Difference In Least Squares Mean Change Research Articles

Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC).

8012 Background: Neoadjuvant pembrolizumab + cisplatin-based chemotherapy (neoadj pembro + chemo), resection, and adjuvant (adj) pembro (pembro arm; n=397) significantly improved EFS, OS, pCR, and mPR and had an expected safety profile versus neoadj placebo (pbo) + chemo, resection, and adj pbo (pbo arm; n=400) in patients (pts) with resectable stage II, IIIA, or IIIB (N2) NSCLC. We present prespecified pt-reported outcome (PRO) endpoints from KEYNOTE-671. Methods: Pts completed EORTC QLQ-C30 and QLQ-LC13 questionnaires at baseline (BL), the last scheduled presurgery visit, adj cycles 1-4, 7, 10, and 13, and each post treatment visit. A constrained longitudinal data analysis model was used to estimate least squares mean (LSM) score changes from BL to neoadj wk 11 and adj wk 10 (latest time of ≥60% completion and ≥80% compliance) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), role functioning (RF), and dyspnea and QLC-LC13 cough and chest pain in all treated pts who completed ≥1 PRO assessment. Data are from interim analysis 2 (10 Jul 2023 cutoff). Results: Across arms, questionnaire completion was ≥87% at neoadj wk 11 and ≥62% at adj wk 10; compliance was ≥87% and ≥92%, respectively. There were no differences in LSM change from BL in the neoadj or adj phase for any PRO score (Table). Conclusions: Adding perioperative pembro maintained HRQoL in both the neoadj and adj settings versus neoadj chemo and surgery alone in pts with resectable early-stage NSCLC. Together with the significant efficacy improvements and absence of new safety signals, HRQoL data support the perioperative pembro regimen as a new standard of care. Clinical trial information: NCT03425643 . [Table: see text]

Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

In patients with Alagille syndrome, cholestasis-associated clinical features can include high serum bile acids and severe pruritus that can necessitate liver transplantation. We aimed to evaluate the efficacy and safety of the ileal bile acid transporter inhibitor odevixibat versus placebo in patients with Alagille syndrome. The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries (Belgium, France, Germany, Italy, Malaysia, the Netherlands, Poland, Türkiye, the UK, and the USA). Eligible patients had a genetically confirmed diagnosis of Alagille syndrome, a history of significant pruritus, and elevated serum bile acids. Patients were randomly assigned (2:1) to receive oral odevixibat 120 μg/kg per day or placebo for 24 weeks (in a block size of six and stratified by age: <10 years and ≥10 years to <18 years) via a web-based system. Patients, clinicians, study staff, and people analysing the data were masked to treatment allocation. The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0-4) from baseline to weeks 21-24. The prespecified key secondary efficacy endpoint was change in serum bile acid concentration from baseline to the average of weeks 20 and 24. Outcomes were analysed in patients who received at least one dose of study drug (the full analysis set for efficacy outcomes and the safety analysis set for safety outcomes). This trial is registered on ClinicalTrials.gov (NCT04674761) and EudraCT (2020-004011-28), and is completed. Between Feb 26, 2021, and Sept 9, 2022, 52 patients were randomly assigned to receive odevixibat (n=35) or placebo (n=17), all of whom were included in the analysis sets. The median age was 5·5 years (IQR 3·2 to 8·9). 27 (52%) of 52 patients were male and 25 (48%) were female. The mean scratching score was elevated at baseline in both groups (2·8 [SD 0·5] for odevixibat vs 3·0 [0·6] for placebo). Mean scratching scores at weeks 21-24 were 1·1 (0·9) for odevixibat and 2·2 (1·0) for placebo, representing a least-squares (LS) mean change of -1·7 (95% CI -2·0 to -1·3) for odevixibat and -0·8 (-1·3 to -0·3) for placebo, which was significantly greater for odevixibat than for placebo (difference in LS mean change from baseline -0·9 [95% CI -1·4 to -0·3]; p=0·0024). Odevixibat also resulted in significantly greater reductions in mean serum bile acids from baseline versus placebo (237 μmol/L [SD 115] with odevixibat vs 246 μmol/L [121] with placebo) to the average of weeks 20 and 24 (149 μmol/L [102] vs 271 μmol/L [167]; LS mean change -90 μmol/L [95% CI -133 to -48] with odevixibat vs 22 μmol/L [-35 to 80] with placebo; difference in LS mean change -113 μmol/L [95% CI -179 to -47]; p=0·0012). The most common treatment-emergent adverse events were diarrhoea (ten [29%] of 35 patients in the odevixibat group vs one [6%] of 17 in the placebo group) and pyrexia (eight [23%] vs four [24%]). Seven patients had serious treatment-emergent adverse events during the treatment period: five (14%) in the odevixibat group and two (12%) in the placebo group. No patients discontinued treatment and there were no deaths. Odevixibat could be an efficacious non-surgical intervention to improve pruritus, reduce serum bile acids, and enhance the standard of care in patients with Alagille syndrome. Longer-term safety and efficacy data of odevixibat in this population are awaited from the ongoing, open-label ASSERT-EXT study. Albireo Pharma, an Ipsen company.

Durable Symptom Improvement for Patients with Non-Transfusion Dependent Thalassemia Treated with Luspatercept: Patient-Reported Outcomes from the BEYOND Study

Background: Patients with non-transfusion dependent beta-thalassemia (NTDT) suffer from chronic anemia due to ineffective erythropoiesis. The phase 2, randomized, placebo-controlled BEYOND study demonstrated that luspatercept increased hemoglobin (Hb), reduced transfusion burden, and improved NTDT-related symptoms based on the data with 48 weeks of follow-up (Taher A, et al. Lancet Haematol. 2022;9(10):E733). Objective: The purpose of this analysis was to investigate the long-term effect of luspatercept + best supportive care (BSC) vs placebo + BSC on NTDT-related symptoms through 96 weeks using data collected in the BEYOND study. Methods: 145 patients with NTDT were randomized 2:1 to luspatercept (Q3W) + BSC or placebo + BSC. BSC included red blood cell (RBC) transfusions and iron chelation therapy as deemed necessary by investigators. Patients completed the NTDT Patient Reported Outcome (NTDT-PRO) and Patient Global Impression of Severity (PGI-S) in a daily electronic diary starting 7 days prior to the first dosing day until Week 24, and thereafter over the 7 days prior to dosing at every other dosing visit. The Patient Global Impression of Change (PGI-C) was administered at every other dosing visit, starting with the first dosing day. The NTDT-PRO consists of 6 questions measuring 2 NTDT anemia-related symptom domains: Tiredness/Weakness (T/W) and Shortness of Breath (SoB), each with a score range of 0 (no symptoms) to 10 (extreme symptoms). The PGI-S asks patients to rate the overall severity of their NTDT-related symptoms (range of 0 to 10, with a higher score indicating greater severity), whereas the PGI-C asks patients to rate the overall change in their NTDT-related symptoms since the start of the study (7-level verbal rating scale ranging from “a great deal better” to “a great deal worse”). Least squares (LS) mean changes from baseline at each visit (up to Week 96) in NTDT-PRO T/W and SoB scores, as well as the PGI-S score, were estimated using a mixed model for repeated measures (MMRM). Responses to the PGI-C were descriptively summarized by treatment group. All analyses were performed in the health-related quality of life (HRQoL)-evaluable population, defined as all randomized patients with a valid QoL assessment and at least 1 post-baseline assessment. All p-values reported from the analyses were nominal. Results: The HRQoL-evaluable population consisted of 95 of the 96 patients randomized to the luspatercept arm and all 49 patients randomized to the placebo arm. LS mean changes from baseline in both the NTDT-PRO T/W and SoB scores for the luspatercept arm consistently demonstrated greater improvement (i.e., lower scores) than the placebo arm across visits. Improvement in both T/W and SoB domains were more pronounced starting at Week 24 and sustained through Week 96, with differences in LS mean changes from baseline ranging from -0.89 to -0.21 in the T/W domain and from -0.80 to -0.45 in the SoB domain over this time period (both domains on a 0 to 10 scale). Between-treatment differences were significant (p&amp;lt;0.05) at Week 30 (between-treatment difference in LS mean change from baseline, 95% confidence interval: -0.76, -1.42 to -0.10), Week 36 (-0.89, -1.55 to -0.22), and Week 72 (-0.81, -1.54 to -0.09) in the T/W domain and at Week 30 (-0.71, -1.36 to -0.06), Week 48 (-0.77, -1.43 to -0.10), and Week 72 (-0.80, -1.51 to -0.10) in the SoB domain. LS mean changes from baseline in the severity of overall NTDT-related symptoms, assessed by the PGI-S, showed a marked improvement through Week 96 in the luspatercept arm ( Figure 1), whereas patients receiving placebo tended to worsen over time. The between-treatment difference was statistically significant (p&amp;lt;0.05) across most assessment visits from Weeks 18 to 96. For the PGI-C, most patients treated with luspatercept reported “a little better” or more on their overall NTDT-related symptoms at Weeks 72 (89%) and 96 (87%), whereas most patients receiving placebo reported no change at either Week 72 (61%) or 96 (75%) ( Figure 2). Conclusions: Analysis of the PRO data collected in BEYOND suggests that, in addition to improvements in Hb, patients with NTDT treated with luspatercept experienced durable improvement in NTDT-related symptoms, from a patient perspective, through at least 96 weeks of treatment.

0573 Application of AASM Clinical Significance Thresholds to Once-Nightly Sodium Oxybate for Improvement in Narcolepsy Symptoms

Abstract Introduction Once-nightly sodium oxybate (ON-SXB; FT218), an investigational, extended-release treatment, was evaluated for the treatment of narcolepsy in adults in the phase 3 REST-ON clinical trial (NCT02720744). The 3 co-primary endpoints, mean sleep latency on the Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement rating, and weekly number of cataplexy attacks (NCA), and the secondary endpoint of Epworth Sleepiness Scale (ESS) score were significant for ON-SXB vs placebo at weeks 3 (6-g dose), 8 (7.5-g dose), and 13 (9-g dose; all P&amp;lt; 0.001). These data were published after the cutoff for inclusion in the American Academy of Sleep Medicine (AASM) clinical practice guidelines for narcolepsy treatment; thus, REST-ON results were analyzed according to AASM clinical significance thresholds (CSTs). Methods Individuals with narcolepsy type 1/2 and age ≥16 years were randomized 1:1 to receive double-blind ON-SXB (4.5 g, 1 week; 6 g, 2 weeks; 7.5 g, 5 weeks; 9 g, 5 weeks) or matching placebo. For each dose (6 g, week 3; 7.5 g, week 8; and 9 g, week 13), least-squares mean (LSM) difference from placebo was calculated for change from baseline in mean sleep latency on the MWT, ESS score, and percentage reduction in NCA. As defined in the 2021 AASM guidelines, CSTs were the following changes vs placebo: MWT, ≥2-minute increase; ESS, ≥2-point decrease; and cataplexy, ≥25% decrease in NCA. Results 190 participants (ON-SXB, n=97; placebo, n=93) were in the modified intent-to-treat population. On the MWT, difference in LSM change from baseline was 5.0, 6.2, and 6.1 minutes for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM change from baseline ESS scores were −2.1, −3.2, and −3.9 for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Differences in LSM percentage reduction in NCA were 26.0%, 34.2%, and 36.1% for ON-SXB 6, 7.5, and 9 g vs placebo, respectively. Conclusion Clinically significant improvement in excessive daytime sleepiness and cataplexy per AASM-established criteria was met with ON-SXB 6, 7.5, and 9 g doses. If FDA approved, ON-SXB will provide a once-nightly treatment for improving EDS and cataplexy in adults with narcolepsy. Support (if any) Avadel Pharmaceuticals

Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration

To evaluate the efficacy, safety, and immunogenicity of a ranibizumab biosimilar candidate (XSB-001) versus reference product (Lucentis) for neovascular age-related macular degeneration (nAMD). Phase III, multicenter, randomized, double-masked, parallel-group study. Patients with nAMD. Eligible patients were randomized (1:1) to receive intravitreal injections of XSB-001 or reference ranibizumab (0.5 mg [0.05 ml]) in the study eye once every 4 weeks for 52 weeks. Efficacy and safety assessments continued through 52 weeks of treatment. Primary end point was change from baseline in best-corrected visual acuity (BCVA) by ETDRS letters at week 8. Biosimilarity was concluded if the 2-sided 90% confidence interval (CI) (United States) or 95% CI (rest of world) for the difference in least-squares (LS) mean change in BCVA at week 8 between treatment groups was within the predefined equivalence margin of ± 3.5 letters. In total, 582 patients (n= 292 XSB-001, n= 290 reference ranibizumab) were randomized. Mean age was 74.1 years, most patients (85.2%) were White, and 55.8% were women. Mean BCVA score at baseline was 61.7 and 61.5 ETDRS letters in the XSB-001 and reference ranibizumab groups, respectively. At week 8, the LS mean (standard error [SE]) change in BCVA from baseline was 4.6 (0.5) ETDRS letters in the XSB-001 group and 6.4 (0.5) letters in the reference ranibizumab group (LS mean [SE] treatment difference:-1.8 [0.7] ETDRS letters; 90% CI,-2.9 to-0.7; 95% CI,-3.1 to-0.5). The 90% CI and 95% CI for LS mean difference in change from baseline were within the predefined equivalence margin. At week 52, LS mean (SE) change in BCVA was 6.4 (0.8) and 7.8 (0.8) letters, respectively (LS mean [SE] treatment difference,-1.5 [1.1] ETDRS letters; 90% CI,-3.3 to 0.4; 95% CI,-3.6 to 0.7). There were no clinically meaningful differences between treatments in anatomical, safety, or immunogenicity end points through week52. XSB-001 demonstrated biosimilarity to reference ranibizumab in patients with nAMD. Treatment with XSB-001 for 52 weeks was generally safe and well tolerated, with a safety profile similar to the reference product. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

One-year Data from ENDEAVOR, a Phase 1b Trial of Delandistrogene Moxeparvovec (SRP-9001) in Patients with Duchenne Muscular Dystrophy (DMD) (S48.003)

One-year Data from ENDEAVOR, a Phase 1b Trial of Delandistrogene Moxeparvovec (SRP-9001) in Patients with Duchenne Muscular Dystrophy (DMD) (S48.003)

Galcanezumab Effects on Migraine Severity and Symptoms in Japanese Patients with Episodic Migraine: Secondary Analysis of a Phase 2 Randomized Trial.

Galcanezumab, a humanized monoclonal antibody against calcitonin gene-related peptide, is a preventive migraine treatment. In global, randomized, placebo-controlled trials, galcanezumab reduced migraine headache severity and the frequency of migraine headaches associated with nausea and/or vomiting, photophobia and phonophobia, prodromal symptoms, or aura. We report secondary analyses from a Japanese phase 2 trial that assessed the effect of galcanezumab on migraine headache severity, frequency of migraine-associated symptoms, and frequency of migraine headaches during menstrual periods in Japanese patients with episodic migraine. Adults with migraine (International Classification of Headache Disorders, 3rd edition; 4-14 migraine headache days/month) were randomized (2:1:1) to amonthly placebo (n = 230), 120mg galcanezumab (240mg loading dose; n = 115), or 240mg galcanezumab (n = 114) for 6months (double-blind). Patients recorded migraine headache days, severity, and symptoms in an electronic diary. Changes from baseline were analyzed (mixed model for repeated measures). Both galcanezumab doses significantly reduced the number of monthly moderate-to-severe and severe migraine headache days compared with placebo, overall (difference in least-squares mean change from baseline, 120mg/240mg versus placebo: moderate-to-severe, -1.9/-1.8days; severe: -0.4/-0.4days) and in each month;mean severity score was significantly reduced in the 240mg group. Both galcanezumab doses significantly reduced the number of migraine headache days with nausea/vomiting (-1.1/-1.0days), photophobia/phonophobia (-2.3/-1.7days), prodromal symptoms (-0.7/-0.8days), and aura (-0.7/-0.7days). In most cases, the proportion of migraine headache days with these symptoms was reduced by galcanezumab. Both galcanezumab doses reduced the number of migraine headache days occurring during menstrual periods (n = 269; -0.8/-0.9days). Once-monthly galcanezumab significantly reduced the frequency of migraine headache days with moderate-to-severe or severe headache, migraine headache days with migraine-associated symptoms, and migraine headache days during menstrual periods in Japanese patients with episodic migraine, consistent with results from global studies. ClinicalTrials.gov (NCT02959177).

Effect of a Multilayer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adolescents with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind, Fixed-Dose, Placebo-Controlled Trial Followed by a 6-Month Open-Label Follow-Up.

Objectives: We analyzed patient-reported sleep parameters for an extended-release methylphenidate formulation (PRC-063) in adolescents with attention-deficit/hyperactivity disorder. Methods: Clinical efficacy and long-term safety/tolerability data from a 4-week, double-blind, placebo-controlled, fixed-dose study (NCT02139111) and a subsequent 6-month, optimized-dose, open-label extension (OLE) study (NCT02168127) were used. In the double-blind study, participants were randomly assigned 1:1:1:1:1 to one of four doses of PRC-063 (25, 45, 70, or 85 mg/day) or placebo. In both the double-blind and OLE studies, sleep outcomes were assessed using the Pittsburgh Sleep Quality Index (PSQI). Results: During double-blind treatment, no statistically significant least-squares mean difference in change from baseline between PRC-063 (all doses combined; N = 293) and placebo (N = 74) was found for either global PSQI score (-0.3 vs. -0.5; p = 0.6110) or scores for any of the seven PSQI subscales. Compared with the placebo group, a marginally higher proportion of patients in the PRC-063 group (all doses combined) went from being poor to good sleepers (global PSQI score ≤5; 14.4% vs. 11.3%). In a logistic regression analysis, study treatment was not a predictor of poor sleep (p = 0.5368) at the end of the double-blind study. In the OLE study, there was a trend of improvement in sleep after 1 month of individualized dosing that was maintained through 6 months. Sleep efficiency (time asleep as a proportion of time in bed) showed improvement at the end of the OLE study. Conclusion: While individual patients may experience changes in sleep as an adverse event, group data evaluating sleep as an outcome found there were no differences between PRC-063 and placebo in self-reported sleep outcomes on the PSQI.

Health-related quality of life in advanced gastric/gastroesophageal junction cancer with second-line pembrolizumab in KEYNOTE-061

BackgroundIn the primary analysis population (i.e., PD-L1 combined positive score [CPS] ≥ 1) of the phase 3 KEYNOTE-061 study (NCT02370498), pembrolizumab did not significantly prolong overall survival or progression-free survival. Pembrolizumab had a favorable safety profile in the all-patient population. We present results of prespecified health-related quality of life (HRQoL) analyses.MethodsHRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ gastric cancer questionnaire (QLQ-STO22), and EuroQol 5-dimension, 3-level questionnaire (EQ-5D-3L). Data were analyzed from patients who received ≥ 1 dose of study treatment and who completed ≥ 1 HRQoL assessment. Key analyses included baseline to week 12 least-squares mean (LSM) change in global health status (GHS)/QoL, functional/symptom subscales, and time to deterioration (TTD; ≥ 10-point decrease from baseline) for specific subscales.ResultsThe HRQoL population included 371 patients (pembrolizumab, n = 188; paclitaxel, n = 183). Compliance and completion rates for all 3 questionnaires were similar in both groups at baseline and week 12. There was no difference in LSM change between groups (– 3.54; 95% CI – 8.92 to 1.84) in GHS/QoL at week 12. LSM change from baseline to week 12 for most QLQ-C30, QLQ-STO22, and EQ-5D-3L subscales indicated some worsening of QoL in both groups. TTD for GHS/QoL, nausea/vomiting, and appetite loss subscales in QLQ-C30 and the pain subscales in QLQ-STO22 were similar between treatment groups.ConclusionsIn this population with advanced gastric and GEJ cancer receiving second-line treatment, HRQoL was similar in patients receiving pembrolizumab and those receiving paclitaxel.Clinical trial registry and numberClinicalTrials.gov, NCT02370498.

Improvement in quality of life among Sri Lankan patients with haemorrhoids after invasive treatment: a longitudinal observational study.

BackgroundHaemorrhoids is a common chronic disease that can significantly impact patients’ quality of life. Yet, few studies have evaluated health-related quality of life (HRQoL) of patients with haemorrhoids before and after treatment. This study investigated the HRQoL of patients with haemorrhoids before and after treatment and the change in HRQoL from baseline.MethodsA prospective observational study of patients with haemorrhoids was conducted at two public hospitals in Kandy, Sri Lanka. Two questionnaires assessing symptom severity and haemorrhoid-specific QoL were administered at initial consultation and at 4- and 8-week follow-ups after treatment (sclerotherapy, rubber band ligation (RBL), haemorrhoidectomy or evacuation of haematoma). The primary outcome was the least squares (LS) change of HRQoL score from baseline, measured using the Short Health Scale adapted for Haemorrhoidal Disease (4 domains: symptom load, interference with daily activities, concern, general well-being).ResultsIn 48 patients selected for this study, LS mean change from baseline showed significant improvement in HRQoL across all domains and total Short Health Scale adapted for Haemorrhoidal Disease score at 4- and 8-week follow-ups (P < 0.001). Difference in LS mean change from baseline also showed continued improvement of HRQoL from week 4 to week 8 (P < 0.010). ‘Concern’ showed greatest improvement at 4 and 8 weeks (P < 0.001). Averaged LS mean changes from baseline showed RBL had greater improvement of HRQoL compared with sclerotherapy (P = 0.004).ConclusionPatients with haemorrhoids had improved HRQoL after invasive treatment. Haemorrhoid-specific QoL is an important component of the extent of disease and can serve as an aid to guide treatment, assess outcomes and monitor disease.

Trial of SAGE-217 in Patients with Major Depressive Disorder

BackgroundAltered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown.MethodsIn this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse).ResultsA total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was −17.4±1.3 points in the SAGE-217 group and −10.3±1.3 points in the placebo group (least-squares mean difference in change, −7.0 points; 95% confidence interval, −10.2 to −3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence.ConclusionsAdministration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.)

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

BackgroundNusinersen is an antisense oligonucleotide drug that modulates pre–messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).MethodsWe conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills.ResultsIn the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by –1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).ConclusionsAmong children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537.)

Mometasone furoate nasal spray in the treatment of nasal polyposis in Chinese patients: a double-blind, randomized, placebo-controlled trial.

Although mometasone furoate nasal spray (MFNS) has demonstrated efficacy in nasal polyposis (NP) in Western populations, data in Asian populations is limited. This randomized, double-blind study evaluated MFNS 200 μg twice per day (BID) vs placebo in Chinese adults with bilateral nasal polyps (graded as 1, 2, or 3 by the investigator). A 14-day placebo run-in period was followed by a 16-week treatment period with MFNS 200 μg BID vs placebo (1:1 ratio). The co-primary endpoints were change from baseline in nasal congestion/obstruction averaged over the first 4 weeks of treatment and change from baseline in the total polyp size score (sum of scores from the left and right nasal fossa) at week 16. Secondary endpoints included other sinonasal symptoms scores and safety outcomes such as monitoring laboratory measurements, vital signs, and adverse events (AEs). There were 748 patients randomized, 375 received MFNS 200 μg BID and 373 received placebo. The between-treatment difference in least squares (LS) mean change from baseline in nasal congestion/obstruction over 4 weeks of treatment was -0.14 (95% confidence interval [CI], -0.22 to -0.06) for MFNS vs placebo (p = 0.0007). The between-treatment difference in LS mean change from baseline in total polyp size score at week 16 was -0.30 (95% CI, -0.45 to -0.15) for MFNS vs placebo (p < 0.0001). Serious AEs were rare (0.5% and 0.8% in MFNS and placebo groups, respectively) and considered not drug-related. There were significantly more AEs of epistaxis with MFNS vs placebo (p = 0.009). This study demonstrated that MFNS was effective and well tolerated in this population of adult, Chinese patients with NP.

EPA-0685 – Guanfacine XR (GXR) for children and adolescents with attention-deficit/hyperactivity disorder (ADHD): phase 3, randomized, double-blind, multicenter, placebo- and active-reference study

Introduction GXR, a selective α2A-adrenergic agonist, is a non-stimulant treatment for ADHD (approved in the USA for children and adolescents and in Canada for children). Objectives To assess the efficacy (symptoms and function) and safety of dose-optimized GXR compared with placebo in children and adolescents with ADHD. Aims To evaluate the efficacy (symptom and function) and safety of GXR for the treatment of ADHD. An atomoxetine (ATX) arm was included to provide reference data against placebo (NCT01244490). Methods Patients (6–17 years) were randomly assigned at baseline to dose-optimized GXR (6–12 years, 1–4 mg/day; 13–17 years, 1–7 mg/day), ATX (10–100mg/day) or placebo for 4 or 7 weeks. The primary efficacy measure is change from baseline in ADHD-Rating Scale-version IV (ADHD-RS-IV). Key secondary measures were defined as Clinical Global Impressions-Improvement (CGI-I) and the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P). Safety assessments included treatment-emergent adverse events (TEAEs), electrocardiograms, and vital signs. Results Of 338 patients randomized, 272 (80.5%) completed the study. Placebo-adjusted differences in least squares (LS) mean in ADHD-RS-IV total score, percent improvement versus placebo for CGI-I, placebo-adjusted differences in LS mean change from baseline in WFIRS-P score (family and learning and school domains) are shown in the Table. The most common TEAEs for GXR were somnolence, headache, and fatigue; 8 (7%) TEAEs were severe. Conclusions GXR was effective and well tolerated in children and adolescents with ADHD. GXR ATX Placebo-adjusted difference in LS mean change from baseline in ADHD-RS-IV total score (95% Cl, p-value; effect size) −8.9 (−11.9, −5.8, p −3.8 (−6.8, −0.7, p Difference in improvement from placebo for CGI-I (95% Cl, p-value) 23.7% (11.1, 36.4; p 12.1% (−0.9, 25.1; p Placebo-adjusted difference in LS mean change from baseline in WFIRS-P; learning and school domain score (95%CI, p-value; effect size) −0.22 (−0.36, −0.08, p −0.16 (−0.31, −0.02, p Placebo-adjusted difference in LS mean change from baseline in WFIRS-P; family domain score (95%CI, p-value; effect size) −0.21 (−0.36, −0.06, p −0.09 (−0.24, 0.06, p=0.242; 0.16)

Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention-deficit/hyperactivity disorder: results from a randomized, controlled trial

Lisdexamfetamine dimesylate (LDX) is a long-acting, prodrug stimulant therapy for patients with attention-deficit/hyperactivity disorder (ADHD). This randomized placebo-controlled trial of an optimized daily dose of LDX (30, 50 or 70 mg) was conducted in children and adolescents (aged 6–17 years) with ADHD. To evaluate the efficacy of LDX throughout the day, symptoms and behaviors of ADHD were evaluated using an abbreviated version of the Conners’ Parent Rating Scale-Revised (CPRS-R) at 1000, 1400 and 1800 hours following early morning dosing (0700 hours). Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment, but the study was not designed to support a statistical comparison between LDX and OROS-MPH. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107). At baseline, CPRS-R total scores were similar across treatment groups. At endpoint, differences (active treatment − placebo) in least squares (LS) mean change from baseline CPRS-R total scores were statistically significant (P < 0.001) throughout the day for LDX (effect sizes: 1000 hours, 1.42; 1400 hours, 1.41; 1800 hours, 1.30) and OROS-MPH (effect sizes: 1000 hours, 1.04; 1400 hours, 0.98; 1800 hours, 0.92). Differences in LS mean change from baseline to endpoint were statistically significant (P < 0.001) for both active treatments in all four subscales of the CPRS-R (ADHD index, oppositional, hyperactivity and cognitive). In conclusion, improvements relative to placebo in ADHD-related symptoms and behaviors in children and adolescents receiving a single morning dose of LDX or OROS-MPH were maintained throughout the day and were ongoing at the last measurement in the evening (1800 hours).

P-339 - Effect of lisdexamfetamine dimesylate on functional impairment in children and adolescents with attention-deficit/hyperactivity disorder

Lisdexamfetamine dimesylate (LDX) is the first long-acting, prodrug stimulant, and is approved in the USA, Canada and Brazil for the treatment of attention-deficit/hyperactivity disorder (ADHD). To evaluate the effect of LDX on functional impairment in patients with ADHD, using the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P). A randomized, double-blind, placebo-controlled trial of an optimized daily dose of LDX was conducted in children and adolescents (6–17 years) with ADHD in Europe. A 4-week dose-optimization period was followed by 3-weeks of dose-maintenance. The WFIRS-P was completed at baseline, day 28 and endpoint. A decrease from baseline indicated an improvement in functional outcomes. Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment arm. Of 336 randomized patients, 317 were included in the full analysis set and 196 completed the study. Baseline mean (SD) WFIRS-P total scores were similar across treatment groups: LDX, 1.01 (0.45); placebo, 1.10 (0.46); OROS-MPH, 1.07 (0.44). The least squares (LS) mean decrease (95% confidence intervals) in WFIRS-P total score from baseline to endpoint was statistically significantly greater with LDX than with placebo (difference of −0.3 [−0.4, −0.2], p < 0.001), with an effect size of 0.924 for LDX. The difference in LS mean change from baseline to endpoint between OROS-MPH and placebo was −0.2 (−0.3, −0.1; p < 0.001) in favour of OROS-MPH (effect size, 0.772). LDX was more effective than placebo in improving functional impairments in children and adolescents with ADHD. By funding from Shire Development Inc.

P177 Fluticasone propionate/formoterol fumarate combination therapy is as effective as fluticasone propionate/salmeterol xinafoate in the treatment of asthma: a randomised controlled trial

Introduction and ObjectivesA new asthma therapy combining fluticasone propionate and formoterol fumarate (FP/FORM) in a single pressurised metered dose inhaler has been developed. The efficacy and safety of FP/FORM and...

Effect of Donepezil on Cognition in Severe Alzheimer's Disease: A Pooled Data Analysis

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6-9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17-0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

A randomized, placebo‐ and active‐controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder

To evaluate the antimanic efficacy and safety of paliperidone extended-release (ER) tablets in patients with bipolar I disorder. This study included a 3-week, double-blind, acute treatment phase (paliperidone ER versus placebo, with quetiapine as control), and a 9-week, double-blind, maintenance phase (paliperidone ER versus quetiapine). Patients [n = 493; Young Mania Rating Scale (YMRS) score >or= 20] were randomized (2:2:1) to flexibly dosed paliperidone ER (3-12 mg/day), quetiapine (400-800 mg/day), or placebo for the acute treatment phase. During the maintenance phase, patients assigned to placebo were switched to paliperidone ER but not included in analysis of efficacy. Paliperidone ER was superior to placebo at the 3-week endpoint {primary outcome; least-squares mean difference in change from baseline in YMRS scores [95% confidence interval (CI)]: -5.5 (-7.57; -3.35); p < 0.001} and noninferior to quetiapine at the 12-week endpoint [least-squares mean difference (95% CI): 1.7 (-0.47; 3.96)]. The median mode dose during the 12-week treatment period was 9 mg for paliperidone ER and 600 mg for quetiapine. The most common (>or= 10%) treatment-emergent adverse events during the 12-week period were: headache (16%), somnolence (10%), and akathisia (10%) for paliperidone ER; somnolence (21%), sedation and dry mouth (17% each), headache (14%), and dizziness (13%) for quetiapine. Body weight increase >or= 7% from baseline to 12-week endpoint was 8% with paliperidone ER and 17% with quetiapine. A higher percentage of paliperidone ER (13.9%) versus quetiapine patients (7.5%) 'switched to depression' at the12-week endpoint. Paliperidone ER (3-12 mg/day) was efficacious and tolerable in the treatment of acute mania.

Randomized, placebo-controlled study of a selective PDE4 inhibitor in the treatment of asthma

Phosphodiesterase-4 (PDE4) inhibitors have potential utility as a new therapeutic approach to improving symptoms and pulmonary function in asthma and COPD. This study evaluated the efficacy and safety of MK-0359, a selective and potent oral PDE4 inhibitor, in chronic asthma. Adults (N=88) with > or =1 year asthma history and an FEV(1) 50-80% predicted were randomized to double-blind treatment with MK-0359 (15mg/day) or placebo for 14 days, then crossed-over to the other treatment for 14 days. The primary endpoint was the change from baseline in FEV(1) at the end of each 2-week treatment period. Secondary and other endpoints included the changes from baseline in Daytime asthma symptom score, Nighttime asthma symptom score, Total daily beta-agonist use (puffs/day), AM and PM peak expiratory flow (PEF) and overall asthma-specific quality-of-life. Safety and tolerability were assessed by clinical adverse experiences. MK-0359 significantly improved the primary endpoint (versus placebo): the least-squares mean difference in change from baseline in FEV(1) (L) was 0.09L (95% CI 0.01, 0.18). Endpoints of Daytime asthma symptom score, Nighttime asthma symptom score, Total daily beta-agonist use, AM PEF, PM PEF, and quality-of-life were also significantly improved. Nineteen patients (24.1%) on MK-0359 and 8 patients (10.4%) on placebo reported gastrointestinal clinical adverse experiences. Serious gastrointestinal clinical adverse experiences were reported in 3 patients while receiving MK-0359. Over a 14-day treatment period, the oral PDE4 inhibitor MK-0359 improved lower airway function, symptoms and rescue medication use in chronic asthma, although at the expense of gastrointestinal adverse experiences. (Clinical trial registry number: NCT00482898.).