Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202103893112947 Date of Approval: 05/03/2021
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Warfarin pharmacogenetics
Official scientific title Pilot study evaluating the effect of pharmacogenetics on warfarin dosing and shortening the time to a therapeutic International Normalised Ratio
Brief summary describing the background and objectives of the trial Warfarin is the available oral anticoagulant in the South African public health sector due to its low cost, established efficacy for multiple indications and decades of clinical experience. Warfarin-bleeding, however, it is frequently implicated in adverse drug reaction-related admissions in South Africa with significant morbidity and mortality. There are pharmacokinetic, pharmacodynamic and pharmacogenetic characteristics of warfarin which contribute to its high adverse drug reaction rate. Warfarin has a narrow therapeutic range making dosing challenging. Supra-therapeutic warfarin increases the risk of bleeding whereas sub-therapeutic warfarin can leave patients more vulnerable to clotting. Clinicians monitor the therapeutic range of warfarin by using the International Normalized Ratio (INR). Several factors have been noted to affect warfarin variability and therefore dosing. Warfarin pharmacogenetic variation has been identified as one of the most important factors affecting warfarin requirements and dosing. Several international studies have demonstrated that warfarin pharmacogenetics assessment to inform individualised dosing of warfarin results in more rapid achievement of a therapeutic INR compared to conventional dosing. The aim of this study is to assess whether warfarin point of care genotyping can be used to improve warfarin dosing in a South African setting using a prospective design. The study population will comprise of patients who require oral anticoagulation as part of standard of care at Tygerberg Hospital.
Type of trial RCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Genetic Diseases
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 15/03/2021
Actual trial start date
Anticipated date of last follow up 30/09/2021
Actual Last follow-up date
Anticipated target sample size (number of participants) 60
Actual target sample size (number of participants)
Recruitment status Not yet recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
18679 Stellenbosch University Health Research Ethics Committee
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Permuted block randomization Allocation was determined by the holder of the sequence who is situated off site Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group Warfarin genotyped group Warfarin with be dosed according to genotyping using the NHS warfarin dosing algorithm Patients will be followed up until INR is therapeutic A buccal swab will be collected on all patients in the intervention group and will be assessed for 3 SNPs, CYP2C9*2, CYP2C9*3 and VKORC1. This will be done using HyBeacon® probes that will be used to detect and identify polymorphic DNA sequences and a paraDNA point-of-care genotyping kit. The paraDNA point-of-care genotyping kit, is a rapid DNA-based point of care assay that was developed to identify warfarin sensitivity in patients and improve the accuracy of warfarin dosing. Results are available within 1 hour. The assay can also be used on whole blood. POC genotyping results will be compared with laboratory based genotyping using real time PCR to confirm the accuracy of the POC genotyping results. Once the genotyping is complete the lead investigator will use the NHS warfarin dosing calculator to determine the starting dose and the maintenance dose of warfarin. The NHS warfarin dosing calculator is the same calculator that was used in the Pirmohamed study in 2013. The calculator has been validated to look at 3 genetic variants in CYP2C9 and VKORC1 genes. It is important to note that the algorithm for this calculator was designed for patients of European ethnicity. The full details on the calculations for the algorithm is available in the supplementary appendix of the Pirmohamed study. The dosing recommendation will be provided to the clinical team looking after the patient within 24hours of patients being referred. This will not impact patient care as the patient will already be on enoxaparin (low molecular weight heparin) and oral anticoagulation is only started 2 – 3 days later. Recommendations will be made on the starting dose and on the maintenance dose of warfarin. Dosing recommendations will be rounded to the nearest 2.5mg, as warfarin comes in a scored 5mg tablet. Once a recommendation is made, the dispensing record will be reviewed to confirm that the dosing recommendation has been implemented. 30
Control Group Standard of care group Warfarin will be dosed according to standard of care Patients will be followed-up until INR is therapeutic Patients who are randomized to the control group, will not be genotyped. However, an EDTA blood sample will be collected and stored for future genetic research related to warfarin genotyping. These patients will be treated according to standard of care. The starting dose of warfarin will be recorded along with any dose adjustments of warfarin while the patient is in hospital. All INRs done in hospital until the patient is discharged will be recorded. The time taken to reach a therapeutic INR in days will be counted and recorded. Patients will be monitored for any adverse events and this will be recorded and treated by the attending physician. 30 Dose Comparison
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Age > 18 years old Patients who require warfarin anticoagulation as part of standard of care Patients who do not have informed consent Patients with mechanical heart valves Patients who were anticoagulated with warfarin in the last 30 days Patients with liver failure 80 and over: 80+ Year,Adolescent: 13 Year-18 Year,Adult: 19 Year-44 Year,Aged: 65+ Year(s),Middle Aged: 45 Year(s)-64 Year(s) 18 Year(s) 105 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 20/01/2021 Stellenbosch University Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Francie van Zijl Drive, Parow Cape Town 7505 South Africa
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome To compare the time of reaching one therapeutic INR in patients whom warfarin is dosed with using point-of-care genotyping (Intervention Group) to time of reaching one therapeutic INR in patients where conventional warfarin dosing was used (Control Group). Depends on how long it takes to achieve a therapeutic INR.
Secondary Outcome To determine the incidence of supratherapeutic and subtherapeutic INR values in the Intervention Group compared with the Control Group. Will depend on the INR value
Secondary Outcome The number of times the warfarin dose is adjusted to achieve a therapeutic INR in the Intervention Group compared with the Control Group. Will depend on when warfarin is started and when a therapeutic INR is achieved.
Secondary Outcome To assess the incidence of adverse events related to warfarin in the Intervention Group compared with the Control Group. Will be assessed throughout the study
Secondary Outcome To compare the dosing recommendations of two internationally accepted dosing algorithms (the NHS warfarin dosing algorithm and the warfarindosing.org algorithm). Will be measured in the intervention group only and after genotyping has taken place.
Secondary Outcome To assess the acceptability of warfarin POC genotype-guided dosing by clinicians. Will be assessed at completion of patient visit
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Tygerberg Hospital Francie van Zijl Drive, Parow Cape Town 7505 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Harry Crossley Foundation Francie van Zijl Drive, Parow Cape Town 7505 South Africa
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Ilhaam Fredericks Francie van Zijl Drive, Parow Cape Town 7505 South Africa Individual
COLLABORATORS
Name Street address City Postal code Country
Professor Maritha Kotze Francie van Zijl Drive, Parow Cape Town 7505 South Africa
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Ilhaam Fredericks ilhaam.fredericks@gmail.com 0834106242 Francie van Zijl Drive, Parow
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Internal Medicine Registrar
Role Name Email Phone Street address
Public Enquiries Ilhaam Fredericks ilhaam.fredericks@gmail.com 0834106242 Francie van Zijl Drive, Parow
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Internal Medicine Registrar
Role Name Email Phone Street address
Scientific Enquiries Ilhaam Fredericks ilhaam.fredericks@gmail.com 0834106242 Francie van Zijl Drive, Parow
City Postal code Country Position/Affiliation
Cape Town 7505 South Africa Internal Medicine Registrar
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Individual patient data will not be shared. However, after data has been collected and analysed it will be published in an accredited scientific journal and will be made public. Informed Consent Form,Statistical Analysis Plan,Study Protocol Study protocol, statistical analysis plan and informed consent form documents are all available. Data will only be available to the study team. Data will be made available to public on completion of the study.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information