Least-squares Mean Difference Research Articles

A Randomized Controlled Trial of Mobile Health Intervention in Patients With Heart Failure and Diabetes

Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials. We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM). We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling. The mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change -0.08 in mHealth vs -0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P < 0.05). In patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence. Heart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P < 0.05). These data have important implications for designing effective lifestyle interventions in HF and DM.

Efficacy and Safety of Add-on Mirogabalin to NSAIDs in Lumbar Spinal Stenosis with Peripheral Neuropathic Pain: A Randomized, Open-Label Study.

IntroductionIn Japan, conservative therapy for patients with lumbar spinal stenosis (LSS) includes non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandin E1, tramadol, physical/exercise therapy, and nerve blocks. Mirogabalin, a selective oral α2δ ligand, is approved for treating peripheral neuropathic pain, though data regarding visual analog scores (VAS) for pain in patients with LSS are limited. We investigated the efficacy and safety of mirogabalin as an add-on treatment in patients with LSS taking NSAIDs compared with patients taking NSAIDs only.MethodsThis multicenter, randomized, open-label study (MiroTAS) was conducted at 32 centers in Japan between June 2020 and October 2021. Patients were randomly assigned to mirogabalin and NSAIDs or NSAIDs alone in a 1:1 ratio. NSAIDs were administered according to their Japanese package inserts; mirogabalin was administered based on renal function [creatinine clearance (CrCL) ≥ 60 mL/min, 5 mg twice daily (BID) in Weeks 1–2, 10 mg BID in Weeks 3–4, and 15 or 10 mg BID after Week 5; CrCL 30 to < 60 mL/min, 2.5 mg BID Weeks 1–2, 5 mg BID Weeks 3–4, and 7.5 or 5 mg BID after Week 5]. The primary endpoint was the change in VAS score for leg pain from baseline to Week 12. Secondary endpoints were quality of life, evaluated using the EuroQol five-dimensional descriptive system (EQ-5D-5L) (at baseline and Week 12) and Patient Global Impression of Change (PGIC) (at Week 12), and safety. Change in VAS score at Week 12 was calculated using a linear mixed model for repeated measures. The safety endpoints were treatment-emergent adverse events (TEAEs) and adverse drug reactions.ResultsIn total, 220 patients who met the eligibility criteria were enrolled. In the mirogabalin and NSAIDs and NSAIDs groups, mean ages (67.8 vs. 70.9 years), proportions of female patients (54.5% vs. 49.0%), mean body weights (63.9 vs. 62.0 kg), mean CrCL values (81.5 vs. 70.7 mL/min), proportions of patients with CrCL 30 to < 60 mL/min (27.3% vs. 33.7%), mean VAS scores (63.8 vs. 62.8 mm), and proportions of patients with VAS score ≥ 60 (53.6% vs. 52.9%) at enrollment were similar. The median durations of LSS were 9.0 and 11.0 months and the spine pain DETECT questionnaire (SPDQ) scores were 6.8 and 7.8, respectively. The least square (LS) mean change in VAS score from baseline to Week 12 was − 24.1 mm in the mirogabalin and NSAIDs group and − 14.2 mm in the NSAIDs group (both P < 0.0001 vs. baseline). The difference in LS mean was − 9.9 [95% confidence interval (CI), − 18.0, − 1.8] (P = 0.0174). The improvement in EQ-5D-5L score at Week 12 was significantly greater in the mirogabalin and NSAIDs group versus the NSAIDs group [mean difference, 0.0529 (95% CI, 0.0036, 0.1022), P = 0.0357]. At Week 12, the proportions of patients with PGIC scores ≤ 3 and ≤ 2 were higher in the mirogabalin and NSAIDs group vs. the NSAIDs group (76.2% vs. 50.0%, P = 0.0006, and 47.6% vs. 32.4%, P = 0.0523). In the mirogabalin and NSAIDs group, the incidences of TEAEs and adverse drug reactions were 60.9% and 57.3%, respectively, and the most common TEAEs were somnolence (30.0%) and dizziness (25.5%).ConclusionsThe addition of mirogabalin to NSAIDs improved VAS, EQ-5D-5L, and PGIC. The main TEAEs were somnolence and dizziness. The addition of mirogabalin to NSAIDs improved peripheral neuropathic pain associated with LSS and raised no new safety concerns.Trial RegistrationJapan Registry of Clinical Trials (jRCTs021200007).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40122-022-00410-z.

Comparing a daily versus weekly titration algorithm in people with type 2 diabetes switching from basal insulin to iGlarLixi in the LixiLan ONE CAN randomized trial.

AimTo compare the efficacy and safety of a simple daily titration algorithm compared with a weekly dose adjustment of iGlarLixi in people with type 2 diabetes.Materials and MethodsLixiLan ONE CAN (NCT03767543), a randomized, 26‐week, open‐label, multicentre phase 3 trial conducted in Canada, involved 265 people with type 2 diabetes and an HbA1c of ≥7.5% to ≤ 10.5% or less (≥58 to ≤91 mmol/mol) on basal insulin for 6 months or longer. Participants were randomized 1:1 with instructions to self‐titrate iGlarLixi daily (1 unit/day) or once weekly (2 or 4 units/week) to a common target fasting plasma glucose of 4.4 to 5.6 mmol/L (79 to 101 mg/dl). The primary objective was to show non‐inferiority of the daily versus weekly titration algorithm.ResultsAt 26 weeks, daily titration of iGlarLixi was not inferior to a weekly titration for both the prespecified primary endpoint of change in HbA1c from baseline (least square [LS] mean change: −1.24% vs. −0.92%, respectively; LS mean difference: 0.32%; 95% CI [0.07, 0.57]; P < .0001) and for the secondary endpoint of change in weight from baseline (LS mean change: −0.22 vs. +0.81 kg, respectively; LS mean difference: 1.03 kg; 95% CI [0.01, 2.06]; P < .0001). Indeed, for both the primary and secondary outcome, the daily titration of iGlarLixi was superior. There were no statistically significant differences in hypoglycaemia incidence between the two titration strategies during the 26‐week study.ConclusionA daily titration algorithm for switching basal insulin to iGlarLixi was shown to be non‐inferior and superior for glycaemic control and weight compared with weekly titration.

Efficacy and safety of self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (MND-2119) versus highly purified eicosapentaenoic acid ethyl ester in patients with hypertriglyceridemia: Results from a 12-week randomized, double-blind, active-controlled, phase 3 study

BackgroundIn Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E, which can be administered once-daily. ObjectiveThe objective of this study was to assess non-inferiority in the efficacy of MND-2119 in patients with hypertriglyceridemia compared with highly purified EPA-E. MethodsIn this multicenter, 12-week, double-blind study, patients with high triglyceride (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=145), MND-2119 4 g/day (n=145), EPA-E 1.8 g/day (n=145) or EPA-E 2.7 g/day (n=145). The primary endpoint was percentage change in TG levels from baseline to end of treatment. ResultsMND-2119 2, 4 g/day and EPA-E 1.8, 2.7 g/day reduced TG levels from baseline by −10.09%, −15.51%, −9.30%, and −8.80%, respectively. The TG reduction rate of MND-2119 2 g/day was non-inferior to that of EPA-E 1.8 g/day (LS mean difference: -0.42, 95%CI: -5.76 to 4.91). Moreover, the TG reduction rate of MND-2119 4 g/day was superior to that of MND-2119 2 g/day (LS mean difference: -5.74, 95%CI: -10.59 to -0.89). There were no remarkable safety differences between MND-2119 2 g/day and EPA-E 1.8 g/day and between MND-2119 4 g/day and EPA-E 2.7 g/day. ConclusionNon-inferiority of MND-2119 2 g/day to EPA-E 1.8 g/day for efficacy, and superiority of MND-2119 4 g/day over MND-2119 2 g/day for efficacy were verified. MND-2119 was safe and well tolerated.

Health-related quality of life (HRQoL) impact of pembrolizumab (pembro) plus best supportive care (BSC) versus placebo (PBO) plus BSC as second-line (2L) therapy in patients (pts) in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study.

4088 Background: In the randomized, double-blind, phase 3 KEYNOTE-394 trial (NCT03062358), pembro + BSC vs PBO + BSC as 2L therapy significantly reduced the risk of death by 21% (HR 0.79, 95% CI 0.63-0.99, P= 0.0180), prolonged PFS (HR 0.74, 95% CI 0.60-0.92, P= 0.0032), and improved ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P= 0.00004) with a manageable safety profile in pts in Asia with advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy. Here we present the results of prespecified exploratory HRQoL analyses. Methods: EORTC QLQ-C30 and EuroQol-5D3L (EQ5D-3L) questionnaires were administered at baseline (BL); wks 3, 6, 9, 12, 18; every 9 wks thereafter up to 1 yr or end of treatment; at treatment discontinuation, and at the 30-day safety follow-up visit. Pts who received ≥1 dose of study treatment and completed ≥1 HRQoL assessment were included in the analyses. Least squares mean (LSM) score changes from BL to wk 12 were compared using a constrained longitudinal data analysis model, including treatment by study visit interaction and stratification factors as covariates. Kaplan-Meier method was used to estimate time to deterioration (TTD) (time to 1st onset of ≥10-point decline from BL/confirmed by a 2nd adjacent ≥10-point decline from BL) for EORTC QLQ-C30 global health status (GHS)/QoL. Stratified Cox proportional hazards model was used to assess the magnitude of the treatment difference (HR) between treatment arms in TTD with nominal, one-sided P value calculated. Results: The HRQoL population included 450 pts (298 pembro; 152 PBO). HRQoL compliance rate at wk 12 was 95.7% for pembro for both questionnaires and 94.4% for EORTC QLQ-C30 and 95.3% for EQ5D-3L for PBO. There was a statistically significant difference in LSM for change from BL to wk 12, between the two arms for the QLQ-C30 GHS/QoL score and EQ-5D VAS score, with more decline observed in the PBO arm. Difference in LSM for QLQ-C30 GHS/QoL score between pembro (-3.97; 95% CI, -6.38, -1.56) and PBO (-8.40; 95% CI, -11.71, -5.10) arms was 4.43 (95% CI, 0.47, 8.40; P= 0.0142). Difference in LSM for EQ-5D VAS score between pembro (-2.74; 95% CI, -4.51, -0.96) and PBO (-6.94; 95% CI, -9.40, -4.48) arms was 4.20 (95% CI, 1.21, 7.19; P= 0.0030). GHS/QOL mean scores generally remained stable over time in pembro arm. TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (HR, 0.85; 95% CI, 0.58, 1.25; P= 0.1993). Conclusions: Over 12 wks, pts treated with PBO + BSC showed more decline in HRQoL than those receiving pembro + BSC. Combined with the efficacy and safety results from KEYNOTE-394, as well as other global 2L trials with pembro, including KEYNOTE-240 and KEYNOTE-224, our data support the benefit of pembro as 2L therapy for pts with advanced HCC. Clinical trial information: NCT03062358.

A multicenter, randomized, double-blind, phase III trial comparing denosumab biosimilar QL1206 and denosumab in patients with bone metastases from solid tumors.

2526 Background: This phase III study compared clinical efficacy, safety of the first biosimilar QL1206 with denosumab in solid tumor patients with bone metastases. Methods: Patients aged 18-80 years, with bone metastatic solid tumors and ECOG performance status of 0-2 were randomly assigned 1:1 to receive subcutaneous QL1206 or denosumab (120 mg Q4W, both) based on stratification factors (tumor types, previous skeletal-related event [SRE], and current systemic anti-tumor therapy). The primary efficacy endpoint was the percentage changes from baseline to week 13 in urinary N-telopeptide/creatinine ratio (uNTX/uCr); Clinical equivalence would be confirmed if the two-sided 90% confidence intervals (CI) of the least-squares mean (LSM) difference of natural log-transformed ratio of week 13 uNTX/uCr to baseline calculated by analysis of covariance were within the margins of ±0.135. The secondary endpoints included the percentage changes from baseline to week 25 and 53 in uNTX/uCr, the percentage changes from baseline to week 13, 25 and 53 in serum bone-specific alkaline phosphatase (s-BALP) and the time to on-study SRE. Adverse events (AE), immunogenicity (IG) and pharmacokinetics (PK) were also assessed. Population PK was analyzed using nonlinear mixed effects model. Results: 717 patients were randomized to the QL1206 (n = 357) and denosumab (n = 360) groups, respectively. The median percentage changes at week 13 in uNTX/uCr were -75.2% for QL1206 and -75.8% for denosumab. LSM of natural log-transformed ratio of week 13 uNTX/uCr to baseline were -1.429 (standard error 0.130) and -1.441 (0.130) in the two groups. The LSM difference between the two groups was 0.012 (90% CI -0.078 to 0.103; P = 0.8208), within the equivalence margins. Analyses for subgroups of sex, age, and randomization strata showed almost no significant differences. The secondary endpoints were also similar between the two groups (median percentage changes in s-BALP from baseline to week 13: -38.0% vs -37.1%; hazard ratio of time to SRE: 1.264 [95% CI 0.670 to 2.383]; both P &gt; 0.05). In the safety set, treatment-emergent AE occurred in 332 of 356 patients (93.3%) in the QL1206 group and 348 of 361 (96.4%) in the denosumab group. The proportions of positive anti-drug antibody (14/345 [4.1%] vs 16/352 [4.5%]), neutralizing antibody (three [0.9%], each), and PK characteristics were similar between the two groups. Conclusions: The results suggest that QL1206, the first biosimilar denosumab, is similar to denosumab with respect to clinical efficacy, acceptable safety, IG, and PK characteristics. The totality of evidence supports clinical equivalence of QL1206 and denosumab. Clinical trial information: NCT04550949.

Health-related quality of life (HRQoL) with pembrolizumab (pembro) in resected high-risk stage II melanoma in the phase 3 KEYNOTE-716 study.

9581 Background: Adjuvant pembro improved RFS vs placebo (HR, 0.61; 95% CI, 0.45-0.82) and had manageable safety in patients (pts) with resected high-risk stage II melanoma at second interim analysis of KEYNOTE-716 (NCT03553836). HRQoL results are presented. Methods: Pts aged ≥12 y with resected stage IIB/C melanoma were randomized 1:1 to adjuvant pembro 200 mg (2 mg/kg for pts ≥12 and &lt; 18 y) Q3W or placebo for ≤17 cycles. Change from baseline in HRQoL was an exploratory end point. EORTC QLQ-C30 and EQ-5D-5L were administered at baseline; cycles 5, 9, 13, and 17 in y 1; every 12 wk in y 2; and every 6 mo in y 3. The HRQoL population included all pts who received ≥1 dose of study treatment and had ≥1 HRQoL assessment available. Least-squares mean (LSM) change from baseline to wk 48 in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) and physical functioning (PF) and EQ-5D-5L visual analog scale (VAS) were calculated using a constrained longitudinal data analysis model; HRQoL score was the response variable with treatment by time interaction and T stage at baseline as covariates. Empirical mean change from baseline in QLQ-C30 GHS/QoL and PF scores over time was evaluated. A ≥10-point improvement or decline in QLQ-C30 scores was considered clinically meaningful. Data cutoff was June 21, 2021. Results: Of 976 pts enrolled, 969 were included in the HRQoL population (483 pembro; 486 placebo). Median follow-up in the ITT population was 20.5 mo (range, 4.6-32.7). At wk 48, compliance (adherence) for EORTC QLQ-C30 was 83.4% for pembro and 89.3% for placebo and completion was 70.6% and 75.7%, respectively. At wk 48, compliance for EQ-5D-5L was 84.1% for pembro and 90.0% for placebo and completion was 71.2% and 76.3%, respectively. QLQ-C30 GHS/QoL and PF and EQ-5D-5L VAS scores were similar between arms at baseline. LSM change from baseline to wk 48 in QLQ-C30 GHS/QoL score was −4.49 (95% CI, −6.19 to −2.79) for pembro and −0.82 (95% CI, −2.47 to 0.83) for placebo (LSM difference: −3.67; 95% CI, −5.91 to −1.44). LSM change from baseline to wk 48 in QLQ-C30 PF score was −3.27 (95% CI, −4.61 to −1.92) for pembro and −1.77 (95% CI, −3.07 to −0.46) for placebo (LSM difference: −1.50; 95% CI, −3.33 to 0.32). LSM change from baseline to wk 48 in EQ-5D-5L VAS score was −2.19 (95% CI, −3.52 to −0.85) for pembro and −0.25 (95% CI, −1.54 to 1.04) for placebo (LSM difference: −1.94; 95% CI, −3.72 to −0.16). LSM change from baseline to wk 48 in other QLQ-C30 functioning and symptom scales was similar in both arms. Empirical mean change from baseline in QLQ-C30 GHS/QoL and PF was similar over 96 wk in both arms. Conclusions: No clinically meaningful decreases in EORTC QLQ-C30 or EQ-5D-5L VAS scores were observed for adjuvant pembro or placebo. These results, along with improved RFS and manageable safety, support the use of adjuvant pembro in resected high-risk stage II melanoma. Clinical trial information: NCT03553836.

Cariprazine’s efficacy in treating affective symptoms – pooled data from schizophrenia and bipolar depression trials

IntroductionAffective symptoms are a common feature of schizophrenia and define bipolar disorder. Alterations in dopamine neurotransmission and activity at D3-D2 receptors is associated with depressive symptoms providing the rationale for targeting D3-D2 receptors with partial agonists.ObjectivesThe aim of the analysis herein is to examine and compare the efficacy of cariprazine in treating affective symptoms in both schizophrenia and bipolar depression.MethodsData from 3 schizophrenia [NCT00694707, NCT01104766, NCT01104779] and 3 bipolar I depression studies [NCT013896447, NCT02670538, NCT0267055] were pooled for the analyses. To investigate efficacy across individual affective symptoms, the Marder anxiety/depression and negative symptom items of the Positive and Negative Syndrome Scale (PANSS) and single items of the Montgomery-Asberg Depression Rating Scale (MADRS) were analysed. Improvement across affective symptoms was examined primarily evaluating least square mean differences (LSMDs) in comparison to placebo in mean change from baseline.ResultsThe pooled ITT population was comprised of persons with schizophrenia (placebo=442, cariprazine=1024) and bipolar disorder (placebo=460, cariprazine=923). Cariprazine resulted in a significantly greater reduction when compared to placebo in three out of the four Marder anxiety/depression items; anxiety (p&lt;0.01), tension (p&lt;0.001) and depression (p&lt;0.05). Similarly, cariprazine was significantly better than placebo in 9 out of the 10 MADRS individual items; apparent sadness (p&lt;0.001), reported sadness (p&lt;0.001), reduced sleep (p&lt;0.05), reduced appetite (p&lt;0.001), concentration difficulties (p&lt;0.001), lassitude (p&lt;0.001), inability to feel (p&lt;0.001), pessimistic thoughts (p&lt;0.01) and suicidal thoughts (p&lt;0.05).ConclusionsThe results herein indicate that cariprazine treatment is significantly effective at treating affective symptoms in persons with both schizophrenia and bipolar I depression.DisclosureI am an employee of Gedeon Richter Plc.

Efficacy and Safety of AXS-05 (Dextromethorphan-Bupropion) in Patients With Major Depressive Disorder

Objective: Altered glutamatergic neurotransmission has been implicated in the pathogenesis of depression. This trial evaluated the efficacy and safety of AXS-05 (dextromethorphan-bupropion), an oral N-methyl-D-aspartate (NMDA) receptor antagonist and σ1 receptor agonist, in the treatment of major depressive disorder (MDD).Methods: This double-blind, phase 3 trial, was conducted between June 2019 and December 2019. Patients with a DSM-5 diagnosis of MDD were randomized in a 1:1 ratio to receive dextromethorphan-bupropion (45 mg-105 mg tablet) or placebo, orally (once daily for days 1-3, twice daily thereafter) for 6 weeks. The primary endpoint was the change from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Other efficacy endpoints and variables included MADRS changes from baseline at week 1 and 2, clinical remission (MADRS score ≤ 10), clinical response (≥ 50% reduction in MADRS score from baseline), clinician- and patient-rated global assessments, Quick Inventory of Depressive Symptomatology-Self-Rated, Sheehan Disability Scale, and quality of life measures.Results: A total of 327 patients were randomized: 163 patients to dextromethorphan-bupropion and 164 patients to placebo. Mean baseline MADRS total scores were 33.6 and 33.2 in the dextromethorphan-bupropion and placebo groups, respectively. The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36; P = .002). Dextromethorphan-bupropion was superior to placebo for MADRS improvement at all time points including week 1 (P = .007) and week 2 (P < .001). Remission was achieved by 39.5% of patients with dextromethorphan-bupropion versus 17.3% with placebo (treatment difference, 22.2; 95% CI, 11.7 to 32.7; P < .001), and clinical response by 54.0% versus 34.0%, respectively (treatment difference, 20.0%; 95% CI, 8.4%, 31.6%; P < .001), at week 6. Results for most secondary endpoints were significantly better with dextromethorphan-bupropion than with placebo at almost all time points (eg, CGI-S least-squares mean difference at week 6, -0.48; 95% CI, -0.48 to -0.79; P = .002). The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, headache, somnolence, and dry mouth. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction.Conclusions: In this phase 3 trial in patients with MDD, treatment with dextromethorphan-bupropion (AXS-05) resulted in significant improvements in depressive symptoms compared to placebo starting 1 week after treatment initiation and was generally well tolerated.Trial Registration: ClinicalTrials.gov Identifier: NCT04019704.

0383 Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With High Burden of Narcolepsy Symptoms

Abstract Introduction This post hoc analysis evaluated the clinical impact of pitolisant for the reduction of excessive daytime sleepiness (EDS) and cataplexy in adults with a high burden of narcolepsy symptoms. When evaluating results of randomized, placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen’s d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person). Methods Data were pooled from 2 randomized, placebo-controlled, 7- and 8-week studies of pitolisant (individually titrated; potential maximum dose, 35.6 mg/day) in adults with narcolepsy. Analyses included 3 independent patient subgroups with high symptom burden: (1) baseline score of ≥16 on the Epworth Sleepiness Scale (ESS), (2) sleep latency of ≤8 minutes on the Maintenance of Wakefulness Test (MWT), and (3) ≥15 cataplexy attacks per week. Efficacy measures included the ESS, MWT, weekly rate of cataplexy (WRC), and Clinical Global Impression of Change (CGI-C). Cohen’s d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Missing values were imputed using a last observation carried forward approach. Results The high-burden populations included 118 patients for the ESS subgroup (pitolisant, n=60; placebo, n=58), 105 for MWT (pitolisant, n=59; placebo, n=46), and 31 for cataplexy (pitolisant, n=20; placebo, n=11). Cohen’s d effect size values for pitolisant versus placebo were 0.80 for ESS, 0.31 for MWT, and 1.31 for WRC. NNTs for pitolisant were 3 for ESS score reduction (≥3-point decrease from baseline or final score ≤10) in the ESS subgroup and 2 for WRC reduction (≥50% decrease from baseline) in the cataplexy subgroup. For the CGI-C for EDS (“much” or “very much” improved), NNT was 5 in the ESS subgroup and 4 in the MWT subgroup; for the CGI-C for cataplexy, NNT was 3 in the cataplexy subgroup. Conclusion The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction of both EDS and cataplexy in patients with severe narcolepsy symptom burden. Support (If Any) Bioprojet Pharma and Harmony Biosciences, LLC.

A prospective study on the difference of clinical outcomes between elderly and adult patients with allergic rhinitis

ObjectiveThe guiding significance of existing guidelines for the diagnosis, treatment and health management of AR in elderly patients is unclear. The aim of this study is to analyze the clinical characteristics and therapeutic effects of elderly and adult AR patients by prospective study. MethodsA total of 131 AR patients were recruited and divided into elderly group and adult group according to age. After receiving the same pharmacological treatment for 4 weeks, the differences of the two groups in clinical scores including TNSS-4, RQLQ and VAS were compared. ResultsAfter 4 weeks treatment, all clinical scores in the adult group were improved compared with the baseline levels, while in the elderly group, only the TNSS-4 score was significantly reduced, and the RQLQ and VAS scores were not significantly improved. The changes of TNSS-4, RQLQ, and VAS scores in the elderly group were significantly inferior to those in the adult group (LS mean differences were 1.60, 8.80, and 11.10, respectively; P < 0.001). ConclusionWe confirmed that elderly and adult AR patients had different clinical characteristics and outcomes, and the degree of improvement in the adult group was significantly better than that in the elderly group. Therefore, it is urgent for us to establish a clinical guideline suitable for the elderly AR population to give more scientific and reasonable recommendations for diagnosis and treatment.

Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease.

The goal of this work was to determine whether locally acting ACE-083 is safe and well tolerated and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1. This phase 2 study enrolled adults with CMT1 or CMTX (N = 63). Part 1 was open label and evaluated the safety and tolerability of different dose levels of ACE-083 for use in part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally into the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-m walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests. In part 1 (n = 18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious adverse events, TEAEs of grade 3 or greater, or death reported. In part 2 (n = 45 enrolled, n = 44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (least-squares mean difference 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate to mild injection-site reactions were the most common TEAEs. Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo. Clinical Trials Registration: NCT03124459. This study provides Class II evidence that intramuscular ACE-083 is safe and well tolerated and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

Efficacy and Safety of LY2963016 Insulin Glargine in Chinese Patients with Type1 Diabetes Previously Treated with Insulin Glargine (Lantus®): a Post Hoc Analysis of a Randomized, Open-Label, Phase3 Trial.

IntroductionLY2963016 insulin glargine (LY IGlar), a biosimilar of Lantus® insulin glargine (IGlar), demonstrated comparable efficacy and safety versus the reference product in Chinese patients with type 1 diabetes mellitus (T1DM) in the randomized, phase III ABES trial. This post hoc analysis aimed to provide the first evidence for switching from IGlar to LY IGlar in Chinese patients with T1DM.MethodsThis analysis included 210/272 patients with T1DM (77.2%) from the ABES trial who were receiving IGlar at screening. We compared antihyperglycemic efficacy, safety, and immunogenicity in patients randomized to LY IGlar (n = 104) versus those who continued to receive IGlar (n = 106).ResultsThere was no significant difference between groups in least-squares mean (LSMean) change in HbA1c from baseline to 24 weeks (LY IGlar − 0.10%, IGlar − 0.08%; LSMean difference [95% confidence interval] − 0.02% [− 0.24, 0.19]). At 24 weeks (last observation carried forward), a similar proportion of patients in each group achieved glycated hemoglobin less than 7.0% (LY IGlar 26.5%, IGlar 32.1%; P = 0.447) and 6.5% or less (LY IGlar 16.7%, IGlar 20.8%; P = 0.482). There were no significant differences between groups in LSMean of self-monitored blood glucose values, or total or basal insulin dose at 24 weeks. Patients in the LY IGlar and IGlar groups had a similar incidence of total hypoglycemia (blood glucose level 70 mg/dL or less, 91.4% vs. 92.5%) and treatment-emergent adverse events (AEs; 75.0% vs. 67.0%), and a low and similar incidence of serious AEs, injection site AEs, and allergic AEs. Similar proportions of patients in the LY IGlar and IGlar groups had treatment-emergent antibody responses (LY IGlar 27.2%, IGlar 28.3%) and detectable insulin antibodies (LY IGlar 52.4%, IGlar 53.8%).ConclusionIn Chinese patients with T1DM previously treated with IGlar, switching to LY IGlar for 24 weeks resulted in similar efficacy and safety outcomes as remaining on IGlar therapy.Clinical Trial RegistrationNCT03338023.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01262-8.

Use of a Liquid Supplement Containing 2 Human Milk Oligosaccharides: The First Double-Blind, Randomized, Controlled Trial in Pre-term Infants.

There is growing evidence supporting the benefit of human milk oligosaccharides (HMOs) on reducing risk of illnesses and improving immune function in newborn infants, but evidence in pre-term infants is lacking. This randomized, double-blind, placebo-controlled trial (NCT03607942) of pre-term infants evaluated the effects of HMO supplementation on feeding tolerance, growth, and safety in 7 neonatal units in France. Pre-term infants (27–33 weeks' gestation, birth weight <1,700 g) were randomized early after birth to receive HMO supplement (n = 43) [2′-fucosyllactose (2′FL) and lacto-N-neotetraose (LNnT) in a 10:1 ratio (0.374 g/kg body weight/day)] or an isocaloric placebo (n = 43) consisting of only glucose (0.140 g/kg/day) until discharge from the neonatal unit. Anthropometric z-scores were calculated using Fenton growth standards. Primary outcome was feeding tolerance, measured by non-inferiority (NI) in days to reach full enteral feeding (FEF) from birth in HMO vs. placebo group (NI margin = 4+ days). Mean number of days on intervention prior to FEF was 8.9 and 10.3 days in HMO and placebo, respectively. Non-inferiority in time to reach FEF in HMO (vs. placebo) was achieved [LS mean difference (95% CI) = −2.16 (−5.33, 1.00); upper bound of 95% CI < NI margin] in full analysis set and similar for per protocol. Adjusted mean time to reach FEF from birth was 2 days shorter in HMO (12.2) vs. placebo (14.3), although not statistically significant (p = 0.177). There was no difference in weight-for-age z-scores between groups throughout the FEF period until discharge. Length-for-age z-scores were higher in HMO at FEF day 14 [0.29 (0.02, 0.56), p = 0.037] and 21 [0.31 (0.02, 0.61), p = 0.037]. Head circumference-for-age z-score was higher in HMO vs. placebo at discharge [0.42 (0.12, 0.71), p = 0.007]. Occurrence of adverse events (AEs) was similar in both groups and relatively common in this population, whereas 2.3 and 14.3%, respectively, experienced investigator-confirmed, related AEs. HMO supplementation is safe and well-tolerated in pre-term infants. After 9 days of supplementation, the HMO group reached FEF 2 days earlier vs. placebo, although the difference was not statistically significant. In addition, HMO supplementation supports early postnatal growth, which may have a positive impact on long-term growth and developmental outcomes.

Changes in acute headache medication use and health care resource utilization: Results from a randomized, double-blind, placebo-controlled clinical trial evaluating galcanezumab in adults with treatment-resistant migraine (CONQUER).

BACKGROUND: Patients with migraine, particularly with multiple prior preventive treatment failures, often have high rates of acute headache medication use and are at risk for overuse (acute or symptomatic headache medication use between 10 and 15 days per month [depending on the medication] for > 3 months). Furthermore, these patients have greater health care resource utilization (HCRU). OBJECTIVE: To examine acute headache medication use and HCRU with galcanezumab compared with placebo in a population with multiple prior migraine preventive treatment failures. METHODS: In the 3-month double-blind phase, patients with episodic or chronic migraine and treatment failures to 2 to 4 standard-of-care migraine preventive categories (lack of effectiveness or safety/tolerability) received galcanezumab 120 mg/month (following a 240-mg loading dose) or placebo; an optional 3 month open-label phase followed. Acute headache medication use (monthly days with acute headache medication utilization) was self-reported daily. The change from baseline in monthly days with acute headache medication used a mixed-model repeated measures analysis. HCRU was reported at baseline (for the previous 6 months) and at monthly visits. Migraine-related HCRU rates were evaluated in the total population per 100 patient-years. RESULTS: Of the 462 patients (galcanezumab n=232, placebo n=230), baseline mean days/month of acute headache medication was 12.3; 44.8% had acute headache medication overuse. Across months 1-3, least squares (LS) mean reductions in acute headache medication use were greater for the galcanezumab group (4.2) compared with placebo (0.9); the LS mean difference was 3.4 (95% CI = 2.7-4.1; P < 0.0001). Greater reductions in the galcanezumab group were observed as early as month 1; statistical separation continued at months 2 and 3 (all P < 0.0001). During the open-label phase, reductions from baseline ranged from 4.7 to 5.3 days and were similar in patients who transitioned from placebo to patients continuing galcanezumab. Reductions from baseline of migraine-specific health care visits (double-blind phase) were numerically greater with galcanezumab than placebo (215.5 vs 155.3). Patients switching to galcanezumab had reductions (212.9 days) similar to patients continuing galcanezumab (222.6 days). Migraine-specific emergency department visits decreased by two-thirds at month 3 in the galcanezumab group compared with nearly no reduction in the placebo group that experienced a similar reduction during the open-label phase. For both groups, migraine-specific hospitalizations were less than 2 per 100 patient-years. CONCLUSIONS: These results demonstrate that galcanezumab has the potential to reduce acute headache medication use and overuse and HCRU in patients with prior migraine preventive treatment failures. DISCLOSURES: Data were presented in part as a poster presentation at the 14th European Headache Congress (European Headache Federation), Virtual Meeting, July 3-5, 2020. Dr Ambrosini is on the advisory board for Eli Lilly and Company and received honorarium from Teva, Novartis, and Eli Lilly and Company. Dr Estemalik is on the advisory boards for Eli Lilly and Company, Lundbeck, and Allergan and the speakers' bureau for Teva, Lundbeck, Eli Lilly and Company, Allergan, and Biohaven. He received consulting fees from Eli Lilly and Company, Teva, Lundbeck, and Allergan and support for attending meetings and/or travel from Eli Lilly and Company, Allergan, Biohaven, Teva, and Lundbeck. Dr Pascual received research support from Instituto de Salud Carlos III, Ministry of Economy, Spain. He was also on advisory boards for Allergan, Amgen-Novartis, Eli Lilly and Company, and Stendhal and received consulting fees or honoraria from Allegan, Eli Lilly and Company, Novartis-Amgen, and Teva. Dr Rettiganti is an employee of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. She is also a minor stock and restricted stockholder of Eli Lilly and Company. Mr. Stroud and Ms. Day are employees of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. Dr Ford is an employee of and holds stock of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. She also received support for attending meetings and/or travel from Eli Lilly and Company.

Ixekizumab Citrate-Free Formulation: Results from Two Clinical Trials

IntroductionSubcutaneous (SC) injection is a common route of drug administration; however, injection site pain (ISP) might create a negative patient experience. We evaluated ISP, bioequivalence, and overall safety of the citrate-free (CF) formulation of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A.MethodsTwo phase 1, single-blind studies were conducted in healthy participants. The crossover study A (NCT03848403) evaluated pain intensity on injection as measured by visual analog scale of pain (VAS) scores. Subjects (N = 70) were randomized 1:1:1 at the beginning to three possible treatment sequences and received a 1 mL SC injection of the three formulations sequentially in the abdomen on days 1, 8, and 15, respectively. A mixed-effects repeated measures analysis model was used to analyze VAS score by time post-injection. Study B (NCT04259346) evaluated the bioequivalence of a single 80 mg dose of CF formulation compared to the original commercial formulation. Subjects (N = 245) were randomized 1:1 to either commercial or CF formulation and received a single SC injection into the abdomen, arm, or thigh.ResultsPrimary endpoint was achieved in both studies. In study A, least-squares mean (LSM) difference of VAS scores immediately post injection between commercial (n = 61) and CF formulation (n = 63) was − 21.7 (p < 0.0001), indicating a lower degree of pain associated with CF formulation. In study B, bioequivalence of the CF formulation was established as 90% CIs for the ratio of geometric LSM AUC0–tlast, AUC0–∞, and Cmax between treatments were contained within the prespecified limits of 0.8 and 1.25. Except for less ISP in the CF formulation, overall safety profile was comparable.ConclusionIxekizumab CF formulation proved to be bioequivalent, was associated with less ISP, and had no other notable differences in the safety profile compared to the original commercial formulation.Trail RegistrationClinicalTrials.gov identifier NCT03848403, NCT04259346. Video Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02126-0.

The Interplay between Multimorbidity, Physical Work Demands and Work Ability: Cross-Sectional Study among 12,879 Senior Workers.

Background: Aging increases the risk of chronic diseases, which can challenge the ability to work and thereby push senior workers out of the labour market. This study investigates the association between non-communicable diseases (NCDs) and work ability among workers ≥50 years (senior workers) with physically demanding and sedentary work, respectively. Methods: In the SeniorWorkingLife study, 12,879 senior workers replied to a questionnaire survey on work and health in 2018. Associations between the type and number of NCD and work ability (scale 0–10) were modelled using a general linear model adjusting for potential confounders and combined with model-assisted weights from national registers. Results: A higher number of NCD (multimorbidity) was progressively associated with a lower work ability (trend test, p-value < 0.001). Physical work influenced the association between the number of NCDs and work ability. For specific diseases, mental disorders, including burn-out syndrome (least square mean difference (LSMD): −1.46, 95% CI: −1.61 to −1.32) and stress ( LSMD: −1.18, 95% CI: −1.29 to −1.07), demonstrated a stronger association with a lower work ability compared with somatic diseases, such as back diseases (LSMD: −0.72, 95% CI: −0.80 to −0.64). Conclusions: Multimorbidity was progressively associated with a lower work ability in senior workers, especially among those with physical work.

Biosimilar Insulin Aspart Premix SAR341402 Mix70/30 Versus Originator Insulin Aspart Mix70/30 (NovoMix30) in People with Diabetes: A 26-Week, Randomized, Open-Label Trial (GEMELLIM).

IntroductionThis study compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (SARAsp-Mix) with European-approved insulin aspart mix 70/30 − NovoMix® 30 (NN-Mix) in people with type 1 (T1D) or type 2 diabetes (T2D).MethodsThis 26-week, open-label, phase 3 trial enrolled 402 people with T1D (n = 105) or T2D (n = 297) previously treated with premix insulin, who were randomized (1:1) to SARAsp-Mix (n = 204) or NN-Mix (n = 198).ResultsAfter 26 weeks, the least squares (LS) mean [median] change in HbA1c from baseline was similar in both treatment groups (SARAsp-Mix − 0.55% [− 0.60%]; NN-Mix − 0.64% [− 0.60%]). The LS mean difference for SARAsp-Mix versus NN-Mix was 0.08%, with the upper bound of the two-sided 95% confidence interval (− 0.139 to 0.303) slightly above the prespecified noninferiority margin of 0.3%. Noninferiority of SARAsp-Mix over NN-Mix was not demonstrated in the primary intent-to-treat analysis, primarily because of one extreme outlying value impacted by the COVID-19 pandemic in the SARAsp-Mix group. Noninferiority was achieved in all secondary analyses, including prespecified per-protocol supportive and COVID-19 sensitivity analyses, as well as post hoc sensitivity analyses. Other efficacy endpoints, insulin dosages, anti-insulin aspart antibody response, hypoglycemia, and adverse events were similar between groups.ConclusionsThe totality of evidence indicates that SARAsp-Mix provides effective glycemic control with a similar safety and immunogenicity profile to NN-Mix in people with diabetes treated for 26 weeks.Trial RegistrationEudraCT number 2017-000092-84.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01255-7.

Tafamidis Reduces The Decline In Longitudinal Strain And Stroke Volume In Patients With Transthyretin Amyloid Cardiomyopathy

<h3>Introduction</h3> Left ventricular (LV) longitudinal strain and stroke volume are significant predictors of mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and CV-related hospitalizations. Further analysis of changes in echocardiographic measures in ATTR-ACT may provide additional insight into the efficacy of tafamidis. <h3>Hypothesis</h3> Treatment with tafamidis significantly reduces the worsening of echocardiographic variables including LV longitudinal strain and stroke volume in ATTR-CM patients. <h3>Methods</h3> In ATTR-ACT, ATTR-CM patients (variant or wild-type) were treated with tafamidis 80 mg (n=176) or placebo (n=177) for 30 months. Echocardiography was conducted at enrollment, and at Months 6, 18 and 30, using a standardized protocol and analyzed by an independent central laboratory. We compared changes in LV stroke volume (SV), global longitudinal strain (GLS) and mitral inflow E wave/annular diastolic early (e') wave (E/e') in patients treated with tafamidis 80 mg (the approved dose) vs placebo. <h3>Results</h3> Baseline mean (SD) SV (mL), GLS (%) and septal and lateral E/e' were similar in the tafamidis and placebo groups (<b>Table</b>). Each measure worsened over the duration of the trial, as shown by least-squares (LS) mean (SE) change from baseline at Month 30 for each group (<b>Table</b>). This decline was more pronounced in placebo-treated patients, with a significant reduction in LS mean difference (95% CI) with tafamidis vs placebo for each measure (<i>P</i><0.05 for all). Decline in SV and GLS was apparent from Month 6 in all patients; difference between tafamidis and placebo groups was apparent from Month 18. Decline in E/e' (indicative of elevated LV filling pressures) was apparent from Month 6 with placebo but only minimally changed with tafamidis at each time point; difference between tafamidis and placebo was apparent from Month 6. <h3>Conclusions</h3> LV longitudinal strain and stroke volume are significant predictors of mortality in ATTR-CM patients. Treatment with tafamidis significantly reduced worsening progression of LV systolic (GLS, SV) and diastolic function (E/e') over 30 months in ATTR-CM patients. These echocardiographic data provide additional insight into the efficacy of tafamidis.

Randomized Ablation-Based Rhythm-Control Versus Rate-Control Trial in Patients With Heart Failure and Atrial Fibrillation: Results from the RAFT-AF trial.

Atrial fibrillation (AF) and heart failure (HF) frequently coexist and can be challenging to treat. Pharmacologically based rhythm control of AF has not proven to be superior to rate control. Ablation-based rhythm control was compared with rate control to evaluate if clinical outcomes in patients with HF and AF could be improved. This was a multicenter, open-label trial with blinded outcome evaluation using a central adjudication committee. Patients with high-burden paroxysmal (>4 episodes in 6 months) or persistent (duration <3 years) AF, New York Heart Association class II to III HF, and elevated NT-proBNP (N-terminal pro brain natriuretic peptide) were randomly assigned to ablation-based rhythm control or rate control. The primary outcome was a composite of all-cause mortality and all HF events, with a minimum follow-up of 2 years. Secondary outcomes included left ventricular ejection fraction, 6-minute walk test, and NT-proBNP. Quality of life was measured using the Minnesota Living With Heart Failure Questionnaire and the AF Effect on Quality of Life. The primary analysis was time-to-event using Cox proportional hazards modeling. The trial was stopped early because of a determination of apparent futility by the Data Safety Monitoring Committee. From December 1, 2011, to January 20, 2018, 411 patients were randomly assigned to ablation-based rhythm control (n=214) or rate control (n=197). The primary outcome occurred in 50 (23.4%) patients in the ablation-based rhythm-control group and 64 (32.5%) patients in the rate-control group (hazard ratio, 0.71 [95% CI, 0.49-1.03]; P=0.066). Left ventricular ejection fraction increased in the ablation-based group (10.1±1.2% versus 3.8±1.2%, P=0.017), 6-minute walk distance improved (44.9±9.1 m versus 27.5±9.7 m, P=0.025), and NT-proBNP demonstrated a decrease (mean change -77.1% versus -39.2%, P<0.0001). Minnesota Living With Heart Failure Questionnaire demonstrated greater improvement in the ablation-based rhythm-control group (least-squares mean difference of -5.4 [95% CI, -10.5 to -0.3]; P=0.0036), as did the AF Effect on Quality of Life score (least-squares mean difference of 6.2 [95% CI, 1.7-10.7]; P=0.0005). Serious adverse events were observed in 50% of patients in both treatment groups. In patients with high-burden AF and HF, there was no statistical difference in all-cause mortality or HF events with ablation-based rhythm control versus rate control; however, there was a nonsignificant trend for improved outcomes with ablation-based rhythm control over rate control. URL: https://www. gov; Unique identifier: NCT01420393.