for ALS, 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, Smoker of > 10 cigarettes per day (e-cigarettes and nicotine patches are permitted), Known hypersensitivity to any of the ingredients or excipients of the IMPs, Pregnant, lactating women, 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, Patient who has forfeited their freedom by administrative or legal award, or who is under guardianship or under limited judicial protection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomised in a 2:1 allocation ratio to receive either IFB-088 + riluzole 100 mg or placebo + riluzole 100 mg.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IFB-088 50 mg/day + riluzole 100 mg/day<br>The test product, IFB-088, will be administered orally in 50 mg/day dosage consisting of two uptakes of 25 mg each (morning and evening uptakes), as an add-on therapy to riluzole 100 mg. Intervals for dosing should ideally be about 12 hours (± one hour). Tablets will be swallowed with a glass of water 30 minutes before the meal, in fasting condition. Administration of riluzole 100 mg, tablet or suspension, will be at the patient's and/or investigator's choice, as per summary of product characteristics. The daily dose of 100 mg will be taken in two 50 mg doses every 12 hours, at the same time than the IMPs. Patients will be treated for a period of 6 months (26 weeks). | Drug: IFB-088 50mg/day<br>* Tested product<br>* Other names: Icerguastat;Drug: Riluzole 100mg/day<br>* Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo<br>* Other names: Riluzole;|
| Placebo Comparator: placebo + riluzole 100 mg/day<br>The placebo will be administered orally in two uptakes (morning and evening uptakes), as an add-on therapy to riluzole 100 mg. Intervals for dosing should ideally be about 12 hours (± one hour). Tablets will be swallowed with a glass of water 30 minutes before the meal, in fasting condition. Administration of riluzole 100 mg, tablet or suspension, will be at the patient's and/or investigator's choice, as per summary of product characteristics. The daily dose of 100 mg will be taken in two 50 mg doses every 12 hours, at the same time than the IMPs. Patients will be treated for a period of 6 months (26 weeks). | Drug: Placebo<br>* Placebo<br>Drug: Riluzole 100mg/day<br>* Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo<br>* Other names: Riluzole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessment of IFB-088 50 mg/day in patients with bulbar-onset ALS. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Incidence, grade and relationship to IFB-088 for treatment emergent AEs, SAEs, and AESIs, AEs leading to dose interruption or premature discontinuation. | from beginning of IMP intake up to 30 days after stopping the intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy with scale : ALSFRS-R (ALS Functional Rating Scale Revised) | ALSFRS-R (ALS Functional Rating Scale Revised) 12 items, clinician rated including 5 choices from normal to disabled. | Efficacy scale from baseline to 3 months and 6 months. | 
| Efficacy with scale : ALS_MITOS (ALS Milano-Torino Staging) | ALS_MITOS (ALS Milano-Torino Staging), 4 domains, clinician rated, Staging determined by the sum of functional score of 1 for each domain. | Efficacy scale from baseline to 3 months and 6 months. | 
| Efficacy with scale : King's college Scale (ALS staging form) | King's college Scale (King's ALS staging form), clinician rated, 8 items. | Efficacy scale from baseline to 3 months and 6 months. | 
| Efficacy based on assessment of respiratory function (slow vital capacity [SVC]) | Assessment of respiratory function (slow vital capacity [SVC]). | Respiratory function at screening, 3 and 6 months. | 
| Efficacy based on assessment of respiratory function (Arterial Blood Gases [ABG]) | Assessment of respiratory function (Arterial Blood Gases [ABG]). | Respiratory function at screening, 3 and 6 months. | 
| Efficacy based on assessment of nutritional status (exploratory) | change of nutritional status (fat mass) evaluated by bioelectrical impedance | At baseline and 6 months | 
| Efficacy based on assessment of body composition (exploratory) | change of body composition (% of water, muscle, bone in the body) evaluated by bioelectrical impedance | At baseline and 6 months | 
| Pharmacokinetic parameters (Plasma concentration) | Plasma concentration of IFB-088 and IFB-139. | PK parameters will be analysed after 4 weeks of treatment. | 
| Pharmacokinetic parameters (Area Under Curve [AUC]) | AUC of IFB-088 and IFB-139. | PK parameters will be analysed after 4 weeks of treatment. | 
| Pharmacokinetic parameters (Cmax) | Maximum observed plasma concentration (Cmax) | PK parameters will be analysed after 4 weeks of treatment. | 
| Pharmacokinetic parameters (Tmax) | Time at which maximum plasma concentration (Cmax) is measured | PK parameters will be analysed after 4 weeks of treatment. | 
| Pharmacokinetic parameters (t1/2) | Terminal or apparent terminal half-life (t1/2). | PK parameters will be analysed after 4 weeks of treatment. | 
| Pharmacokinetic parameters (clearance) | Apparent systemic clearance. | PK parameters will be analysed after 4 weeks of treatment. | 
| Pharmacokinetic parameters (Vd) | Apparent volume of distribution (Vd). | PK parameters will be analysed after 4 weeks of treatment. | 
| Biomarkers (TDP-43) | Change in TDP-43 plasmatic concentration from baseline to 6 months, compared to placebo (concentration in pg/mL, technology Simoa®). | At baseline and 6 months. | 
| Biomarkers (neurofilament light chain) | Change in neurofilament (NfL) light chain plasmatic concentration from baseline to 6 months, compared to placebo (concentration in pg/mL, technology Simoa®). | At baseline and 6 months. | 
| Biomarkers (Inflammation biomarkers) | Inflammation biomarkers (interleukin [IL]-6, tumour necrosis factor-α [TNFα], interferon γ [IFNγ], IL-1β, IL-8, IL-10, monocyte chemoattractant protein-1 [MCP-1], nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]): at baseline, 3 and 6 months (concentration of each biomarker in ng/mL, technology Luminex®)). | At baseline, 3 months, and 6 months. | 
| Biomarkers (3-Nitrotyrosine) | 3-Nitrotyrosine (Oxidative stress biomarker): at baseline, 3 and 6 months (concentration in ng/mL, ELISA method). | At baseline, 3 months, and 6 months. | 
| Quality of Life with ALSAQ-40 (ALS Assessment Questionnaire) | Change in ALS assessment questionnaire (ALSAQ-40). ALSAQ-40 (ALS Assessment Questionnaire) Quality of Life questionnaire 40 items, patient rated including 5 choices from never to always. | QoL will be assessed from baseline to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IFB-088, Icerguastat, ALS, Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neurodegenerative Disease