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Amyotrophic Lateral SclerosisPhase 2Co-ALSNCT03693781

Colchicine for Amyotrophic Lateral Sclerosis

A Phase 2 study testing Colchicine 1 MG Oral Tablet in people with Amyotrophic Lateral Sclerosis, run by Azienda Ospedaliero-Universitaria di Modena at 8 sites in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

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. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Amyotrophic Lateral Sclerosis
What is being tested?
Colchicine 1 MG Oral Tablet
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
54 participants
Where
8 sitesItaly
Study dates
10 Apr 2019to 3 Jan 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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),
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  • 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).

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

Italy8 sites

  • Centro Sla, University of Bari

    Bari

  • Centro Sla, Istituto Auxologico Italiano, University of Milano, Milano

    Milan

  • Irccs Carlo Besta

    Milan

  • Irccs St. Raffaele Institute of Milano

    Milan

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

    Modena, 41126

  • Università della Campania Gianluigi Vanvitelli

    Naples

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

    Pavia

  • , Neuromuscular Omnicentre Centre, Rome, Catholic University, Rome

    Roma

Other trials in Italy

About this study

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

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.

Read the 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.

Being tested
Colchicine 1 MG Oral Tablet, Placebo Oral Tablet
Keywords
amyotrophic lateral sclerosis, stress granules, HSPB8, protein quality control, colchicine, ALSFRS-r, survival, safety
Medical subject headings
Amyotrophic Lateral Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Colchicine 1 MG Oral TabletDrug

    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 TabletDrug

    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 TabletDrug

    Corresponding tablets for 30 weeks

Study groups in NCT03693781
Study groupRoleWhat they receive
Colchicine 0.01mg/kg/day + Riluzole 100 mgActive comparatorOral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
Receives: Drug: Colchicine 1 MG Oral Tablet
Colchicine 0.005 mg/kg/day + Riluzole 100 mgActive comparatorOral colchicine will be administered at fast, at specified dose pro kilograms for 30 weeks, while taking Riluzole 100 mg/day
Receives: Drug: Colchicine 1 MG Oral Tablet
Placebo + Riluzole 100 mgPlacebo comparatorPlacebo pills will be administered at fast, while taking Riluzole 100 mg/day
Receives: Drug: Placebo Oral Tablet

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: comparison between baseline and treatment end (week 30)

Secondary outcomes (10)

  1. Incidence of Treatment-Emergent Adverse Events (safety and tolerability)

    Number of serious adverse events (SAEs) and AEs in placebo and treatment arms

    Measured: week 30 and 54

  2. Tracheostomy-free survival rate

    Overall survival from randomization to date of death or tracheostomy

    Measured: Up to week 54

  3. Changes in Forced Vital Capacity (FVC)

    Changes in FVC score from baseline to week 8, 18, 30, 54 in treatment and placebo arms.

    Measured: Up to week 54

  4. 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

    Measured: at 8,18,30 and 54 week

  5. 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);

    Measured: at week 30 and 54, compared to baseline

  6. 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).

    Measured: at week 30 compared to baseline

  7. 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

    Measured: at week 30 compared to baseline

  8. 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.

    Measured: at week 30 compared to baseline

  9. effects on biomarkers of neurodegeneration

    creatinine, albumin, CK, and vitamin D in plasma as markers of disease severity; phosphorylated neurofilaments heavy chain

    Measured: at week 30 compared to baseline

  10. effects on biomarkers of inflammation

    assessment of plasma/CSF IL18, its endogenous inhibitor IL-18BP, MCP1 and IL17

    Measured: at week 30 compared to baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Oct 2018
  2. Study start10 Apr 2019
  3. Primary completion14 Apr 2022
  4. Study completion3 Jan 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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 blind
Who is masked
Participant, Investigator
Enrolment
54 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03693781
Sponsor's protocol ID
Co-ALS
Acronym
Co-ALS
Status last verified
Feb 2023
First submitted
30 Sep 2018
Last updated
1 Mar 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: de-identified individual participant data will be made available after study completion upon specific request

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.

    PubMed 23474849

  • 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.

    PubMed 27694913

  • 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.

    PubMed 26961006

  • 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.

    PubMed 27466192

  • 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.

    PubMed 28608264

  • 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.

    PubMed 28402699

  • 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.

    PubMed 18094623

  • 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.

    PubMed 20570967

  • 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.

    PubMed 18973929

  • 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.

    PubMed 27830784

  • 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.

    PubMed 22419278

  • 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.

    PubMed 31152038

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Colchicine 1 MG Oral Tablet in people with Amyotrophic Lateral Sclerosis, run by Azienda Ospedaliero-Universitaria di Modena at 8 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03693781, which also lists 12 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Mar 2023.

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