Strategies to Promote ResiliencY (SPRY): a randomised embedded multifactorial adaptative platform (REMAP) clinical trial protocol to study interventions to improve recovery after surgery in high-risk patients

Abstract

Introduction: As the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features.

Methods and analysis: Within a multihospital, single healthcare system, the Core Protocol for Strategies to Promote ResiliencY (SPRY) will be embedded within both the electronic health record (EHR) and the healthcare culture generating a continuously self-learning healthcare system. Embedding reduces the administrative burden of a traditional trial while accessing and rapidly analysing routine patient care EHR data. SPRY-Metformin is a placebo-controlled trial and is the first SPRY domain evaluating the effectiveness of three metformin dosages across three preoperative durations within a heterogeneous set of major surgical procedures. The primary outcome is 90-day hospital-free days. Bayesian posterior probabilities guide interim decision-making with predefined rules to determine stopping for futility or superior dosing selection. Using response adaptative randomisation, a maximum of 2500 patients allows 77%-92% power, detecting >15% primary outcome improvement. Secondary outcomes include mortality, readmission and postoperative complications. A subset of patients will be selected for substudies evaluating the microbiome, cognition, postoperative delirium and strength.

Ethics and dissemination: The Core Protocol of SPRY REMAP and associated SPRY-Metformin Domain-Specific Appendix have been ethically approved by the Institutional Review Board and are publicly registered. Results will be publicly available to healthcare providers, patients and trial participants following achieving predetermined platform conclusions.

Trial registration number: NCT03861767.

Keywords: adult surgery; clinical trials; information management; surgery.

Figure 1

Concentric consort diagram: SPRY Core Protocol (A) and Domain-Specific Appendix SPRY-Metformin overlying the Core Protocol (B). (A) The Core Protocol creates a research platform or infrastructure within clinical care for all enrolled into any SPRY Domain-Specific Appendix. This infrastructure includes virtual screening, informed consent and randomisation at preoperative clinic, automated perioperative electronic health record (EHR) monitoring, and a primary outcome of 90-day hospital-free days. Patient privacy is maintained and protected by the embedded application functioning behind the institutional firewall. (B) The SPRY-Metformin Domain-Specific Appendix functions within the infrastructure of the SPRY Core Protocol. Prior to preoperative clinic, the SPRY-Application screens the scheduled preoperative clinic appointments and generates a list of potential patients for enrolling clinicians. In preoperative clinic recruitment, informed consent and randomisation are completed. Patients undergo baseline testing. Study drug exposure begins and continues through postoperative day 90 (green). The SPRY-Application (light blue) supports patient safety monitoring by generating EHR and email alerts, as needed. As possible, all trial aspects are embedded within the standard of care perioperative course. When 500 patients surpass postoperative day 90, a priori interim analysis is completed. Future enrolment is then guided by the predetermined response adaptive randomisation schemes and predetermined stopping rules. HIPAA, Health Insurance Portability and Accountability Act; POD, postoperative day; REMAP, randomised embedded multifactorial adaptive platform; SPRY, Strategies to Promote ResiliencY.

Figure 2

Virtual and in-person screening and randomisation. ^a<7 or >180 preoperative days. ^bCharlson Comorbidity Index (CCI) required within the 365 days prior to screening. Virtual recruitment is completed by Strategies to Promote ResiliencY (SPRY)-Application (light blue) reviewing a subset of SPRY and SPRY-Metformin enrolment criteria. The SPRY-Application then guides the clinical provider to complete the in-person screening and informed consent. Any discrepancies found between the clinical parameters within SPRY-Application and the patient’s reported health state are manually updated within the electronic health record (EHR) and patients are randomised. eGFR, estimated glomerular filtration rate.

Figure 3

SPRY-Metformin timeline. ^aIf patients are discharged on the day of the surgical intervention, laboratory sample 4 will be omitted. If hospital discharge occurs prior to postoperative day 3, laboratory sample 4 occur immediately prior to discharge. ^bLongitudinal testing at contact point 6 testing is dependent on participation in the motor subgroup (table 1). Patients are recruited, consented by providers, randomised, undergo baseline venous blood sampling and are provided study drug at preoperative clinic (contact point 1). In the 7–180 preoperative days, patients undergo baseline testing (table 1), and both patient safety and study drug compliance are monitored via phone interview (contact point 2). Three venous blood samples are coupled with clinical blood draws throughout the operative hospital admission (contact point 3). A final venous sample is collected in standard of care postoperative clinic (contact point 4). At postoperative days 30 and 90, patients are contacted to monitor both patient safety and study drug compliance, collect postoperative outcomes (box 2) and complete additional outcome testing (table 1).

Figure 4

Randomised, embedded, multifactorial, adaptative platform (REMAP) Strategies to Promote ResiliencY (SPRY) administrative organisation. The Trial Steering Committee receives trial updates from the Statistical Monitoring Committee as well as recommendations from the Data and Safety Monitoring Board to oversee all trial conduct.