Short-term Clinical Trials Research Articles

White matter functional and structural alterations of spinocerebellar ataxia type 3: A longitudinal MRI study.

Widespread white matter (WM) microstructural abnormalities have been reported in patients with spinocerebellar ataxia type 3 (SCA3) using diffusion tensor imaging (DTI), whereas the ability of DTI to detect WM degeneration over short-term period remains insufficiently explored. Additionally, WM dysfunction remains entirely unknown in this disease. This study aims to investigate WM structural and functional alterations in SCA3, and provide promising progression biomarkers for short-term clinical trials. DTI and resting-state functional magnetic resonance imaging data of 52 SCA3 patients and 56 healthy controls (HCs) were collected at baseline. After a mean follow-up of 1year, MRI scans were performed on a subset of 28 SCA3 patients. Compared with HCs, widespread WM structural and functional abnormalities were observed in patients with SCA3. Between-group differences of both structural and functional MR metrics showed remarkable similarities, with large differences located in pons and corticospinal tracts, involving cerebellar WM, cerebellar and cerebral peduncles, medial lemniscus and bilateral posterior limb of internal capsule (PLIC). The longitudinal analysis further showed decreased ALFF in the right PLIC and increased mean diffusivity in the left inferior cerebellar peduncle and right medial lemniscus over time in SCA3 patients. These findings emphasized that pons and the CST were the most vulnerable WM areas in SCA3, and have the potential to become therapeutic targets of SCA3 for upcoming interventional trials. In addition, both DT metrics and WM ALFF were efficient progression biomarkers for SCA3 even in short-term period.

A systematic review of the psychometric properties of the Leicester Cough Questionnaires based on the COSMIN guidelines

BackgroundChronic cough affects around 10 % of the general adult population, impairing all aspects of quality of life. Research questionWhat are the Leicester Cough Questionnaire's psychometric properties? Study design and methodsElectronic searches of PubMed, CINAHL, and ScienceDirect databases were conducted from inception until October 1rst 2022. All full-text articles, published in French or English, aimed at evaluating the LCQ's content validity or psychometric properties were included. The COSMIN Risk of Bias checklist was applied to assess their methodological quality and results. Results were qualitatively summarised and rated by a modified GRADE approach. Results40 studies were included accounting for 8731 adults, subject to cough or a respiratory condition. Chronic cough (>8 weeks) was the most represented. The LCQ's total score is relevant and comprehensible for the assessment of the impact of cough on QoL. The original 3-factor model showed a satisfactory model fit. Good convergent validity was found for the total and physical domain scores. These scores demonstrate good internal consistency and test retest reliability, with some variability noted and they are responsive to change. Recent estimates of MID thresholds were 1.7 and 0.4 for total and domain scores respectively. The quality of the studies is globally poor. InterpretationThe LCQ is a valid outcome to assess the intra-individual impact of cough on QoL and to detect large changes in quality of life mainly in a short-term clinical trial setting. Clinical trial registrationThe protocol was registered with PROSPERO (CRD42022355191).

When cardiovascular medicines should be discontinued.

An integral component of the practice of medicine is focused on the initiation of medications, based on clinical practice guidelines and underlying trial evidence, which usually test the addition of novel medications intended for life-long use in short-term clinical trials. Much less attention is given to the question of medication discontinuation, especially after a lengthy period of treatment, during which patients age gets older and diseases may either progress or new diseases may emerge. Given the paucity of data, clinical practice guidelines offer little to no guidance on when and how to deprescribe cardiovascular medications. Such decisions are often left to the discretion of clinicians, who, together with their patients, express concern of potential adverse effects of medication discontinuation. Even in the absence of adverse effects, the continuation of medications without any proven effect may cause harm due to drug-drug interactions, the emergence of polypharmacy, and additional preventable spending to already strained health systems. Herein, several cardiovascular medications or medication classes are discussed that in the opinion of this author group should generally be discontinued, either for the prevention of potential harm, for a lack of benefit, or for the availability of better alternatives.

Cost-effectiveness of empagliflozin as add-on to standard of care for chronic kidney disease management in the United Kingdom

Objective The sodium-glucose co-transporter-2 inhibitor empagliflozin was approved for treatment of adults with chronic kidney disease (CKD) on the basis of its demonstrated ability to slow CKD progression and reduce the risk of cardiovascular death. This analysis was performed to assess the cost-effectiveness of empagliflozin plus standard of care (SoC) vs SoC alone in the treatment of CKD in the UK. Methods A comprehensive, patient-level CKD progression model that simulates the evolution of risk factors for disease progression based on CKD-specific equations and clinical data was used to project a broad range of CKD-related complications. Patient baseline characteristics, distribution across Kidney Disease Improving Global Outcomes (KDIGO) health states, and changes in estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (uACR), and other parameters while on treatment were derived from the EMPA-KIDNEY trial. UK cost and utilities/disutilities were sourced from the literature. Univariate and probabilistic sensitivity analyses were conducted. Annual discounting of 3.5% was applied on costs and outcomes. Results Over a 50-year horizon, SoC resulted in per-patient costs, life years, and QALYs of £95,930, 8.55, and 6.28, respectively. Empagliflozin plus SoC resulted in an incremental gain in life years (+1.04) and QALYs (+0.84), while decreasing per-patient costs by £6,019. Empagliflozin was more effective and less costly (dominant) with a net monetary benefit of £22,849 at the willingness-to-pay threshold of £20,000. Although treatment cost was higher for empagliflozin, this was more than offset by savings in kidney replacement therapy. Empagliflozin remained highly cost-effective in patients with and without diabetes, and across scenario and sensitivity analyses. Limitations This analysis is limited by reliance on short-term clinical trial data and by uncertainties in modelling CKD progression. Conclusions Empagliflozin as an add-on to SoC for treatment of adults with CKD represents cost-effective use of UK National Health Service (NHS) resources.

Closed sinus lift and fixed prostheses versus implant-assisted overdentures in management of atrophied distal extension maxillary ridges: A one-year randomized clinical trial

Rehabilitation of elderly or medically compromised patients with an atrophied unilateral posterior maxillary ridge by an implant-supported prosthesis may be complicated by maxillary sinus pneumatization with insufficient bone for implant placement. This short-term clinical trial assessed clinical results of closed sinus lift and fixed prosthesis versus implant-assisted overdentures in the management of participants with atrophied distal extension maxillary ridges. Forty participants with unilateral atrophying distal extension maxillary ridges were randomly assigned into 2 groups. The CSL group (n=20) participants received fixed prostheses supported by 3 implants following a closed sinus lift. The IOD group (n=20) participants received removable partial overdentures assisted by a single implant that was positioned mesially to the maxillary sinus. The modified plaque index (MPI), modified gingival index (MGI), pocket depth (PD), implant stability (IS), and vertical bone loss (VBL) were measured at prosthesis delivery (T0), and 6 (T6) and 12 months (T12) after delivery. The oral health impact profile (OHIP-14) questionnaire was used to assess oral health-related quality of life (OHRQoL) at T12. Significant differences between observation times were performed using Friedman and Wilcoxon signed-rank tests for MPI and MGI and using repeated measures ANOVA with Bonferroni correction of P values for PD, IS, VBL, and OHIP. Between-group comparison of MPI and MGI the Mann-Whitney test was used, while for PD, IS, VBL, and OHIP comparison was made using independent samples t test (α=.05 for all tests). The implant survival rates were 100% for both groups. MPI and PD significantly increased with time for both groups. MGI significantly increased with time for the CSL group only (P=.049). The IS significantly decreased with time for the IOD group. VBL increased significantly from T6 to T12 for the CSL (P=.042) and the IOD (P=.002) groups. The CSL group recorded higher MPI, MGI, PD, and IS values than the IOD group (P<.05). The IOD group recorded higher VBL than the CSL group (P<.001). The CSL group scored significantly lower OHIP-14 values (better OHRQoL) than the IOD group for all values (P<.05). In comparison with implant-assisted partial overdentures, closed sinus lift with fixed prostheses had higher implant stability, reduced bone loss, and higher participant OHRQoL. However, peri-implant soft tissue health was found to be better with implant overdentures.

Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study

It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study. We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models. We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87). Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS. This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

Estimating Changes in Weight and Metabolic Parameters Before and After Treatment With Cariprazine: A Retrospective Study of Electronic Health Records

Weight gain and associated negative cardiometabolic effects can occur as a result of mental illness or treatment with second-generation antipsychotics (SGAs), leading to increased rates of morbidity and mortality. In this analysis, we evaluated the effect of the SGA cariprazine on weight and metabolic parameters in a real-world, retrospective, observational dataset. Electronic health records from the Optum Humedica database (October 1, 2014-December 31, 2020) were analyzed during the 12-month period before starting cariprazine (baseline) and for up to 12 months following cariprazine initiation; approved and off-label indications were included. Body weight trajectories were estimated in the overall patient cohort and at 3-, 6-, and 12-month timepoints (primary objective). Changes in hemoglobin A1c (HbA1c), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were also evaluated (secondary objectives). Percentages of patients with clinically relevant shifts in body weight, total cholesterol, and fasting triglycerides were also determined. Discontinuation rates for metabolic regulating medications were calculated. Average predicted values were estimated by linear mixed-effects regression models. A total of 2,301 patients were included; average duration of follow-up was 133.7 days. Average predicted weight change for patients during the cariprazine overall follow-up period was +2.4 kg, with predicted weight changes of +0.8 kg (n=811), +1.1 kg (n=350), and +1.4 kg (n=107) at months 3, 6, and 12, respectively. Overall, the majority of patients did not experience clinically significant (≥7%) weight gain (82.8%) or loss (90.5%) after starting cariprazine. Average predicted HbA1c levels (n=189) increased during baseline (0.15%/year) and decreased during cariprazine treatment (-0.2%/year). Average predicted triglyceride levels (n=257) increased during baseline (15.0 mg/dL/year) and decreased during cariprazine treatment (-0.7 mg/dL/year). Predicted LDL (n=247) and HDL (n=255) values decreased during baseline (-7.3 and -1.1 mg/dL/year, respectively); during cariprazine treatment, LDL increased by 5.6 mg/dL/year and HDL decreased by -0.6 mg/dL/year. During follow-up, most patients did not shift from normal/borderline to high total cholesterol (<240 to ≥240 mg/dL; 522 [90.2%]) or fasting triglyceride (<200 to ≥200 mg/dL; 143 [88.8%] patients) levels; shifts from high to normal/borderline levels occurred in 44 (61.1%) patients for total cholesterol and 38 (57.6%) patients for fasting triglycerides. After starting cariprazine, the discontinuation rate per 100 patient-years was 60.4 for antihyperglycemic medication and 87.4 for hyperlipidemia medication. These real-world results support short-term clinical trial findings describing a neutral weight and metabolic profile associated with cariprazine treatment and they expand the dataset to include long-term follow-up.

Real-world outcomes of concomitant antidepressant and statin use in primary care patients with depression: a population-based cohort study

BackgroundAntidepressants are licensed for use in depressive disorders, but non-response and poor adherence to treatment affect a considerable number of patients. Pre-clinical and clinical evidence suggest that statins can augment the effects of antidepressants. However, the acceptability and tolerability of combining statins with antidepressants are unclear, and their add-on efficacy has only been shown in small, short-term clinical trials. Observational data can provide complementary information about treatment effects on larger samples over longer follow-ups. In this study, we therefore assessed the real-world acceptability, tolerability, and efficacy of concomitant antidepressant and statin treatment in depression.MethodsWe conducted a population-based cohort study investigating QResearch primary care research database, which comprises the anonymised electronic healthcare records of 35 + million patients over 1574 English general practices. Patients aged 18–100 years, registered between January 1998 and August 2020, diagnosed with a new episode of depression, and commencing an antidepressant were included. Using a between-subject design, we identified two study groups: antidepressant + statin versus antidepressant-only prescriptions.Outcomes of interest included the following: antidepressant treatment discontinuations due to any cause (acceptability) and due to any adverse event (tolerability) and effects on depressive symptoms (efficacy) measured as response, remission, and change in depression score on the Patient Health Questionnaire-9. All outcomes were assessed at 2, 6, and 12 months using multivariable regression analyses, adjusted for relevant confounders, to calculate adjusted odds ratios (aORs) or mean differences (aMDs) with 99% confidence intervals (99% CIs).ResultsCompared to antidepressant-only (N 626,335), antidepressant + statin (N 46,482) was associated with higher antidepressant treatment acceptability (aOR2months 0.88, 99% CI 0.85 to 0.91; aOR6months 0.81, 99% CI 0.79 to 0.84; aOR12months 0.78, 99% CI 0.75 to 0.81) and tolerability (aOR2months 0.92, 99% CI 0.87 to 0.98; aOR6months 0.94, 99% CI 0.89 to 0.99, though not long term aOR12 months 1.02, 99% CI 0.97 to 1.06). Efficacy did not differ between groups (range aOR2-12 months 1.00 and 1.02 for response and remission, range aOR2-12 months − 0.01 and − 0.02 for change in depression score).ConclusionsOn real-world data, there is a positive correlation between antidepressant treatment adherence and statin use, partly explained by fewer dropouts due to adverse events. The main limitation of our study is its observational design, which restricts the potential to make causal inferences.

Electrical Stimulation for Treatment of Dysphagia Post Head Neck Cancer: A Systematic Review and Meta-Analysis.

Introduction Dysphagia induced by radiotherapy in the head and neck region comprises a challenging scenario and sometimes difficult rehabilitation due to the severity of the adverse effects. Some resources such as electrical stimulation have emerged as an alternative to complement the therapeutic process, but there is still no consensus on its use. Objective The purpose of the present study was to evaluate, through a meta-analysis, the effect of electrical stimulation on the rehabilitation of dysphagia generated after head and neck cancer treatment. Data Synthesis Four randomized controlled trials with a total of 146 participants were included. The age of the participants was 58.37 ± 1.8 years old and there was a predominance of males. The time to start the intervention ranged from 50.96 ± 40.12 months after cancer treatment. The intervention showed great heterogeneity regarding the positioning of the electrodes, parameters, duration of the stimulus, number of sessions, and intensity. No difference was identified in the following aspects: oral transit time, hyoid elevation, penetration and/or aspiration after electrostimulation. The quality of the evidence ranged from very low to moderate and high risk of bias. Conclusion In this meta-analysis, we found weak evidence for small and moderate swallowing benefits in patients after radiotherapy for head and neck cancer in short-term clinical trials.

Cost-effectiveness analysis of baricitinib versus dupilumab for moderate to severe atopic dermatitis: an Italian healthcare system perspective

AimsTo assess, within the Italian healthcare system, the cost-effectiveness of baricitinib versus dupilumab, both in combination with topical corticosteroids (TCS), in adults with moderate to severe atopic dermatitis (AD) who are eligible for but have failed, have contraindications to, or cannot tolerate ciclosporin.Materials and methodsUsing the perspective of the Italian healthcare payer, direct medical costs associated with each intervention were estimated over a lifetime horizon. A Markov cohort model utilized the proportions of patients with ≥75% improvement Eczema Area and Severity Index obtained from clinical trials. Health outcomes were evaluated in quality-adjusted life years (QALYs) to assess the cost effectiveness of baricitinib against a willingness-to-pay threshold of €35,000 per QALY gained.ResultsIn the base case, with secondary censoring applied, patients treated with dupilumab or baricitinib, in combination with TCS, accumulated total costs of €135,780 or €129,586, and total QALYs of 18.172 or 18.133, respectively. The incremental cost-effectiveness ratio of dupilumab versus baricitinib was estimated at €160,905/QALY.LimitationsCore assumptions were needed to extrapolate available short-term clinical trial data to lifelong data, adding uncertainty. Benefits of baricitinib seen in clinical trials and not assessed in dupilumab clinical trials were not included. Discontinuation rates for each treatment were derived from different sources potentially introducing bias. Results may not be generalizable to other populations.ConclusionsThis cost-effectiveness analysis shows that, from the Italian healthcare payer perspective, in the treatment of patients with moderate to severe AD who have experienced failure on, are intolerant to, or have contraindication to ciclosporin, dupilumab cannot be considered cost-effective when compared with baricitinib. Given its oral administration, favorable risk/benefit profile and lower acquisition cost compared with dupilumab, baricitinib may offer a valuable, cost-effective treatment option—after failure on conventional systemic agents—for patients with moderate to severe AD in Italy.

Blood phytosterols in relation to cardiovascular diseases and mediating effects of blood lipids and hematological traits: a Mendelian randomization analysis.

Short-term clinical trials have shown the cholesterol-lowering potentials of phytosterols, but their impacts on cardiovascular disease (CVD) remain controversial. This study used the Mendelian randomization (MR) to investigate the relationships between genetic predisposition to blood sitosterol concentration and 11 CVD endpoints, along with the potential mediating effects of blood lipids and hematological traits. Random-effect inverse-variance weighted method was used as the main analysis of MR. Genetic instruments of sitosterol (seven SNPs, F=253, and R2=15.4%) were derived from an Icelandic cohort. Summary-level data of the 11 CVDs were obtained from UK Biobank, FinnGen, and publicly available genome-wide association study results. Genetically predicted one unit increment in log-transformed blood total sitosterol was significantly associated with a higher risk of coronary atherosclerosis (OR: 1.52; 95% CI: 1.41, 1.65; n=667,551), myocardial infarction (OR: 1.40; 95% CI: 1.25, 1.56; n=596,436), all coronary heart disease (OR: 1.33; 95% CI: 1.22, 1.46; n=766,053), intracerebral hemorrhage (OR: 1.68; 95% CI: 1.24, 2.27; n=659,181), heart failure (OR: 1.16; 95% CI: 1.08, 1.25; n=1,195,531), and aortic aneurysm (OR: 1.74; 95% CI: 1.42, 2.13; n=665,714). Suggestive associations were observed for an increased risk of ischemic stroke (OR: 1.06; 95% CI: 1.01, 1.12; n=2,021,995) and peripheral artery disease (OR: 1.20; 95% CI: 1.05, 1.37; n=660,791). Notably, blood non-high-density lipoprotein cholesterol (nonHDL-C) and apolipoprotein B mediated about 38-47%, 46-60%, and 43-58% of the associations between sitosterol and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively. However, the associations between sitosterol and CVDs were less likely to depend on hematological traits. The study suggests that genetic predisposition to higher blood total sitosterol is linked to a greater risk of major CVDs. Moreover, blood nonHDL-C and apolipoprotein B might mediate a significant proportion of the associations between sitosterol and coronary diseases.

Low-carbohydrate diets, low-fat diets, and mortality in middle-aged and older people: A prospective cohort study.

Short-term clinical trials have shown the effectiveness of low-carbohydrate diets (LCDs) and low-fat diets (LFDs) for weight loss and cardiovascular benefits. We aimed to study the long-term associations among LCDs, LFDs, and mortality among middle-aged and older people. This study included 371,159 eligible participants aged 50-71 years. Overall, healthy and unhealthy LCD and LFD scores, as indicators of adherence to each dietary pattern, were calculated based on the energy intake of carbohydrates, fat, and protein and their subtypes. During a median follow-up of 23.5 years, 165,698 deaths were recorded. Participants in the highest quintiles of overall LCD scores and unhealthy LCD scores had significantly higher risks of total and cause-specific mortality (hazard ratios [HRs]: 1.12-1.18). Conversely, a healthy LCD was associated with marginally lower total mortality (HR: 0.95; 95% confidence interval: 0.94, 0.97). Moreover, the highest quintile of a healthy LFD was associated with significantly lower total mortality by 18%, cardiovascular mortality by 16%, and cancer mortality by 18%, respectively, versus the lowest. Notably, isocaloric replacement of 3% energy from saturated fat with other macronutrient subtypes was associated with significantly lower total and cause-specific mortality. For low-quality carbohydrates, mortality was significantly reduced after replacement with plant protein and unsaturated fat. Higher mortality was observed for overall LCD and unhealthy LCD, but slightly lower risks for healthy LCD. Our results support the importance of maintaining a healthy LFD with less saturated fat in preventing all-cause and cause-specific mortality among middle-aged and older people.

Time-restricted feeding's effect on overweight and obese patients with chronic kidney disease stages 3-4: A prospective non-randomized control pilot study.

Time-restricted feeding (TRF) has become a popular weight loss method in recent years. It is widely used in the nutritional treatment of normal obese people and obese people with chronic diseases such as diabetes mellitus and hypertension, and has shown many benefits. However, most TRF studies have excluded chronic kidney disease (CKD) patients, resulting in a lack of sufficient evidence-based practice for the efficacy and safety of TRF therapy for CKD. Therefore, we explore the efficacy and safety of TRF in overweight and obese patients with moderate-to-severe stage CKD through this pilot study, and observe patient compliance to assess the feasibility of the therapy. This is a prospective, non-randomized controlled short-term clinical trial. We recruited overweight and obese patients with CKD stages 3-4 from an outpatient clinic and assigned them to either a TRF group or a control diet (CD) group according to their preferences. Changes in renal function, other biochemical data, anthropometric parameters, gut microbiota, and adverse events were measured before the intervention and after 12 weeks. The change in estimated glomerular filtration rate (eGFR) before and after intervention in the TRF group (Δ = 3.1 ± 5.3 ml/min/1.73m2) showed significant improvement compared with the CD group (Δ = -0.8 ± 4.4 ml/min/1.73m2). Furthermore, the TRF group had a significant decrease in uric acid (Δ = -70.8 ± 124.2 μmol/L), but an increase in total protein (Δ = 1.7 ± 2.5 g/L), while the changes were inconsistent for inflammatory factors. In addition, the TRF group showed a significant decrease in body weight (Δ = -2.8 ± 2.9kg) compared to the CD group, and body composition indicated the same decrease in body fat mass, fat free mass and body water. Additionally, TRF shifted the gut microbiota in a positive direction. Preliminary studies suggest that overweight and obese patients with moderate-to-severe CKD with weight loss needs, and who were under strict medical supervision by healthcare professionals, performed TRF with good compliance. They did so without apparent adverse events, and showed efficacy in protecting renal function. These results may be due to changes in body composition and alterations in gut microbiota.

Response Evaluation Criteria in Tumors of the Bladder (RECIT-Bladder) for future window of opportunity trials as a platform to accelerate drug development.

571 Background: There are abundant potential permutations of novel or combination therapeutics that could be tested in non-muscle invasive bladder cancer (NMIBC), but the ability to study these therapies is limited. Window of opportunity trials (WOOT) may accelerate otherwise costly and slow drug evaluation by testing response to treatment during the time between the surveillance office cystoscopy that diagnoses a recurrent tumor and removal by transurethral resection (TURBT), but the accuracy of endoscopic tumor measurement is unknown. Through an iterative process modifying the RECIST criteria used for metastatic cancer response assessment; we developed RECIT-Bladder as a short-term endpoint for NMIBC WOOTs. Here, we report the feasibility and reproducibility of paired tumor measurement at office cystoscopy and TURBT in “untreated” patients as the development cohort for RECIT-Bladder. Methods: Bladder tumors were measured at office cystoscopy and again at formal TURBT in a standardized fashion compared to a calibrated object (flexible biopsy forceps). If multiple tumors were present, the two largest, measurable, representative tumors were measured. Patients were excluded if tumor location did not allow for accurate measurement (e.g., bladder neck) or if the lesion was not amenable to measurement (e.g., diffuse CIS or papillary carpeting). Results: We characterized 69 papillary tumors from 34 patients (4 patients with recurrent tumors included ≥2 times). 38% (13/34) had LGTa and the remainder had high grade (HG) bladder cancer (1 CIS, 15 HGTa, 2 HGT1, and 1 HGT2). 98.6% (68/69) were measurable at TURBT. There was a median 23 (16-37 IQR) days between cystoscopy and TURBT during which lesion size increased by a median 0.25 mm (0-0.1mm IQR, p=0.4). Measurements on cystoscopy and at TURBT were highly correlated (correlation coefficient 1.04, p&lt;0.01, r2 = 0.88). There was no correlation between tumor growth and time between cystoscopy and TURBT (correlation coefficient 0.00, p=0.5, r2 = 0.00). MSK-IMPACT targeted exome sequencing was available in 62% of patients (21/34) of whom 71% (15/21) had an FGFR3 mutation (median growth 1 mm over median 23 days). Conclusions: Using a standardized protocol (RECIT-Bladder), tumor measurement at office cystoscopy and follow-up TURBT appears precise and reproducible. RECIT-Bladder may offer a practical short-term clinical trial endpoint for evaluating progression, stable disease, or response to therapy. If validated, RECIT-Bladder offers a pathway to rapidly discover novel therapeutic agents. We have begun a prospective multi-surgeon protocol to validate these results and evaluate potential pharmacodynamic endpoints. RECIT-Bladder is also currently being assessed in the context of an ongoing investigator-initiated WOOT testing oral erdafitinib in FGFR3 altered recurrent NMIBC (NCT04917809).

Efficacy of lumateperone in pooled short-term late-phase clinical trials for treatment of major depressive episodes associated with bipolar II disorder

Efficacy of lumateperone in pooled short-term late-phase clinical trials for treatment of major depressive episodes associated with bipolar II disorder

A Flexible Ensemble Learning Method for Survival Extrapolation.

Survival extrapolation is an important statistical concept for estimating long-term survival from short-term clinical trial data. It is widely used in health technology assessment (HTA). Survival extrapolation is often performed by fitting one or two parametric models selected based on experience or selecting a model based on some goodness of fit statistics from a predefined collection of models. The main challenge in survival extrapolation is that the result is sensitive to model misspecification. In this study, we aim to propose a new approach that has a robust performance for survival extrapolation. We propose a new method called Ensemble Learning for Survival Extrapolation (ELSE). Instead of selecting one best model from a predefined collection, ELSE builds an ensemble model based on a collection of models from the model library. Under this framework, we construct a point estimate of the long-term survival with a weighted average of the estimates of all candidate models and derive confidence intervals using nonparametric bootstrap. With our extensive numerical simulation studies, the proposed ELSE method shows better performance than the traditionally used model selection procedure based on Akaike Information Criterion (AIC). With a real data application to the Therapeutically Applicable Research to Generate Effective Treatment Wilms Tumor project (TARGET-WT) data, the ELSE method produces better survival extrapolation results in point estimate accuracy and confidence interval coverage. We developed an ensemble learning method for survival extrapolation (ELSE) which is robust for the underline data model and has good real data performance.

Efficacy and Safety of Peginterferon Alfa-2b in 95 Patients with Myeloproliferative Neoplasms:a Single Center Retrospective Analysis

Background Polycythemia vera (PV) and essential thrombocythemia (ET) are a common type of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) driven by the JAK2,CALR or MPL mutation, which are associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution to myelofibrosis and acute myeloid leukemia. Pegylated interferon has obtained high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 allele burden lies within the timeline of most studies. Objective To investigate the efficacy and safety of Peginterferon alfa-2b in patients with myeloproliferative neoplasms Methods The clinical data of 95 patients with MPNs treated with Peginterferon alfa-2b in Peking Union Medical College Hospital (Beijing, China) from January 2018 to May 2022 were retrospectively analyzed. Peginterferon alfa-2b was administered subcutaneously once weekly at a starting dose of 180ug, and could be decreased over time to 180ug every 2 to 4 weeks if hematological control was achieved. Hematological control was defined as HCT<45% in the absence of phlebotomy in patients with PV and PLT<400x109/L in patients with ET. Molecular response was defined as JAK2 allele burden decreased＞50% from baseline (partial remission) or undetectable at a lower limit of quantitation at 1% by the central laboratory (complete remission) which was measured by next-generation sequencing Results Among the 95 patients, 48 were male and 47 were female. There were 61 cases of PV and 34 cases of ET. The median age at diagnosis was 45 (17-69) years, and the median time from onset to diagnosis was 5.1 (0-413) months. All patients had next-generation sequencing for the driver mutations, there were 84 cases of JAK2 mutation, 8 cases of CALR mutation, 1 case of MPL mutation, and 2 cases of triple negative. The median duration of Peginterferon alfa-2b exposure was 13.2（2~51）months. 54 (88.5%) of 61 patients with PV achieved hematological control and 24 (70.6%) of 34 patients with ET achieved hematological control. The median onset of action was 1.4 (0.5-6.7) months. 47 patients with JAK2 mutation were detected with JAK2 allele burden for molecular evaluation. A total of 17 (36.2%) patients obtained molecular partial remission by 6 months and 26 (55.3%) patients achieved molecular partial remission by 12 months while no one achieved molecular complete remission. The most common treatment-emergent adverse events were influenza-like symptoms (88.4%), hyperglobulinemia (14.7%), elevated alanine aminotransferase (13.7%), and subclinical hypothyroidism (7.4%). A total of 4 patients (4.2%) discontinued the treatment, 2 due to intolerance of adverse effects, 1 due to disease progression to myelofibrosis, and 1 due to pregnancy. Conclusion This study demonstrates that Peginterferon alfa-2b was safe, well tolerated, and efficacious in patients with PV and ET. Keywords: Peginterferon alfa-2b, myeloproliferative neoplasms, hematological control molecular response

Evaluation of emerging NASH therapies: the impact of treatment efficacy profiles on long-term health outcomes.

Aim: Evaluations of nonalcoholic steatohepatitis (NASH) treatments require predicting lifetime outcomes from short-term clinical trials. Materials & methods: A Markov model with NASH fibrosis stages F0-F3, NASH resolution, compensated cirrhosis (F4/CC), and liver-related complication (LRC) states was developed using literature-based standard of care (SoC) data. Hypothetical efficacy profiles were defined affecting resolution (100%-increase), fibrosis improvement (100% increase), or fibrosis worsening (50% decrease). Results: For the SoC, 10-year LRC rates increased with baseline fibrosis stage (F1: 3.0%; F2: 9.8%; F3: 27.2%; F4/CC: 64.9%). The fibrosis worsening profile reduced predicted 10-year LRC rates (F1: 1.9%; F2: 6.5%; F3: 19.1%; F4/CC: 55.0%) more than the resolution and fibrosis improvement profiles (F1: 2.6%/2.6%; F2: 8.5%/8.3%; F3: 23.3%/23.0%; F4/CC: NA/59.0%). Scenario analyses considered alternative SoC progression, treatment efficacy and treatment-stopping rules. Conclusion: Potential NASH efficacy profiles have differing impacts on predicted long-term outcomes, providing insights for future stakeholders.

Adherence patterns in naïve and prevalent use of infliximab and its biosimilar

IntroductionAlthough short-term clinical trials have demonstrated that switching from infliximab (INF) bio-originator to its biosimilar is safe with no significant loss of efficacy, there are limited real-world data comparing their patterns of use and adherence.MethodsUsing 2015–2018 IBM Marketscan data, we established 4 cohorts of patients with at least one administration or pharmacy claim for INF bio-originator or biosimilar in 2017, including INF naïve biosimilar users, INF prevalent biosimilar users, INF naïve bio-originator users, and INF prevalent bio-originator users, defined according to their prior use of INF from 2015 to their first INF administration in 2017. The proportion of days covered (PDC) was calculated for patients with at least 6, 12, or 18 months of follow-up time. Factors associated with optimal adherence (PDC > 80%) were evaluated using log-binomial models.ResultsWe identified 96 INF naïve biosimilar users, 223 INF prevalent biosimilar users, 2,149 INF naïve bio-originator users, and 10,970 INF prevalent bio-originator users. At the end of 18 months of follow-up, 64% of INF prevalent bio-originators, 48% of INF naïve biosimilars, 41% of INF naïve bio-originators, and 36% of INF prevalent biosimilars had optimal adherence. Depression, previous hospitalization, and greater use of prior biologics were negatively associated with adherence, whereas IBD diagnoses (referent to RA) and age 55–64 (referent to < 35) were positively associated with high adherence.ConclusionINF prevalent users had higher adherence in our analyses than INF naïve users. However, further studies with larger sample size are needed to evaluate INF biosimilar users’ adherence.

Effectiveness of Dry Needling and Ischemic Trigger Point Compression in the Gluteus Medius in Patients with Non-Specific Low Back Pain: A Randomized Short-Term Clinical Trial.

Background: The presence of latent myofascial trigger points (MTrPs) in the gluteus medius is one of the possible causes of non-specific low back pain. Dry needling (DN) and ischemic compression (IC) techniques may be useful for the treatment of these MTrPs. Methods: For this study, 80 participants were randomly divided into two groups: the dry needling group, who received a single session of DN to the gluteus medius muscle plus hyperalgesia (n = 40), and the IC group, who received a single session of IC to the gluteus medius muscle plus hyperalgesia (n = 40). Pain intensity, the pressure pain threshold (PPT), range of motion (ROM), and quality of life were assessed at baseline, immediately after treatment, after 48 h, and one week after treatment. Results: Statistically significant differences were shown between the two groups immediately after the intervention, showing a decrease in PPT (p < 0.05) in the DN group and an increase in PPT in the IC group. These values increased more and were better maintained at 48 h and after one week of treatment in the DN group than in the IC group. Quality of life improved in both groups, with greater improvement in the DN group than in the IC group. Conclusions: IC could be more advisable than DN with respect to UDP and pain intensity in the most hyperalgesic latent MTrPs of the gluteus medius muscle in subjects with non-specific low back pain, immediately after treatment. DN may be more effective than IC in terms of PPT, pain intensity, and quality of life in treating latent plus hyperalgesic gluteus medius muscle MTrPs in subjects with non-specific low back pain after 48 h and after one week of treatment.