Anthem

DATA COORDINATING CENTER FOR THE PEDIATRIC HEART NETWORK

BEST-CLI TRIAL-DCC

TYRO CHAMPION DAD

PEDIATRIC HEART NETWORK DATA COORDINATING CENTER - PROJECT SUMMARY/ABSTRACT THE PEDIATRIC HEART NETWORK (PHN) IS A COOPERATIVE NETWORK OF CORE AND AUXILIARY CLINICAL CENTERS, A DCC, AND NATIONAL HEART, LUNG AND BLOOD INSTITUTE (NHLBI) PROJECT SCIENTISTS. NEW ENGLAND RESEARCH INSTITUTES (NERI) IS APPLYING TO CONTINUE ITS 22-YEAR ROLE AS THE DATA COORDINATING CENTER (DCC) FOR THE PHN. THE OBJECTIVES OF THE PHN DCC ARE TO 1) COORDINATE AND MANAGE THE PHN INFRASTRUCTURE TO ENSURE PHN GOALS ARE MET; 2) COLLABORATE TO EXECUTE PHN STUDIES AND TRIALS; 3) DISSEMINATE PHN DATA AND RESULTS; AND 4) CREATE A PLATFORM FOR EARLY-STAGE INVESTIGATOR TRAINING AND DEVELOPMENT. AS THE DCC, NERI WILL PROVIDE ROBUST SCIENTIFIC OVERSIGHT AND PROVEN LOGISTICAL SUPPORT FOR THE NEXT CYCLE OF THE NETWORK. KEY RESPONSIBILITIES AND FUNCTIONS INCLUDE LEADERSHIP IN PROJECT MANAGEMENT OF THE NETWORK, OVERALL STUDY COORDINATION AND EFFICIENT MANAGEMENT OF DATA ACQUISITION; LEADERSHIP IN DEVELOPMENT AND DEPLOYMENT OF INNOVATIVE INFRASTRUCTURE AND TOOLS, ELECTRONIC INFORMATION AND DATA SYSTEMS; LOGISTICAL AND SUPPORT SERVICES; NOVEL STUDY DESIGN AND STATISTICAL METHODOLOGIES; AND MANAGEMENT AND DISTRIBUTION OF NETWORK FUNDS. OUR PROPOSED APPROACH PRESENTS A STRONG, EXPERIENCED TEAM, WHICH BUILDS UPON DECADES OF SUCCESSFUL CLOSE COLLABORATION WITH NHLBI AND ENSURES EFFICIENT SCIENTIFIC AND ADMINISTRATIVE SUPPORT TO THE PHN, USING 21ST CENTURY TECHNOLOGIES. A MULTIPLE PI LEADERSHIP PLAN IS PROPOSED TO CONTINUE THE LEADERSHIP ROLES SHARED BY MS. MILLER (NETWORK OPERATIONS) AND DR. TRACHTENBERG (STATISTICS), WITH CLEARLY DELINEATED ROLES AND RESPONSIBILITIES FOR LEADING AND DIRECTING THE DCC.

TYRO CHAMPION DADS

FAMILY CHAMPIONS PROJECT

STRONG FAMILIES DALLAS

COACHING AND COMPREHENSIVE HEALTH SUPPORTS (COACHES) PROGRAM

HEALTHY MARRIAGE DEMONSTRATION GRANT: PRIORITY AREA 2

UNDERACTIVE BLADDER: EPIDEMIOLOGIC ANALYSES, SCREENER DEVELOPMENT AND VALIDATION

THE PTSD PRACTIONER REGISTRY: AN INNOVATIVE TRACKING, DISSEMINATION, AND SUPPORT TOOL FOR PROVIDERS IN MILITARY AND NONMILITARY SETTINGS

STRONG START FOR MOTHERS AND NEWBORNS - CENTERING LOUISIANA PROJECT

2/2 CIRCULATORY SUPPORT IN PEDIATRIC HEART FAILURE PATIENTS USING THE JARVIK 2015 LVAD: A PIVOTAL TRIAL - PROJECT SUMMARY/ABSTRACT THIS COLLABORATIVE GRANT APPLICATION PROPOSES (A) TO CONDUCT A MULTICENTER SINGLE-ARM PIVOTAL CLINICAL TRIAL OF THE JARVIK 2015 LEFT VENTRICULAR ASSIST DEVICE (LVAD) AS A BRIDGE-TO-TRANSPLANT IN 22 HOSPITALIZED CHILDREN WITH SEVERE HEART FAILURE (HF) REFRACTORY TO MEDICAL THERAPY; AND (B) TO GENERATE THE SAFETY AND EFFECTIVENESS DATA NECESSARY TO SUPPORT REGULATORY REVIEW AND POTENTIAL FDA APPROVAL OF THE JARVIK 2015 LVAD UNDER THE HUMANITARIAN DEVICE EXEMPTION (HDE) PATHWAY. THE HDE PATHWAY IS FDA’S APPROVAL PROCESS FOR HIGH-RISK MEDICAL DEVICES INTENDED TO TREAT RARE AND/OR ORPHAN DISEASES. THE NEED FOR SAFE, RELIABLE, AND DISCHARGEABLE LVADS FOR SMALLER CHILDREN WITH HF IS WELL-ESTABLISHED. CURRENTLY, THE BERLIN HEART EXCOR PEDIATRIC VAD IS THE ONLY FDA-APPROVED DURABLE VAD FOR SMALLER CHILDREN. WHILE OUTCOMES HAVE IMPROVED, THE BERLIN HEART HAS IMPORTANT LIMITATIONS: (1) PATIENTS CANNOT BE DISCHARGED ON VAD SUPPORT; (2) THE PARACORPOREAL DESIGN, WITH LARGE-BORE CANNULAE TRAVERSING THE ABDOMINAL WALL RESULTS IN A HIGH INCIDENCE OF WOUND COMPLICATIONS; AND (3) THE HIGH PUMP THROMBOGENICITY (ESPECIALLY AROUND THE VALVES) REQUIRES INTRAVENOUS ANTICOAGULANTS AND INTERMITTENT PUMP EXCHANGES TO PREEMPT THE RISK OF STROKE. THERE IS AN ENORMOUS TECHNOLOGY GAP BETWEEN CONTEMPORARY ADULT VADS (CONTINUOUS FLOW [CF], MAGNETICALLY-LEVITATED, AND SAFELY DISCHARGEABLE) AND CONTEMPORARY PEDIATRIC VADS (PULSATILE, PNEUMATICALLY DRIVEN, NON-DISCHARGEABLE). IN RECENT YEARS, THE JARVIK 2015 LVAD, A FULLY IMPLANTABLE CF DEVICE HAS EMERGED AS AN ALTERNATIVE TO THE BERLIN HEART. DATA FROM THE FDA’S EARLY FEASIBILITY STUDY (EFS) SUGGEST THE JARVIK 2015 LVAD CAN SUPPORT SMALLER CHILDREN SUCCESSFULLY FOR UP TO A YEAR OR LONGER AS A BRIDGE TO TRANSPLANT. HOWEVER, SYSTEMATIC DATA IN A 22-SUBJECT INVESTIGATIONAL DEVICE EXEMPTION (IDE) PIVOTAL TRIAL IS REQUIRED FOR FDA REVIEW AND APPROVAL. THE SAFETY ENDPOINT IS FREEDOM FROM DEVICE-RELATED STROKE. THE EFFECTIVENESS ENDPOINT IS SURVIVAL TO TRANSPLANT OR 180 DAYS IN THE ABSENCE OF SEVERE STROKE. THE IDE RECEIVED CONDITIONAL FDA APPROVAL ON JUNE 4, 2021 (IDE# G160185). THE TRIAL WILL BE CONDUCTED AT 14 CENTERS IN THE US AND EUROPE WITH A CLINICAL COORDINATING CENTER AT STANFORD UNIVERSITY AND A DATA COORDINATING CENTER AT HEALTHCORE, INC. THE INVESTIGATOR GROUP HAS A STRONG HISTORY OF COLLABORATIVE RESEARCH AND MULTICENTER CLINICAL TRIALS, FACILITATING SMOOTH EXECUTION OF THE PROPOSED STUDY. IN ACCORDANCE WITH FDA’S REQUIREMENTS FOR APPROVAL OF HUMANITARIAN DEVICES, A PRE-SPECIFIED PERFORMANCE GOAL WILL DEMONSTRATE SAFETY AND EFFECTIVENESS (≥17 OF 22 SUBJECTS FREE OF STROKE, AND ≥17SUBJECTS SURVIVING TO TRANSPLANT OR 180 DAYS FREE OF SEVERE STROKE: WITH CENTRAL REVIEW OF CLINICAL EVENTS AND NEUROIMAGING STUDIES). WHILE SAFE, RELIABLE, AND DISCHARGEABLE LVADS ARE WIDELY AVAILABLE FOR ADULTS, PEDIATRIC VAD TECHNOLOGY LAGS BEHIND BY MULTIPLE GENERATIONS OF TECHNOLOGY. MOREOVER, CHILDREN WHO SAFELY SURVIVE THEIR VAD COURSE HAVE A SUBSTANTIALLY LONGER POTENTIAL LIFE EXPECTANCY MAKING EVALUATION OF NEWER PEDIATRIC VADS AN URGENT PRIORITY FOR THE HEART FAILURE COMMUNITY. THIS TRIAL HAS THE POTENTIAL TO TAKE A CRUCIAL STEP IN ACHIEVING THAT GOAL.

2/2 CLINICAL TRIAL OF A MEK INHIBITOR FOR RASOPATHY-ASSOCIATED SEVERE INFANTILE HYPERTROPHIC CARDIOMYOPATHY - PROJECT SUMMARY/ABSTRACT NOONAN SYNDROME AND THE RELATED GENETIC DISORDERS, THE RASOPATHIES, ARE ASSOCIATED WITH SEVERE INFANTILE HYPERTROPHIC CARDIOMYOPATHY (RAS-HCM), WHICH HAS A 35% ONE-YEAR SURVIVAL AND FOR WHICH CONVENTIONAL THERAPIES ARE INEFFECTIVE. PRECLINICAL AND RETROSPECTIVE CLINICAL STUDIES SUGGEST THAT THE MEK INHIBITOR TRAMETINIB MIGHT BE AN EFFECTIVE TREATMENT FOR THIS CONDITION. TRAMETINIB HAS FDA APPROVAL FOR PEDIATRIC BRAIN TUMORS AND HAS ADVERSE EFFECTS (AES), PRIMARILY DERMATOLOGIC, THAT ARE LARGELY MANAGEABLE. EQUIPOISE REMAINS DUE TO METHODOLOGICAL LIMITATIONS IN DATA ABOUT INFANTS RECEIVING STANDARD OF CARE (SOC) OR TREATED WITH TRAMETINIB. WE ARE PROPOSING A 12-MONTH PHASE 3, MULTI-SITE, OPEN-LABEL TRIAL, ENROLLING 25 AFFECTED INFANTS < 6 MONTHS OLD WITH CLASS III OR IV HF THROUGH PEDIATRIC HEART NETWORK (PHN) SITES IN THE US. OUTCOMES WILL BE COMPARED TO REAL-WORLD DATA FOR ~100 INFANTS WHO RECEIVED SOC. PARTICIPANTS WILL BE FOLLOWED OFF TREATMENT FOR ANOTHER 12 MONTHS, WITH RESUMPTION OF TRAMETINIB FOR THOSE IN WHOM HCM RELAPSES. WE WILL LEVERAGE THE PHN’S CLINICAL TRIALS INFRASTRUCTURE AND ITS DATA COORDINATING CENTER. FOR AIM 1, WE HYPOTHESIZE THAT INFANTS PRESENTING WITH ROSS CLASS III OR IV HF DUE TO HCM CAUSED BY MOLECULARLY DOCUMENTED GAIN-OF-FUNCTION GERMLINE CAUSAL VARIATION FOR A RASOPATHY WILL HAVE A LOWER RATE OF A COMPOSITE ENDPOINT OF DEATH, HEART TRANSPLANT, OR SEPTAL MYOMECTOMY AFTER ONE YEAR OF ORAL TRAMETINIB TREATMENT THAN COMPARABLE PATIENTS RECEIVING ONLY SOC BETWEEN 2015-2019. AS A SECONDARY AIM, WE HYPOTHESIZE THAT THE TREATED PARTICIPANTS WILL HAVE A LOWER RATE OF DEATH. FOR AIM 2, WE WILL COMPARE THE TRAMETINIB-TREATED VS. SOC GROUPS WITH RESPECT TO SEVERAL SECONDARY OUTCOMES: 1) ECHOCARDIOGRAPHIC PARAMETERS OF HCM AND LV OUTFLOW TRACT GRADIENTS AND 2) LEVELS OF HF AS ASSESSED WITH THE ROSS SCALE AND SERUM MARKER NT-PROBNP. FOR AIM 3, WE WILL ASSESS THE FREQUENCY AND NATURE OF RELAPSE IN THE YEAR AFTER CESSATION OF TRAMETINIB, AS WELL AS TO ASSESS THE RESPONSE TO REINSTITUTION OF TREATMENT IN THE EVENT OF RELAPSE. FOR AIM 4, WE WILL ASSESS THE RATES OF AES OF TRAMETINIB TREATMENT, EITHER DURING THE FIRST YEAR OR IF IT IS RESTARTED, FOCUSING ON THE RATES, NATURE AND SEVERITY OF DERMATOLOGIC ISSUES, ALREADY KNOWN TO BE COMMON, AS WELL AS THE CONSIDERABLY RARER EYE AND CARDIAC ADVERSE EFFECTS OF TRAMETINIB. WHETHER OR NOT TRAMETINIB IS FOUND TO BE SUPERIOR TO SOC FOR TREATMENT OF INFANTILE RAS-HCM, THE PROPOSED TRIAL WILL IMPACT CARE OF THIS DEVASTATING DISORDER. IF PROVEN EFFECTIVE, IT WILL CLEAR THE WAY FOR INSURANCE APPROVAL. THE TRIAL WILL ALSO PROVIDE NOVEL AND IMPORTANT INFORMATION ABOUT THE IMPACT OF TRAMETINIB ON OTHER RASOPATHY- RELATED COMPLICATIONS THAT IMPACT QUALITY OF LIFE. IF NEGATIVE, THIS TRIAL WILL CURTAIL THE GROWING TREND TO TREAT RAS- HCM WITH TRAMETINIB, REDUCING SUBSTANTIAL INDIVIDUAL AND SOCIETAL COSTS ASSOCIATED WITH ITS ADMINISTRATION.

MULTIFAMILY HOUSING SERVICE COORDINATORS

MULTIFAMILY HOUSING SERVICE COORDINATORS