Drs. Sasha Bernatsky and Louise Pilote received funding from the Drug Safety and Effectiveness Network (DSEN) Rapid Funding for DSEN Targeted Research to continue developing novel methods using prospective longitudinal cohorts and responding to key knowledge gaps regarding drug safety and effectiveness through the Enhanced Cohort project.
Research Project Title: Canadian Early Arthritis Cohort (CATCH)
NPI: Sasha Bernatsky
Co PI: Vivian Bykerk and Louise Pilote
Duration: 1 year
We have been funded to answer a query related to the comparative effectiveness and safety between currently available agents (biologics, traditional DMARDs) and JAK inhibitors. We will expand our aims in CATCH (Canadian Early Arthritis Cohort) to more carefully track safety events in relation to patient and disease related factors, extent of inflammation and effectiveness of prior therapies.
This project was funded by CIHR and aims to enhance a multicenter ongoing observational cohort study of patients with early rheumatoid arthritis (ERA). This project has been focused on expanding the aims in CATCH to more carefully track safety events in relation to patient and disease related factors extent of inflammation and effectiveness of prior therapies.
The longitudinal CATCH research database is a global resource enabling multiple types of discoveries. The present study combining detailed medication tracking (including switches and SAEs) with longitudinal measures of disease activity/ severity, disease flare, radiographic progression and multiple PROMs in a large sample of rheumatologist confirmed ERA cases seen in routine practice creates an ideal platform for carrying out robust real-time and real-world comparative effectiveness research. Outputs from this research program can help describe real-world practice patterns surrounding use of RA therapies as well as identify associations between RA therapies, outcomes and costs with the goal of improving health services and quality of care for RA patients.
We conducted analysis in the CATCH cohort to describe treatment failure, discontinuation, and switching across various treatment strategies. Over the study interval, 61% patients had a treatment failure, primarily due to inefficacy. In further analysis among patients exposed to MTX who had an initial treatment failure, we found that those on biologics and those on triple therapy had a longer time to failure, compared to the group taking MTX oral monotherapy.
We retired long legacy questionnaires in favour of shorter forms shown to have stronger psychometric properties (e.g. MD-HAQ and PROMIS-29). We also shifted to longitudinal measures of patient reported comorbidities validated for use in rheumatic disease populations (Sangha Self-Administered Comorbidity Questionnaire /Rheumatic Disease Comorbidity Index).
Detailed recording of all RA medications are confirmed & entered by rheumatology team member, including steroids, csDMARDs, tsDMARDs, bDMARDs, SEBs/ biosimilars. Each medication entry includes the following information:
- Name of medication
- Start/ stop dates
- Reason for stopping therapy (drop down list selection with additional option for free text entry)
- Side effect (drop down list selection of 30+ potential with additional option for free text entry)
We added questions to be completed by the treating physician at each visit, asking about any comorbidities or serious adverse events (SAEs) possibly attributable to the patient’s RA medication, which medication(s) could be attributed, type of SAE/comorbidity, physician certainty the event is attributable to the medication, whether the medication needed to be interrupted, and the outcome/status of the event.
Joint counts, global assessments and labs used to calculate multiple clinical disease activity indices (DAS, CDAI, SDAI) are collected longitudinally at each catch visit. Serial radiographs allow for analyses of radiographic progression.
We added multiple key PROMs assessing the following:
- Patients’ attitudes, beliefs and behaviors surrounding medication use including the beliefs about medications questionnaire (BMQ), Medications Adherence Questionnaire (MAQ), Patient activation measure (PAM)
- Patient reports of RA disease flares (Rheumatoid Arthritis Flare Questionnaire (RA-FQ))
- Mental health (Patient Health Depression Scale – 8 (PHQ-8)
- Impacts on Work (Work productivity Impairment Scale)
We also added questions about potential economic and system factors related to medication use (e.g. insurance coverage, average costs of medication, access to local co-pay or subsidized medication programs. More detailed questions were developed with respect to patient infections and hospitalizations.
Progress with innovations to CATCH EDC
We built a modern and flexible electronic data capture (EDC) system enabled for real-time data entry within the clinical encounter. The EDC system supports multiple devices and platforms (e.g. desktop, tablet, mobile phones, IOS, Android etc.). All sites are provided with one or more tablets for data entry. The EDC program also allows for:
- Within form and cross-form real-time data logic checks
- Forward propagation and adaptive form customization based on previously entered fields.
- Embedded data query system for centralized tracking and management of missing data
- Automated withdrawal forms recording reasons for withdraw
- Automated study visit scheduler with push electronic reminders. For use by site personnel to notify patients of upcoming appointments as well as when/ which study forms to complete.
- Dynamic data entry to capture medication adjustments /switches and patient flares that may occur between protocolized visits
- Ability to easily upload scanned lab and imaging reports
- Customizable physician dashboard to review patient summaries of clinical and prognostic indicators to help support medical decision making
CATCH continues to provide support to sites with the transition to electronic data entry.
Kerbachi M, et al. Incidence of Infections in Early Arthritis. Poster presented at: Canadian Rheumatology Association Annual Scientific Meeting; February 21-24, 2018; Vancouver, CA.
Moura CS, et al. Methotrexate Treatment Strategies in an Early Rheumatoid Arthritis Cohort. Poster presented at: Canadian Rheumatology Association Annual Scientific Meeting; February 21-24, 2018; Vancouver, CA.
Moura CS, et al. Additions to Methotrexate with Conventional and Biologic DMARDs in Rheumatoid Arthritis: Are There Differences in Subsequent Time to Treatment Failure? Poster presented at: Canadian Rheumatology Association Annual Scientific Meeting; February 21-24, 2018; Vancouver, CA.
Bernatsky S, et al. Additions to Methotrexate with Conventional and Biologic Dmards in Rheumatoid Arthritis: Are There Differences in Subsequent Time to Treatment Failure? Poster presented at: American College of Rheumatology/ Association of Rheumatology Health professionals (ACR/ARHP) Annual Scientific Meeting; November 3-8, 2017; San Diego, CA.
Bernatsky S, et al. Methotrexate Treatment Strategies in an Early Rheumatoid Arthritis Cohort. Poster presented at: American College of Rheumatology/ Association of Rheumatology Health professionals (ACR/ARHP) Annual Scientific Meeting; November 3-8, 2017; San Diego, CA.
Kerbachi M, et al. Incidence of Infections in Early Arthritis. Poster presented to: American College of Rheumatology/ Association of Rheumatology Health professionals (ACR/ARHP) Annual Scientific Meeting; November 3-8, 2017; San Diego, CA.
Moura CS, et al. Treatment strategies in early rheumatoid arthritis methotrexate management: Results from a prospective cohort. Arthritis Care & Research (Manuscript under review)
Research Project Title: Pharmacoepidemiology in Multiple Sclerosis (PiMS) Research Group
NPI: Sasha Bernatsky
Co-PI: Helen Tremlett and Louise Pilote
Duration: 1 year
We have been funded to enhance the clinical cohort in multiple sclerosis (MS) and new oral disease-modifying drugs (DMDs) agents. With the enhanced cohort project, we will focus on the linkage of prospectively collected, patient-level population-based data to create a unique and powerful dataset of administrative health, prescription, and laboratory monitoring information to describe the use of new oral DMD and MS as well as the incidence and potential predictors of adverse events. Additionally, we will enable the study to be expanded and we plan to include a pharmacogenomic component to enable saliva collection.
The following activities were completed:
- We have recruited 149 patients for the pharmacogenomic sub-study from Vancouver and Winnipeg, and are expecting an estimated 15 additional samples in the coming weeks from these two sites. Our collaborators in Bern, Switzerland are currently summarizing their clinical data and coordinating sample collection from the MS clinic at the Universität Bern
- We are currently working through expanding the collection of samples and acquiring research ethics board approvals to include the largest MS clinic in Canada, located at St. Michael’s Hospital in Toronto, Ontario with Dr. Dalia Rotstein and Dr. Jiwon Oh. We are also currently working through expanding the collection of samples and acquiring REB approval from the University of Saskatchewan (Saskatoon MS clinic), including Dr. Michael Levin and Dr. Charity Evans.
- 18 patients were recruited for a micro-biome sub-study: This pilot study was exploratory in nature; we were primarily test piloting our study design. No sample size estimation was performed. However, we anticipate findings to enable us to both design and perhaps power future studies. With the samples now collected, we are discussing the options: to either sequence now or contribute/combine with a larger study. We are currently proceeding with the possibility of collaborating with other research groups to use these samples alongside larger studies of the gut microbiome.
The PiMS research team was awarded a pilot grant from the National Multiple Sclerosis Society in the United States for $50,000 USD in October 2018. The pilot’s aim is to investigate the genomic variants associated with dimethyl fumarated-induced lymphopenia in MS. This would provide funding for genotyping.
Our broad objective for this DSEN study was to investigate the relationship between the disease modifying therapies for multiple sclerosis (MS) and drug safety by utilising genomic information.
The intersection between microbiomics and drug safety is a highly novel field of inquiry, but holds potential to improve drug safety and patient outcomes. While pharmacogenomics has become established as a useful (although often underused) tool for minimizing the risk of adverse drug reactions, there is newly emerging and significant interest in the role of the gut microbiota in drug safety.1,2 There is a major knowledge gap and a real need to understand and explore this intersection between microbiomics and drug safety.
Specifically, for the microbiome sub-study, we aimed to test pilot the feasibility of sampling stool longitudinally from people with MS (pre- and post-drug) and from those with progressive forms of MS. We dedicated one research assistant to identify, recruit, and follow up with potential study participants for 6 months. After 6 months, we evaluated the study progress. Our evaluation showed that recruitment was challenging and resource intensive. Major reasons included: a) setting: we primarily approached patients via the MS clinic. However, there are many competing factors in this environment e.g., anxiety related to car-parking, missing an appointment, nature of the appointment etc and b) return rates on mailed in (stool) samples was low; increasing this return rate was very time intensive, requiring multiple follow-up calls and/or emails from the research assistant. We concluded that the resources required to recruit a sufficient sample size for a study of the microbiome in MS needs to be funded separately from this DSEN funding. We would also make significant changes to the methods of recruitment, including budgeting for a full-time staff member and allowing a much longer recruitment period.
We have created a unique and powerful dataset of administrative health, prescription and laboratory monitoring information by linking prospective data from British Columbia, as it relates to the use of MS disease modifying therapies. We have leveraged the value from DSEN funding to acquire separate funding from the MS Society of Canada to fund this work.
We have enabled saliva collection for a case-control sub-study to develop genetic predictors of adverse drug reactions for two separate adverse drug reactions related to MS drugs: interferon-beta induced liver injury and dimethyl fumarate induced lymphopenia. Recruitment, analysis, and publication are complete for interferon-beta induced liver injury (During the course of this DSEN funding, we finalised the analyses and submitted the manuscript for publication). For dimethyl fumarate induced lymphopenia, we now have saliva from 149 patients from Vancouver and Winnipeg, and are currently working with collaborators in Toronto (St. Michael’s Hospital) and Switzerland (Universität Bern) to increase our sample size, and are aiming to complete recruitment and analysis within the next 12 months.
Following the publication of our pharmacogenomics study on interferon-beta induced liver injury, we anticipate that individuals with MS who are positive for the specific genetic risk variant could be tested prior to commencing this drug. We are currently determining the feasibility of replicating these findings in a separate cohort, and determine whether testing for this genetic variant in clinic would be feasible in the future.
Additionally, as part of the course of this DSEN funded work, if a genetic variant is identified to be associated with dimethyl fumarate lymphopenia, this would represent an additional area for a potential policy implication.
For the pharmacogenomics sub-study, we have communicated the results by the following means:
- Scientific publication in Nature Genetics, published 16 July 2018
- The publication has received an Altmetric Score of 70, since publication on 16/7/2018
- Top 5% of all research outputs scored by Altmetric
- It is in the 96th percentile compared to outputs of the same age
- Twitter, which reached 239,940 followers from 60 tweets, as captured by Altmetric
- Presentation at three large international conferences (listed below, under Abstracts)
- Published a news release: We collaborated with the public affairs office at the University of British Columbia to create a news release, which has since been covered by the following media outlets:
(underline indicates presenting author)
- Kowalec K, Kingwell E, Carruthers R, Traboulsee A, Wright GEB, Drögemöller BI, Aminkeng F, Bernatsky S, Ross CJD, Carleton BC, Tremlett H. The pharmacogenomics of serious adverse drug reactions associated with disease modifying therapies for multiple sclerosis: work in progress. Poster presentation to the American Society of Human Genetics 2016 Annual Meeting, Vancouver B.C., October 18-22, 2016.
- Kowalec K, Wright GEB, Drögemöller BD, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell T, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton B. Genome-wide scan identifies association between an interferon regulatory factor variant and interferon-beta induced liver injury in multiple sclerosis patients. Oral presentation at the Canadian Society for Pharmacology and Therapeutics/Safety Pharmacology Society Annual Meeting, Vancouver B.C., September 2016. Winner of Top Trainee Oral Presentation Award.
- Kowalec K, Wright GEB, Drögemöller BD, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell T, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton B. Genome-wide scan identifies association between an interferon regulatory factor variant and interferon-beta induced liver injury in multiple sclerosis patients. Poster presentation at the European Committee for Treatment and Research in Multiple Sclerosis Annual Congress, London, U.K., September 2016. Short-listed for poster prize (Top 5% of 1,985 abstracts).
- Kowalec K, Wright GEB, Drögemöller BD, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell T, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton B. Genome-wide scan identifies association between an interferon regulatory factor variant and interferon-beta induced liver injury in multiple sclerosis patients. Poster presentation at the EndMS National Conference, Toronto, ON, December 2016.
- Kowalec K, Wright GEB, Drögemöller BI, Aminkeng F, Bhavsar AP, Kingwell E, Yoshida EM, Traboulsee A, Marrie RA, Kremenchutzky M, Campbell TL, Duquette P, Chalasani N, Wadelius M, Hallberg P, Xia Z, De Jager P, Ross CJD, Tremlett H, Carleton BC. (2018) Common variation near IRF6 is associated with IFN-̟ß-induced liver injury in multiple sclerosis. Nat Genet, 50(8) :1081-85.
- Kowalec K, Kingwell E, Carruthers R, Marrie RA, Traboulsee A, Bernatsky S, Ross CJD, Carleton B, Tremlett H. (2017) Application of pharmacogenomics to investigate adverse drug reactions to the disease-modifying treatments for multiple sclerosis: a case-control study protocol for dimethyl fumarate induced lymphopenia. BMJ Open, 7(5): e016276.
Research Project Title: Canadian Network on Hepatitis C (CanHepC)
NPI: Sasha Bernatsky
Co-PI: Marina Klein, Jordan Feld, and Louise Pilote
Duration: 1 year
We have been funded to answer a query related to the comparative effectiveness and safety of direct-acting antiviral agents (DAA) in combination or not with PEG + RBV (triple therapy). For the current project, aimed at enhancing drug safety and effectiveness research through the CanHepC network, we aim to harmonize existing data already collected around the country in varying clinical settings, as well as broadening the focus, to enroll on populations poorly represented in prior studies. In addition to merging existing data, we will collect new data in a prospective manner.
This project aims to enhance the clinical cohort on hepatitis C and the first generation of direct-acting antivirals (DAAs). This project has been focused on collecting high quality observational data on the use of novel therapeutics for HCV infection and to harmonizing datasets on HCV collected at centres across Canada. It also involves broadening the scope of the original cohort to enroll on populations poorly represented in prior studies. We are actively collecting data. We have over 1,000 patients with more than 2,5000 visits in the prospective database so far and we are expecting that to increase significantly very soon as we added five new sites.
Data collection is carried out using related but independent approaches:
- Retrospective Cohort: Existing clinical and research databases from Canadian academic sites and community-based clinics will be combined onto a single platform to allow for analysis of treatment outcomes that have already occurred.
- Prospective Cohort: A prospectively followed cohort, the Canadian Network Undertaking against Hepatitis C (CANUHC) will collect prospective data on all patients seen in HCV treatment clinics. The CANUHC database will be housed at the University of Calgary.
- Registry Linkage Cohort
The Canadian Network on Hepatitis C (CanHepC) is a national collaborative HCV research and training network funded by and modeled on the structure of the Canadian Institutes for Health Research (CIHR). The CanHepC network brings together researchers studying all aspects of HCV infection ranging from fundamental questions of virology and immunology to social sciences and health policy that influence HCV transmission. The network has 4 research cores: Basic Science Discovery, Clinical Research, Behavioural and Epidemiology Research and Health System and Policy Research, as well as a Training Core to facilitate research development for trainees and a Knowledge Translation core to ensure that the findings of the network are tangibly put into practice.
The main focus of the Clinical Research Core is to understand the real-world effectiveness of new HCV therapies with a particular focus on short and long-term outcomes in populations of high interest to Canada, many of which have not been well represented in registries in other regions.
The core will focus on the following areas of research:
- Clinical effectiveness of HCV therapy with a focus on short-term (SVR rate, adherence, treatment-related toxicity) and long-term (resistance, reinfection) outcomes with comparisons between different clinical populations and models of care
- Assessment of long-term clinical outcomes (HCC, liver transplantation, liver-related mortality, all-cause mortality, regression of fibrosis) in different clinical populations
- Access to care and treatment uptake in different HCV-infected populations
Approved Sub-Study Proposals
- Dan Smyth, et al. Real world outcomes with hepatitis C (HCV) direct-acting antivirals (DAAs) in Canada: overall summary analysis and key and neglected populations of interest.
- Dan Smyth, et al. Real world, prospective multicentre cohort study of HCV re-infection among patients enrolled in the Canadian Network Undertaking against Hepatitis C (CANUCH) prospective registry.
- Curtis Cooper, et al. HCV infected Canadian immigrant characteristics and treatment outcomes.
- Alnoor Ramji, et al.: Correlation of non-invasive fibrosis markers prior to HCV therapy and impact on SVR.
Presented to the European Association for the Study of the Liver (EASL) 2018:
- Ramji A, Tam E, Feld J, Cooper C, Wong A. Prevalence of baseline NS5A resistance associated substitutions in treatment naive patients with genotype 1a or 3. Journal of Hepatology. 68(1):S105–S364.
- Krassenburg L, Zanjir W.R, Georgie F, Munawar K, Cerocchi O, Stotland E, Lau J, Janssen H, Hansen B, Feld J. Comparison of event-free survival between DAA and IFN-based antiviral therapy for HCV, adjusted for disease severity. Journal of Hepatology. 68(1):S365–S604. S526.
- Mitchell R, Ou G, Leung A, Feizi J, Howe A, Cerocchi O, Kuriry H, Feld J, Ko H. H, Ramji A. Hepatitis C direct-acting antiviral failures: clinical characteristics and resistance testing from a realworld setting. Journal of Hepatology. 68(1):S105–S364. S291.
- Krassenburg L, Hansen B, Zanjir W.R, Georgie F, Cerocchi O, Lau J, Van der Meer A, Janssen H, Feld JJ The number needed to treat to prevent one clinical event at 2 years after antiviral treatment for HCV with DAAs compared to IFN-based therapy. Journal of Hepatology. 68(1):S365–S604. S527.
Accepted to the International Symposium on Hepatitis Care in Substance Users (INSHU) 2018:
- Materniak S, Smyth D, et al. HCV-infected youth characteristics and representation in the CanHepC Retrospective National Registry.
- Materniak S, Smyth D, et al. Differences in sustained virological response to direct-acting antiviral therapy for chronic Hepatitis C by sex: results from the CanHepC Retrospective National Registry.
Accepted to American Association for the Study of Liver Diseases 2018:
- Lau J, Krassenburg L, Zanjir W, Georgie G, Cerrochi O, Stotland E, Morales H, Janssen H, Hansen B, Feld JJ. Factors associated with a low risk of hepatocellular carcinoma (HCC) after sustained virological response (SVR).
Research Project Title: GENdEr and Sex DetermInantS of Cardiovascular Disease (GENESIS-PRAXY)
NPI: Louise Pilote
Co-PI Sasha Bernatsky
Duration: 1 year
This project aims to determine whether sex differences in clopidogrel metabolism genes in young acute coronary syndrome (ACS) patients exist. The GENESIS PRAXY cohort was enriched through the genotyping of the relevant CYP genes. DNA from the PRAXY cohort was sent to the genome center for genotyping. The results were analysed and provided pilot data to calculate the required sample size for more definitive results. Since, our collaborations with similar cohorts have been established, including the VIRGO cohort (an international collaboration between United States, Spain, and Australia). The VIRGO database is especially useful given its large sample size and similar patient baseline characteristics. In November 2017, we received funding from CIHR catalyst grant to amalgamate these aforementioned cohorts. We have signed the Data User Agreement for acquiring VIRGO data with collaboration of PI Dr. Rachel Dreyer from Yale University. Since we now have access to the VIRGO cohort data along with whole genome sequencing data, we have a large collation cohort with a higher proportion of female patients. All the analyses have been performed and a manuscript is now in progress. Our abstract was accepted as a poster presentation and presented at the American College of Cardiology meeting in New Orleans March 16-19, 2019.
Our PRAXY cohort had 743 patients genotyped. We also obtained data from the VIRGO cohort, including an additional 2,080 patients with whole genome sequencing data. This provides a total of 2,823 patients who have been genotyped.
A Genetic Risk Score (GRS) for CYP alleles was calculated. Women had a higher mean score as compared to men though not significant. Sex differences in thrombotic and bleeding risk were explored through sex-gene interactions in patients on clopidogrel at the time of AMI presentation and discharge respectively. Among clopidogrel users at AMI onset (n=164), thrombotic risk was greater in female carriers of CYP2C9*3 loss-of-function allele (likely explained by a higher on-clopidogrel platelet reactivity. The gain of function variant (CYP2C9*17) was not associated with bleeding risk in clopidogrel users at discharge (n=481) regardless of sex.
CYP3A (hepatic cytochrome enzymes) has been shown to have an increased effect in females (Hunt CM, et al. 1992). This sexually dimorphic expression of CYP3A is caused in response to sex-dependent growth hormone secretion (Li J, et al. 2015). Since limited data is available on the effect of sex on CYP alleles, we propose to investigate the sex-drug-gene interaction of clopidogrel with CYP alleles.
As drug efficacy and safety can differ between men and women, our study aims to demonstrate that sex-specific policies would be better suited for female patients as women are highly underrepresented in drug trials. Our collection of two large, highly characterized cohorts of patients with ACS with oversampling of women has provided us with a powerful investigation of sex-drug-gene interaction. Therefore, we anticipate policy implications in prescribing drugs based on patients’ sex.
Health Canada could request more information on sex-specific data to be able to determine drug prescriptions better suited for women.
DSEN stakeholders could raise queries related to sex and gender interactions in the safety and effectiveness of medications, leading to sex-specific drugs tailored for women and to personalized medicine.
- Moura et al. Treatment discontinuation and clinical events in type 2 diabetes patients treated with dipeptidyl peptidase-4 inhibitors or NPH insulin as third-line therapy. Journal of Diabetes Research, 2018: 4817178
- Moura et al. Treatment discontinuation and rates of hypoglycemia in type 2 diabetes patients treated with dipeptidyl peptidase-4 (DDP4) inhibitors or NPH insulin as third line therapy. 2016 (ICPE abstract)
- Elharram M, Pilote L. Novel glucose lowering agents are associated with a lower risk of cardiovascular and adverse events in type 2 diabetes: a population-based analysis. Abstract– Moderated Presentation. Canadian Cardiovascular Congress (CCC), Toronto, Ontario, October 20-23, 2018.
- Elharram M, Pilote L. Risk of cardiovascular events in type 2 diabetes patients initiating novel agents as second line therapy with glucose lowering drugs: a population-based analysis. Oral Presentation. McGill Cardiovascular Research Day, Jewish General Hospital, Montreal, Quebec, May 2, 2018.
For more information contact: Autumn Neville. Research Coordinator. [email protected] 514.934.1934 ext.44844 or ext.44718