Colchicine for Amyotrophic Lateral Sclerosis (Co-ALS)

• ClinicalTrials.gov Identifier: NCT03693781
• Recruitment Status: Recruiting
• First Posted: October 3, 2018
• Last Update Posted: February 5, 2020
• Sponsor: Azienda Ospedaliero-Universitaria di Modena
• Collaborators: University of Modena and Reggio Emilia; University of Turin, Italy; Istituto Auxologico Italiano; IRCCS National Neurological Institute "C. Mondino" Foundation; University of Bari; IRCCS San Raffaele; University of Padova; University of Milan; Istituto Di Ricerche Farmacologiche Mario Negri; University of Campania "Luigi Vanvitelli"; Catholic University of the Sacred Heart
• Information provided by (Responsible Party): Jessica Mandrioli, Azienda Ospedaliero-Universitaria di Modena

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Colchicine 1 MG Oral Tablet; Drug: Placebo Oral Tablet	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 54 participants
• 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: Double (Participant, Investigator)
• Masking Description: placebo will be unrecognizable from active treatment (both in tablets)
• Primary Purpose: Treatment
• Official Title: Colchicine for Amyotrophic Lateral Sclerosis: a Phase II, Randomized, Double Blind, Placebo Controlled, Multicenter Clinical Trial
• Actual Study Start Date: April 10, 2019
• Estimated Primary Completion Date: October 1, 2021
• Estimated Study Completion Date: December 1, 2021

Arms and Interventions

Arm	Intervention/treatment
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	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.
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	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.
Placebo Comparator: Placebo + Riluzole 100 mg; Placebo pills will be administered at fast, while taking Riluzole 100 mg/day	Drug: Placebo Oral Tablet; Corresponding tablets for 30 weeks

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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
2. Tracheostomy-free survival rate [ Time Frame: Up to week 54 ]
   Overall survival from randomization to date of death or tracheostomy
3. 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.
4. 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
5. 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);
6. 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).
7. 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
8. 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.
9. 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
10. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Contacts

Contact: Jessica Mandrioli, MD; 059-3961640; j.mandrioli@ausl.mo.it

Contact: Nicola Fini, MD; 0593961640; n.fini@ausl.mo.it

Locations

Italy

Centro Sla, University of Bari; Recruiting

Bari, Italy

Contact: Isabella L Simone, Prof.

Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano; Recruiting

Milano, Italy

Contact: Vincenzo Silani, Prof.

Irccs Carlo Besta; Not yet recruiting

Milano, Italy

Contact: ELEONORA DALLA BELLA, MD

Irccs St. Raffaele Institute of Milano; Recruiting

Milano, Italy

Contact: Nilo Riva, MD

Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena; Recruiting

Modena, Italy, 41126

Contact: Jessica Mandrioli, MD +390593961722

Università della Campania Gianluigi Vanvitelli; Recruiting

Napoli, Italy

Contact: Maria R Monsurrò, MD

Centro Sla, Universita' Di Padova; Not yet recruiting

Padova, Italy

Contact: Gianni Sorarù, MD

Als Centre, "C. Mondino" National Neurological Institute, University of Pavia; Recruiting

Pavia, Italy

Contact: Mauro Ceroni, Prof.

, Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome; Recruiting

Roma, Italy

Contact: Mario Sabatelli, MD

Centro Sla, Universita' Di Torino; Not yet recruiting

Torino, Italy

Contact: Adriano Chiò, Prof.

Sponsors and Collaborators

Azienda Ospedaliero-Universitaria di Modena

University of Modena and Reggio Emilia

University of Turin, Italy

Istituto Auxologico Italiano

IRCCS National Neurological Institute "C. Mondino" Foundation

University of Bari

IRCCS San Raffaele

University of Padova

University of Milan

Istituto Di Ricerche Farmacologiche Mario Negri

University of Campania "Luigi Vanvitelli"

Catholic University of the Sacred Heart

Investigators

• Principal Investigator: Jessica Mandrioli; Azienda Ospedaliero-Universitaria di Modena

More Information

Publications:

Thomas M, Alegre-Abarrategui J, Wade-Martins R. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain. 2013 May;136(Pt 5):1345-60. doi: 10.1093/brain/awt030. Epub 2013 Mar 9. Review.

Cadwell K. Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol. 2016 Nov;16(11):661-675. doi: 10.1038/nri.2016.100. Epub 2016 Oct 3. Review.

Crippa V, D'Agostino VG, Cristofani R, Rusmini P, Cicardi ME, Messi E, Loffredo R, Pancher M, Piccolella M, Galbiati M, Meroni M, Cereda C, Carra S, Provenzani A, Poletti A. Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases. Sci Rep. 2016 Mar 10;6:22827. doi: 10.1038/srep22827.

Crippa V, Cicardi ME, Ramesh N, Seguin SJ, Ganassi M, Bigi I, Diacci C, Zelotti E, Baratashvili M, Gregory JM, Dobson CM, Cereda C, Pandey UB, Poletti A, Carra S. The chaperone HSPB8 reduces the accumulation of truncated TDP-43 species in cells and protects against TDP-43-mediated toxicity. Hum Mol Genet. 2016 Sep 15;25(18):3908-3924. doi: 10.1093/hmg/ddw232. Epub 2016 Jul 27.

Cristofani R, Crippa V, Vezzoli G, Rusmini P, Galbiati M, Cicardi ME, Meroni M, Ferrari V, Tedesco B, Piccolella M, Messi E, Carra S, Poletti A. The small heat shock protein B8 (HSPB8) efficiently removes aggregating species of dipeptides produced in C9ORF72-related neurodegenerative diseases. Cell Stress Chaperones. 2018 Jan;23(1):1-12. doi: 10.1007/s12192-017-0806-9. Epub 2017 Jun 12.

Cristofani R, Crippa V, Rusmini P, Cicardi ME, Meroni M, Licata NV, Sala G, Giorgetti E, Grunseich C, Galbiati M, Piccolella M, Messi E, Ferrarese C, Carra S, Poletti A. Inhibition of retrograde transport modulates misfolded protein accumulation and clearance in motoneuron diseases. Autophagy. 2017 Aug 3;13(8):1280-1303. doi: 10.1080/15548627.2017.1308985.

Carra S, Seguin SJ, Landry J. HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy. Autophagy. 2008 Feb;4(2):237-9. Epub 2007 Dec 11. Review.

Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti C, De Biasi S, Poletti A. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet. 2010 Sep 1;19(17):3440-56. doi: 10.1093/hmg/ddq257. Epub 2010 Jun 22.

Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2009 Jun;38(6):411-9. doi: 10.1016/j.semarthrit.2008.08.006. Epub 2008 Oct 29. Review.

Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016 Nov 10;539(7628):197-206. doi: 10.1038/nature20413. Review.

Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;(3):CD001447. doi: 10.1002/14651858.CD001447.pub3. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mandrioli J, Crippa V, Cereda C, Bonetto V, Zucchi E, Gessani A, Ceroni M, Chio A, D'Amico R, Monsurrò MR, Riva N, Sabatelli M, Silani V, Simone IL, Sorarù G, Provenzani A, D'Agostino VG, Carra S, Poletti A. Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS). BMJ Open. 2019 May 30;9(5):e028486. doi: 10.1136/bmjopen-2018-028486.

• Responsible Party: Jessica Mandrioli, Principal Investigator, Azienda Ospedaliero-Universitaria di Modena
• ClinicalTrials.gov Identifier: NCT03693781
• Other Study ID Numbers: Co-ALS
• First Posted: October 3, 2018
• Last Update Posted: February 5, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: de-identified individual participant data will be made available after study completion upon specific request
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: The data will become available at study completion (after final data analysis)
• Access Criteria: specific personal request by the subject

• 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 Jessica Mandrioli, Azienda Ospedaliero-Universitaria di Modena:

amyotrophic lateral sclerosis; stress granules; HSPB8; protein quality control; colchicine; ALSFRS-r; survival; safety

Additional relevant MeSH terms:

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; Colchicine; Gout Suppressants; Antirheumatic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents