Colchicine for Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis Clinical Trial

— Co-ALS  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03693781
• Other study ID #: Co-ALS
• Status: Completed
• Phase: Phase 2
• Start date: April 10, 2019
• Est. completion date: January 3, 2023

Study information

• Verified date: February 2023
• Source: Azienda Ospedaliero-Universitaria di Modena
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: January 3, 2023
• Est. primary completion date: April 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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).

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

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.
• 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

Locations

Country	Name	City	State
Italy	Centro Sla, University of Bari	Bari
Italy	Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano	Milano
Italy	Irccs Carlo Besta	Milano
Italy	Irccs St. Raffaele Institute of Milano	Milano
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

Sponsors (12)

Lead Sponsor	Collaborator
Azienda Ospedaliero-Universitaria di Modena	Catholic University of the Sacred Heart, IRCCS National Neurological Institute "C. Mondino" Foundation, IRCCS San Raffaele, Istituto Auxologico Italiano, Istituto Di Ricerche Farmacologiche Mario Negri, University of Bari, University of Campania "Luigi Vanvitelli", University of Milan, University of Modena and Reggio Emilia, University of Padova, University of Turin, Italy

Country where clinical trial is conducted

Italy, 

References & Publications (11)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Decrease in ALS disease progression as measured by ALS Functional rating Scale Revised (ALSFRS-R)	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.	comparison between baseline and treatment end (week 30)
Secondary	Incidence of Treatment-Emergent Adverse Events (safety and tolerability)	Number of serious adverse events (SAEs) and AEs in placebo and treatment arms	week 30 and 54
Secondary	Tracheostomy-free survival rate	Overall survival from randomization to date of death or tracheostomy	Up to week 54
Secondary	Changes in Forced Vital Capacity (FVC)	Changes in FVC score from baseline to week 8, 18, 30, 54 in treatment and placebo arms.	Up to week 54
Secondary	Changes in quality of life	Changes in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) from baseline to week 8, 18, 30 and week 54, in placebo and treatment arms	at 8,18,30 and 54 week
Secondary	enhancement of autophagy	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);	at week 30 and 54, compared to baseline
Secondary	changes in stress granules size, number and composition	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).	at week 30 compared to baseline
Secondary	quantification of insoluble species	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	at week 30 compared to baseline
Secondary	modifications on extracellular vesicles secretion in blood and CSF	assessment of TDP-43, hyperphosphorylated TDP-43, SQSTM1/p62, UBQLN and OPTN in extracellular vesicles by plasma and CSF.	at week 30 compared to baseline
Secondary	effects on biomarkers of neurodegeneration	creatinine, albumin, CK, and vitamin D in plasma as markers of disease severity; phosphorylated neurofilaments heavy chain	at week 30 compared to baseline
Secondary	effects on biomarkers of inflammation	assessment of plasma/CSF IL18, its endogenous inhibitor IL-18BP, MCP1 and IL17	at week 30 compared to baseline