Colchicine for Amyotrophic Lateral Sclerosis

Sponsor:

Collaborators:

Information provided by (Responsible Party):

Jessica Mandrioli，Azienda Ospedaliero-Universitaria di Modena

Tracking Information

First Submitted Date ^ICMJE

September 30, 2018

First Posted Date ^ICMJE

October 3, 2018

Last Update Posted Date

October 4, 2018

Actual Study Start Date ^ICMJE

November 1, 2018

Estimated Primary Completion Date

November 1, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)[ Time Frame: comparison between baseline and treatment end (week 30) ]

ALSFRS-R is a scale that measures disability in ALS; the scores range from 0 (maximum disability, the worst score) to 48 (no disability, the best score). We will measure total score changes from baseline to week 30 in treatment and placebo arms.

Original Primary Outcome Measures ^ICMJE

Same as current

Current Secondary Outcome Measures ^ICMJE

Incidence of Treatment-Emergent Adverse Events (safety and tolerability)[ Time Frame: week 30 and 54 ]
Number of serious adverse events (SAEs) and AEs in placebo and treatment arms
Tracheostomy-free survival rate[ Time Frame: Up to week 54 ]
Overall survival from randomization to date of death or tracheostomy
Changes in Forced Vital Capacity (FVC)[ Time Frame: Up to week 54 ]
Changes in FVC score from baseline to week 8, 18, 30, 54 in treatment and placebo arms.
Changes in quality of life[ Time Frame: at 8,18,30 and 54 week ]
Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms
enhancement of autophagy[ Time Frame: at week 30 and 54, compared to baseline ]
assessment of mRNA and protein levels of p62, LC3, TFEB, ATGs, HSPB8, BAG3, BAG1, HSP70, and HSF1, in patients' PBMCs, lymphoblasts and fibroblasts (transcriptome profile);
changes in stress granules size, number and composition[ Time Frame: at week 30 compared to baseline ]
identification of changes in stress granules response and composition in patients' fibroblasts and lymphoblasts will be carried out by measuring granules size, number and composition by confocal microscopy using automated systems. The aberrant recruitment or sequestration of specific mRNA inside stress granules will be assessed by FISH using specific probes, followed by densitometric analysis as previously described by Gareau et al. (2011).
quantification of insoluble species[ Time Frame: at week 30 compared to baseline ]
assessment of overall levels and the relative ratio between soluble and insoluble species of TDP-43, TDP-43 fragments, SQSTM1/p62, UBQLN, OPTN in fibroblasts and lymphoblasts derived from the same patients
modifications on extracellular vesicles secretion in blood and CSF[ Time Frame: at week 30 compared to baseline ]
assessment of TDP-43, hyperphosphorylated TDP-43, SQSTM1/p62, UBQLN and OPTN in extracellular vesicles by plasma and CSF.
effects on biomarkers of neurodegeneration[ Time Frame: at week 30 compared to baseline ]
creatinine, albumin, CK, and vitamin D in plasma as markers of disease severity; phosphorylated neurofilaments heavy chain
effects on biomarkers of inflammation[ Time Frame: at week 30 compared to baseline ]
assessment of plasma/CSF IL18, its endogenous inhibitor IL-18BP, MCP1 and IL17

Descriptive Information

Brief Title ^ICMJE

Colchicine for Amyotrophic Lateral Sclerosis

Official Title ^ICMJE

Colchicine for Amyotrophic Lateral Sclerosis: a Phase II, Randomized, Double Blind, Placebo Controlled, Multicenter Clinical Trial

Brief Summary

The study evaluates the effects of two different Colchicine doses (0.01mg/kg/day or 0.005 mg/kg/day) compared to placebo in Amyotrophic Lateral Sclerosis (ALS) patients. Disease progression as defined by changes in ALSFRS-r is the primary outcome measure. Other measures of clinical progression and survival, together with safety and tolerability of Colchicine in ALS patients will be assessed.

Detailed Description

Recent evidence supports the disruption of the ubiquitin-proteasome-system and autophagy as central events in ALS. ALS is characterized by the presence of misfolded proteins prone to oligomerize into aggregates, which exert a toxic effect by affecting several intracellular functions. Heat shock protein B8 (HSPB8) recognizes and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs). Moreover, HSPB8-BAG3-HSP70 maintains the so called "granulostasis", a surveillance mechanism that avoids the conversion of dynamic stress granules (SGs) into aggregation-prone assemblies, which are a hallmark of ALS. Colchicine enhances the expression of HSPB8 and of several autophagy players while blocking TDP-43 accumulation in neurons. Moreover, given the cross-talk between infalmmation and autophagy, the well-known antinflammatory action of Cochicine may contribute to cell homeostasis. Based on these premises, this is a phase II randomized, double-blind, placebo-controlled, multicenter (9 MND Centres in Italy: 2 centres in Milan, Pavia, Turin, Modena, Padua, Rome, Naples, Bari), clinical trial to test efficacy of Colchicine in ALS.

Study Type ^ICMJE

Interventional

Study Phase

Phase 2

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Three arms of 18 patients each; in two arms two colchicine dosages will be tested compared to placebo in the control arm. The three arms will undergo treatment vs placebo in parallel
Masking: Interventional
Masking Description:placebo will be unrecognizable from active treatment (both in tablets)
Primary Purpose: Treatment

Condition ^ICMJE

Intervention ^ICMJE

Drug: Colchicine 1 MG Oral Tablet
Colchicine tablets depending on arm (0.01 mg/kg/day, 0.005 mg/kg/day, placebo) and on weight (>70 kg or <71 kg) for 30 weeks of duration.
Drug: Colchicine 1 MG Oral Tablet
Colchicine tablets depending on arm (0.01 mg/kg/day, 0.005 mg/kg/day, placebo) and on weight (>70 kg or <71 kg) for 30 weeks of duration.
Drug: Placebo Oral Tablet
Corresponding tablets for 30 weeks

Study Arms

Active Comparator: Colchicine 0.01mg/kg/day + Riluzole 100 mg
Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
Active Comparator: Colchicine 0.005 mg/kg/day + Riluzole 100 mg
Oral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
Placebo Comparator: Placebo + Riluzole 100 mg
Placebo pills will be administered at fast, while taking Riluzole 100 mg/day

Recruitment Information

Recruitment Status ^ICMJE

Not yet recruiting

Estimated Enrollment ^ICMJE

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date

November 1, 2020

Estimated Primary Completion Date

November 1, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria: - Patients diagnosed with a laboratory supported, clinically "probable" or "definite" amyotrophic lateral sclerosis according to the Revised El Escorial criteria (Brooks, 2000) - Sporadic ALS - ALS phenotypes: classic or bulbar - Female or male patients aged between 18 and 80 years old - Disease duration from symptoms onset no longer than 18 months at the screening visit - Patients treated with a stable dose of Riluzole (100 mg/day) for at least 30 days prior to screening - Patients with a weight > 50 kg and a BMI ≥18 - Patients with a FVC (Forced Vital Capacity) equal or more than 65 % predicted normal value for gender, height, and age at the screening visit Patients able and willing to comply with study procedures as per protocol - Patients able to understand, and capable of providing informed consent at screening visit prior to any protocol-specific procedures - Use of highly effective contraception Exclusion Criteria: - Prior use of Colchicine - Prior allergy/sensitivity to Colchicine - Receiving Colchicine or other anti-inflammatory drugs (such as corticosteroids, methotrexate, anti-neoplastic, Interleukin 1-1b antagonist, Tumor necrosis factor-alpha inhibitor) - Receiving food or co-medications such as strong-moderate cytochrome P450 3A4 inhibitors that will result in elevated plasma level of Colchicine - Inflammatory disorders (SLE, Rheumatoid arthritis, connective tissue disorder) or chronic infections (HIV, hepatitis B or C infection) or significant history of malignancy - Severe renal (eGFR< 30ml/min/1.73m2), or liver failure or liver aminotransferase (ALT/AST > 2x Upper limit of normal), - Existing blood dyscrasia (e.g., myelodysplasia) - White blood cells<4,000/mm³, platelets count<100,000/mm³, hematocrit<30% - Severe comorbidities (heart, renal, liver failure), autoimmune diseases or any type of interstitial lung disease - Patients who underwent non invasive ventilation, tracheotomy and /or gastrostomy - Women who are pregnant or breastfeeding - Participation in pharmacological studies within the last 30 days before screening - Patients with the following ALS phenotypes: flail arm, flail leg, UMN-p, respiratory, PLS, progressive muscular atrophy. - Patients with familial ALS defined as presence of at least one first degree family member (parents/son/daughter/brother/sister) affected by ALS. - Patients with known pathogenic mutations (SOD1, TARDBP, FUS, C9ORF72).

Sex/Gender

Sexes Eligible for Study:

All

Ages

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Listed Location Countries ^ICMJE

Italy

Removed Location Countries

Administrative Information

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

Plan to Share IPD:

Yes

Responsible Party

Jessica Mandrioli，Azienda Ospedaliero-Universitaria di Modena

Study Sponsor ^ICMJE

Azienda Ospedaliero-Universitaria di Modena

Collaborators ^ICMJE

Investigators ^ICMJE

Principal Investigator: Jessica Mandrioli Azienda Ospedaliero-Universitaria di Modena

PRS Account

Azienda Ospedaliero-Universitaria di Modena

Verification Date

October 2018

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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