STRESS Trial: Steroids to Reduce Systemic inflammation after Neonatal Heart Surgery

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Oswald Heath
5 years ago
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STRESS Trial: Steroids to Reduce Systemic inflammation after Neonatal Heart Surgery Leveraging Existing Resources to Improve Clinical Trials

1 STRESS Trial: Steroids to Reduce Systemic inflammation after Neonatal Heart Surgery Leveraging Existing Resources to Improve Clinical Trials U01 TR Duke University (Jennifer S. Li, Kevin D. Hill) Vanderbilt University (H. Scott Baldwin) Johns Hopkins University (Jeffrey Jacobs)

2 The Vanderbilt Institute for Clinical and Translational Research (VICTR) functions to help researchers and clinicians do their jobs better by providing tools and support to improve the quality of research, publications, grant writing, and training for future doctors and researchers. The Johns Hopkins Institute for Clinical and Translational Research (ICTR) addresses obstacles in translating basic science discoveries into research in humans, translating clinical discoveries into the community and communicating experience from clinical practice back to researchers. The Duke Clinical and Translational Science Institute (CTSI) works to make the research process faster and easier for investigators by breaking down the traditional barriers of administrative burden, logistics, and a complex regulatory environment that keep health innovations from reaching our communities.

3 Clinical trials are resource-intensive and costly; many patient populations are understudied. A trial within a registry is a transformative approach that can reduce costs and expand the reach of RCTs, particularly in patients with rare diseases. Use registry data to provide optimal trial design Provide quality control measures for data collection Leverage mature infrastructure to compile, analyze, and disseminate data at a lower cost

4 Neonates undergoing congenital heart surgery are a prime example of an understudied population. The STS-Congenital Heart Surgery Database Currently enrolls >98% of children undergoing surgery at more than 127 centers collecting demographic, peri-operative, anesthesia, hospital, and outcome variables (morbidity, mortality, LOS)

Congenital Heart Disease CHD is the most common birth defect, affecting 1 in 110 births STS data for neonates undergoing CPB operations Mortality: 9.1% Mortality or major complication: 30.

5 Congenital Heart Disease CHD is the most common birth defect, affecting 1 in 110 births STS data for neonates undergoing CPB operations Mortality: 9.1% Mortality or major complication: 30.7% Poor outcomes often related to an accentuated neonatal post-cpb inflammatory response Opinions vary on whether perioperative steroids might reduce this response and improve outcomes 52% use in STS neonatal surgeries ( )

6 Specific Aims AIM 1. Use Monte Carlo simulations based on registry data to design a high yield, low cost trial. AIM 2. Conduct a trial within a registry of methylprednisolone in neonates undergoing CPB. AIM 3. Demonstrate cost savings and efficiency of our approach in neonates with CHD.

7 STRESS Trial Network NCATS CTSA Trial Innovation Network Executive Steering Committee Data Safety Monitoring Board Data Coordinating Center: DCRI

8 Aim 1: Trial Simulations Existing registry data to optimize design and approach 11,408 neonatal CPB operations from 102 centers ( ) STS data 50,000 simulated trial datasets Parameters: Trial endpoint occurs in ~30% (based on composite outcomes) Binary, composite, co-variate adjusted outcomes (death, death or major complication, post-op LOS, global rank)

9 Simulations Feasible sample size: 1200 based on yearly volume of eligible subjects at sites Global rank endpoint -Covariate adjustment adds an additional ~2-6% 82% power for trial of 800 subjects using global rank, with PLOS and covariate adjustment

10 Steroid dosing PK, PD, biomarker analysis No difference in post-op Drug levels 65 subjects randomized to preop + intraop (n=35) versus intraop only (n=30) Methylprednisolone

11 Primary Endpoint: Global rank Outcome Assigned Rank Cumulative prevalence, N (%) Operative mortality /11408 (9.1%) Heart transplant (during hospitalization) /11408 (9.5%) Renal failure with permanent dialysis, neurologic deficit persists at DC, or respiratory failure requiring tracheostomy Post-operative mechanical circulatory support or unplanned cardiac reoperation (exclusive of reoperation for bleeding) Reoperation for bleeding, delayed sternal closure or post-op unplanned interventional cardiac catheterization Post-op cardiac arrest, multi-system organ failure, renal failure with temporary dialysis, or prolonged vent support (> 7 days) /11408 (11.0%) /11408 (19.2%) /11408 (27.0%) /11408 (35.7%) Prolonged post-op length of stay (> 90 days, binary endpoint) /11408 (36.2%) Post-op length of stay (assigned rank = length of stay in days) /11408 (100.0%)

12 Safety Endpoints Occurrence of any one or more of the following STS-CHSD-defined major post-operative infectious complications: Post-procedural infective endocarditis Pneumonia Sepsis Deep wound infection Mediastinitis Other post-operative complications Including post-op hyperglycemia, AKI, adrenal insufficiency requiring hydrocortisone administration Study drug-related SAEs

13 Trial Design Inclusion criteria Neonates < 30 days of age at time of surgery Undergoing planned heart surgery with CPB as part of standard clinical care Availability and willingness of the parent/legally authorized representative to provide written informed consent Exclusion criteria < 37 weeks adjusted gestational age at time of surgery Any oral or intravenous steroid treatment within two days of surgery Infection contraindicating steroid use Preoperative mechanical circulatory support or active resuscitation at the time of randomization

14 Timeline Timeline

16 Site Start Up Site Start-Up More than minimal risk/neonatal trial Low site budget (start up fees + $500/pt) Central IRB (Vanderbilt) Electronic consent Execute standard agreements Assistance from CTSA TIN

17 Central IRB Central IRB 3 Steps Prior to Study Specific Reliance and Approval SMART IRB agreement: A master, reciprocal reliance agreement IRB Reliance Exchange, IREX (formerly SMART IRB Exchange): Central portal for documentation and communication CIRB Letter of Indemnification Generally took about 1 month to sign agreements Two sites have not completed this step: Wisconsin, Cincinnati

18 Central IRB Central IRB Trial Specific Steps Local IRB Indicates Reliance on Central IRB for the Specific Study Study specific documents submitted to local IRB/HRPP for local considerations/context Local considerations/context finalized and site submits for Central IRB approval in the IREX system Review and approval of site by the Central IRB

19 Central IRB Central IRB Days from Site Outreach to Key Central IRB Steps Local IRB Indicates Reliance on Central IRB Site Submits to Local IRB/HRPP for Review of Local Context Local HRPP Context Final/Site Submits for Central IRB Approval Central IRB Approval Vanderbilt Duke Colorado MUSC Northwestern 140 No Data UTSW * Columbia 210 No Data Hopkins/All Childrens Johns Hopkins Wisconsin Cincinnati Indicates task in process * Local PI changed at site; new PI engaged two FWAs, requiring both to complete all agreements, cede review and complete local context CIRB Information packet sent to all sites on 7/28/2017

20 Standard Agreements Standard Agreements Days from FDP Standard Agreement sent to Full Execution Standard Agreement Execution Duke 62 Vanderbilt 80 Colorado 80 MUSC 102 Prior to CIRB approval Johns Hopkins 213 Finances primary concern Cincinnati 221 Prior to CIRB approval Hopkins/All Children s - Finances primary concern Northwestern - Held until CIRB approval Wisconsin - Holding for CIRB and financial concerns Columbia - Held until CIRB approval UTSW - Finances primary concern - Indicates task in progress FDP Standard Agreements were sent to all sites on 8/11/2017

21 Current status Current Status Active sites: 5 Enrolling sites: 3 Randomized subjects: 27

22 Plans Plans Focus on activating sites Additional sites Children s Hospital Los Angeles UPMC/Children s Hospital Pittsburgh University of Washington/Seattle Children s University of Missouri-Kansas City Additional site payments with carry-over

2018 OPTIONS FOR INDIVIDUAL MEASURES: REGISTRY ONLY. MEASURE TYPE: Process

Quality ID #358: Patient-Centered Surgical Risk Assessment and Communication National Quality Strategy Domain: Person and Caregiver-Centered Experience and Outcomes 2018 OPTIONS FOR INDIVIDUAL MEASURES: