| 1. |
- Clerx, Lies, et al.
(författare)
-
Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment
- 2013
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 34:8, s. 2003-2013
-
Tidskriftsartikel (refereegranskat)abstract
- Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1-42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1-42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI. (c) 2013 Elsevier Inc. All rights reserved.
|
|
| 2. |
- Anthony, Lowell, et al.
(författare)
-
Understanding the Patient Experience with Carcinoid Syndrome : Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl
- 2017
-
Ingår i: Clinical Therapeutics. - : Elsevier. - 0149-2918 .- 1879-114X. ; 39:11, s. 2158-2168
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in FELESTAR, a Phase HI study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview sub study was conducted to provide insight into the patient experience in ILLESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving >= 30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoidsyndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Implications: Patient interviews revealed that I ELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl. (C) 2017 The Authors. Published by Elsevier HS Journals, Inc.
|
|
| 3. |
- Hudgens, Stacie, et al.
(författare)
-
Evaluation of meaningful change in bowel movement frequency for patients with carcinoid syndrome
- 2019
-
Ingår i: JOURNAL OF PATIENT-REPORTED OUTCOMES. - : Springer Nature. - 2509-8020. ; 3:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Carcinoid syndrome is associated with a reduced quality of life that can be attributed to symptoms such as diarrhea and fatigue as well as social and financial issues. This study was conducted to psychometrically assess meaningful change in bowel movement frequency among carcinoid syndrome patients using data from the TELESTAR clinical study. Methods: An anchor-based approach for deriving meaningful change thresholds consisted of mapping change from baseline bowel movement frequency to other patient-reported assessments of change. These included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core Questionnaire (QLQ-C30) Diarrhea Symptom responders, the EORTC Gastrointestinal NET questionnaire (GI.NET21) GI Symptom responders, and reported adequate relief at Week 12 (>= 10-point score decrease from Day 1 to Week 12). Parameters included within-group mean change from baseline to Week 12, t-tests of the change (Wilcoxon rank sum for adequate relief), and effect size. Results: There were 135 carcinoid syndrome patients with a mean baseline frequency of 5.7 bowel movements a day. A distribution-based method yielded meaningful change estimates of 0.62 bowel movements a day for overall frequency and 0.83 bowel movements a day at Week 12. Anchor-based analysis indicated a large effect size among patients who reported adequate relief at Week 12 (- 1.58; n = 18; P = 0.014), the QLQ-C30 Diarrhea domain responders (- 1.24; n = 40; P < 0.001), and the GI.NET21 GI Symptoms Domain responders (- 1.49; n = 25; P = 0.005). Exit interview data for meaningful change yielded effect size estimates of - 1.57 for overall change during the Double-blind Treatment Period and - 1.97 for change between Baseline and Week 12. Conclusions: Meaningful change derivation is critical to interpret patient outcomes for evaluating treatment efficacy. In this study, carcinoid syndrome patients experienced clinically meaningful reductions in bowel movement frequency of >= 30% over 12 weeks with telotristat ethyl treatment.
|
|
| 4. |
|
|
| 5. |
- Anthony, Lowell B., et al.
(författare)
-
Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome
- 2019
-
Ingår i: The Oncologist. - : WILEY. - 1083-7159 .- 1549-490X. ; 24:8, s. E662-E670
-
Tidskriftsartikel (refereegranskat)abstract
- Background Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome. Subjects, Materials, and Methods Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated. Results Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4. Conclusion Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome. Implications for Practice Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.
|
|
| 6. |
|
|
| 7. |
- Dillon, Joseph S., et al.
(författare)
-
Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl : Analyses of Phase III Studies in Carcinoid Syndrome
- 2021
-
Ingår i: Journal of Gastrointestinal Cancer. - : Springer Science and Business Media LLC. - 1941-6628 .- 1941-6636. ; 52:1, s. 212-221
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundTelotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods.MethodsFirst occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial.ResultsIn TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3–4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2–3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6–11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7–11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR.ConclusionThe time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency.
|
|
| 8. |
|
|
| 9. |
- Hörsch, Dieter, et al.
(författare)
-
Long-Term Treatment with Telotristat Ethyl in Patients with Carcinoid Syndrome Symptoms : Results from the TELEPATH Study
- 2022
-
Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 112:3, s. 298-309
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Telotristat ethyl is indicated for use in combination with somatostatin analogs (SSAs) to treat carcinoid syndrome (CS) diarrhea uncontrolled by SSAs alone in adults, but long-term safety and efficacy data beyond 48 weeks are needed.Objectives: The aims of the study were to evaluate the long-term safety and tolerability of telotristat ethyl and its effect on quality of life (QOL) in patients with CS.Methods: In this phase 3, nonrandomized, multicenter, open-label, long-term extension study (TELEPATH), patients who participated in phase 2 or 3 trials of telotristat ethyl continued treatment at their present dose level (250 or 500 mg thrice daily) for 84 weeks. Safety and tolerability, the primary endpoint, were assessed by monitoring adverse events (AEs), serious AEs, AEs of special interest (AESIs; including liver-related AEs, depression, and gastrointestinal AEs), and deaths. The secondary objective was to evaluate changes in patients’ QOL using validated cancer questionnaires and a subjective global assessment of CS symptoms.Results: In 124 patients exposed to telotristat ethyl for a mean of 102.6 ± 53.2 weeks, the type and frequency of AEs were consistent with those reported in previous trials. The occurrence of AESIs was not related to dosage or duration of therapy. Most AEs were mild to moderate in severity, and no deaths were related to telotristat ethyl. QOL scores remained stable, and the majority of patients reported adequate symptom relief throughout the study.Conclusions: Safety results of TELEPATH support the long-term use of telotristat ethyl in patients with CS diarrhea. Telotristat ethyl was well-tolerated and associated with sustained improvement in QOL scores (NCT02026063).
|
|
| 10. |
- Kulke, Matthew H., et al.
(författare)
-
Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome
- 2017
-
Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 35:1, s. 14-23
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1: 1: 1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg (P < .001) and -0.69 for telotristat ethyl 500 mg (P,.001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction >= 30% from baseline for >= 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 (P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.
|
|
