Jaeb Center For Health Research Inc

DRCR NETWORK

DIABETIC RETINOPATHY CLINICAL RESEARCH NETWORK

PEDIATRIC EYE DISEASE INVESTIGATOR GROUP NETWORK

PEDIATRIC EYE DISEASE INVESTIGATOR GROUP

COOPERATIVE MULTICENTER DIABETES RESEARCH NETWORK FOR HYPOGLYCEMIA PREVENTION

EFFECT OF CORNEAL PRESERVATION TIME ON LONG-TERM GRAFT SUCCESS (CPTS)

DIABETES ENDOTHELIAL KERATOPLASTY STUDY: IMPACT OF DIABETES ON CORNEAL TRANSPLANT SUCCESS AND CELL LOSS - PROJECT SUMMARY THIS PROPOSAL ADDRESSES A SIGNIFICANT PUBLIC HEALTH QUESTION: DOES DIABETES, THE 3RD LEADING CAUSE OF DEATH IN THE UNITED STATES (US), IMPACT SUITABILITY OF DONOR CORNEAL TISSUE FOR TRANSPLANTATION? THIS QUESTION TAKES ON INCREASING URGENCY AS RECENT EYE BANK DATA SUGGESTS DONORS WITH DIABETES NOW COMPRISE ABOUT 30-35% OF THE CORNEA DONOR POOL, A 50-72% INCREASE IN JUST OVER A DECADE. THE IMPACT OF DIABETES ON KERATOPLASTY OUTCOMES REMAINS UNKNOWN, WITH CONFLICTING EVIDENCE FROM SECONDARY OR RETROSPECTIVE ANALYSES OF MULTIPLE CLINICAL STUDIES. PREVIOUS LARGE CLINICAL STUDIES DID NOT SHOW A DIABETIC DONOR EFFECT ON PENETRATING KERATOPLASTY (PKP) AND DESCEMET MEMBRANE ENDOTHELIAL KERATOPLASTY (DMEK) GRAFT SUCCESS, YET OUR RECENT CORNEA PRESERVATION TIME STUDY (CPTS) FOUND THE DIABETIC DONOR ADVERSELY AFFECTED GRAFT OUTCOMES FOLLOWING DESCEMET STRIPPING AUTOMATED ENDOTHELIAL KERATOPLASTY (DSAEK). ALTHOUGH CURRENT STANDARD OF CARE IS TO USE DIABETIC DONOR CORNEAS FOR ALL TYPES OF KERATOPLASTIES, SOME EYE BANKS AND SURGEONS ARE INCREASINGLY AVOIDING THEM FOR DMEK. AS BOTH THE DIABETIC DONOR POPULATION AND DMEK DEMAND INCREASES, A DEFINITIVE SUPERIORITY STUDY EVALUATING EFFECT OF DONOR DIABETES STATUS ON GRAFT OUTCOMES WILL ALLAY AND/OR DEFINE THESE CONCERNS. THE DIABETES ENDOTHELIAL KERATOPLASTY STUDY (DEKS) WILL ADDRESS THESE IMPORTANT QUESTIONS THROUGH A PROSPECTIVE MASKED CLINICAL TRIAL ENROLLING 1420 PARTICIPANT-EYES AT 30 CLINICAL SITES AND 15 EYE BANKS ACROSS THE US. THE DEKS WILL DETERMINE IF THE 3-YEAR GRAFT SUCCESS RATE FOLLOWING DMEK PERFORMED WITH CORNEAS FROM DONORS WITHOUT DIABETES IS SUPERIOR TO THE GRAFT SUCCESS RATE WITH CORNEAS FROM DONORS WITH DIABETES. IT WILL ALSO DETERMINE IF THE 3-YEAR CENTRAL ENDOTHELIAL CELL LOSS (ECL) AFTER DMEK WITH CORNEAS FROM DONORS WITHOUT DIABETES IS LESS THAN THE CENTRAL ECL WHEN CORNEAS FROM DONORS WITH DIABETES ARE USED. LASTLY, THE DEKS WILL EXPLORE THE RELATIONSHIP OF DONOR DIABETES SEVERITY, AS MEASURED BY EYE BANK-DETERMINED DIABETES RISK CATEGORIZATION SCORES, POST- MORTEM HBA1C, AND SKIN ADVANCED GLYCATION ENDPRODUCTS AND OXIDATION MARKERS, WITH DMEK GRAFT OUTCOMES 3 YEARS POSTOPERATIVELY IN CORNEAS FROM DIABETIC DONORS. THE DEKS COULD HAVE A MAJOR IMPACT ON THE TARGETED USE OF CORNEAS FROM AN INCREASING NUMBER OF DONORS WITH DIABETES WITH A RANGE OF DISEASE SEVERITY IN A DONOR POOL THAT MUST CONTINUE TO EXPAND TO MEET THE CLINICAL DEMANDS OF AN AGING POPULATION AND DMEK GROWTH.

WEB-BASED METHODS RESOURCE CENTER FOR EYE DISEASE TRIALS

IN HOME CLOSED LOOP REDUCTION OF NOCTURNAL HYPOGLYCEMIA AND DAYTIME HYPERGLYCEMIA

CORNEA DONOR STUDY

A RANDOMIZED CROSS-OVER TRIAL EVALUATING AUTOMATED INSULIN DELIVERY TECHNOLOGIES ON GLYCEMIC OUTCOMES AND QUALITY OF LIFE IN OLDER ADULTS WITH TYPE 1 DIABETES

CARE PARTNER-ASSISTED IMPLEMENTATION OF PATCH HYBRID CLOSED LOOP INSULIN DELIVERY FOR OLDER ADULTS WITH T1D (COPILOT) - RESPONSE: DIABETES TECHNOLOGY, INCLUDING CONTINUOUS GLUCOSE MONITORING (CGM), INSULIN PUMPS, AND HYBRID CLOSED LOOP (HCL), IS THE GOLD STANDARD FOR IMPROVING OUTCOMES FOR PATIENTS WITH T1D. RECENTLY, THE CONSORTIUM APPLYING TO THIS NOFO COMPLETED A RANDOMIZED, CROSSOVER, AUTOMATED INSULIN DELIVERY IN ELDERLY (AIDE) TRIAL, WHICH DEMONSTRATED THAT OLDER ADULTS WITH T1D CAN SAFELY USE HCL AND IMPROVE HBA1C WITH LESS HYPOGLYCEMIA. DESPITE THESE PROMISING RESULTS, A SIGNIFICANT PROPORTION OF OLDER ADULTS WITH T1D ARE NOT CONSIDERED FOR HCL THERAPY BECAUSE OF AN INABILITY TO INDEPENDENTLY MANAGE THEIR DIABETES DUE TO COGNITIVE IMPAIRMENT. “HOW CAN TECHNOLOGY BE HARNESSED FOR OLDER PEOPLE WITH SPECIAL NEEDS WITH COGNITIVE OR FUNCTIONAL DEFICITS” HAS BEEN RECOGNIZED AS A CRUCIAL KNOWLEDGE GAP IN A KEY CONSENSUS PAPER (PMID: 32946822). YET, THERE CURRENTLY EXIST NO DATA TO SUPPORT HCL USE IN THIS COMPLEX AND IMPORTANT POPULATION. IT HAS BEEN SAID THAT THE CONTRIBUTION OF CLOSED-LOOP TECHNOLOGY TO DIABETES MANAGEMENT WILL DEPEND LESS ON TECHNOLOGICAL FACTORS THAN ON 'THE REAL-LIFE INTERACTIONS BETWEEN PEOPLE AND TECHNOLOGY' INCLUDING CLINICIANS, FAMILY MEMBERS, AS WELL AS PEOPLE WITH DIABETES THEMSELVES.” WE PROPOSE RESEARCH TO ASSESS THE FEASIBILITY AND ACCEPTABILITY OF IMPLEMENTING A PATCH HCL SYSTEM IN OLDER ADULTS WITH COGNITIVE IMPAIRMENT WHO REQUIRE ADDITIONAL SUPPORT FROM A CARE PARTNER. BEFORE THE INTERVENTION PHASE BEGINS, WE WILL CONDUCT NECESSARY FORMATIVE RESEARCH TO ANTICIPATE BARRIERS TO SUCCESSFUL HCL ADOPTION AND SUSTAINED USE VIA A SERIES OF FOCUS GROUPS. RESULTS WILL INFORM TAILORED TRAINING MATERIALS AND PROTOCOLS. IN THE INTERVENTION PHASE, WE WILL ENROLL 54 COGNITIVELY AND FUNCTIONALLY IMPAIRED (I.E., CANNOT MANAGE T1D INDEPENDENTLY) OLDER ADULTS WITH T1D ALONGSIDE THEIR 54 CARE PARTNERS, OVER 3 MONTHS OF FOLLOW-UP. PATIENT PARTICIPANTS AND CARE PARTNERS WILL PROCEED TO THE CGM RUN-IN PHASE, FOLLOWED BY TAILORED TRAINING ON STUDY PATCH PUMP INTEGRATED WITH CGM BY CLINIC STUDY STAFF. GLYCEMIC MANAGEMENT BASED ON HBA1C AND CGM METRICS WILL BE STUDIED AT PRE-SPECIFIED TIME POINTS, ALONGSIDE PATIENT-REPORTED, AND CARE PARTNER-REPORTED, PSYCHOSOCIAL OUTCOMES, INCLUDING BURDEN. AN IMPORTANT FEASIBILITY OUTCOME IS THE ABILITY TO IMPLEMENT/EVALUATE TREATMENT STRATEGIES ACROSS MULTIPLE CLINICS; THREE SITES WILL BE USED IN COPILOT. WE WILL CONDUCT A MIXED-METHODS INTERVENTION EVALUATION TO COMPLEMENT THE OUTCOMES BY CHARACTERIZING THE KEY CONTEXTUAL FACTORS AND ADDITIONAL RESOURCES NEEDED TO SCALE AN EFFICACIOUS INTERVENTION IN THIS VULNERABLE COHORT. FINDINGS FROM COPILOT WILL INFORM, FOR THE FIRST TIME, EFFECTS OF AND STRATEGIES REQUIRED TO IMPLEMENT HCL IN OLDER ADULTS WITH T1D WHO ARE NOT INDEPENDENT IN THEIR SELF-CARE DUE TO MODERATE-SEVERE COGNITIVE IMPAIRMENT.

DATA COORDINATING CENTER FOR ARTIFICIAL PANCREAS STUDIES

SAFETY AND FEASIBILITY OF CULTIVATED AUTOLOGOUS LIMBAL EPITHELIAL CELL (CALEC) TRANSPLANTATION IN THE TREATMENT OF LIMBAL STEM CELL DEFICIENCY

GYRATE ATROPHY OCULAR AND SYSTEMIC STUDY (GYROS) - 1 PROJECT SUMMARY/ABSTRACT FOR GYROS 2 GYRATE ATROPHY IS A RARE INHERITED CHORIORETINAL DEGENERATION THAT IS ASSOCIATED WITH 3 HYPERORNITHINEMIA CAUSED BY AUTOSOMAL RECESSIVE MUTATIONS IN THE ORNITHINE AMINOTRANSFERASE 4 (OAT) GENE AND LEADS TO SEVERE LOSS OF VISION. THE CURRENT STANDARD OF CARE TREATMENT IS A 5 HIGHLY BURDENSOME ARGININE-RESTRICTED DIET (ARD) FRAUGHT WITH MANAGEMENT COMPLICATIONS. THE 6 PRINCIPAL INVESTIGATORS ARE CURRENTLY DEVELOPING A GENE AUGMENTATION THERAPY, A POTENTIAL 7 TREATMENT STRATEGY THAT MAY PRESERVE OR IMPROVE VISION WHILE AVOIDING OR REDUCING THE 8 NEED FOR ARD. TO FACILITATE A FUTURE INTERVENTIONAL CLINICAL TRIAL, THERE IS A NEED TO CHARACTERIZE 9 THE NATURAL HISTORY OF OAT-RELATED OCULAR AND SYSTEMIC DISEASE PROGRESSION. THE STUDY AIMS ARE: 10 1. NATURAL HISTORY – CHARACTERIZE THE NATURAL HISTORY OF ORNITHINE LEVELS AND RETINAL 11 DEGENERATION (RD) ASSOCIATED WITH DISEASE-CAUSING OAT VARIANTS IN THE PRESENCE OF 12 STANDARD DIETARY TREATMENT REGIMENS OVER 4 YEARS, USING METABOLIC MEASURES OF FASTING 13 PLASMA AND BLOOD SPOT AMINO ACIDS PANELS, FUNCTIONAL AND STRUCTURAL MEASURES OF RD, 14 AND PATIENT-REPORTED OUTCOME MEASURES. 15 2. METABOLIC-STRUCTURE-FUNCTION RELATIONSHIPS – EXPLORE THE RELATIONSHIPS BETWEEN 16 STRUCTURAL AND FUNCTIONAL RD OUTCOME MEASURES AND PLASMA ORNITHINE LEVELS. 17 3. IDENTIFY RAPID PROGRESSORS – EXPLORE THE RELATIONSHIP OF POSSIBLE RISK FACTORS 18 (GENOTYPE, PHENOTYPE, ENVIRONMENTAL, STANDARD CARE DIETARY REGIMEN) WITH SEVERITY AND 19 PROGRESSION OF OUTCOME MEASURES. 20 THIS NATURAL HISTORY STUDY WILL INFORM THE FUTURE INTERVENTIONAL CLINICAL TRIAL DESIGN AS FOLLOWS: 21 DETERMINE WITHIN-PATIENT VARIABILITY OF ORNITHINE LEVELS 22 DEVELOP QUANTITATIVE MEASURES OF PROGRESSION OF THE AREA OF PRESERVED RETINA AND 23 ESTABLISH ITS REPRODUCIBILITY, SENSITIVITY TO CHANGE, AND RELATIONSHIP WITH OTHER MEASURES 24 ESTABLISH RATES OF PROGRESSION OF FUNCTIONAL RD, STRUCTURAL RD, AND PATIENT-REPORTED 25 OUTCOME MEASURES, AND DETERMINE WHICH MEASURES ARE MOST SENSITIVE TO CHANGE 26 DETERMINE PRIMARY TIME POINTS AND DURATION FOR A PLANNED FUTURE TREATMENT TRIAL 27 USE VARIABILITY AND INTER-EYE CORRELATION OF OUTCOMES FOR TRIAL SAMPLE SIZE CALCULATIONS 28 IDENTIFY CANDIDATES FOR THE FUTURE TRIAL, INCLUDING ELIGIBILITY CRITERIA BASED ON RISK FACTORS 29 AND CUT POINTS FOR SEVERITY OF DISEASE MOST LIKELY TO BENEFIT FROM TREATMENT 30 ESTABLISH STUDY PROCEDURES AND WORKFLOWS