Effectiveness of NextDose for Warfarin Dose Individualization

NCT04510805 | Unknown Phase 4 DMC

• 1 other identifier: 2020025
• Study Type: interventional
• Target: 240
• Locations: 0 countries
• Sites: N/A

Brief Summary

Objectives: To understand whether the implementation of warfarin dose management using NextDose (nextdose.org) at The First Affiliated Hospital of Soochow University (Suzhou, China) improves the quality of anticoagulation therapy. Endpoint Primary 1\. Percentage of time within the acceptable INR range estimated using linear interpolation during the 28 days after initiation of warfarin. Secondary 2.1 Percentage of Time Measures 2.2 Time to Stable Dose 2.3 Safety Outcomes 2.4 Acceptability of NextDose Recommendations Exploratory 3.1 Percentage of Time Measures 3.2 Time to Stable Dose 3.3 Safety Outcomes 3.4 Acceptability of NextDose Recommendations 3.5 Model Evaluation 3.6 INR Variability Population: 240 participants of any sex between the age of 18 and 80 years. Patients requiring treatment with warfarin following cardiac surgery.

Conditions

Thrombosis Embolism

Keywords

warfarin; PKPD; Bayesian forecasting

Outcome Measures

Primary Outcomes (1)

• Percentage of Time Within Range

  The percentage of time spent within the acceptable INR range (± 0.5 of target INR) as estimated using linear interpolation during the 28 days after initiation of warfarin.

  28 days after initiation of warfarin

Secondary Outcomes (6)

• Percentage of Time Measure

  day 90 after initiation of warfarin

• Percentage of Time Measure

  day 28, and 90 after initiation of warfarin

• Time to Stable Dose

  90 days after initiation of warfarin

• Number of participants who experience at least one of the following safety events:

  60 days of surgery.

• Percentage of prescribed doses within 0.625 mg of the NextDose proposed dose.

  90 days after initiation of warfarin

Study Arms (2)

Intervention Arm

EXPERIMENTAL

NextDose guided warfarin management taking into consideration covariates (sex, age, weight, height CYP2C9 (rs1057910) and VKORC1 (rs9923231), the dosing and INR history of each patient to predict an individualized dose in accordance with the theory-based warfarin model and target concentration intervention principles. Initial recommended warfarin dose, up to the first INR, will be the maintenance dose predicted from group values, subsequently the NextDose predicted maintenance dose will be recommended. The treating clinician will also be provided with the NextDose report to inform the choice of the prescribed dose.

Device: NextDose (nextdose.org)

Control Arm

NO INTERVENTION

Usual standard of care. Clinical experience of the treating physician taking into account the covariates, dosing and INR history of each patient, to determine the initial, and subsequent maintenance doses.

Interventions

NextDose (nextdose.org) DEVICE

NextDose guided warfarin management taking into consideration covariates (sex, age, weight, height CYP2C9 (rs1057910) and VKORC1 (rs9923231), the dosing and INR history of each patient to predict an individualized dose in accordance with the theory-based warfarin model and target concentration intervention principles. Initial recommended warfarin dose, up to the first INR, will be the maintenance dose predicted from group values, subsequently the NextDose predicted maintenance dose will be recommended. The treating clinician will also be provided with the NextDose report to inform the choice of the prescribed dose.

Intervention Arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Scheduled to undergo cardiac surgery with planned warfarin anticoagulation for at least three months.
• Age ≥ 18 and \< 80 years.
• Written informed consent has been obtained.

You may not qualify if:

• Allergy to warfarin tablet or excipients.
• Enrollment or planned enrollment in other research that would conflict with full participation in the study or confound the observation or interpretation of the study findings.
• Patients who in the opinion of the recruiting clinician are:
• unwilling or unable to comply with the protocol requirements and/or,
• considered unreliable concerning the requirements for follow-up during the study and/or, compliance with drug administration.
• Patient with life expectancy less than the expected duration of the trial due to concomitant disease.
• Contraindication to warfarin therapy. The following are examples but not an exhaustive list:
• Pregnancy.
• Cerebral infarction or cerebral haemorrhage (from patients' medical record) within the 3 months prior to heart valve replacement
• Severe heart failure (New York Heart Function Class IV)
• Severe renal failure (CLcr (Cockcroft-Gault) ≤20mL / min)
• Severe liver failure (Child-Pugh≥10)
• Abnormal liver function (elevated transaminase more than three times the upper limit of the local hospital clinical laboratory).

Sponsors & Collaborators

• The First Affiliated Hospital of Soochow University: lead
• National Natural Science Foundation of China: collaborator

Related Publications (7)

• Sheiner LB. Computer-aided long-term anticoagulation therapy. Comput Biomed Res. 1969 Dec;2(6):507-18. doi: 10.1016/0010-4809(69)90030-5. No abstract available.

  PMID: 5367362 RESULT

• Boyle DA, Ludden TM, Carter BL, Becker AJ, Taylor JW. Evaluation of a Bayesian regression program for predicting warfarin response. Ther Drug Monit. 1989;11(3):276-84. doi: 10.1097/00007691-198905000-00010.

  PMID: 2728086 RESULT

• Xue L, Holford N, Ding XL, Shen ZY, Huang CR, Zhang H, Zhang JJ, Guo ZN, Xie C, Zhou L, Chen ZY, Liu LS, Miao LY. Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients. Br J Clin Pharmacol. 2017 Apr;83(4):823-835. doi: 10.1111/bcp.13157. Epub 2016 Nov 25.

  PMID: 27763679 RESULT

• Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA. 2002 Apr 3;287(13):1690-8. doi: 10.1001/jama.287.13.1690.

  PMID: 11926893 RESULT

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

  PMID: 15842354 RESULT

• Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 2011 Jan 18;57(3):253-69. doi: 10.1016/j.jacc.2010.12.005. Epub 2011 Jan 7.

  PMID: 21216553 RESULT

• Xue L, Ma G, Holford N, Qin Q, Ding Y, Hannam JA, Ding X, Fan H, Ji Z, Yang B, Shen H, Shen Z, Miao L. A Randomized Trial Comparing Standard of Care to Bayesian Warfarin Dose Individualization. Clin Pharmacol Ther. 2024 Jun;115(6):1316-1325. doi: 10.1002/cpt.3207. Epub 2024 Mar 4.

  PMID: 38439157 DERIVED

Related Links

• NextDose

MeSH Terms

Conditions

Embolism and Thrombosis

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Study Officials

• Li Y Miao, PhD

  The First Affiliated Hospital of Soochow University

  PRINCIPAL INVESTIGATOR

• Zhen Y Shen, PhD

  The First Affiliated Hospital of Soochow University

  PRINCIPAL INVESTIGATOR

• Nick Holford, MBChB

  University of Auckland, New Zealand

  STUDY DIRECTOR

• Ling Xue, MS

  The First Affiliated Hospital of Soochow University

  STUDY DIRECTOR

• Guangda Ma, MHSc

  University of Auckland, New Zealand

  STUDY DIRECTOR

• Ying L Ding, MS

  The First Affiliated Hospital of Soochow University

  STUDY DIRECTOR

• Qiong Qin, MS

  The First Affiliated Hospital of Soochow University

  STUDY DIRECTOR

• Jacqui Hannam, PhD

  University of Auckland, New Zealand

  STUDY DIRECTOR

Central Study Contacts

Ling Xue, MS

CONTACT

+8651267972699; xueling726@126.com

Qiong Qin, MS

CONTACT

+8651267973022; q-q2456@163.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: All patients who are screened for enrolment will be allocated an enrolment number. The recruiting clinician will record into a logbook the details of all patients screened for enrolment, including the reason for exclusion from trial entry. A randomization sequence using block randomization with random block sizes of 4, 6 and 8 (to maintain equal sample size in each arm) will be created by researchers using PASS. Assignments will be enclosed in sequentially numbered, opaque, sealed envelopes. Participants who provide written informed consent and are enrolled will be allocated to study arm by the study pharmacists. The pharmacist will be responsible for opening envelopes sequentially, writing the participant enrollment number on the envelope prior to opening, and recording the envelope number and study arm allocation in the CRF. On conclusion of the data collection phase, the (actual) study allocation status of the participants will be compared to the randomization sequence.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: vice-president

Model Details: Current warfarin dose individualization methods tend to be empirical, rather than based upon pharmacological and statistical principles. A theory-based model of warfarin pharmacokinetics and pharmacodynamics (PKPD) has been developed for dose individualization when used in conjunction with a Bayesian forecasting tool (NextDose). This study compares standard of care clinician judgement for warfarin management with the use of a web-based dosing tool (NextDose). Computer-assisted anticoagulant dosing has been shown to be helpful using empirical models. This study will evaluate a theory-based model which has shown superior performance over empirical models in predicting clinical doses of warfarin. The study is also guided by quality and service improvement principles.

Study Record Dates

• First Submitted: August 11, 2020
• First Posted: August 12, 2020
• Study Start: August 1, 2020
• Primary Completion: September 1, 2021
• Study Completion: December 1, 2021
• Last Updated: August 19, 2020

Record last verified: 2020-08