Clinical trial NCT03693781: Colchicine for Amyotrophic Lateral Sclerosis
Official title: Colchicine for Amyotrophic Lateral Sclerosis: a Phase II, Randomized, Double Blind, Placebo Controlled, Multicenter Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Keywords: amyotrophic lateral sclerosis
stress granules
HSPB8
protein quality control
colchicine
ALSFRS-r
survival
safety
Lead sponsor: Azienda Ospedaliero-Universitaria di Modena
Sponsor class: OTHER
Collaborators: name: University of Modena and Reggio Emilia
name: University of Turin, Italy
name: Istituto Auxologico Italiano
name: IRCCS National Neurological Institute "C. Mondino" Foundation
name: University of Bari
name: IRCCS San Raffaele
name: University of Padova
name: University of Milan
name: Istituto Di Ricerche Farmacologiche Mario Negri
name: University of Campania Luigi Vanvitelli
name: Catholic University of the Sacred Heart
First posted: 2018-10-03
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)
timeFrame: comparison between baseline and treatment end (week 30)
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (safety and tolerability)
timeFrame: week 30 and 54
measure: Tracheostomy-free survival rate
timeFrame: Up to week 54
measure: Changes in Forced Vital Capacity (FVC)
timeFrame: Up to week 54
measure: Changes in quality of life
timeFrame: at 8,18,30 and 54 week
measure: enhancement of autophagy
timeFrame: at week 30 and 54, compared to baseline
measure: changes in stress granules size, number and composition
timeFrame: at week 30 compared to baseline
measure: quantification of insoluble species
timeFrame: at week 30 compared to baseline
measure: modifications on extracellular vesicles secretion in blood and CSF
timeFrame: at week 30 compared to baseline
measure: effects on biomarkers of neurodegeneration
timeFrame: at week 30 compared to baseline
measure: effects on biomarkers of inflammation
timeFrame: at week 30 compared to baseline
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Centro Sla, University of Bari
city: Milano
country: Italy
facility: Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano
city: Milano
country: Italy
facility: Irccs Carlo Besta
city: Milano
country: Italy
facility: Irccs St. Raffaele Institute of Milano
city: Modena
country: Italy
facility: Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena
city: Napoli
country: Italy
facility: Università della Campania Gianluigi Vanvitelli
city: Pavia
country: Italy
facility: Als Centre, "C. Mondino" National Neurological Institute, University of Pavia
city: Roma
country: Italy
facility: , Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome
Study officials:
affiliation: Azienda Ospedaliero-Universitaria di Modena
name: Jessica Mandrioli
role: PRINCIPAL_INVESTIGATOR
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