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

InFlectis BioScience51 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Amyotrophic Lateral Sclerosis

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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

Secondary Outcomes

Efficacy With Scale : ALSFRS-R (ALS Functional Rating Scale Revised)

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)

Time frame: Efficacy scale from baseline to V3 (3 months) and V4 (6 months).

Efficacy With Scale : ALS_MITOS (ALS Milano-Torino Staging)

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).

Time frame: baseline, V3 (3 months), V4 (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. 0=best, 5=death

Time frame: 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 \[SVC\]).

Time frame: Respiratory function at screening, 3 and 6 months.

Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), PaCO2)

Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of PaCO2 (mmHg), at screening, 3 and 6 months.

Time frame: Respiratory function at screening, 3 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

Time frame: At baseline and 6 months

Pharmacokinetic Parameters (Area Under Curve [AUC])

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.

Time frame: 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).

Pharmacokinetic Parameters (Cmax)

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.

Time frame: 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).

Pharmacokinetic Parameters (Tmax)

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

Time frame: 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).

Pharmacokinetic Parameters (t1/2)

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.

Time frame: 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).

Pharmacokinetic Parameters (Clearance)

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.

Time frame: 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).

Pharmacokinetic Parameters (Vd)

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.

Time frame: 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®).

Time frame: 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®).

Time frame: 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 \[VEGF\]): (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)

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.

Quality of Life With ALSAQ-40 (ALS Assessment Questionnaire)

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

Time frame: QoL will be assessed from baseline to 6 months

Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), PO2 (mmHg)

Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of PO2 (mmHg) at screening, 3 and 6 months.

Time frame: Respiratory function at screening, 3 and 6 months.

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.

Time frame: Respiratory function at screening, 3 and 6 months.

Efficacy Based on Assessment of Respiratory Function (Arterial Blood Gases [ABG]), Oxygen Saturation (%)

Assessment of respiratory function (Arterial Blood Gases \[ABG\]): description of Oxygen saturation (%) at screening, 3 and 6 months.

Time frame: Respiratory function at screening, 3 and 6 months.

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

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes