Publications by authors named "Graziela Cerchiaro"

5 Publications

  • Page 1 of 1

Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial.

CMAJ Open 2021 Apr-Jun;9(2):E693-E702. Epub 2021 Jun 18.

Division of Infectious Diseases (Schwartz, Mponponsuo), Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alta.; Alberta Strategy for Patient Oriented Research SUPPORT Unit (Boesen); Cumming School of Medicine (Boesen, Cerchiaro, Greenfield, Kenney, Ryckborst), University of Calgary; Section of Infectious Diseases (Edwards), Department of Medicine, and Department of Clinical Neurosciences (Doram, Ganesh, Karnik), Cumming School of Medicine, University of Calgary, Calgary, Alta.; Quality Management in Clinical Research Office (Jamieson, Stewart), University of Alberta, Edmonton, Alta.; Division of Respirology (Lim), Department of Medicine, Cumming School of Medicine, and Departments of Clinical Neurosciences and Community Health Sciences (Menon, Metz), Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alta.; Women and Children's Research Institute (Rathwell, Yaskina), and Department of Pediatrics (Richer), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alta.; Departments of Clinical Neurosciences, Community Health Sciences, and Medicine (Hill), Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alta.

Background: Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death.

Methods: This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data.

Results: Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety.

Interpretation: There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered.

Trial Registration: ClinicalTrials.gov, no. NCT04329611.
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http://dx.doi.org/10.9778/cmajo.20210069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248582PMC
June 2021

Repurposing Domperidone in Secondary Progressive Multiple Sclerosis: A Simon 2-Stage Phase 2 Futility Trial.

Neurology 2021 05 23;96(18):e2313-e2322. Epub 2021 Mar 23.

From the Departments of Clinical Neurosciences (M.W.K., K.S., S.K., J.K., G.C., V.W.Y., L.M.M.) and Community Health Sciences (M.W.K.), University of Calgary, Alberta, Canada; and Department of Biostatistics (G.R.C.), University of Alabama at Birmingham.

Objective: To assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon 2-stage design.

Methods: We enrolled patients in an open-label, Simon 2-stage, single-center, phase 2, single-arm futility trial at the Calgary Multiple Sclerosis Clinic if they met the following criteria: age of 18 to 60 years, SPMS, screening Expanded Disability Status Scale score of 4.0 to 6.5, and screening timed 25-ft walk (T25FW) of ≥9 seconds. Patients received domperidone 10 mg 4 times daily for 1 year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by ≥20% at 12 months compared to baseline. This trial is registered with ClinicalTrials.gov (NCT02308137).

Results: Between February 13, 2015, and January 3, 2020, 110 patients were screened, 81 received treatment, and 64 completed follow-up, of whom 62 were analyzed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40% and above the predefined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.

Conclusions: Domperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon 2-stage trial model may be a useful model for phase 2 studies in progressive MS.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02308137.

Classification Of Evidence: This study provides Class III evidence that in individuals with SPMS participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.
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http://dx.doi.org/10.1212/WNL.0000000000011863DOI Listing
May 2021

Multimodal peripheral fluid biomarker analysis in clinically isolated syndrome and early multiple sclerosis.

Mult Scler Relat Disord 2021 May 3;50:102809. Epub 2021 Feb 3.

Departments of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS.

Methods: We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

Results: When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1β, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI.

Conclusion: The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.
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http://dx.doi.org/10.1016/j.msard.2021.102809DOI Listing
May 2021

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

N Engl J Med 2017 06;376(22):2122-2133

From the Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, AB (L.M.M., G.C., J.G., M.Y., M.D.H., V.W.Y.), the University of British Columbia, Vancouver (D.K.B.L., A.L.T., A.R.), the University of Montreal, Montreal (P.D.), Western University, London, ON (M.K.), Fraser Health MS Clinic, Burnaby, BC (G.V.), the University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (M.S.F.), Dalhousie University, Halifax, NS (V.B.), the University of Alberta, Edmonton (G.B.), the University of Manitoba, Winnipeg (J.J.M.), Clinique Neuro Rive-Sud, Greenfield Park, QC (F.G.), the University of Toronto, Toronto (L.L.), and CHA-Hôpital Enfant-Jésus, Quebec, QC (M.T.) - all in Canada; and Tufts University, Boston (M.E.).

Background: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.

Methods: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T-weighted MRI, cumulative number of new lesions enhanced on T-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T-weighted MRI plus new and newly enlarged lesions on T-weighted MRI]).

Results: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.

Conclusions: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).
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http://dx.doi.org/10.1056/NEJMoa1608889DOI Listing
June 2017

A novel biological activity for galectin-1: inhibition of leukocyte-endothelial cell interactions in experimental inflammation.

Am J Pathol 2003 Oct;163(4):1505-15

Department of Biochemical Pharmacology and the Bone and Joint Research Unit, The William Harvey Research Institute, London, United Kingdom.

Galectin-1 (Gal-1), the prototype of a family of beta-galactoside-binding proteins, has been shown to attenuate experimental acute and chronic inflammation. In view of the fact that endothelial cells (ECs), but not human polymorphonuclear leukocytes (PMNs), expressed Gal-1 we tested here the hypothesis that the protein could modulate leukocyte-EC interaction in inflammatory settings. In vitro, human recombinant (hr) Gal-1 inhibited PMN chemotaxis and trans-endothelial migration. These actions were specific as they were absent if Gal-1 was boiled or blocked by neutralizing antiserum. In vivo, hrGal-1 (optimum effect at 0.3 micro g equivalent to 20 pmol) inhibited interleukin-1beta-induced PMN recruitment into the mouse peritoneal cavity. Intravital microscopy analysis showed that leukocyte flux, but not their rolling velocity, was decreased by an anti-inflammatory dose of hrGal-1. Binding of biotinylated Gal-1 to resting and postadherent human PMNs occurred at concentrations inhibitory in the chemotaxis and transmigration assays. In addition, the pattern of Gal-1 binding was differentially modulated by PMN or EC activation. In conclusion, these data suggest the existence of a previously unrecognized function of Gal-1, that is inhibition of leukocyte rolling and extravasation in experimental inflammation. It is possible that endogenous Gal-1 may be part of a novel anti-inflammatory loop in which the endothelium is the source of the protein and the migrating PMNs the target for its anti-inflammatory action.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868297PMC
http://dx.doi.org/10.1016/s0002-9440(10)63507-9DOI Listing
October 2003
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