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

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ClinicalTrials.gov Identifier: NCT05508074
Recruitment Status : Recruiting
First Posted : August 19, 2022
Last Update Posted : November 25, 2022
Sponsor:
Information provided by (Responsible Party):
InFlectis BioScience

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. 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.


Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis ALS Drug: IFB-088 50mg/day Drug: Placebo Drug: Riluzole 100mg/day Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Double (Participant, Investigator)
Masking Description: Study double-blind.
Primary Purpose: Treatment
Official Title: 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.
Estimated Study Start Date : November 2022
Estimated Primary Completion Date : January 2025
Estimated Study Completion Date : January 2025


Arm Intervention/treatment
Experimental: 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).

Drug: IFB-088 50mg/day
Tested product
Other Names:
  • IFB-088
  • Icerguastat

Drug: Riluzole 100mg/day
Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo
Other Name: Riluzole

Placebo Comparator: 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).

Drug: Placebo
Placebo

Drug: Riluzole 100mg/day
Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo
Other Name: Riluzole




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


Secondary Outcome Measures :
  1. Efficacy with scale : ALSFRS-R (ALS Functional Rating Scale Revised) [ Time Frame: Efficacy scale from baseline to 3 months and 6 months. ]
    ALSFRS-R (ALS Functional Rating Scale Revised) 12 items, clinician rated including 5 choices from normal to disabled.

  2. Efficacy with scale : ALS_MITOS (ALS Milano-Torino Staging) [ Time Frame: Efficacy scale from baseline to 3 months and 6 months. ]
    ALS_MITOS (ALS Milano-Torino Staging), 4 domains, clinician rated, Staging determined by the sum of functional score of 1 for each domain.

  3. Efficacy with scale : King's college Scale (ALS staging form) [ Time Frame: Efficacy scale from baseline to 3 months and 6 months. ]
    King's college Scale (King's ALS staging form), clinician rated, 8 items.

  4. Efficacy based on assessment of respiratory function (slow vital capacity [SVC]) [ Time Frame: Respiratory function at screening, 3 and 6 months. ]
    Assessment of respiratory function (slow vital capacity [SVC]).

  5. Efficacy based on assessment of respiratory function (Arterial Blood Gases [ABG]) [ Time Frame: Respiratory function at screening, 3 and 6 months. ]
    Assessment of respiratory function (Arterial Blood Gases [ABG]).

  6. Pharmacokinetic parameters (Plasma concentration) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    Plasma concentration of IFB-088 and IFB-139.

  7. Pharmacokinetic parameters (Area Under Curve [AUC]) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    AUC of IFB-088 and IFB-139.

  8. Pharmacokinetic parameters (Cmax) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    Maximum observed plasma concentration (Cmax)

  9. Pharmacokinetic parameters (Tmax) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    Time at which maximum plasma concentration (Cmax) is measured

  10. Pharmacokinetic parameters (t1/2) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    Terminal or apparent terminal half-life (t1/2).

  11. Pharmacokinetic parameters (clearance) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    Apparent systemic clearance.

  12. Pharmacokinetic parameters (Vd) [ Time Frame: PK parameters will be analysed after 4 weeks of treatment. ]
    Apparent volume of distribution (Vd).

  13. Biomarkers (TDP-43) [ Time Frame: 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®).

  14. Biomarkers (neurofilament light chain) [ Time Frame: 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®).

  15. Biomarkers (Inflammation biomarkers) [ Time Frame: At baseline, 3 months, and 6 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]): at baseline, 3 and 6 months (concentration of each biomarker in ng/mL, technology Luminex®)).

  16. Biomarkers (3-Nitrotyrosine) [ Time Frame: At baseline, 3 months, and 6 months. ]
    3-Nitrotyrosine (Oxidative stress biomarker): at baseline, 3 and 6 months (concentration in ng/mL, ELISA method).

  17. Quality of Life with ALSAQ-40 (ALS Assessment Questionnaire) [ Time Frame: QoL will be assessed from baseline to 6 months ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, with score 3 or 4 for item 3 (swallowing),
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05508074


Contacts
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Contact: Anne VISBECQ, MD 33 6 30 63 20 20 annevisbecq@inflectisbioscience.com

Locations
Show Show 20 study locations
Sponsors and Collaborators
InFlectis BioScience
Investigators
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Principal Investigator: Shahram Attarian, Pr Assistance Publique Hôpitaux de Marseille (APHM) Hospital La Timone Adultes, France
Principal Investigator: Giuseppe Lauria, Pr IRCCS Carlo Besta Institute of Milan, Italy
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Responsible Party: InFlectis BioScience
ClinicalTrials.gov Identifier: NCT05508074    
Other Study ID Numbers: P288ALS
2021-003875-32 ( EudraCT Number )
First Posted: August 19, 2022    Key Record Dates
Last Update Posted: November 25, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by InFlectis BioScience:
IFB-088
Icerguastat
ALS
Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Neurodegenerative Disease
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Riluzole
Anticonvulsants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Neuroprotective Agents
Protective Agents