Treatment Combining Riluzole and IFB-088 in Bulbar Amyotrophic Lateral Sclerosis (TRIALS Protocol)
Study Details
Study Description
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 |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| 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:
Drug: Riluzole 100mg/day
Standard of care treatment, co-administered with tested product (IFB-088 50mg/day) or placebo
Other Names:
|
| 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 Names:
|
Outcome Measures
Primary Outcome Measures
- Safety assessment of IFB-088 50 mg/day in patients with bulbar-onset ALS. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [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
- Efficacy with scale : ALSFRS-R (ALS Functional Rating Scale Revised) [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.
- Efficacy with scale : ALS_MITOS (ALS Milano-Torino Staging) [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.
- 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.
- 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]) [Respiratory function at screening, 3 and 6 months.]
Assessment of respiratory function (Arterial Blood Gases [ABG]).
- Pharmacokinetic parameters (Plasma concentration) [PK parameters will be analysed after 4 weeks of treatment.]
Plasma concentration of IFB-088 and IFB-139.
- Pharmacokinetic parameters (Area Under Curve [AUC]) [PK parameters will be analysed after 4 weeks of treatment.]
AUC of IFB-088 and IFB-139.
- Pharmacokinetic parameters (Cmax) [PK parameters will be analysed after 4 weeks of treatment.]
Maximum observed plasma concentration (Cmax)
- Pharmacokinetic parameters (Tmax) [PK parameters will be analysed after 4 weeks of treatment.]
Time at which maximum plasma concentration (Cmax) is measured
- Pharmacokinetic parameters (t1/2) [PK parameters will be analysed after 4 weeks of treatment.]
Terminal or apparent terminal half-life (t1/2).
- Pharmacokinetic parameters (clearance) [PK parameters will be analysed after 4 weeks of treatment.]
Apparent systemic clearance.
- Pharmacokinetic parameters (Vd) [PK parameters will be analysed after 4 weeks of treatment.]
Apparent volume of distribution (Vd).
- 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) [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®)).
- 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 (ALS Assessment Questionnaire) Quality of Life questionnaire 40 items, patient rated including 5 choices from never to always.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diagnosis of probable or definite ALS according to the revised El Escorial criteria [29], with bulbar onset of disease, familial or sporadic form,
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Onset of symptoms ≤ 18 months prior to screening, as reported by the patient,
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Adult males or females, aged at least 18 years old,
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SVC > 60% of predicted value for age and sex,
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ALSFRS-R score ≥ 36, with score 3 or 4 for item 3 (swallowing),
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Treatment with riluzole 100 mg/day, at stable dose since at least one month and well tolerated,
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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,
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Patient who read, understood and signed the ICF,
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Patient who is willing to adhere to the study visit schedule and is capable to understand and comply with protocol requirements.
Exclusion Criteria:
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Known other significant neurological disease(s),
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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,
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Abnormal renal function at screening defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2,
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Abnormal liver function at screening defined as total bilirubin levels >1.5 ULN, and/or AST and/or ALT >3 ULN,
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Neutropenia (ANC <1.5 x 109/L) at screening,
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Other causes of neuromuscular weakness,
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Non progressive or very rapidly progressing ALS (ALSFRS-R decline from disease onset to randomisation ≤ 0.1 / month or ≥ 1.2 / month)11,
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Non-invasive ventilation,
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Tracheotomy,
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Weight loss ≥ 10% compared to weight at symptoms onset as declared by the patient or BMI <18 kg/m2 at screening,
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Dementia or other severe active psychiatric illness, including suicidal ideation assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS),
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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,
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Patient treated by edaravone for ALS,
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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,
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Smoker of > 10 cigarettes per day (e-cigarettes and nicotine patches are permitted),
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Known hypersensitivity to any of the ingredients or excipients of the IMPs,
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Pregnant, lactating women,
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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,
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Patient who has forfeited their freedom by administrative or legal award, or who is under guardianship or under limited judicial protection.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | CHU d'Angers | Angers | France | 49100 | |
| 2 | CHRU Hôpital de la Cavale Blanche | Brest | France | 29200 | |
| 3 | Hôpital Neurologique Pierre Wertheimer | Bron | France | 69677 | |
| 4 | CHU de Clermont-Ferrand, Hôpital Gabriel Montpied | Clermont-Ferrand | France | 63003 | |
| 5 | Hôpital Roger Salengro - Centre SLA | LILLE cedex | France | 59037 | |
| 6 | CHU Dupuytren | Limoges | France | 87042 | |
| 7 | APHM Hôpital La Timone Adultes SCE Maladies Neuromusculaires / SLA | Marseille Cedex 05 | France | 13385 | |
| 8 | Hôpital Central | NANCY Cedex | France | 54035 | |
| 9 | CHU de Nantes - Hôpital Laennec | Nantes | France | 44093 | |
| 10 | CHU de Nice Pasteur 2-zone C | NICE Cedex 1 | France | 06001 | |
| 11 | Hôpital Pitié-Salpêtrière | Paris | France | 75013 | |
| 12 | CHU de Toulouse - Hôpital Pierre-Paul Riquet | Toulouse Cedex 9 | France | 31059 | |
| 13 | CHU Bretonneau | Tours Cedex 1 | France | 37044 | |
| 14 | Ospedale Civile Sant'Agostino Estense | Baggiovara | Italy | 41126 | |
| 15 | Clinica Neurologica Amaducci (tertiary motor neuron Centre) | Bari | Italy | 70124 | |
| 16 | Centro Clinico NeMO per le Malattie Neuromuscolari | Gussago | Italy | 25064 | |
| 17 | IRCSS Istituto Neurologico Carlo Besta | Milano | Italy | 20133 | |
| 18 | AOU Università degli Studi della Campania "Luigi Vanvitelli" | Napoli | Italy | 80138 | |
| 19 | Sant'Andrea Hospital Unit of Neuromuscular Disorders | Roma | Italy | 00189 | |
| 20 | Centro Regionale Esperto per la Sclerosi Laterale Amiotrofica (C.R.E.S.L.A.) | Torino | Italy | 10126 |
Sponsors and Collaborators
- InFlectis BioScience
Investigators
- 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
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- P288ALS
- 2021-003875-32