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

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.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05508074

Enrollment

Registered

2022-08-19

Start date

2022-12-02

Completion date

2025-01-20

Last updated

2025-10-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

ALS, Amyotrophic Lateral Sclerosis

Keywords

IFB-088, Icerguastat, ALS, Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neurodegenerative Disease

Brief summary

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.

Interventions

DRUGIFB-088 50mg/day

Tested product

DRUGPlacebo

Placebo

DRUGRiluzole 100mg/day

Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Masking description

Study double-blind.

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	from beginning of IMP intake up to 30 days after stopping the intake, an average of 7 months	* Incidence, grade and relationship to IFB-088 for treatment emergent AEs (TEAEs), SAEs, and AESIs, * AEs leading to dose interruption or premature discontinuation.

Secondary

Measure	Time frame	Description
Efficacy With Scale : ALS_MITOS (ALS Milano-Torino Staging)	baseline, V3 (3 months), V4 (6 months)	ALS\_MITOS (Amyotrophic Lateral Sclerosis Milano-Torino Staging) scale scores the total points of points given in 4 domains (movement, swallowing, communicating, breathing), clinician rated. The ALS8MITOS score is determined by the sum of functional score of 1 for each domain, up to 5, being death. The score may go from 0= no functionnal domain lost, up to 5=death (1 to 4 corresponding to the number of domains lost by the patient).
Efficacy With Scale : King's College Scale (ALS Staging Form)	Efficacy scale from baseline to 3 months and 6 months.	King's college Scale (King's ALS staging form), clinician rated, 8 items. 0=best, 5=death
Efficacy Based on Assessment of Respiratory Function (Slow Vital Capacity [SVC])	Respiratory function at screening, 3 and 6 months.	Assessment of respiratory function (slow vital capacity \[SVC\]).
Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), PaCO2)	Respiratory function at screening, 3 and 6 months.	Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of PaCO2 (mmHg), at screening, 3 and 6 months.
Efficacy Based on Assessment of Body Composition (Exploratory)	At baseline and 6 months	change of body composition (% of water, muscle, bone in the body) evaluated by bioelectrical impedance
Pharmacokinetic Parameters (Area Under Curve [AUC])	PK parameters will be analysed after 4 weeks of treatment. Blood samples were collected at V2 (5 samples/patient: pre-IMP dose, and at one, 2, 4 and 6 hours post dose).	Area Under the Curve (AUC (0-12h)) of IFB-088 and its metabolite IFB-139. As study was double blinded, the analysis was done on all the patients, either receiving IFB-088 or placebo. Dosage of IFB-088 in patients under placebo was equal to 0 ng.h/mL.
Pharmacokinetic Parameters (Cmax)	PK parameters will be analysed after 4 weeks of treatment. Blood samples were collected at V2 (5 samples/patient: pre-IMP dose, and at one, 2, 4 and 6 hours post dose).	Maximum observed plasma concentration (Cmax) of IFB-088 and its metabolite IFB-139. As study was double blinded, the analysis was done on all the patients, either receiving IFB-088 or placebo. Dosage of IFB-088 in patients under placebo was equal to 0 ng/mL.
Pharmacokinetic Parameters (Tmax)	PK parameters will be analysed after 4 weeks of treatment. Blood samples were collected at V2 (5 samples/patient: pre-IMP dose, and at one, 2, 4 and 6 hours post dose).	Time at which maximum plasma concentration (Cmax) of IFB-088 and its metabolite IFB-139 is measured As study was double blinded, the analysis was done on all the patients, either receiving IFB-088 or placebo. Dosage of IFB-088 in patients under placebo was equal to 0 h
Pharmacokinetic Parameters (t1/2)	PK parameters will be analysed after 4 weeks of treatment. Blood samples were collected at V2 (5 samples/patient: pre-IMP dose, and at one, 2, 4 and 6 hours post dose).	Terminal or apparent terminal half-life (t1/2) of IFB-088 and its metabolite IFB-139. As study was double blinded, the analysis was done on all the patients, either receiving IFB-088 or placebo. Dosage of IFB-088 in patients under placebo was equal to 0 h.
Efficacy With Scale : ALSFRS-R (ALS Functional Rating Scale Revised)	Efficacy scale from baseline to V3 (3 months) and V4 (6 months).	ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised) 12 items, clinician rated including 5 choices from normal to disabled. Maximal score: 48, minimal score: 0 (death)
Pharmacokinetic Parameters (Vd)	PK parameters will be analysed after 4 weeks of treatment.	IFB-088 Apparent volume of distribution (Vd). As study was double blinded, the analysis was done on all the patients, either receiving IFB-088 or placebo. Dosage of IFB-088 in patients under placebo was equal to 0 L.
Biomarkers (TDP-43)	At baseline and 6 months.	Change in TDP-43 plasmatic concentration from baseline to 6 months, compared to placebo (concentration in pg/mL, technology Simoa®).
Biomarkers (Neurofilament Light Chain)	At baseline and 6 months.	Change in neurofilament (NfL) light chain plasmatic concentration from baseline to 6 months, compared to placebo (concentration in pg/mL, technology Simoa®).
Biomarkers (Inflammation Biomarkers)	All assessed at baseline and V4 visit (6 months). Only GDF15, MCP1, BDNF, and TGFb1 also assessed at V3 visit (3 months)	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 \[VEGF\]): (concentration of each biomarker in ng/mL, technology Luminex®)).
Biomarkers (3-Nitrotyrosine)	At baseline, 3 months, and 6 months.	3-Nitrotyrosine (Oxidative stress biomarker): at baseline, 3 and 6 months (concentration in ng/mL, ELISA method).
Quality of Life With ALSAQ-40 (ALS Assessment Questionnaire)	QoL will be assessed from baseline to 6 months	Change in ALS assessment questionnaire (ALSAQ-40). ALSAQ-40 (Amyotrophic Lateral Sclerosis Assessment Questionnaire) Quality of Life questionnaire 40 items, patient rated including 5 choices from never to always. best=0, worse=100
Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), PO2 (mmHg)	Respiratory function at screening, 3 and 6 months.	Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of PO2 (mmHg) at screening, 3 and 6 months.
Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), HCO3 (mEq/L)	Respiratory function at screening, 3 and 6 months.	Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of HCO3 (mEq/L) at screening, 3 and 6 months.
Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), Oxygen Saturation (%)	Respiratory function at screening, 3 and 6 months.	Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of Oxygen saturation (%) at screening, 3 and 6 months.
Pharmacokinetic Parameters (Clearance)	PK parameters will be analysed after 4 weeks of treatment. Blood samples were collected at V2 (5 samples/patient: pre-IMP dose, and at one, 2, 4 and 6 hours post dose).	IFB-088 Apparent systemic clearance calculation (CL/F) As study was double blinded, the analysis was done on all the patients, either receiving IFB-088 or placebo. Dosage of IFB-088 in patients under placebo was equal to 0 L/h.

Countries

France, Italy

Participant flow

Participants by arm

Arm	Count
IFB-088 50 mg/Day + Riluzole 100 mg/Day 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). IFB-088 50mg/day: Tested product Riluzole 100mg/day: Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo	34
Placebo + Riluzole 100 mg/Day 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). Placebo: Placebo Riluzole 100mg/day: Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo	17
Total	51

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	0	1
Overall Study	Death	2	5
Overall Study	non-compliance	0	1
Overall Study	Physician Decision	0	1
Overall Study	Withdrawal by Subject	1	2
Overall Study	wrongly randomized	0	1

Baseline characteristics

Characteristic	IFB-088 50 mg/Day + Riluzole 100 mg/Day	Total	Placebo + Riluzole 100 mg/Day
Age, Continuous	62.4 years STANDARD_DEVIATION 9.6	62.0 years STANDARD_DEVIATION 10	61.1 years STANDARD_DEVIATION 11
BMI	24.49 kg/m^2 STANDARD_DEVIATION 3.6	24.29 kg/m^2 STANDARD_DEVIATION 3.75	23.88 kg/m^2 STANDARD_DEVIATION 4.12
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	34 Participants	51 Participants	17 Participants
Region of Enrollment France	20 participants	28 participants	8 participants
Region of Enrollment Italy	14 participants	23 participants	9 participants
Sex: Female, Male Female	16 Participants	22 Participants	6 Participants
Sex: Female, Male Male	18 Participants	29 Participants	11 Participants
Tobacco smoking, n (%) Missing data	0 Participants	1 Participants	1 Participants
Tobacco smoking, n (%) No	30 Participants	46 Participants	16 Participants
Tobacco smoking, n (%) Yes	4 Participants	4 Participants	0 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	2 / 17	5 / 34
other Total, other adverse events	10 / 17	25 / 34
serious Total, serious adverse events	4 / 17	8 / 34

Outcome results

Primary

Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]

* Incidence, grade and relationship to IFB-088 for treatment emergent AEs (TEAEs), SAEs, and AESIs, * AEs leading to dose interruption or premature discontinuation.

Time frame: from beginning of IMP intake up to 30 days after stopping the intake, an average of 7 months

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE	10 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE related to study drug	4 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Serious TEAE	4 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Serious TEAE related to study drug	0 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Fatal TEAE	2 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Fatal TEAE related to study drug	0 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade 1 TEAE	7 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade 2 TEAE	5 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade > or = 3 TEAE	3 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade > or = 3 TEAE related to study drug	0 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade > or = 3 serious TEAE	2 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade >or = 3 serious TEAE related to study drug	0 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE leading to temporary discontinuation of study drug	1 Participants
Placebo + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE leading to definitive discontinuation of study drug	0 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade > or = 3 serious TEAE	8 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE	25 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade 2 TEAE	11 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE related to study drug	13 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE leading to temporary discontinuation of study drug	1 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Serious TEAE	8 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade > or = 3 TEAE	10 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Serious TEAE related to study drug	2 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade >or = 3 serious TEAE related to study drug	2 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Fatal TEAE	5 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade > or = 3 TEAE related to study drug	3 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Fatal TEAE related to study drug	2 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	TEAE leading to definitive discontinuation of study drug	3 Participants
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Safety Assessment of IFB-088 50 mg/Day in Patients With Bulbar-onset ALS. Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]	Grade 1 TEAE	19 Participants

Secondary

Biomarkers (3-Nitrotyrosine)

3-Nitrotyrosine (Oxidative stress biomarker): at baseline, 3 and 6 months (concentration in ng/mL, ELISA method).

Time frame: At baseline, 3 months, and 6 months.

Secondary

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 \[VEGF\]): (concentration of each biomarker in ng/mL, technology Luminex®)).

Time frame: All assessed at baseline and V4 visit (6 months). Only GDF15, MCP1, BDNF, and TGFb1 also assessed at V3 visit (3 months)

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	FGF21 V4 visit	230.51 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	BDNF V4 visit	1777.28 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	NGFR/p75ECD baseline	5143.46 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	GDF15 V3 visit	711.31 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	NGFR/p75ECD V4 visit	6675.13 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TGFb1 baseline	30524.88 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL-6 baseline	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	MCP1 V4 visit	171.21 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL-6 V4 visit	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TGFb1 V3 visit	25955.30 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TNFa baseline	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	MCP1 baseline	168.00 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TNFa V4 visit	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TGFb1 V4 visit	20906.55 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IFNg baseline	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	BDNF baseline	2348.36 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IFNg V4 visit	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	8-OxoDG baseline	203.01 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL1b baseline	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	GDF15 V4 visit	704.90 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL1b V4 visit	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	8-OxoDG V4 visit	220.68 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL8 baseline	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	BDNF V3 visit	1892.51 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL8 V4 visit	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	FGF21 baseline	302.11 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL10 baseline	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	MCP1 V3 visit	163.47 ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL10 V4 visit	NA ng/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	GDF15 baseline	704.26 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL10 V4 visit	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	GDF15 baseline	580.31 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	GDF15 V3 visit	572.30 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	GDF15 V4 visit	580.13 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	MCP1 baseline	149.61 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	MCP1 V3 visit	131.92 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	MCP1 V4 visit	127.53 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	BDNF baseline	2717.82 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	BDNF V3 visit	2277.30 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	BDNF V4 visit	2717.49 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TGFb1 baseline	34174.62 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TGFb1 V3 visit	28333.44 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TGFb1 V4 visit	37702.08 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	8-OxoDG baseline	175.29 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	8-OxoDG V4 visit	215.11 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	FGF21 baseline	274.81 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	FGF21 V4 visit	298.73 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	NGFR/p75ECD baseline	4281.16 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	NGFR/p75ECD V4 visit	6108.71 ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL-6 baseline	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL-6 V4 visit	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TNFa baseline	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	TNFa V4 visit	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IFNg baseline	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IFNg V4 visit	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL1b baseline	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL1b V4 visit	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL8 baseline	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL8 V4 visit	NA ng/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Inflammation Biomarkers)	IL10 baseline	NA ng/mL

Secondary

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®).

Time frame: At baseline and 6 months.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Placebo + Riluzole 100 mg/Day	Biomarkers (Neurofilament Light Chain)	Baseline	86.57 pg/mL
Placebo + Riluzole 100 mg/Day	Biomarkers (Neurofilament Light Chain)	V4 visit	92.91 pg/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Neurofilament Light Chain)	Baseline	65.29 pg/mL
IFB-088 50 mg/Day + Riluzole 100 mg/Day	Biomarkers (Neurofilament Light Chain)	V4 visit	76.19 pg/mL

Comparison: based on available data at V4p-value: 0.60995% CI: [0.89, 1.21]ANCOVA

Secondary

Biomarkers (TDP-43)

Change in TDP-43 plasmatic concentration from baseline to 6 months, compared to placebo (concentration in pg/mL, technology Simoa®).

Time frame: At baseline and 6 months.

Secondary

Efficacy Based on Assessment of Body Composition (Exploratory)

change of body composition (% of water, muscle, bone in the body) evaluated by bioelectrical impedance

Time frame: At baseline and 6 months

Secondary

Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), HCO3 (mEq/L)

Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of HCO3 (mEq/L) at screening, 3 and 6 months.