Clinical Trial Design in Ulcerative Colitis: Interpreting Evolving Endpoints Based on Post Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1.

Background: The 12-point total Mayo score including a Physician's Global Assessment (PGA) of disease activity has been used to assess outcomes in clinical trials for ulcerative colitis (UC). In 2016, the US Food and Drug Administration (FDA) issued guidance advising the removal of the PGA in future trials. We examined how endpoints in UC trials have evolved and conducted a post hoc analysis of the GEMINI 1 and VISIBLE 1 trials to understand how the use of a 9-point modified Mayo score, excluding PGA, compares with the total Mayo score. Methods: Endpoint definitions of clinical remission in phase 3 trials were extracted from published literature and ClinicalTrials.gov. The difference (%Δ) between the proportions of patients in GEMINI 1 and VISIBLE 1 achieving clinical remission with vedolizumab versus placebo at week 52 was measured according to 4 endpoint definitions. Results: Trials completed up to the end of 2019 used the total Mayo score to assess clinical remission. Most trials that were completed or estimated to be completed by June 2020 or later used modified Mayo scores. Post hoc analysis revealed decreasing endpoint stringency was associated with increasing %Δ values. The modified Mayo score definition most like the definition recommended by the FDA produced %Δ values like those reported using the total Mayo score in GEMINI 1 and VISIBLE 1. Conclusions: Endpoint definitions for UC clinical trials have evolved following FDA guidance. The efficacy of vedolizumab, measured using modified Mayo scoring, was comparable to values reported using the total Mayo score.

Effects of Teduglutide on Diarrhea in Pediatric Patients with Short Bowel Syndrome-Associated Intestinal Failure.

OBJECTIVES: This post-hoc analysis evaluated the effect of teduglutide treatment on diarrhea in patients with short bowel syndrome-associated intestinal failure (SBS-IF). METHODS: Data from 2 open-label, multicenter, phase 3 pediatric SBS-IF clinical trials of teduglutide (NCT01952080 and NCT02682381) were pooled where possible. The primary objective was to evaluate the change in stool consistency, frequency, and volume from baseline to weeks 12 and 24 of treatment in patients who received any teduglutide dose from both studies ("total teduglutide"). Safety assessments included gastrointestinal adverse event reporting. RESULTS: Overall, 101 patients were analyzed. Among the total teduglutide group (n = 87), there were significant changes from baseline to weeks 12 and 24 in mean (standard error) Bristol Stool Form Scale (BSFS) score [-1.8 (0.26; P < 0.0001) and -2.2 (0.27; P < 0.0001), respectively], parenteral nutrition and/or intravenous fluid (PN/IV) volume [-16.9 (1.7; P < 0.0001) and -20.1 (2.3; P < 0.0001) mL/kg/day, respectively], and enteral nutrition volume [9.2 (1.7; P < 0.0001) and 9.6 (2.3; P = 0.0002) mL/kg/day, respectively]. Among patients in the standard of care group (n = 14) there were numerical changes in BSFS score, and enteral nutrition volume at weeks 12 and 24; significant changes in PN/IV volume [-6.9 (1.5) mL/kg/day; P = 0.0041] were observed at 24 weeks, but not at 12 weeks. CONCLUSION: In this post-hoc analysis, short-term treatment with teduglutide was associated with improved stool consistency, as well as trends towards reductions in PN/IV requirements and advancements in enteral nutrition volume in children with SBS-IF. Further research assessing the impact of patient-level factors on stool characteristics when using teduglutide is warranted.

Practical Primer Addressing Real-World Use Scenarios of Subcutaneous Vedolizumab in Ulcerative Colitis and Crohn's Disease: Post Hoc Analyses of VISIBLE Studies.

Background: Vedolizumab, an anti-α4ß7 integrin approved for intravenous (IV) treatment of moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD), was evaluated as a subcutaneous (SC) formulation in maintenance therapy for UC and CD in phase 3 VISIBLE 1, 2, and open-label extension studies, and recently approved in Europe, Australia, and Canada. Our aim was to evaluate efficacy and safety of IV and SC vedolizumab in clinically relevant UC and CD scenarios. Methods: Post hoc data analyses from VISIBLE trials examined: (1) whether baseline characteristics predict clinical response to 2 vs 3 IV vedolizumab induction doses; (2) efficacy and safety of switching during maintenance vedolizumab IV to SC in patients with UC; (3) vedolizumab SC after treatment interruption of 1-46 weeks; (4) increasing dose frequency of vedolizumab SC from every 2 weeks (Q2W) to every week (QW) after disease worsening. Results: No baseline characteristics were identified as strong predictors of response to 2 vs 3 vedolizumab infusions. Most patients achieved clinical response after 2 or 3 doses of IV vedolizumab maintained with SC treatment. Clinical remission and response rates were maintained in patients transitioned from maintenance vedolizumab IV to SC treatment. Of patients with UC, ≥75% achieved response following resumption after dose interruption. Escalation to QW dosing resulted in ≥45% of patients regaining response after loss while receiving vedolizumab Q2W. Conclusions: Clinical real-world scenarios with vedolizumab SC were reviewed using VISIBLE studies data. Vedolizumab SC provides an additional dosing option for patients with UC and CD.

An App-Based Digit Symbol Substitution Test for Assessment of Cognitive Deficits in Adults With Major Depressive Disorder: Evaluation Study.

BACKGROUND: Cognitive dysfunction is an impairing core symptom of depression. Among adults with major depressive disorder (MDD) treated with antidepressants, residual cognitive symptoms interfere with patient-reported outcomes. The foregoing characterization of cognitive symptoms provides the rationale for screening and assessing the severity of cognitive symptoms at point of care. However, clinical neurocognitive assessments are time-consuming and difficult, and they require specialist expertise to interpret them. A smartphone-delivered neurocognitive test may offer an effective and accessible tool that can be readily implemented into a measurement-based care framework. OBJECTIVE: We aimed to evaluate the use of a smartphone-delivered app-based version of the established Cognition Kit Digit Symbol Substitution Test (DSST) neurocognitive assessment compared to a traditional paper-and-pencil version. METHODS: Convergent validity and test-retest reliability of the 2 versions were evaluated. Patient satisfaction with the app was also assessed. RESULTS: Assessments made using the app-based Cognition Kit DSST were highly correlated with the standard paper-and-pencil version of the test, both at the baseline visit (r=0.69, df=27; P<.001) and at the end-of-study visit (r=0.82, df=27; P<.001), and they were positively evaluated by 30 patients as being user-friendly, easy to navigate, and preferable over the paper-and-pencil version of the DSST. However, although the app-based Cognition Kit DSST was validated in patients with MDD, it still needs to be evaluated in healthy controls. CONCLUSIONS: App-based DSST may facilitate a more personalized, convenient, and cost-effective method of cognitive assessment, helping to guide measurement-based care and psychotherapeutic and pharmacologic treatment options for patients with MDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT03999567; https://tinyurl.com/2p8pnyv7.

Wavelet and Spectral Analysis of Normal and Abnormal Heart Sound for Diagnosing Cardiac Disorders.

Body auscultation is a frequent clinical diagnostic procedure used to diagnose heart problems. The key advantage of this clinical method is that it provides a cheap and effective solution that enables medical professionals to interpret heart sounds for the diagnosis of cardiac diseases. Signal processing can quantify the distribution of amplitude and frequency content for diagnostic purposes. In this experiment, the use of signal processing and wavelet analysis in screening cardiac disorders provided enough evidence to distinguish between the heart sounds of a healthy and unhealthy heart. Real-time data was collected using an IoT device, and the noise was reduced using the REES52 sensor. It was found that mean frequency is sufficiently discriminatory to distinguish between a healthy and unhealthy heart, according to features derived from signal amplitude distribution in the time and frequency domain analysis. The results of the present study indicate the adequate discrimination between the characteristics of heart sounds for automatic detection of cardiac problems by signal processing from normal and abnormal heart sounds.

An open-label phase 2 trial to assess the efficacy, safety and pharmacokinetics of lanthanum carbonate in hyperphosphatemic children and adolescents with chronic kidney disease undergoing dialysis.

BACKGROUND: This study assessed the efficacy, tolerability and pharmacokinetics (PK) of lanthanum carbonate (LC) in hyperphosphatemic children and adolescents with chronic kidney disease (CKD) undergoing dialysis. METHODS: This was a three-part, multicenter, open-label study of LC (oral powder formulation) in patients 10 to < 18 years old with CKD undergoing dialysis. In part 1, the single-dose PK of LC (500 mg, ≤12 years old; 1000 mg, > 12 years old) were summarized. In part 2, patients received calcium carbonate (CC [chewable tablet formulation]) (1500-6500 mg [total daily dose]) followed by LC (powder formulation) (1500-3000 mg [total daily dose]), or LC only (1500-3000 mg [total daily dose]), each for 8 weeks. During part 3, patients received LC (1500-3000 mg [total daily dose]) for up to 6 months. The primary efficacy endpoint was the proportion of LC-treated patients achieving serum phosphorus control after 8 weeks during parts 2 and/or 3, defined as: ≤1.94 mmol/L, < 12 years old; ≤1.78 mmol/L, ≥12 years old. Secondary efficacy endpoints included: the proportion of patients who achieved serum phosphorus control after 8 weeks of treatment with CC followed by 8 weeks of treatment with LC (with a washout period between treatments). The safety of LC and CC was also evaluated. RESULTS: In part 1, 20 patients received a single dose of LC. In part 2, 53 and 51 patients were treated with CC and LC for 8 weeks, respectively. During part 3, 42 patients received LC for up to 6 months. Most patients were white and male. For the primary efficacy endpoint, 50% (17/34) of patients who received LC for 8 weeks during parts 2 and/or 3 achieved serum phosphorus control. After 8 weeks of treatment with CC, 58.8% of patients achieved serum phosphorus control; after a subsequent washout period and 8 weeks of treatment with LC, 70.6% of patients achieved serum phosphorus control. Tmax and t1/2 occurred within 3-8 h and ~ 19 h, respectively; however, variability was observed. LC and CC were generally well tolerated. CONCLUSIONS: These data support the use of LC to manage hyperphosphatemia in pediatric patients with CKD undergoing dialysis. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01696279; EudraCT identifier: 2012-000171-17. Date of registration: 01/10/2012.

Randomized, Double-Masked, Placebo-Controlled Dose Escalation Study of TAK-639 Topical Ophthalmic Solution in Subjects with Ocular Hypertension or Primary Open-Angle Glaucoma.

PURPOSE: TAK-639 is a topical, nine-amino acid, synthetic, C-type natriuretic peptide analog in Phase 1 development for the treatment of ocular hypertension (OHT) and primary open-angle glaucoma (POAG). TAK-639 is postulated to lower intraocular pressure (IOP) through a novel mechanism of action (MOA) that increases trabecular meshwork outflow. We investigated the safety and tolerability of TAK-639 in subjects with OHT or POAG. METHODS: This was a phase 1, multicenter, randomized, double-masked, placebo-controlled, single- and multiple-dose escalation study. Subjects (aged 18-90 years) with OHT or POAG were randomized 5:2 to TAK-639 or placebo. Three dose levels were planned (0.1%, 0.3%, 0.6% TAK-639), each with four dosing regimens (QD, BID, TID, QID). Safety measures included treatment-emergent adverse events (TEAEs) and ophthalmologic examinations. Pharmacokinetics and pharmacodynamics (reduction of IOP) were also evaluated. RESULTS: In total, 63 subjects were randomized and received 0.1%, 0.3% and 0.6% TAK-639, as single dose, QD, or BID, and 0.1% and 0.3% TID. The study was terminated before 0.6% TID or QID dosing cohorts were studied; instead, 0.6% BID was repeated in a new cohort. TEAEs were instillation related and of mild-to-moderate intensity. There were no TEAEs leading to premature discontinuation, and no serious TEAEs. The most common treatment-related TEAEs were instillation site pain and transient corneal staining with fluorescein. There were no clinically significant concerns across dose groups for all other safety measures, including drop comfort, best corrected visual acuity, slit-lamp biomicroscopy, and corneal epithelial integrity. Little or no systemic exposure was observed. There was a marginal reduction in IOP in one cohort at the highest dose (0.6%) and regimen (BID) tested, suggesting biological plausibility of targeting the trabecular meshwork through this mechanism. CONCLUSION: TAK-639 was generally well tolerated up to 0.6% BID. Further non-clinical studies will improve understanding of the MOA and the penetration of TAK-639 to the anterior chamber.

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

OBJECTIVE: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). CONCLUSIONS: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity - data from the EU-AIR.

CONTEXT AND OBJECTIVE: Treatment for adrenal insufficiency (AI) remains suboptimal. Despite glucocorticoid replacement, patients with AI have reduced life expectancy and quality of life. This study aimed to describe the spectrum of management of glucocorticoid replacement in patients with AI enrolled in the European Adrenal Insufficiency Registry (EU-AIR). DESIGN, SETTING AND PATIENTS: EU-AIR is a prospective, multinational, multicentre, observational study initiated in August 2012 to monitor the long-term safety of glucocorticoid replacement in routine clinical practice in Germany, the Netherlands, Sweden and the UK (ClinicalTrials.gov identifier: NCT01661387). This analysis included 1166 patients with primary and secondary AI (mean disease duration 16·1 ± 11·6 years) receiving long-term glucocorticoid replacement therapy. MAIN OUTCOME MEASURE: Glucocorticoid type, dose, frequency and treatment regimen were examined. RESULTS: Most patients (87·4%) were receiving hydrocortisone. The most common dose range, taken by 42·2% of patients, was 20 to <25 mg/day; however, 12·6% were receiving doses of ≥30 mg/day. Hydrocortisone was being taken once daily by 5·5%, twice daily by 48·7%, three times daily by 43·6% and four times daily by 2·1%. Patients with primary AI received higher replacement doses than those with secondary AI (23·4 ± 8·9 and 19·6 ± 5·9 mg/day, respectively). Twenty-five different regimens were being used to deliver a daily hydrocortisone dose of 20 mg. CONCLUSIONS: We have shown significant heterogeneity in the type, dose, frequency and timing of glucocorticoid replacement in real-world clinical practice. This reflects dose individualization based on patient symptoms and lifestyle in the absence of data supporting the optimal regimen.

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency.

OBJECTIVE: Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). DESIGN/METHODS: EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3-6 mg/day, n = 50) or hydrocortisone (15-30 mg/day, n = 909) were identified and grouped at a ratio of 1:3 (prednisolone:hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. RESULTS: Significantly higher mean ± s.d. total (6.3 ± 1.6 vs 5.4 ± 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 ± 1.4 vs 3.2 ± 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. CONCLUSIONS: This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group.

Validation of the Knee Injury and Osteoarthritis Outcome Score subscales for patients with articular cartilage lesions of the knee.

BACKGROUND: The Knee Injury and Osteoarthritis Outcome Score (KOOS) assesses acute and chronic knee injuries or early-onset osteoarthritis in young, active patients. The United States Food and Drug Administration guidelines recommend that patient-reported outcome instruments used to support clinical trial label claims should demonstrate content validity using patient input and have acceptable psychometric properties in the target population. To use the KOOS subscales in safety and efficacy trials assessing new treatments for patients with articular cartilage lesions, additional validation work, using input from patients with articular cartilage lesions, was necessary. PURPOSE: Qualitative and quantitative evaluations of the KOOS subscales' validity among patients with articular cartilage lesions were conducted to support their use as clinically meaningful end points in clinical trials. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: For qualitative analysis, cognitive interviews involving concept elicitation and cognitive debriefing with the KOOS items were conducted with 15 participants aged 25 to 52 years. Participants either were candidates for cartilage repair or had undergone cartilage repair 6 months or more before the study. For the quantitative analysis, a psychometric evaluation of the KOOS was conducted with clinical trial data from 54 patients, aged 18 to 55 years, evaluating the Cartilage Autograft Implantation System in the United States (n = 29) and the European Union (n = 25). Data were collected before surgery and at 7 postsurgical visits up to 12 months. Internal consistency and test-retest reliability, construct validity, responsiveness, and estimates of the minimal detectable change (MDC) were assessed. Test-retest reliability was assessed using data from months 2 and 3 on a subset of stable patients. RESULTS: Qualitative research confirmed that concepts measured on the KOOS are important to patients with articular cartilage lesions. Most participants reported the KOOS was comprehensive and appropriate. In the quantitative research, KOOS subscales showed excellent internal consistency reliability (range, .74-.97 at baseline) and test-retest reliability (range, .78-.82). Construct validity results supported hypothesized relationships, with significant correlations (r ≥ .50) in the expected directions. Responsiveness analyses demonstrated excellent sensitivity to change; standardized response means ranged from 0.8 to 1.2, and MDC estimates ranged from 7.4 to 12.1. CONCLUSION: The study results support the use of the KOOS subscales among patients with articular cartilage lesions.

Total and serotype-specific pneumococcal antibody titres in children with normal and abnormal humoral immunity.

A heptavalent pneumococcal conjugate vaccine (PCV-7) protects children against invasive pneumococcal disease. The aim of this study was to evaluate immunoglobulin subclass and serotype-specific pneumococcal antibody responses to vaccination in children with a history of recurrent or severe bacterial infections. Pneumococcal IgG, IgG1, IgG2 titres were assayed by ELISA, and nine serotype concentrations measured using a nonaplex bead assay in 145 children investigated for recurrent or severe infections. Children mounted an exclusively IgG1 response after vaccination with two doses of PCV-7 and a dose of 23 valent pneumococcal polysaccharide vaccine (PPV-23), with pneumococcal IgG2 antibody titres remaining low to negligible. Measurement of serotype-specific responses demonstrated that although PCV-7 specific serotype responses increased significantly post-vaccination, specific IgG against two of the serotypes not covered by PCV-7 but only by PPV-23 remained low. We conclude that in contrast to antibody response to natural infection with Pneumococcus or pneumococcal polysaccharide vaccines which are often of a IgG2 subclass, responses in children after PCV-7 are of IgG1 subclass. Serotype-specific IgG were useful in determining the protection against specific pneumococcal strains, and showed that the PPV-23 did not broaden protection against non-PCV-7 serotypes.