Mixed-effects Model For Repeated Measures Research Articles

Design and Rationale of Prolonged Nightly Fasting for Multiple Myeloma Prevention (PROFAST): Protocol for a Randomized Controlled Pilot Trial.

Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy. We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM). Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibilityis assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast. The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025. PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention. ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638. DERR1-10.2196/51368.

Guselkumab provides durable improvement across psoriatic arthritis disease domains: post hoc analysis of a phase 3, randomised, double-blind, placebo-controlled study

ObjectiveEvaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA).MethodsPost hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase...

Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.

116 Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer

BackgroundIn monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. MethodsPatients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. ResultsAt baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69–78 %) reported being bothered “a little bit” or “not at all” by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. ConclusionPRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

The effects of treatment with pimavanserin on activities of daily living in patients with Parkinson's disease psychosis: a 16-week, single-arm, open-label study.

More than half of patients with Parkinson's disease will experience psychosis symptoms in the form of hallucinations or delusions at some point over the course of their disease. These symptoms can significantly impact patients' health-related quality of life, cognitive abilities, and activities of daily living (ADLs) and function. Clinical assessment of how psychosis impacts these measures is crucial; however, few studies have assessed this sufficiently, in part due to a lack of appropriate scales for comprehensively assessing function. The objective was to assess how symptoms of Parkinson's disease psychosis (PDP) impact ADLs and function, cognitive function, and health-related quality of life. To address this unmet need, we utilized a modified version of the Functional Status Questionnaire (mFSQ) to measure the impact of psychosis on ADLs and function in patients with PDP treated with pimavanserin, a US Food and Drug Administration-approved medication to treat hallucinations and delusions associated with PDP. Eligible patients entered a 16-week, single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. The primary endpoint was change from baseline to Week 16 on the mFSQ. Secondary endpoints included the Movement Disorders Society-modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I and II; Schwab and England ADL; Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I), and were also measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares mean (LSM). Our results in a proof-of-concept, 16-week, open-label clinical study in 29 patients demonstrated that an improvement in psychosis symptoms following treatment with pimavanserin was associated with improvements in multiple measures of ADLs and function. Notably, a significant improvement was found on the primary endpoint, change from baseline to Week 16 in mFSQ score [LSM [SE] 14.0 [2.50], n = 17; 95% CI (8.8, 19.3); p < 0.0001]. These findings highlight the potential for improvement in function with improvement of psychosis symptoms in patients with PDP and suggest that the mFSQ may be a measurement tool to evaluate the level of improvement in function. ClinicalTrials.gov Identifier: NCT04292223.

Left atrial strain is reduced following trastuzumab in breast cancer patients.

The effect of trastuzumab therapy on left atrial (LA) function remains largely unknown. Our aim was to assess the changes in LA strain parameters longitudinally in patients treated with trastuzumab. We retrospectively studied 170 patients with stage I-IV HER2+ breast cancer. All patients had baseline echocardiograms and repeat echocardiograms at 3months and after 1year. We measured LA strain at all three time points. Changes in LA strain and strain rate (sr) parameters were evaluated using repeated-measures mixed-effects models. The cohort was stratified according to development of cancer therapeutics-related cardiac dysfunction (CTRCD) during follow-up. The mean age was 52.7±13.8years, 25.3% had hypertension and 16.0% had metastatic disease. Multiple LA strain parameters (predicted delta value, [95%CI]) showed statistically significant declines in patients who developed CTRCD from baseline to the 3-month follow-up after multivariable adjustment; LA reservoir strain (LAεres ): -4.7%; [-8.1% to -1.3%], p=.007; LA conduit strain (LAεcon ): -2.8%; [-5.3% to -.4%], p=.021); and LAεres sr: -.2/s; [-.3/s to -.09/s], p<.001). In patients who did not develop CTRCD, LA strain parameters declined significantly but to a smaller degree than in the CTRCD group (LAεres : -1.7%; [-3.1% to -.3%], p=.020, LAεcon : -2.2%; [-3.3% to -1.1%], p<.001, and LA booster pump strain : -2.4%; [-3.5% to -1.4%], p<.001). LA strain rates did not decline significantly in the non-CTRCD group. Trastuzumab treatment was associated with declines in LA strain parameters in patients with breast cancer. The largest declines were observed in patients who developed CTRCD during treatment.

Contribution of Hypersensitivity to Postureteroscopy Ureteral Stent Pain: Findings From Study to Enhance Understanding of Stent-associated Symptoms

To examine the relationships between preoperative hypersensitivity to pain and central sensitization, and postoperative ureteral stent pain after ureteroscopy (URS) for urinary stones. Adults enrolled in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS) underwent quantitative sensory testing (QST) prior to URS and stent placement. Hypersensitivity to mechanical pain was assessed using a pressure algometer. Participants rated their pain intensity to pressure applied to the ipsilateral flank area and lower abdominal quadrant on the side of planned stent placement, and the contralateral forearm (control). Pressure pain thresholds were also assessed. Central sensitization was assessed by applying a pointed stimulator (pinprick) and calculating the temporal summation. Postoperative stent pain intensity and interference were assessed using PROMIS questionnaires. Data were analyzed using repeated-measures mixed-effects linear models. Among the 412 participants, the median age was 54.0years, and 46% were female. Higher preoperative pain ratings to 2 kg and 4 kg mechanical pressure to the ipsilateral flank and abdominal areas were associated with higher postoperative stent pain intensity with the stent in situ. Greater degree of central sensitization preoperatively, manifesting as higher temporal summation, was associated with higher postoperative pain intensity. Factors associated with preoperative hypersensitivity on QST included female sex, presence of chronic pain conditions, widespread pain, and depression. Hypersensitivity to pain and central sensitization preoperatively was associated with postoperative ureteral stent pain, suggesting a physiologic basis for stent symptom variation. QST may identify patients more likely to develop stent pain after URS and could inform selection for preventive and interventional strategies.

Estimating Treatment Effects of Disease‐modifying Drugs: Traditional Methods vs. Accelerated Failure Time Models and Progression Analysis

AbstractBackgroundProgression models for repeated measures (PMRM1) are a class of statistical models that enable estimation of slowing of progression of Alzheimer’s disease, expressed as percentage or time delay. Similarly, accelerated failure time (AFT) models can estimate relative expected time until progression when evaluating disease‐modifying therapies. We compared these methods to mixed‐effects models for repeated measures (MMRM) and Cox time‐to‐event analysis on simulated trial data, evaluating their power and the difference in interpretation when expressing outcomes as a measure of time.MethodPrimary outcomes were Clinical Dementia Rating (CDR) Sum of Boxes (MMRM and PMRM) and time to progression to dementia as assessed by CDR global (Cox regression and AFT models). Weibull and log‐logistic distributions were assumed for random error distribution in AFT models.Subject‐level placebo arm trajectories were jointly simulated based on estimated CDR mean trajectories and joint temporal correlation structure of 538 amyloid‐positive MCI patients meeting typical disease‐modifying trial inclusion criteria from the ADNI study. Active arm trajectories were simulated to show an average 20% slowing of disease progression vs placebo at each visit. A thousand simulations were conducted across scenarios, varying number of subjects per arm (200‐700) and clinical trial duration (18‐36 months).ResultPower of PMRM was shown to be consistently greater than that of MMRM (Table 1). The AFT and Cox models’ power rarely exceeded 40%.PMRM accurately estimated the underlying 20% slowed progression. With greater sample sizes and at least 2 years of follow‐up, the AFT models indicated a slowing of progression, but the median estimated slowing was 5%. The MMRM and Cox model found median estimated reduction in decline of 25% and median estimated hazard ratios of 0.88‐0.91, respectively.ConclusionsPMRM and AFT models estimate slowing of progression. Compared to the MMRM and Cox model, these time‐based models better capture the effect of disease‐modifying therapies and facilitate translation of results to patients and their care partners. Among all methods studied, the PMRM offered the best combination of interpretability and power.

Autoantibodies to Erythropoietin Receptor and Clinical Outcomes in Patients With Type 2 Diabetes and CKD: A Post Hoc Analysis of CREDENCE Trial

IntroductionAuto-antibodies to erythropoietin receptor (anti-EPOR antibodies) have been identified in patients with various kidney diseases. However, data in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) is limited. We assessed the prevalence of anti-EPOR antibodies and their association with clinical outcomes in this population. MethodsThe CREDENCE randomized patients with T2D and CKD to canagliflozin or placebo. Serum anti-EPOR antibodies, the exposure of interest, were measured using enzyme-linked immunosorbent assay. The primary outcome was doubling of serum creatinine, end-stage kidney disease, or death from kidney or cardiovascular causes. Secondary outcomes included cardiovascular and all-cause mortality. Multivariable Cox-regression models estimated associations between anti-EPOR antibodies and outcomes. The effects of canagliflozin on hemoglobin and hematocrit stratified by the presence of anti-EPOR antibodies were assessed with a repeated measures mixed effects model. ResultsOf 2600 participants with available biosamples, 191 (7.3%) were positive for anti-EPOR antibodies. Higher baseline anti-EPOR antibodies were associated with increased risk of primary outcome (HR per 1-SD increase 1.12 [95%CI 1.01, 1.24], p=0.04), cardiovascular death (HR 1.27 [1.08, 1.48], p<0.01) and all-cause mortality (HR 1.26 [1.11, 1.43], p<0.01). During follow-up, canagliflozin, compared to placebo, increased hemoglobin and hematocrit by 7.0g/L (6.2, 7.9) and 2.4% (2.2, 2.7), respectively. These effects were consistent across patients with and without anti-EPOR antibodies (P-interaction=0.39 and 0.70). ConclusionIn patients with T2D and CKD, anti-EPOR antibodies were associated with the composite kidney and cardiovascular outcome, as well as cardiovascular and all-cause mortality. Canagliflozin increased hemoglobin and hematocrit regardless of anti-EPOR antibodies.

Patient-Reported Outcomes in Acute Myeloid Leukemia Patients with FLT3-ITD Mutation Receiving Quizartinib Vs. Standard Chemotherapy: Results from the Quantum-First Trial

Introduction: QuANTUM-First (NCT02668653) is a multicenter, global, randomized, double-blind phase 3 clinical trial evaluating the efficacy and safety of the novel oral fms-like tyrosine kinase 3 inhibitor (FLT3i) quizartinib in combination with standard induction and consolidation chemotherapy, and as maintenance monotherapy for up to 36 cycles in patients 18-75 years old with FLT3-ITD positive acute myeloid leukemia (AML). Quizartinib demonstrated a clinically meaningful and statistically significant improvement in overall survival (OS) versus placebo. An exploratory endpoint of the trial was to assess the impact of quizartinib on patient-reported outcomes (PROs). This is the first report of the longitudinal results of the PRO measures (PROMs) collected in the QuANTUM-First trial. Methods: Patients were randomized to receive chemotherapy + quizartinib or chemotherapy + placebo. PROMs were the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) and EuroQol EQ-5D-5L. Baseline measurement was collected on day 8 of the first induction cycle, and repeated measurements were collected on day 28 of induction cycles 1-2, day 6 and 28 of consolidation cycles 1-4, and day 1 of continuation cycles 1-34 at 3-cycle intervals. EORTC QLQ-C30 and EQ-5D-5L scores were calculated as per their respective scoring manuals and included mean (95% CI, p-value) score for each domain of the EORTC QLQ-C30 and EQ-5D-5L index score, as well as mean change from baseline score at each timepoint. A minimal clinically important difference (MCID) score ≥10 points for each domain of the EORTC QLQ-C30, was considered clinically meaningful. A mixed-effect model for repeated measures (MMRM) and time until definitive deterioration (TUDD) was used to assess the longitudinal impact of treatment on PROs. TUDD was defined as time from baseline PRO score to first deterioration of the score beyond the MCID as compared to the baseline without further improvement of more than one MCID as compared to the reference score or without any further available score. Results: A total of 509 out of 539 patients from the trial (254 quizartinib; 255 placebo) were included for PRO analysis. Patient compliance to questionnaire completion at the beginning of each phase was high and similar for both arms and most scales (Global Health Status [GHS] completion rate (%) on induction cycle 1, consolidation cycle 1, and continuation cycle 1: 99.2, 95.3, 93.4, respectively) Baseline PRO scores were comparable between arms and were lower than the general population norm EORTC QLQ-C30 and EQ-5D-5L scores for EU and US (Table 1). Per MMRM, there were clinically meaningful improvements from baseline in GHS (Figure 1) and fatigue in both arms. However, there was no significant difference between arms for the change from baseline score although placebo arm had numerically better scores specifically during the maintenance phase (treatment difference for quizartinib - placebo was -2.0 [95% CI: -4.8, 0.7], p=0.1479 for GHS and 3.0 [95% CI: -0.1, 6.1], p=0.0600 for fatigue). Similar trends towards clinically meaningful improvement in score over time for both arms and no significant differences between arms were observed in most of the functional and symptom scales of EORTC QLQ-C30 and EQ-5D-5L index scores. By TUDD analysis, quizartinib arm showed slower deterioration in several scales (specifically GHS, cognitive function, appetite loss, and constipation) but the differences did not reach statistical significance. Conclusions: QuANTUM-First is the first study to explore the impact of quizartinib on PROs. Quizartinib showed improvement in OS without any detrimental impact on quality of life and symptoms when added to standard chemotherapy followed by maintenance monotherapy in patients with newly diagnosed FLT3-ITD AML.

Patient-Reported Outcomes Measures, Polycystic Kidney Disease Burden, and Outcomes in Autosomal Dominant Polycystic Kidney Disease

Rationale & ObjectiveUsing OVERTURE (NCT01430494) study data on patient-perceived health, healthcare utilization, and productivity in autosomal dominant polycystic kidney disease (ADPKD), this research was conducted to characterize the burden of illness in ADPKD patients and assess whether patient-reported outcomes (PRO) assessment scores predict clinical and health-economic outcomes. Study DesignAnalyses of data from a prospective, observational study. Setting & ParticipantsThe study cohort comprised 3409 individuals with ADPKD in 20 countries, ages 12–78 years, in chronic kidney disease (CKD) stages G1–G5 and Mayo risk subclasses 1A–1E. PredictorsScores on PRO instruments, including disease-specific assessments (ADPKD-Impact Scale [ADPKD-IS], ADPKD-Urinary Impact Scale [ADPKD-UIS]) and generic measures. OutcomesClinical variables (e.g., height-adjusted total kidney volume [htTKV], estimated glomerular filtration rate [eGFR], abdominal girth) and health-economic outcomes. Analytical ApproachAssociations among variables were evaluated using Spearman correlations, logistic regression, and generalized linear mixed-effects repeated-measures models. ResultsBaseline CKD stage and Mayo risk classification showed little correlation with baseline PRO scores, although scores on disease-specific instruments and measures of physical functioning were worse at more severe CKD stages. PRO scores predicted hospitalizations and sick days at 6–18 months, with associations strongest for the ADPKD-IS. Whereas PRO scores were not associated with htTKV and eGFR, worse PRO scores were associated with greater abdominal girth. Poor baseline ADPKD-IS scores were positively associated with occurrence of ADPKD-related symptoms up to 18 months, including kidney pain (odds ratio [OR] 5.30, 95% confidence interval [CI] 2.75–10.24), hematuria (OR 4.58, 95% CI 1.99–10.53), and urinary tract infection (OR 4.41, 95% CI 1.93–10.11; P<0.001 for all). LimitationsMaximum 18 months of follow-up to assess outcomes. ConclusionsPRO scores predicted clinical and health-economic outcomes such as hospitalization and absence from work, underscoring the importance of quality of life assessment of individuals with ADPKD.

Teclistamab Improves Patient-Reported Symptoms and Health-Related Quality of Life in Relapsed or Refractory Multiple Myeloma: Results From the Phase II MajesTEC-1 Study

IntroductionPatients with relapsed or refractory multiple myeloma (RRMM) report significantly lower HRQoL compared with patients with newly diagnosed MM and experience further deterioration in HRQoL with each relapse and subsequent treatment. Therefore, consideration of the impact of treatment on HRQoL in addition to clinical outcomes is vital. Patients and MethodsIn the phase I/II MajesTEC-1 (NCT03145181, NCT04557098) study, patients with RRMM who received teclistamab, an off-the-shelf, T-cell redirecting BCMA × CD3 bispecific antibody, had deep and durable responses with manageable safety. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30-item and the EuroQol 5 Dimension 5 Level descriptive questionnaire. Changes over time from baseline were measured with a repeated measures mixed-effects model. Proportions of patients with clinically meaningful improvement after starting treatment and time to clinically meaningful worsening were assessed. ResultsCompliance was maintained throughout the study. Compared with baseline, positive changes were observed for pain, global health status, and emotional functioning with treatment; other assessments were largely unchanged from baseline. Post hoc analysis showed patients with deeper clinical response generally reported improved HRQoL outcomes. Following an initial decline in HRQoL in some scales, the proportion of patients reporting clinically meaningful improvements increased, while the proportion reporting clinically meaningful worsening decreased over time. Clinically meaningful improvements in pain were reported in ≥40% of patients at most assessment time points. ConclusionsThese results complement previously reported clinical benefits and support teclistamab as a promising therapeutic option for patients with RRMM.

The effect of ibudilast on thalamic volume in progressive multiple sclerosis

Background: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). Objective: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). Methods: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. Results: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = −0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). Conclusion: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome’s clinical importance.

Eicosapentaenoic acid, arachidonic acid, and triglyceride levels mediate most of the benefit of icosapent ethyl in REDUCE-IT

Abstract Background In REDUCE-IT, icosapent ethyl (IPE) reduced major adverse cardiovascular (CV) events (MACE) relative to placebo (PBO) in 8179 statin-treated patients with residual hypertriglyceridemia and high CV risk. Questions have been raised about the mechanisms of benefit of IPE and the potential effects of the pharmaceutical grade mineral oil PBO on the results. Purpose The contributions of eicosapentaenoic acid (EPA), arachidonic acid (AA), triglycerides (TG), and other biomarkers (listed in Table 1) to MACE reduction by IPE relative to PBO were quantified via mediation analyses to illustrate the mechanisms of IPE. Methods Patients were randomised 1:1 to IPE 4 g/day or PBO and followed for a median 4.9 years. For a biomarker to be a mediator, there had to be both a treatment group difference on the biomarker and an association between the biomarker and risk of MACE. For the first condition, treatment group differences in change from baseline in each biomarker were analysed by mixed effects repeated measures models. For the second condition, time-varying values of each biomarker were related to the risk of MACE by calculating the time-weighted moving average (TWMA) for each variable, using all values for a given patient. Each was analysed in a Cox regression model with time to MACE as the outcome and TWMA values as time-varying covariates. The individual and joint mediation of those biomarkers determined to be mediators were assessed in Cox models that included treatment assignment. Biomarkers individually found to be ³10% mediators in absolute terms were included in the multivariable models. If biomarkers that would otherwise be included in multivariable models were strongly correlated (baseline values R2&amp;gt;0.5), the marker with the greatest univariate mediation was included. All analyses were intention-to-treat. Results IPE reduced MACE by 25% (HR (95% CI) = 0.75 (0.68, 0.83), p&amp;lt;0.0001). Treatment group differences on all potential mediators had p&amp;lt;0.05, and all but oxLDL were significantly related to MACE (p&amp;lt;0.05). Analyses of individual biomarkers showed EPA to be the strongest single mediator (Table 1). EPA, AA, and TG jointly mediated 78.9% of the IPE treatment effect, with EPA driving most of the mediation (57% as a single mediator). The marginal mediation by the remaining 3 biomarkers was 4.5% of the treatment effect, for total joint mediation of 83.4% (Figure 1). Conclusion In this mediation analysis of REDUCE-IT, most of the IPE benefit on MACE reduction was attributable to the two major mechanisms of the drug: (1) increasing EPA while reducing AA and, to a lesser extent, (2) reducing TG. The remainder of measured biomarker changes accounted for a minority of the benefit.Table 1Figure 1

Mediators of the benefit of sotagliflozin in patients with worsening heart failure in SOLOIST-WHF

Abstract Background In SOLOIST-WHF, the dual SGLT1 and SGLT2 inhibitor sotagliflozin (SOTA) reduced primary endpoint events – total occurrences of cardiovascular (CV) death and hospitalizations and urgent visits for heart failure (HF) – by 33% relative to placebo (PBO) among 1222 patients hospitalized for worsening HF. The extent to which treatment group differences in biomarkers assessed during study follow-up contributed to this benefit of SOTA is unknown. Purpose The contributions of 20 biomarkers (identified in published mediation analyses of SGLT2 inhibitors: HbA1c; weight; BMI; systolic and diastolic BP; heart rate; serum creatinine, urate, albumin, sodium, and magnesium; eGFR; hematocrit; hemoglobin; erythrocytes; total cholesterol; LDL-C; HDL-C; non-HDL-C; triglycerides) to the reduction of primary endpoint events by SOTA relative to PBO were quantified via mediation analyses to describe the mechanisms of SOTA. Methods Patients were randomized 1:1 to SOTA 200 mg/day (with possible increase to 400 mg/day) or PBO and followed for a median 9 months. Two conditions must be met for a biomarker to be a mediator: there had to be a treatment group difference on the biomarker and an association between the biomarker and risk of primary endpoint events. For the first condition, treatment group differences in change from baseline in each biomarker were analyzed by mixed effects repeated measures models. For the second condition, time-varying values of each biomarker were related to the risk of primary endpoint events by calculating the time-weighted moving average (TWMA) for each variable, using all values for a given patient. Each was analyzed in a competing risks marginal model for total events (stratified according to left ventricular ejection fraction at baseline and geographic region of enrollment), in which non-CV deaths were treated as competing terminal events and TWMA values were included as a time-varying covariate. The individual and joint mediation of those biomarkers determined to be mediators were assessed in competing risks marginal models that included treatment assignment. If biomarkers that would otherwise be included in multivariable models were strongly correlated (baseline values R2&amp;gt;0.5), the marker with the greatest univariate mediation was included. All analyses were intention-to-treat. Results Among the biomarkers considered, serum urate, hemoglobin, and total cholesterol met the criteria for being mediators. Serum urate was the strongest single mediator, while the joint mediation for these three biomarkers was 22.3% (Figure 1). Conclusion In SOLOIST-WHF, a fraction of the benefit of SOTA was attributable to effects on biomarkers accounting for most of the treatment benefits of other SGLT2 inhibitors on CV death and HF events. Further investigation is therefore needed to identify what unique biomarker treatment effects might account for the majority of SOTA benefit.Figure 1

Patient-reported outcomes in high-risk HR+ /HER2- early breast cancer patients treated with endocrine therapy with or without palbociclib within the randomized PENELOPEB study

BackgroundThe PENELOPEB trial investigating efficacy and safety of additional 1-year post-neoadjuvant palbociclib to standard endocrine therapy (ET) high-risk hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer patients failed to improve invasive disease-free survival (iDFS). This analysis compared patient-reported outcomes (PROs) between treatment groups. Patients and methodsPatients received 13 cycles of palbociclib 125 mg/day (n = 631) or placebo (n = 619) orally for 3 out of 4 weeks + ET. European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30), its breast cancer (BR23) and fatigue (FA13) modules, mood questionnaire GAD7 and European Quality of Life 5 Dimensions (EQ-5D) instruments were used for the assessment of quality of life (QoL). Repeated-measures mixed-effects models were used to evaluate differences in PRO, changes of PRO over time, and treatment-by-time interactions. Results924 of 1250 patients (73.9%) completed baseline and at least one post-baseline questionnaire of all PRO instruments. General health status (GHS)/QoL based on EORTC QLQ-C30 was high in both arms (mean [SD]: palbociclib 70.1 [19.3], placebo 71.4 [18.8]) and was slightly higher in the placebo arm (LeastSquare mean difference: 0.82, p < 0.001). Higher fatigue was reported in the palbociclib arm (mean [SD]: 30.3 [23.8] vs. placebo 28.3 [22.7]; p < 0.001). No statistically significant differences were observed among FA13 physical, cognitive, and emotional fatigue subscales. ConclusionPatient-reported global QoL and fatigue did not substantially change in both treatment arms. Slight differences in GHS, physical functioning, and fatigue favored the placebo arm statistically without achieving clinically meaningful thresholds.

The Efficacy of Roxadustat in Multiple Myeloma Patients with Renal Insufficiency and Anemia: A Real-World Study

Background: Anemia and renal insufficiency are two common symptoms of multiple myeloma (MM). There are currently few treatment options for anemia in MM. Renal anemia appears to be one of the causes of anemia in MM. Roxadustat is an inhibitor of hypoxia-inducible factor prolyl hydroxylase (HIF-PH) that has been proven effective to improve anemia conditions in patients with kidney disease. HIF-PH inhibition with Roxadustat may offer a novel approach to the management of anemia in MM patients with renal insufficiency. This is the first study exploring the efficacy of Roxadustat in multiple myeloma patients with renal insufficiency. Methods: The clinical data of MM patients with renal insufficiency (defined as serum creatinine (Scr) ≥177mol/L) and severe anemia (defined as Hb＜80g/L) in the First Affiliated Hospital, Zhejiang University School of Medicine were analyzed retrospectively in this study. Patients who were treated with Roxadustat complied the drug instructions. Roxadustat was administered three times a week (TIW) at a dose of 100 mg (in patients weighing 45 to 60 kg) or 120 mg (in patients weighing 60 kg) in hemodialysis patients, and 70 mg (in patients weighing 40 to 60 kg) or 100 mg (in patients weighing 60 kg) in patients not receiving hemodialysis. Mann-Whitney U, chi-square test and mixed-effect models for repeated measures (MMRM) were applied to the study. Results: Among a total of 98 MM patients with renal insufficiency (Scr≥177μmol/L) and severe anemia (Hb＜80g/L), 30 MM patients received Roxadustat treatment along with the anti-tumor treatment. The choice anti-tumor therapy was commonly consisted of combination therapy with a bortezomib, cyclophosphamide/thalidomide and dexamethasone or an equivalent regimen. 12 patients in Roxadustat group and 10 patients in control group (40.0% vs. 14.7%, P=0.006) underwent short-term or long-term hemodialysis at the start of the anti-tumor treatment. 25 patients in Roxadustat group and 59 patients in control group (83.3% vs. 86.8%, P=0.655) were newly-diagnosed MM (NDMM). The mean (standard deviation [SD]) baseline hemoglobin (Hb) levels for the Roxadustat and control groups were 62.73 (9.04) g/L and 68.03 (7.32) g/L, respectively. The mean (SD) baseline Scr levels for the Roxadustat and control groups were 441.93 (252.60) g/L and 342.53 (185.38) μmol/L, respectively. The median increase in Hb from baseline to week 4, week 8, week 12 was 5.50 versus 17.00 g/L (P＜0.001), 13.00 versus 30.50 g/L (P＜0.001), and 20.00 versus 41.00 g/L (P＜0.001) in patients from control group and Roxadustat group. Analyzing with mixed models, the interaction of time* Roxadustat was 6.77 g/L (95% CI=4.80-8.73, P＜0.001) in the whole cohort. The proportions of MM patients with Hb increases of ≥10 g/L, ≥20 g/L, and ≥30 g/L at week 12 were 39.7% (n=27) versus 70.0% (n=21) (P=0.006), 61.8% (n=42) versus 93.3% (n=28) (P=0.001), and 66.2% (n=45) versus 100% (n=30) (P＜0.001) in MM patients from control group and Roxadustat group. Roxadustat was well tolerated by MM patients with renal insufficiency and severe anemia. Metabolic acidosis (23.3% vs. 7.4%, P=0.026) and hyperkalemia (33.3% vs. 14.7%, P=0.035) occurred more frequently in the Roxadustat group than in control group. Although there was no significant difference, deep vein thrombosis occurred relatively more frequently in the Roxadustat group than in control group (16.7% vs. 7.4%, P=0.160). Conclusion: This is the first study exploring the efficacy of Roxadustat in multiple myeloma patients with renal insufficiency. According to this study, Roxadustat is well tolerated by MM patients with renal insufficiency and effectively improves their anemia conditions. Metabolic acidosis and hyperkalemia occurred more frequently in the Roxadustat group than in control group. The data indicated that Roxadustat could be proved to be a potential, effective therapy for anemia in MM patients with renal insufficiency.

Influence of CYP2C19, CYP2D6, and ABCB1 Gene Variants and Serum Levels of Escitalopram and Aripiprazole on Treatment-Emergent Sexual Dysfunction: A Canadian Biomarker Integration Network in Depression 1 (CAN-BIND 1) Study.

Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6, and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample. A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n = 91), while responders continued ESC (i.e., ESC-Only, n = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models. In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F(2,54) = 8.00, p < 0.001, q = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF (r = -0.42, p = 0.004, q = 0.034) and SS (r = -0.43, p = 0.003, q = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction (r = -0.39, p = 0.009, q = 0.052). CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Retinal and Choroidal Changes Following Implantable Collamer Lens V4c Implantation in High Myopia Patients-A 1-Year Follow-Up Study.

This prospective study aimed to evaluate the impact of Visian Implantable Collamer Lens (ICL) V4c implantation on retinal and choroidal morphology in patients with high myopia. A total of 97 eyes from 52 high myopic patients who underwent ICL V4c implantation were followed up for 12 months. Preoperative and postoperative evaluations included comprehensive ophthalmic assessments and enhanced depth imaging optical coherence tomography (EDI-OCT) to analyze changes in central retinal thickness (CRT), retinal volume (CRV), choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), and choroidal vascular index (CVI). Repeated measures mixed-effects models were used for comparing pre- and postoperative measurement variables and exploring relationships among age, axial length (AL), spherical equivalent refraction (SER), and postoperative retinal and choroidal changes, with statistical significance set at p < 0.05. Follow-up assessments were conducted at various time points, with participation rates ranging from 21% to 98%. Baseline characteristics showed a median age of 26.7 years, -10.14 diopters of SER, and an AL of 27.44 mm. Throughout the 12-month follow-up, CRT and 3.0 mm CRV consistently increased compared to the baseline, with statistically significant rises observed at postoperative day 1, week 1, and month 12. Most ChT measurements, including subfoveal ChT, declined over the 12 months, except at postoperative 6 months. Horizontal and vertical TCA and LA values significantly increased throughout the follow-up, except for month 6. After surgery, both horizontal and vertical CVI parameters exhibited an increase compared to the baseline, with some changes reaching statistical significance. Correlation analysis performed by repeated measures mixed-effects models showed that no relationship was found between age, AL, and SER and changes in postoperative retinal parameters and CVI parameters. However, postoperative changes in ChT and choroidal area parameters showed a negative correlation with AL and a positive correlation with SER. Our research demonstrated that ICL V4c implantation resulted in noteworthy alterations in retinal and choroidal morphology over a 1-year follow-up period. Moreover, in patients with high myopia, individuals with longer AL and higher degrees of myopia exhibited more pronounced postoperative changes in the choroid and retina. Further studies with extended follow-up durations are necessary to comprehensively understand the long-term effects of ICL implantation on retinal and choroidal morphology and function.

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study

BackgroundUpadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study.MethodsPatients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported.ResultsOf 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population.ConclusionsUpadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure.Trial registrationNCT02049138.