Teva Pharmaceutical Industries Research Articles

THU054 A Post Hoc Analysis Of The Phase IV B2219 Study To Determine Predictive Factors For Hyperglycemia During Treatment With Pasireotide

Abstract Disclosure: S.L. Samson: Consulting Fee; Self; Novartis Pharmaceuticals, Chiasma. M. Bolanowski: Grant Recipient; Self; Amryt, Recordati, Pfizer, Inc., Novartis Pharmaceuticals, Ipsen, IBSA, Teva Pharmaceutical Industries Ltd., Berlin Chemie. Speaker; Self; Amryt, Recordati, Pfizer, Inc., Novartis Pharmaceuticals, Ipsen, IBSA, Teva Pharmaceutical Industries Ltd., Berlin Chemie. S. Zhang: None. Y. Yu: None. P. Witek: Grant Recipient; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. N. Kietsiriroje: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. U. Feldt-Rasmussen: Advisory Board Member; Self; Novartis Pharmaceuticals, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Ipsen, Recordati, Novo Nordisk. Speaker; Self; Ipsen, Recordati, Novo Nordisk. Introduction: Pasireotide efficacy and safety in persons with acromegaly or Cushing’s disease (CD) is confirmed in a comprehensive clinical trial program. Pasireotide-induced hyperglycemia events, expected based on the drug’s mechanism of action, are manageable with low rates of treatment discontinuation. To advance knowledge on pasireotide-induced hyperglycemia management, a prospective randomized Phase IV study (B2219, NCT02060383) was conducted. This secondary analysis assessed factors that might predict development of pasireotide-induced hyperglycemia. Methods: In B2219, participants (Pts) with acromegaly or CD who did not need therapy for hyperglycemia or were managed with metformin alone entered the non-randomized observational arm. Pts who developed hyperglycemia not managed with metformin alone were randomized to incretin-based therapy or insulin. This analysis evaluated Pts according to whether therapy for hyperglycemia during pasireotide treatment was needed. Logistic regression analyses evaluated quantitative and qualitative predictive factors associated with pasireotide-induced hyperglycemia. Results: Of 190 Pts with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication during pasireotide treatment; Pt characteristics were generally balanced across subgroups at study baseline (BL). Most Pts who did not develop hyperglycemia had a mean age of <40 years (acromegaly 62.5%, CD 86.7%), BL glycated hemoglobin (HbA1c) <6.5% (acromegaly 98.9%, CD 100.0%) and BL fasting plasma glucose (FPG) <100 mg/dL (acromegaly 76.1%, CD 100.0%). Age (odds ratio [OR] 1.0, 95% CI 1.0−1.1), BL HbA1c (OR 3.5, 95% CI 1.3−9.9) and prediabetes or diabetes conditions (OR 3.0, 95% CI 1.2−7.6) were identified as risk factors associated with pasireotide-induced hyperglycemia in Pts with acromegaly. BL FPG (OR 1.2, 95% CI 1.0−1.3) was associated with increased risk of pasireotide-induced hyperglycemia in Pts with CD. Overall, adverse events (AEs) of hyperglycemia and diabetes mellitus (investigator reported) occurred in 21.1% and 14.2% of Pts with acromegaly and 28.8% and 11.9% of Pts with CD, respectively. More Pts who had diabetes or prediabetes conditions at BL had hyperglycemia-related AEs than Pts with normal glucose levels. Hyperglycemia-related AEs were managed with antihyperglycemic medication (acromegaly 26.3%, CD 30.5%); few Pts temporarily interrupted treatment (acromegaly 3.7%, CD 10.2%). Conclusions: These data suggest that age, HbA1c, FPG and having prediabetes or diabetes conditions at BL are associated with increased risk of developing pasireotide-induced hyperglycemia. AEs were manageable with antihyperglycemic medication. Potential risk factors associated with pasireotide-induced hyperglycemia may be used to identify Pts who need vigilant monitoring to ensure optimal outcomes during pasireotide treatment. Presentation: Thursday, June 15, 2023

FRI682 Cost Effectiveness Of Four Treatment Approaches For US Women And Men At Very High Risk Of Osteoporotic Fractures

Abstract Disclosure: M. Hiligsmann: Grant Recipient; Self; Radius Health, Inc. S. Silverman: Consulting Fee; Self; Amgen Inc, Radius Health, Inc. Grant Recipient; Self; Amgen Inc, Radius Health, Inc. A.J. Singer: Consulting Fee; Self; Agnovos, Amgen Inc, Radius Health, Inc, UCB. Speaker; Self; Amgen Inc, Radius Health, Inc. L. Pearman: Employee; Self; Radius Health, Inc. Stock Owner; Self; Radius Health, Inc. Y. Wang: Employee; Self; Radius Health, Inc. Stock Owner; Self; Radius Health, Inc. J.N. Caminis: Employee; Self; Radius Health, Inc. Stock Owner; Self; Radius Health, Inc. J. Reginster: Advisory Board Member; Self; Pierre Fabre. Consulting Fee; Self; IBSA-Genevrier, Mylan, Teva Pharmaceutical Industries Ltd. Speaker; Self; IBSA-Genevrier, Mylan, CNIEL, Dairy Research Council, Teva Pharmaceutical Industries Ltd. Background: Cost-effectiveness analyses are becoming increasingly important for efficiency in healthcare resource allocation. This study aims to assess the cost-effectiveness of four common treatment approaches of US men and women at very high risk of fracture: bisphosphonate (alendronate [ALN]) monotherapy, sequential treatment with an anabolic first (either abaloparatide [ABL] or teriparatide [TPTD]) followed by a bisphosphonate, and no treatment, as many patients at very high fracture risk do not receive an osteoporosis medication. Methods: A microsimulation-based Markov model was used to assess the cost-effectiveness of four treatment approaches in US women and men aged 50 to 80 years who had a recent fracture and had densitometry-confirmed osteoporosis (bone mineral density T-score ≤−2.5): ALN monotherapy, sequential ABL/ALN, sequential unbranded TPTD/ALN, and no treatment. Analyses were conducted from the US healthcare decision-maker perspective using $2022 costs, and health outcomes were expressed in quality-adjusted life years (QALYs). Deterministic and probabilistic sensitivity analyses were performed to characterize uncertainty. Results: In both sexes and over the full age range, no treatment and sequential unbranded TPTD/ALN were dominated (ie, they had lower QALYs for more costs than a comparator treatment), and should be excluded. Sequential ABL/ALN was associated with more QALYs and more costs than ALN monotherapy. At the US threshold of $150,000 per QALY gained, sequential ABL/ALN was cost-effective compared to ALN monotherapy in men aged ≥50 years and in women aged ≥65 years. Sensitivity analyses suggested that sequential ABL/ALN was also cost-effective in women with a recent hip or vertebral fracture aged ≥55 years. Conslusion: In both US men (aged ≥50 years) and women (aged ≥65 years) at very high risk of fracture, sequential ABL/ALN is the most cost-effective intervention among the four treatment approaches. Sequential unbranded TPTD/ALN and no treatment were dominated, and are thus not efficient treatment approaches. Treating US men and women at very high fracture risk with sequential ABL/ALN leads to an efficient resource allocation. Presentation: Friday, June 16, 2023

THU032 Osilodrostat Is Effective And Well Tolerated In Patients Of Asian And Non-Asian Origin With Cushing's Disease: A Pooled Analysis From LINC 3 And LINC 4

Abstract Disclosure: P.J. Snyder: Consulting Fee; Self; Teva Pharmaceutical Industries Ltd. B.M. Biller: Consulting Fee; Self; HRA Pharmaceuticals, Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). M. Fleseriu: Consulting Fee; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge), HRA Pharmaceuticals. Grant Recipient; Self; Recordati, Sparrow, Xeris Pharmaceuticals (Strongbridge). R. Pivonello: Consulting Fee; Self; Novartis Pharmaceuticals, Recordati, Corcept Therapeutics, Pfizer, Inc., Bresmed Health Solutions, Damor Farmaceutici, S&R Farmaceutici, Organon Italia, Siunergos Pharma, Biohealth Italia. Research Investigator; Self; Novartis Pharmaceuticals, Recordati, Xeris Pharmaceuticals (Strongbridge), Corcept Therapeutics, Takeda, Neurocrine Biosciences, Camurus AB, Pfizer, Inc., Merck Serono, IBSA. E.J. Lee: None. R. Leelawattana: None. J.H. Kim: None. R. Walia: None. Y. Yu: None. Z. Liao: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. A. Shimatsu: Consulting Fee; Self; Recordati. Speaker; Self; Recordati. Introduction: Osilodrostat, a potent oral 11β-hydroxylase inhibitor, has demonstrated rapid and sustained normalization of cortisol in two Phase III studies (LINC 3, NCT02180217; LINC 4, NCT02697734) in patients (pts) with Cushing’s disease (CD). Relative osilodrostat bioavailability is estimated to be 20% higher in pts of Asian origin than other ethnicities, and body weight is not a major determinant of this difference. This analysis of the LINC 3 and LINC 4 studies evaluated the efficacy and safety of osilodrostat in pts of Asian and non-Asian origin with CD. Methods: Data were pooled from the LINC 3 and LINC 4 Phase III studies. LINC 3 comprised a 48-week (W) core phase, including an 8W randomized withdrawal for eligible pts. LINC 4 included a 12W, double-blind, placebo-controlled period and 36W of open-label osilodrostat. Both studies had an optional extension. Efficacy and safety outcomes were evaluated separately in pts of Asian and non-Asian origin. Periods where pts received placebo were excluded. Results: In total, 56/210 (27%) pts were of Asian origin, enrolled in China (n=16), South Korea (n=14), Japan (n=9), Thailand (n=9), India (n=7) and USA (n=1). Most non-Asian pts were Caucasian (n=138/154, 90%). Median (min−max) osilodrostat dose was 3.8 (1−25) and 7.3 mg/day (1−47) in pts of Asian and non-Asian origin, respectively. mUFC control was achieved at W48 and W72 in 64.3% and 68.1% of Asian pts and in 68.2% and 75.8% of non-Asian pts, respectively. Improvements from baseline in most cardiovascular and metabolic-related parameters and in physical manifestations of hypercortisolism were similar across both groups during osilodrostat treatment. Osilodrostat was well tolerated; the most common investigator-reported adverse events (AEs) in Asian pts were adrenal insufficiency (44.6%), nausea (33.9%) and decreased appetite (26.8%), and in non-Asian pts, nausea (45.5%), fatigue (40.9%) and headache (39.0%). The most common serious AE in Asian and non-Asian pts was adrenal insufficiency (5.4% and 5.2%, respectively). Hypocortisolism-related AEs occurred in 58.9% of Asian pts and 40.3% of non-Asian pts, most commonly reported by the investigator as adrenal insufficiency (44.6% and 22.1%). AEs related to pituitary tumor enlargement occurred in 21.4% of Asian and 9.1% of non-Asian pts. AEs related to arrhythmogenic potential and QT prolongation were infrequent in all pts. Conclusions: Osilodrostat demonstrated similar beneficial effects in Asian and non-Asian pts in terms of mUFC control and improvements in cardiovascular and metabolic-related parameters and physical manifestations of hypercortisolism. The mean dose to achieve beneficial effects was lower in pts of Asian than non-Asian origin. Osilodrostat was generally well tolerated in Asian and non-Asian pts; AEs related to hypocortisolism and pituitary enlargement were reported more frequently in Asian than non-Asian pts. Presentation: Thursday, June 15, 2023

THU066 An 8-year Interim Report Of The B2412 Study, An Open-label, Multicenter Pasireotide Rollover Study For Patients Who Continued To Receive Benefit From Pasireotide At Completion Of An Earlier Trial

Abstract Disclosure: M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Novo Nordisk, Ipsen, Crinetics Pharmaceuticals. M.D. Bronstein: None. E. Grineva: Advisory Board Member; Self; Ipsen, Merck, Pfizer, Inc. Speaker; Self; Recordati, Ipsen, Pfizer Berlin Chemie, Teva Pharmaceutical Industries Ltd., A. Menarini, Siemens Healthineers. N. Kapoor: None. C. De Block: Consulting Fee; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly & Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Indigo Diabetes, Novo Nordisk. Speaker; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly & Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals. J.M. Escalante Pulido: None. G. Rollin: Advisory Board Member; Self; Merck Serono. Speaker; Self; Novo Nordisk, Abbott Laboratories, AstraZeneca, Merck Serono. R. Baggenstoss: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. W. Gallardo: Speaker; Self; Pfizer, Inc., Merck, Ipsen, Novartis Pharmaceuticals. Introduction: A robust clinical development program of 14 trials demonstrated that the second-generation somatostatin receptor ligand, pasireotide, is an effective treatment for patients (pts) with rare endocrine disorders, including acromegaly and Cushing’s disease (CD). Pts with acromegaly or CD have significant morbidity, reduced quality of life and, if inadequately treated, a higher mortality risk than the general population. This 8-year interim analysis evaluated the long-term safety of pasireotide treatment in pts with acromegaly, CD or other endocrine disorders. Methods: This ongoing, open-label, multicenter study allows continued treatment for pts who completed a previous pasireotide parent trial (NCT01794793). Pts who continued to receive clinical benefit, as determined by the investigator in the parent study, entered the rollover study and remained on pasireotide. Depending on the route of administration in the parent study, pts received pasireotide long-acting release (LAR; n=303) or subcutaneous (sc; n=38) as monotherapy (n=36), or sc in combination with cabergoline (n=2). The primary objective was to evaluate long-term safety, determined by frequency of adverse events (AEs)/serious adverse events (SAEs). Results: Overall, 341 pts from 29 countries have entered the study from 14 parent studies; 228 pts had acromegaly, 64 CD and 49 other endocrine disorders, including melanoma, dumping syndrome and neuroendocrine tumors. Median (min−max) exposure to all pasireotide formulations from rollover baseline to data cut-off and across all indications was 45.3 months (0.9−100.8). Median (min−max) dose from rollover baseline was 45.4 mg/month (5.3−128.3) with pasireotide LAR and 1200 µg/day (300−1800) with pasireotide sc. In total, 89 (26.1%) pts discontinued treatment; the most common reason was consent withdrawal (n=21, 6.2%). Most common AEs during rollover (≥10% in all pts) were nasopharyngitis (acromegaly n=13, 5.7%; CD n=14, 21.9%; other diseases n=14, 28.6%), hyperglycemia (acromegaly n=29, 12.7%; CD n=2, 3.1%; other diseases n=7, 14.3%), back pain (acromegaly n=20, 8.8%; CD n=7, 10.9%; other diseases n=8, 16.3%) and headache (acromegaly n=21, 9.2%; CD n=6, 9.4%; other diseases n=7, 14.3%). SAEs were reported in 87 (25.5%) pts; the most common were cholelithiasis and COVID-19 (both n=9, 2.6%). Overall, 18 (5.3%) pts discontinued treatment because of AEs. Incidence of new hyperglycemia-related AEs during rollover was low. No new safety signals were identified. Conclusions: Hyperglycemia is an expected AE during pasireotide treatment, often occurring in the first 3 months of therapy. These data in pts with acromegaly, CD or other endocrine disorders support pasireotide as a well-tolerated long-term treatment and affirm that pts continue to receive long-term benefit, with a low discontinuation rate over 8 years. Presentation: Thursday, June 15, 2023

OR21-04 Long-term Efficacy And Safety Of Once-weekly Somatrogon In Pediatric Subjects With Growth Hormone Deficiency: Results From Up To 8 Years Of Somatrogon Treatment

Abstract Disclosure: Z. Zadik: None. N. Zelinska: Consulting Fee; Self; Novo Nordisk, Berlin-Chemie, Medtronic, Sanofi-Aventis. Research Investigator; Self; MacroGenics, Novo Nordisk, Pfizer, Inc., Merck, OPKO Health, Ferring Pharmaceuticals, Teva Pharmaceutical Industries Ltd., Parexel, Genexine. Speaker; Self; Medtronic, Berlin-Chemie, ACINO, Novo Nordisk, Pfizer, Inc., Sanofi-Aventis, Johnson &Johnson, Wörwag Pharma. V. Iotova: Grant Recipient; Self; Pfizer, Inc. Speaker; Self; Novo Nordisk, Pfizer, Inc., Swixx, Sandoz, Berlin-Chemie. Y. Skorodok: None. O.A. Malievskiy: None. N. Mauras: Consulting Fee; Self; Agios. Grant Recipient; Self; Novo Nordisk, Abbvie. Research Investigator; Self; OPKO Health, Abbvie, Beta Bionics. S.R. Valluri: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. A. Pastrak: Employee; Self; OPKO Health. Stock Owner; Self; OPKO Health. R.G. Rosenfeld: Advisory Board Member; Self; Lumos, DNARx, BioMarin. Consulting Fee; Self; OPKO Health. C.T. Taylor: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M. Nijher: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. C. Roland: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. R. Wang: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. M.P. Wajnrajch: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. J.F. Cara: Employee; Self; Pfizer, Inc. Stock Owner; Self; Pfizer, Inc. Introduction: Somatrogon, a long-acting recombinant human growth hormone, is approved in multiple countries as a once-weekly treatment for pediatric growth hormone deficiency (pGHD). This abstract describes results from up to 8 y of study (main study + open label extension [OLE]) evaluating the efficacy and safety of somatrogon in pGHD. Methods: This randomized, open-label, dose-finding Phase 2 study comprised 5 treatment periods. Subjects were randomized 1:1:1:1 to once-weekly somatrogon (titrated up to 0.25, 0.48, or 0.66 mg/kg/wk) or once-daily Genotropin (0.24 mg/kg/wk) for 12 mo of the main study (periods I and II), after which they were eligible to enroll in the OLE (periods III-V). In period III, somatrogon recipients continued at their previous dose; Genotropin recipients were re-randomized to 1 of the 3 somatrogon doses. In period IV (OLE Year (Y)2–4), all subjects switched to somatrogon 0.66mg/kg/wk; in period V (OLE Y5 onward), all subjects switched from single-use somatrogon vials to prefilled pen devices (somatrogon 0.66 mg/kg/wk). Results: Of 53 subjects who completed the main study, 48 entered the OLE. At OLE entry, 66.7% were male, all but 1 were pubertal Tanner stage 1, and mean (SD) age was 7.7 (2.1) y. At OLE Y6 end, there were 30 subjects with a mean±SD height velocity (HV) of 6.47±2.07 cm/y and a mean±SD height SD score (HT SDS) of 0.43±0.94. At OLE Y7 end, 26 subjects had a mean±SD HV of 5.31±1.68 cm/y and a mean HT SDS of 0.44±0.96. Four subjects achieved final height (defined as HV <1 cm/y). Their HVs in the last 6-mo interval and last assessed heights were: subject 1: 0.54 cm/y, 174.5 cm; subject 2: 0.7 cm/y, 173.2 cm; subject 3: 0.56 cm/y, 179.5 cm; and subject 4: 0.19 cm/y, 168.7 cm. Somatrogon efficacy was not affected by positive test results for antidrug antibodies (ADA). HV and cumulative ΔHT SDS (cΔHT SDS) were similar between subjects who tested ADA+ vs ADA-: at OLE Y6 end, 15 who tested ADA+ had HV 6.47±1.69 cm/y and cΔHT SDS 3.09±1.04; and 15 who tested ADA- had HV 6.48±2.46 cm/y and cΔHT SDS 3.62±1.40. At OLE Y7 end, 14 subjects who tested ADA+ had HV 5.22±1.52 cm/y and cΔHT SDS 3.06±0.98; 12 who tested ADA- had HV 5.42±1.91 cm/y and cΔHT SDS 3.75±1.39. In OLE Y7, TEAEs were reported in 35.5% subjects, which was lower than the main study (69.0%) and OLE Y1–6 (range: 41.9–57.5%). No serious TEAEs or TEAEs leading to study drug withdrawal occurred in OLE Y7. Study drug–related TEAEs occurred in 2 subjects: keeled chest acquired and scoliosis in 1 and arthralgia in 1. No deaths were reported throughout the OLE. Conclusion: Following up to 8 y of somatrogon treatment, including 7 y of the OLE, subjects demonstrated continued growth, 4 achieved final height, and somatrogon maintained a favorable safety profile. Testing ADA+ did not appear to affect subject growth. Clinicaltrials.gov: NCT01592500. Acknowledgements: The authors wish to thank all the investigators involved in this study. Presentation: Saturday, June 17, 2023

156-LB: Nursing Burden Administering/Monitoring Complex Insulin Regimens vs. Basal Insulin/GLP-1 RA Fixed-Ratio Combinations (FRCs) for People with Type 2 Diabetes (PWT2D) in Long-Term Care (LTC)

Aim: Management of older PWT2D in LTC is challenging due to comorbidity, functional dependence, and hypoglycemia risk, and is further complicated by nurse shortages. This cross-sectional survey emailed to LTC nurses assessed perceived nursing burden associated with complex insulin regimens (basal-bolus [BB], sliding scale insulin [SSI]) vs FRCs. Methods: The survey comprised 3 hypothetical cases of PWT2D receiving BB, SSI, or FRC. Perceived burden was assessed using the unweighted NASA-Task Load Index (TLX). Responses for the 6 TLX subscales (mental, physical, and temporal demand; effort, frustration, performance) and perceived frequency of fingerstick use were summarized descriptively. Results: 10,982 nurses received the survey. Of the 250 who qualified (administered BB/SSI/FRC in past 90 days), 87% were female, 51% were ≥45 y, 49% had ≥11 y experience in LTC. TLX scores (max 20 higher = worse) were lower for FRCs vs BB or SSI (Table). Nurses perceived FRCs to require fewer fingersticks vs BB or SSI (Table). Conclusions: FRCs were perceived to reduce nursing burden and fingerstick use compared with complex insulin regimens. These findings, coupled with the lower hypoglycemia risk for FRCs vs complex insulin regimens reported in clinical trials suggest that use of FRCs in LTC has potential to reduce nursing workload. Disclosure H. E. Davidson: Research Support; Sanofi-Aventis U. S. A. Nelson: Research Support; Sanofi-Aventis U. S. L. F. Han: Research Support; Sanofi-Aventis U. S. M. Lamantia: Research Support; Sanofi-Aventis U. S. K. Desai: Employee; Sanofi. X. Li: Employee; Sanofi-Aventis U. S. T. A. Dex: Employee; Sanofi-Aventis U. S., Stock/Shareholder; Pfizer Inc., Viatris Inc., Teva Pharmaceutical Industries Ltd. J. F. Vance: None. K. Overbeck: None. Funding Sanofi

662-P: Diabetes Self-Management in Breast Cancer Survivors—Racial and Ethnic Disparities

Type 2 diabetes (T2DM) is associated with 40% increased breast cancer (BC) mortality. Black and Latina BC survivors have worse BC mortality outcomes and are more likely to have T2DM. We aimed to assess the association of race/ethnicity with adherence to T2DM self-management behaviors (SMBs), medication beliefs, and control in BC survivors. We recruited Stage 0-III BC survivors ≥ 55 years who had preexisting T2DM taking ≥ 1 oral DM medications. Adherence to T2DM SMBs and medication beliefs were assessed with validated questionnaires. Hemoglobin A1c (A1c) was measured at recruitment to assess T2DM control. We compared variables by race/ethnicity using the Fisher's exact (categorical) and Kruskal Wallis (continuous) tests. Multivariable linear regression evaluated the relationship between race/ethnicity and T2DM variables and adjusted for age, education and BC stage. Of 194 participants, median age was 67 years (interquartile range [IQR] 60-72), A1c was 7.4% (IQR 6.4-7.9); 27% self-identified as Black, 41% as non-Hispanic white (NHW), 18% as Latina, and 14% as other/unknown race. NHWs (70 years, IQR 56-83) were older than Black (63 years, IQR 55-87), Latina (64 years, IQR 56-83), and other/unknown race (64 years, IQR 55-77) participants (p=0.01). Black (76%), Latina (49%), and other/unknown race (83%) participants were less likely to have some college education than NHWs (88%, p<0.01). BC stage did not significantly differ by race/ethnicity. In multivariate analyses, Latina participants were more likely to believe T2DM medications disrupted their lives and were not important for their health. However, race/ethnicity was not associated with adherence to T2DM SMBs nor A1c in multivariate analyses. In summary, race/ethnicity was not correlated with T2DM SMBs or control in BC survivors, but Latinas differed regarding some medication beliefs. Future studies should explore other T2DM-related factors, potentially related to medication beliefs, to improve outcomes for Black and Latina BC survivors. Disclosure A. Leiter: None. E. Doron: Other Relationship; Teva Pharmaceutical Industries Ltd. M.S. Goel: None. J.J. Lin: None.

Timing and Predictors of T2-Lesion Resolution in MOGAD (P13-5.028)

Timing and Predictors of T2-Lesion Resolution in MOGAD (P13-5.028)

Time-Varying Functional Connectivity of the Hippocampus Is Associated With Cognitive Performance in Multiple Sclerosis Patients (P10-3.014)

<h3>Objective:</h3> To explore hippocampal static (sFC) and time-varying functional connectivity (TVFC) and assess their association with cognition in multiple sclerosis (MS). <h3>Background:</h3> The hippocampus has a key role in cognition. Hippocampal TVFC in MS needs to be further explored. <h3>Design/Methods:</h3> 3T structural and resting-state (RS) functional MRI scans were acquired from 108 MS patients and 63 healthy controls (HC). Subjects underwent neuropsychological evaluation. Sliding-window correlation analysis using the left (L) and right (R) hippocampus as seed regions assessed TVFC, quantified by the standard deviation of connectivity across windows. Mean connectivity indicated sFC. <h3>Results:</h3> MS patients had decreased sFC <i>vs</i> HC between L hippocampus and temporo-parietal regions, and increased sFC between L and R hippocampus and thalamus, precuneus and superior frontal regions. TVFC was decreased in MS patients between L hippocampus and temporo-parietal regions. Conversely, TVFC was increased in MS patients between L and R hippocampus and L pre- and postcentral gyri, cuneus, orbitofrontal cortex and inferior temporal gyrus (ITG). In MS patients, better global cognition correlated with higher TVFC between L hippocampus and L pre- and postcentral gyri (r=0.21–0.28; p=0.04–0.006). Better verbal memory correlated with higher TVFC between L hippocampus and L precentral gyrus (r=0.21, p=0.03), and better visuospatial memory correlated with higher TVFC between L and R hippocampus and L cuneus, pre- and postcentral gyri and ITG (r=0.19–0.23, p=0.02–0.04). Better information processing speed correlated with higher TVFC between L hippocampus and L postcentral gyrus (r=0.21, p=0.03) and with higher sFC between R hippocampus and L superior frontal cortex (SFC) (r=0.21, p=0.03). Finally, better attention scores correlated with higher TVFC between L hippocampus and L temporal cortex (r=0.24, p=0.01) and with higher sFC between R hippocampus and L SFC (r=0.20, p=0.05). <h3>Conclusions:</h3> Increased hippocampal connectivity contributed to explain better cognitive performances in MS, with a peculiar association between higher hippocampal TVFC and better memory scores. <b>Disclosure:</b> Monica Margoni has received research support from MAGNIMS. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Olga Marchesi has nothing to disclose. Carmen Vizzino has nothing to disclose. Damiano Mistri has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

Characterization of FTLD spectrum through advanced diffusion-weighted MRI metrics: a connectome approach (P11-6.003)

<h3>Objective:</h3> To investigate structural alterations in brain network of patients within the frontotemporal lobar degeneration (FTLD) spectrum using connectome analysis with advanced diffusion-weighted MRI metrics. <h3>Background:</h3> MRI connectomics is a promising tool to describe network-based degeneration in neurodegenerative diseases. Neurite orientation dispersion and density imaging (NODDI) has shown to provide novel insights on structural connectivity alterations. <h3>Design/Methods:</h3> Thirty-four behavioral-variant frontotemporal dementia (bvFTD), 11 semantic variant primary progressive aphasia (svPPA), 11 nonfluent (nfvPPA) patients and 48 healthy controls underwent multi-shell diffusion MRI. Fractional anisotropy (FA) maps were computed. Intra-cellular Volume Fraction (ICVF) maps were also estimated using NODDI, providing a direct quantification of neurite integrity. Graph analysis and connectomics assessed global and local structural topological network properties and regional structural connectivity. <h3>Results:</h3> Overall, widespread structural changes were observed in bvFTD patients relative to healthy controls and svPPA patients in terms of FA-derived network properties. nfvPPA patients also showed altered FA topological properties at global level compared to healthy controls. Sum of node weights (SN) in the sensorimotor lobe revealed that nfvPPA patients showed an altered connection strength compared to svPPA. Moreover, nfvPPA patients showed a significant decreased FA in the left hemispheric fronto-temporal-insular regions relative to controls. Considering ICVF, more severe alterations compared to FA maps allowed to find differences also between svPPA and nfvPPA patients. ICVF graph analysis measures also showed that svPPA had a lower degree centrality and SN in the temporal lobe compared to controls. <h3>Conclusions:</h3> These findings suggest that conventional diffusion-tensor measures might be sensitive enough to highlight vulnerable connections in the FTLD spectrum. However, ICVF demonstrated to be a more specific biomarker to differentiate FTLD syndromes. Specifically, the benefits emerged in the differentiation between svPPA patients and other groups. <b>Disclosure:</b> Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Silvia Basaia has nothing to disclose. Dr. Facente has nothing to disclose. Ms. Cividini has nothing to disclose. Dr. Spinelli has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Castelnovo has nothing to disclose. Giuseppe Magnani has nothing to disclose. Dr. Caso has nothing to disclose. Paola Caroppo has nothing to disclose. Sara Prioni has nothing to disclose. Miss Villa has nothing to disclose. Lucio Tremolizzo has nothing to disclose. Dr. Appollonio has nothing to disclose. Dr. Silani has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Stepwise functional brain architecture from disease epicenter correlates with atrophy in progressive supranuclear palsy (P11-6.001)

<h3>Objective:</h3> This study applied SFC to test the hypothesis that topological stepwise architecture propagating from the disease epicenter would shape patterns of grey matter (GM) atrophy in a cohort of patients with progressive supranuclear palsy (PSP). <h3>Background:</h3> MRI connectomics is an ideal tool to test the model of network-based spread of pathological protein aggregates in neurodegenerative disorders. Stepwise functional connectivity (SFC) is a graph-theory-based neuroimaging method, which detects whole-brain functional couplings of a selected region of interest, at increasing link-step topological distances. <h3>Design/Methods:</h3> Twenty-eight patients with PSP and 50 healthy controls underwent brain magnetic resonance imaging (MRI) on a 3T scanner, including 3D-T1 weighted and resting-state functional MRI sequences. GM was parcellated into 90 regions using the Automated Anatomical Labeling (AAL) atlas. Correlations between SFC architecture in controls and atrophy patterns in PSP patients were tested. The disease epicenter was identified as the peak of atrophy observed in an independent cohort of 13 cases with <i>post mortem</i> confirmation of PSP pathology, and used as seed region for SFC analysis. <h3>Results:</h3> The disease epicenter was identified in the left midbrain tegmental region. Compared with controls, PSP patients showed prevalent atrophy in the subcortical GM (mostly, in the thalami and caudate nuclei), but also in frontal, parietal and cerebellar cortical regions. For each region of the AAL atlas, a strong correlation was found between average link-step distance from the left midbrain in controls and mean normalized GM volume in PSP patients (r=0.37, p&lt;0.001). <h3>Conclusions:</h3> Our findings demonstrate that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP, supporting the view of a network-based pathology propagation in this disease and holding the promise to be used to model disease progression in future longitudinal studies. <b>Disclosure:</b> Dr. Spinelli has nothing to disclose. Miss Ghirelli has nothing to disclose. Miss Bottale has nothing to disclose. Silvia Basaia has nothing to disclose. Ms. Cividini has nothing to disclose. Dr. Volonte has nothing to disclose. Mr. Galantucci has nothing to disclose. Giuseppe Magnani has nothing to disclose. Dr. Caso has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Castelnovo has nothing to disclose. Paola Caroppo has nothing to disclose. Sara Prioni has nothing to disclose. Miss Villa has nothing to disclose. Dr. Josephs has nothing to disclose. Dr. Whitwell has nothing to disclose. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Identification of Neuropsychological Phenotypes in Pediatric Multiple Sclerosis Using Unsupervised Machine Learning (P12-9.001)

<h3>Objective:</h3> To identify cognitive phenotypes in pediatric multiple sclerosis (MS) using an unsupervised machine learning approach. <h3>Background:</h3> Recent studies identified distinct cognitive phenotypes in adult MS patients using unsupervised machine learning approaches. <h3>Design/Methods:</h3> Fifty-three pediatric MS patients underwent clinical examination including Expanded Disability Status Scale (EDSS) to assess global disability. A comprehensive neuropsychological battery (Selective Reminding Test, Spatial Recall Test, Trail Making Test, Symbol Digit Modalities Test, Semantic verbal fluency test and Phonemic verbal fluency test) was administered to all patients. Raw scores of each test were converted to z-scores according to normative data. Cognitive tests z-scores were included in a k-means cluster analysis to identify cognitive phenotypes. Between-group comparisons of demographic, clinical and cognitive variables were computed using linear regression models or nonparametric tests as appropriate. Statistical significance was corrected for multiple comparisons (Bonferroni method). <h3>Results:</h3> In our sample, median age was 15.9 years (interquartile range [IQR] 13.6 – 16.8), 68% (36 patients) were girls and the mean disease duration was 1.8±1.7 years. Cluster analysis identified three cognitive phenotypes: preserved cognition (27 patients [51%]), mild verbal memory/semantic fluency involvement (19 patients [36%]) and severe multidomain involvement (7 patients [13%]). Across groups, there were no significant differences in age, sex and disease duration. Lower EDSS scores were found in patients with preserved cognition (median EDSS 1.0 [IQR 1.0 – 1.0]) than patients with mild verbal memory/semantic fluency involvement (median EDSS 1.5 [IQR 1.0 – 2.0]; p=0.01) and patients with severe multidomain involvement (median EDSS 2.0 [IQR 1.25 – 2.75]; p=0.004). <h3>Conclusions:</h3> Pediatric MS patients present with distinct cognitive phenotypes ranging from preserved cognition to severe multidomain involvement. Cognitive phenotypes are not associated with age, sex and disease duration. Patients with preserved cognition are characterized by low global disability. <b>Disclosure:</b> Damiano Mistri has nothing to disclose. Monica Margoni has received research support from MAGNIMS. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Alessandro Meani has nothing to disclose. Carmen Vizzino has nothing to disclose. Dr. Moiola has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

Efficacy and Safety Profile of Cladribine Tablets in an Italian Real-Life Cohort of Relapsing-Remitting Multiple Sclerosis Patients: A Monocentric Longitudinal Observational Study (P8-3.015)

<h3>Objective:</h3> To report real-world findings about efficacy and safety of cladribine (CLAD) in relapsing-remitting multiple sclerosis (RRMS), identifying predictors of response. <h3>Background:</h3> CLAD induces a transient lymphocyte depletion followed by immune reconstitution, with improved immune tolerance. Real-world data on CLAD performance and its predictors of response are limited. <h3>Design/Methods:</h3> Monocentric, observational, real-world study on pwMS who started CLAD from April 2018 to November 2021, with a minimum 6 month-follow-up. <h3>Results:</h3> Our population comprised 114 pwMS, 71.9% females, 50% naïves, mean age 33.0 years, median disease duration 3.0 years, median baseline EDSS 2.0, mean 1 and 2 year-baseline ARR 1.3 and 1.2. Median follow-up: 23.8 months. 4.4% and 30.7% patients presented relapses and MRI activity in the first 6 months. When considering data re-baselined towards month 6, 12 relapses were reported. 84% (CI 76–92) and 76% (CI 67–87) patients had no MRI activity at 12 and 24 months, respectively. At month 24, NEDA-3 status was reached by 69% of naïves, and 81% and 55% of switchers from low and high-efficacy treatments, respectively. Eleven patients switched to other treatments. Younger age (HR 0.94, CI: 0.89–0.99, <i>p=0.011</i>), baseline EDSS score ≥ 3.0 (HR 4.29, CI: 1.83–10.05, <i>p=0.0008</i>) and gadolinium-enhancing lesion count ≥ 4 (HR 2.24, CI: 0.95–5.26, <i>p=0.065</i>) were risk factors for loss of NEDA-3. 20.0% of pwMS referred side effects: skin rash, fever/infections, fatigue. Lymphopenia was more likely at months 3 and 15. No grade-4 lymphopenia cases were observed. <h3>Conclusions:</h3> CLAD is more effective when placed early in the treatment algorithm: naïves or switchers from lower efficacy drugs seem to benefit more. Baseline age, disability and gadolinium-enhancing lesions are risk factors for loss of NEDA-3. CLAD was overall well tolerated. Real-world data on larger populations with longer follow-up are needed to confirm our findings. <b>Disclosure:</b> Chiara Zanetta has nothing to disclose. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Alessandro Meani has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Laura Ferrè, 3233 has received intellectual property interests from a discovery or technology relating to health care. Dr. Moiola has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Functional Correlates of Intelligence Quotient and Cognitive Abilities Vary According to Maturation in Pediatric MS (P9-3.013)

<h3>Objective:</h3> To test maturation effects on neuropsychological profiles and resting state (RS) functional connectivity (FC) in cognitive and motor networks of pediatric patients with multiple sclerosis (MS). <h3>Background:</h3> Clinical and cognitive features of pediatric MS patients differ from adults. The effect of brain maturation on RS FC and its possible interaction with cognitive features has never been studied. <h3>Design/Methods:</h3> Seventy-six pediatric MS patients underwent a neuropsychological assessment of Wechsler-Intelligence-Scales for Intelligent Quotient (IQ), Semantic/Phonemic Verbal Fluency Test (SVFT/PVFT), Symbol Digit Modalities Test (SDMT), Coding Design (CD) and Block Design (BD) subtests, Trial Making Test (TMT-A/B). In 58 right-handed MS patients and 22 matched healthy controls (HC), RS FC within basal ganglia, executive, language, sensorimotor, and default-mode networks was estimated. Maturation effects were tested by splitting pediatric MS in those below the age of 16 years (B16) (n=46) and those above or equal 16 years (A16) (n=30). <h3>Results:</h3> Most patients (81.6%) achieved IQ scores within or above average values (median IQ=97.5). The highest rate of failure was observed in CD (21.1%), TMT-B (15.8%), TMT-A (10.5%), and SDMT (9.2%). Compared to HC, pediatric MS patients showed reduced RS FC in all networks, mainly involving the caudate nucleus and its connections with cingulate, prefrontal, and sensorimotor cortices. This effect was particularly relevant in younger patients (B16), where reduced basal ganglia, language and executive RS FC was associated with poorer cognitive performances (r range=0.37/0.48), while reduced cingulate RS FC was associated with a lower IQ (r=0.36). In older patients (A16), reduced language and executive RS FC was correlated with lower IQ and CD, BD and PVFT/SVFT scores (r range=0.42–0.67). However, A16 patients also presented increased executive, default-mode and language RS FC <i>vs</i> HC, which was detrimental on performance at the same tests (r range=−0.39/−0.62). <h3>Conclusions:</h3> Maturation significantly impacts on RS FC abnormalities and on their association with cognitive performances. <b>Disclosure:</b> Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Celgene. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Ms. Cacciaguerra has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIOMEDIA. Dr. Curatoli has nothing to disclose. Carmen Vizzino has nothing to disclose. Monica Margoni has received research support from MAGNIMS. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

The Insula Modulates the Effects of Aerobic Training on Cardiovascular Function and Ambulation in Multiple Sclerosis (P10-3.010)

<h3>Objective:</h3> To understand the effects of aerobic training (AT), focusing on the role of insula (differentiating in right and left) in establishing cardiovascular fitness (CF) and AT responses in people with multiple sclerosis (pwMS). <h3>Background:</h3> Impairment in the autonomic control of cardiovascular function is very common in pwMS. Insula is a key region related to this function with differences between left and right hemisphere. Insula lesions and atrophy are frequent in pwMS and appear to be related to cardiovascular alterations. AT targets the cardiopulmonary system and is proposed as a neuroprotective strategy in several neurological conditions. <h3>Design/Methods:</h3> Sixty-one pwMS were randomized in two groups (MS-AT and MS-C) to perform 24 training sessions of 30–40 minutes for 2–3 times per week. MS-AT performed moderate AT, while MS-C underwent non-specific motor training. All patients had a baseline and follow-up evaluation after the training period, including assessment of maximal peak of oxygen consumption (VO2max), heart rate reserve (HRR), 6-minute walk test (6MWT) and a MRI scan to quantify lesion volumes (LV), global and regional brain atrophy. Two age- and sex-matched healthy control (HC) groups were enrolled for baseline comparison of CF and brain volumetry data. <h3>Results:</h3> At baseline, MS patients showed impaired values of VO2max, HRR and 6MWT (p&lt;0.001) and a widespread pattern of atrophy compared to HC, including bilateral insula. In MS, higher left insula LV correlated to higher HRR (R=0.27, p&lt;0.05). After training, MS-AT experienced an improvement in 6MWT compared to MS-C and this enhancement was greater in patients without insular lesions. At follow-up, MS-C showed a reduction of left anterior insula volume compared to baseline (p&lt;0.001). <h3>Conclusions:</h3> In pwMS, AT improves CF and walking capacity. It showed a neuroprotective effect, especially for the left insula that has a stronger relationship with CF, compared to the contralateral region. <b>Disclosure:</b> Dr. Albergoni has nothing to disclose. Loredana Storelli has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Age - related vulnerability of the human brain connectome (P11-6.008)

<h3>Objective:</h3> To evaluate how aging affects functional connectivity of pivotal regions of the human brain connectome (i.e., hubs), which represent potential vulnerability ‘stations’ to aging, and whether such effects influence the functional and structural changes of the whole brain. <h3>Background:</h3> Multifactorial models integrating brain variables at multiple scales are warranted to investigate aging and its relationship with neurodegeneration. <h3>Design/Methods:</h3> We enrolled 128 cognitively unimpaired participants that were divided into two groups according to age: 50 young adults (≤ 35 years old) and 78 older adults (&gt; 35 years old). At study entry, both groups underwent brain MRI scan. We combined the information of the functional connectome vulnerability, studied through an innovative graph-analysis approach (stepwise functional connectivity), with brain cortical thinning in aging. <h3>Results:</h3> First, investigating the topological functional network organization in the optimal healthy condition (i.e., young adults), we observed that fronto-temporo-parietal hubs showed direct functional connectivity with themselves and among each other, while occipital hubs showed direct functional connectivity within occipital regions and sensorimotor areas. Then, modelling cortical thickness changes over lifespan, we observed that fronto-temporo-parietal hubs were among the brain regions that changed the most, whereas occipital hubs showed a quite spared cortical thickness across ages. Finally, cortical regions highly functionally linked to the fronto-temporo-parietal hubs in healthy adults were characterized by the greatest cortical thinning along the lifespan. <h3>Conclusions:</h3> Our findings reveal a significant role of hub connectome topology and geometry in shaping the accumulation of biological damage and distribution of atrophy with aging, supporting the hypothesis that hub functional connectivity rearrangements appear to govern the region-specific structural alterations of the brain regions. <b>Disclosure:</b> Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Ms. Cividini has nothing to disclose. Silvia Basaia has nothing to disclose. Dr. Spinelli has nothing to disclose. Dr. Castelnovo has nothing to disclose. Dr. Leocadi has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Functional Connectivity Modifications in Monoaminergic Circuits Occur in Fatigued MS Patients Treated With Fampridine and Amantadine (P10-3.008)

<h3>Objective:</h3> To investigate changes over time of fatigue severity and concomitant modifications of resting state (RS) functional connectivity (FC) in monoaminergic networks in 45 fatigued multiple sclerosis (MS) patients after different symptomatic treatments. <h3>Background:</h3> Fatigue is common and disabling in MS. Symptomatic treatments for fatigue rely on drugs reinforcing monoaminergic synaptic transmission, suggesting a role of monoaminergic network abnormalities in fatigue pathogenesis. <h3>Design/Methods:</h3> MS patients were randomly, blindly assigned to treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15) and underwent clinical, neuropsychological and 3T RS fMRI at baseline (T0) and after four weeks (W4) of treatment. Fifteen matched healthy controls (HC) were acquired twice. Dopamine-, noradrenaline- and serotonin-related RS FC was derived by independent component analysis (ICA), constrained to PET atlases for dopamine, noradrenaline and serotonin transporters, obtained in HCs’ brain. Changes in modified fatigue impact scale (MFIS) score and monoaminergic-related RS FC were assessed. <h3>Results:</h3> MS patients showed baseline abnormalities <i>vs</i> HC in all three networks, with decreased monoamine-related RS FC in temporal, occipital, insular and cerebellar regions, and increased RS FC in frontal, parietal and subcortical areas. At W4, MFIS scores decreased in all patients’ groups, with no time-by-treatment interaction. At W4, fampridine and amantadine patients showed increased dopamine- and noradrenaline-related RS FC in the insular cortex, as well as increased serotonin-related RS FC in the precuneus/posterior cingulate cortex. Amantadine patients also showed increased dopamine- and noradrenaline-related RS FC in the anterior cingulate cortex (ACC). Conversely, placebo patients mostly showed increased noradrenaline-related RS FC in the precuneus and middle cingulate cortex. Fampridine and placebo groups showed trends towards significant correlations between RS FC modifications and MFIS improvements (r=−0.49: −0.52, p=0.07–0.08). <h3>Conclusions:</h3> Fatigue improved in all groups. Concomitant monoaminergic-related RS FC modifications were found in insular, ACC and parietal regions for fampridine and amantadine MS patients, and in medial parietal regions for placebo patients. <b>Disclosure:</b> Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Dr. Lamanna has nothing to disclose. Bruno Colombo has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis, Biogen, Sanofi Genzyme, TEVA and Merck. Dr. Martinelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck . Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Influence of Cardiorespiratory Fitness and MRI Measures of Neuroinflammation on Hippocampal Volume in Multiple Sclerosis Patients (S27.007)

<h3>Objective:</h3> To investigate whether higher cardiorespiratory fitness (CRF) may limit the detrimental effects of neuroinflammation on hippocampal volume in the main multiple sclerosis (MS) clinical phenotypes. <h3>Background:</h3> The hippocampus is a clinically-relevant brain region that is characterized by neuroplasticity and neurogenesis also in adults. Neuroinflammation and CRF may specifically influence hippocampal integrity, thus modulating the processes promoting neurogenesis and neuroprotection that contribute to the preservation of functions. <h3>Design/Methods:</h3> Brain structural MRI scans and maximum oxygen consumption (VO₂max), a proxy of CRF, were acquired from 81 MS patients (27 relapsing-remitting [RR] and 54 progressive [P]), and 47 age- and sex-matched healthy controls (HC). White matter T2-hyperintense lesion volume (T2-LV) and choroid plexus volume (CPV) were quantified as neuroinflammatory measures. Associations of T2-LV, CPV and CRF with normalized brain (NBV), gray matter (NGMV), thalamic (NTV) and hippocampal volumes were assessed using linear regression analysis. Stepwise hierarchical regression models were used to evaluate the independent contribution of demographic, clinical, T2-LV, CPV and VO₂max in explaining the aforementioned volumes. <h3>Results:</h3> In MS, higher T2-LV was significantly associated with lower global and regional brain volumes (standardized-β from −0.706 to −0.356, p≤0.009), except for NGMV (p=0.105). Higher CPV was significantly associated only with lower NBV and NTV in both RRMS and PMS patients (standardized-β from −0.545 to −0.290, p≤0.045). Higher VO₂max was significantly associated only with higher normalized hippocampal volume only in RRMS patients (standardized-β=0.448, p=0.013). Using stepwise hierarchical regression models, T2-LV in both RRMS (ΔR²=0.124, p=0.043) and PMS patients (ΔR²=0.095, p=0.028) and VO₂max only in RRMS patients (ΔR²=0.153, p=0.014) were found to explain a significant portion of hippocampal volume variance. <h3>Conclusions:</h3> By exerting beneficial neurotrophic effects, a higher CRF may have a specific neuroprotective role for the hippocampus, mainly in the early phases of MS. <b>Disclosure:</b> Mr. Morozumi has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Albergoni has nothing to disclose. Monica Margoni has received research support from MAGNIMS. Elisabetta Pagani has nothing to disclose. Alessandro Meani has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.

Functional and Structural MRI Changes Associated With Cognitive Worsening in Multiple Sclerosis: A 3-Year Longitudinal Study (P11-3.003)

<h3>Objective:</h3> To apply a multiparametric MRI approach to identify mechanisms associated with cognitive worsening in multiple sclerosis (MS). <h3>Background:</h3> Heterogeneous processes may contribute to cognitive impairment in MS; however, its association with brain structural and functional MRI changes still need to be fully explored. <h3>Design/Methods:</h3> Brain dual-echo, 3D T1-weighted, diffusion-weighted imaging, and resting state (RS) functional MRI scans were acquired at baseline and after median follow up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening at Rao’s battery and longitudinal changes in T2-hyperintense lesion location, WM microstructural damage, gray matter (GM) atrophy and RS functional connectivity (FC) were explored using tract-based spatial statistic, tensor-based morphometry and independent component analysis. <h3>Results:</h3> Fifteen (43%) MS patients were cognitively impaired at baseline and 10 (29%) showed cognitive deterioration at follow-up. At baseline, compared to HC, MS patients showed widespread WM damage and GM atrophy, and decreased RS FC in some clusters of executive control (ECN) and working memory networks (WMN). At follow-up, annualized volume loss of caudate nucleus was significantly higher in MS patients with vs without cognitive deterioration (−1.2% vs −0.2%, p&lt;0.05). No significant between-group differences in lesion location, WM microstructural changes or GM atrophy were found. Compared to stable MS patients, worsened patients showed decreased RS FC in right hippocampus of right WMN and in right insula of default mode network. In the opposite comparison, increased RS FC in left insula of ECN was found. <h3>Conclusions:</h3> While cognitively-stable MS patients showed increased RS FC in left insula, possibly reflecting a compensatory mechanism, cognitive deterioration in MS patients was associated with decreased RS FC in several functional brain networks, with limited GM atrophy progression. Our study suggests that, in MS patients already characterized by substantial structural damage, cognitive deterioration might be secondary to functional network collapse. <b>Disclosure:</b> Dr. Azzimonti has nothing to disclose. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb . Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Mr. Preziosa has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Paola Valsasina has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACCMED. Elisabetta Pagani has nothing to disclose. Olga Marchesi has nothing to disclose. Dr. Tedone has nothing to disclose. Carmen Vizzino has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Maria Assunta Rocca has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer, Biogen, Bristol Myers Squibb, Celgene, Genzyme, Merck Serono, Novartis, Roche, and Teva. The institution of Maria Assunta Rocca has received research support from Italian Ministry of Health, MS Society of Canada and Fondazione Italiana Sclerosi Multipla.