Colchicine for Amyotrophic Lateral Sclerosis (Co-ALS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT03693781

Recruitment Status : Not yet recruiting

First Posted : October 3, 2018

Last Update Posted : January 14, 2019

See Contacts and Locations

Sponsor:

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

Layout table for study information

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
Estimated Study Start Date :	January 30, 2019
Estimated Primary Completion Date :	November 1, 2020
Estimated Study Completion Date :	November 1, 2020

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Amyotrophic lateral sclerosis

MedlinePlus related topics: Amyotrophic Lateral Sclerosis

Drug Information available for: Colchicine

Genetic and Rare Diseases Information Center resources: Amyotrophic Lateral Sclerosis

U.S. FDA Resources

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 :

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 :

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

Eligibility Criteria

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.

Layout table for eligibility information

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

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): NCT03693781

Contacts

Layout table for location contacts

Contact: Jessica Mandrioli, MD	059-3961640	j.mandrioli@ausl.mo.it
Contact: Nicola Fini, MD	0593961640	n.fini@ausl.mo.it

Locations

Layout table for location information

Italy
Centro Sla, University of Bari	Not yet recruiting
Bari, Italy
Contact: Isabella L Simone, Prof.
Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano	Not yet recruiting
Milano, Italy
Contact: Vincenzo Silani, Prof.
Irccs St. Raffaele Institute of Milano	Not yet recruiting
Milano, Italy
Contact: Nilo Riva, MD
Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena	Not yet recruiting
Modena, Italy, 41126
Contact: Jessica Mandrioli, MD +390593961722
Università della Campania Gianluigi Vanvitelli	Not yet 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	Not yet recruiting
Pavia, Italy
Contact: Mauro Ceroni, Prof.
, Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome	Not yet 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

Layout table for investigator information

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.

Layout table for additonal information

Responsible Party:	Jessica Mandrioli, Principal Investigator, Azienda Ospedaliero-Universitaria di Modena
ClinicalTrials.gov Identifier:	NCT03693781 History of Changes
Other Study ID Numbers:	Co-ALS
First Posted:	October 3, 2018 Key Record Dates
Last Update Posted:	January 14, 2019
Last Verified:	January 2019
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

Layout table for additional information

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:

Layout table for MeSH terms

Sclerosis Motor Neuron Disease Amyotrophic Lateral 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 Riluzole	Gout Suppressants Antirheumatic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Anticonvulsants Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents Neurotransmitter Agents Physiological Effects of Drugs Neuroprotective Agents Protective Agents

To Top