Study Results
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Basic Information
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COMPLETED
PHASE2
54 participants
INTERVENTIONAL
2019-04-10
2023-01-03
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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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
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.
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
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 + Riluzole 100 mg
Placebo pills will be administered at fast, while taking Riluzole 100 mg/day
Placebo Oral Tablet
Corresponding tablets for 30 weeks
Interventions
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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.
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 Oral Tablet
Corresponding tablets for 30 weeks
Eligibility Criteria
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Inclusion Criteria
* 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 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).
18 Years
80 Years
ALL
No
Sponsors
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University of Modena and Reggio Emilia
OTHER
University of Turin, Italy
OTHER
Istituto Auxologico Italiano
OTHER
IRCCS National Neurological Institute "C. Mondino" Foundation
OTHER
University of Bari
OTHER
IRCCS San Raffaele
OTHER
University of Padova
OTHER
University of Milan
OTHER
Istituto Di Ricerche Farmacologiche Mario Negri
OTHER
University of Campania Luigi Vanvitelli
OTHER
Catholic University of the Sacred Heart
OTHER
Azienda Ospedaliero-Universitaria di Modena
OTHER
Responsible Party
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JESSICA MANDRIOLI
Principal Investigator
Principal Investigators
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Jessica Mandrioli
Role: PRINCIPAL_INVESTIGATOR
Azienda Ospedaliero-Universitaria di Modena
Locations
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Centro Sla, University of Bari
Bari, , Italy
Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano
Milan, , Italy
Irccs Carlo Besta
Milan, , Italy
Irccs St. Raffaele Institute of Milano
Milan, , Italy
Centro Sla, Ospedale Civile S. Agostino Estense, A.O.U. Modena
Modena, , Italy
Università della Campania Gianluigi Vanvitelli
Napoli, , Italy
Als Centre, "C. Mondino" National Neurological Institute, University of Pavia
Pavia, , Italy
, Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome
Roma, , Italy
Countries
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References
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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.
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.
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. doi: 10.4161/auto.5407. Epub 2007 Dec 11.
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.
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.
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3.
Mandrioli J, Crippa V, Cereda C, Bonetto V, Zucchi E, Gessani A, Ceroni M, Chio A, D'Amico R, Monsurro MR, Riva N, Sabatelli M, Silani V, Simone IL, Soraru 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.
Other Identifiers
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Co-ALS
Identifier Type: -
Identifier Source: org_study_id
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