Double-blind Placebo-controlled Period Research Articles

Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1: Results from a Phase III Clinical Trial

Patients with primary hyperoxaluria type 1 (PH1), a genetic disorder associated with hepatic oxalate overproduction, frequently experience recurrent kidney stones and worsening kidney function. Lumasiran is indicated for the treatment of PH1 to lower urinary and plasma oxalate (POx). ILLUMINATE-A (NCT03681184) is a phase III trial in patients aged≥6 years with PH1 and estimated glomerular filtration rate (eGFR)≥30 ml/min per 1.73 m2. A 6-month double-blind placebo-controlled period is followed by an extension period (≤54 months; all patients receive lumasiran). We report interim data through month36. Of 39 patients enrolled, 24 of 26 (lumasiran/lumasiran group) and 13 of 13 (placebo/lumasiran group) entered and continue in the extension period. At month 36, in the lumasiran/lumasiran group (36 months of lumasiran treatment) and placebo/lumasiran group (30 months of lumasiran treatment), mean 24-hour urinary oxalate (UOx) reductions from baseline were 63% and 58%, respectively; 76% and 92% of patients reached a 24-hour UOx excretion≤1.5× the upper limit of normal (ULN). eGFR remained stable. Kidney stone event rates decreased from 2.31 (95% confidence interval: 1.88-2.84) per person-year (PY) during the 12 months before consent to 0.60 (0.46-0.77) per PY during lumasiran treatment. Medullary nephrocalcinosis generally remained stable or improved; approximately one-third of patients (both groups) improved to complete resolution. The most common lumasiran-related adverse events (AEs) were mild, transient injection-site reactions. In patients with PH1, longer-term lumasiran treatment led to sustained reduction in UOx excretion, with an acceptable safety profile and encouraging clinical outcomes.See for Video Abstract.

Evolution of atrophied T2 lesion volume in primary-progressive multiple sclerosis: results from the phase 3 ORATORIO study

BackgroundAtrophied T2-lesion volume (aT2-LV) is an exploratory imaging marker in multiple sclerosis (MS) reflecting the volume of lesions subsumed into cerebrospinal fluid (CSF).ObjectiveTo investigate the effect of ocrelizumab (OCR) versus...

THU402 New Heterotopic Ossification Lesions In Patients With Fibrodysplasia Ossificans Progressiva Measured By PET/CT vs CT Only

Abstract Disclosure: D. Gonzalez Trotter: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. McGinniss: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.N. Economides: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. K. Mohammadi: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.J. Rankin: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B. Musser: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Mellis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E. Forleo-Neto: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. G. Herman: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder caused by mutations in the activin-A receptor type 1 (ACVR1) gene that render it responsive to activin-A, a ligand that normally antagonizes signaling from ACVR1. FOP is characterized by the deposition of bone in soft tissues known as heterotopic ossification (HO) and episodic painful flare-ups. Garetosmab, a fully human monoclonal antibody against activin-A, is being investigated for the prevention of new HO lesions in patients with FOP. This post hoc analysis compared the change from baseline in the number and volume of new HO lesions identified by 18F-labeled sodium fluoride (a bone-seeking tracer that measures bone deposition and turnover) positron emission tomography (PET/CT) and X-ray computed tomography (CT) imaging (which measures bone volume). Methods: Baseline and 28-week PET/CT and CT-only scans acquired during the initial double-blind placebo-controlled period of the LUMINA-1 (NCT03188666) phase 2 study were independently read by two sets of blinded readers and an adjudicator for the presence and volume of new lesions. Number and volume of new lesions were compared between the two imaging modalities. Results: The number of patients with new lesions as detected by PET/CT and CT only was 14/44 (31.8%) and 12/44 (27.3%), respectively. The mean number (standard deviation) of new lesions per patient by PET/CT through Week 28 was 0.68 (1.57) vs 0.86 (1.95) as detected by CT only. In patients with new lesions, the mean number of new lesions per patient was 2.14 (2.18) vs 3.17 (2.62) as detected by PET/CT vs CT only, respectively. The mean volume (cm3) of new lesions per patient detected by PET/CT was 6.05 (14.88) vs 5.94 (21.13) by CT only, through Week 28. In the subset of patients with new lesions, the mean volume of new lesions per patient detected by PET/CT was 19.02 (21.60) vs 21.79 (36.98) by CT only. Moderate agreement between PET/CT and CT-only detection was observed when identifying patients with new lesions, with a kappa coefficient of 0.46 (standard error: 0.146; 95% confidence interval: 0.17, 0.74). Placebo vs garetosmab groups, respectively, showed aggregate new lesion number/volume (cm3) of 27/245.0 vs 3/21.3 by PET/CT, and 37/261.5 vs 1/0.05 by CT only. Conclusions: CT imaging showed similar performance to PET/CT in the detection and characterization of new HO lesions and provides a viable option for the assessment of therapies that may inhibit the formation of new HO lesions in patients with FOP. Presentation: Thursday, June 15, 2023

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial

Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Neurocrine Biosciences.

P194 Bimekizumab is associated with improvement in quality of life in patients across the full spectrum of axial spondyloarthritis at week 16: results from two phase 3 studies

Abstract Background/Aims Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A and has demonstrated rapid and clinically meaningful improvements in disease activity (ASAS40, primary outcome measure) in patients across the full spectrum of axial spondyloarthritis (axSpA; active non-radiographic axSpA [nr-axSpA; BE MOBILE 1, NCT03928704] and ankylosing spondylitis [AS] / radiographic axSpA [r-axSpA; BE MOBILE 2, NCT03928743]). Here we report results related to HRQoL instruments (EQ-5D-3L, ASQoL and SF-36) from the two ongoing phase 3 studies at week (wk) 16. Methods BE MOBILE 1 and 2 were conducted in parallel with similar study designs: 16-wk double-blind placebo-controlled period followed by a 36-wk maintenance period. Patients were randomised (1:1 in BE MOBILE 1 and 2:1 in BE MOBILE 2) to BKZ 160 mg Q4W or placebo (PBO). All patients received BKZ 160 mg Q4W from wk16. We report change from baseline (CfB) in the overall EQ-5D-3L utility index, ASQoL and SF-36 Physical component Summary (PCS) scores at wk16 compared to PBO. Missing data is imputed using multiple imputation. Results Overall, 240/254 (94.5%; nr-axSpA) and 313/332 (94.3%; r-axSpA) patients completed the studies up to wk24. Both studies met their primary and all ranked secondary endpoints at wk16. In both studies, BKZ treatment resulted in improved health status as measured with the EQ-5D-3L utility score versus PBO. This improvement at wk16 was consistent across both tumour necrosis factor inhibitor (TNFi)-naive and TNFi-inadequate responders (IR) patients. Significantly greater improvements were also observed with BKZ compared to PBO in ASQoL and SF-36 PCS in both studies (p &amp;lt; 0.001, all comparisons) at wk16 (Table). At wk16, a higher proportion of BKZ- versus PBO-treated patients achieved ≥5-point improvement in SF-36 PCS (nr-axSpA: 64.8% vs 41.3% and r-axSpA: 63.8% vs 49.5%) and ≥4-point improvement in ASQoL (nr-axSpA: 58.6% vs 33.3% and r-axSpA: 57.5% vs 45.0%), respectively. Conclusion Dual inhibition of IL-17A and IL-17F with BKZ improved quality of life measured by EQ-5D-3L, ASQoL and SF-36 PCS scores compared with PBO in patients across the full spectrum of axSpA. Disclosure N. McKay: Member of speakers’ bureau; NM has received Speaker' bureau from Gilead. Other; NM has received travel fees from UCB Pharma and Gilead. A. Bennett: Honoraria; AB has received teaching honorarium from Abbvie Ltd, Pfizer, UCB Pharma, Novartis and Biogen. Grants/research support; AB has received research grants from Pfizer. Other; AB has received advisory board fees from Abbvie Ltd, Pfizer, UCB Pharma, MSD, Novartis and Eli Lilly. N. Goodson: Honoraria; NG has received honoraria from UCB Pharma and Novartis. C. Fleurinck: Other; CF is an employee of UCB Pharma. C. de la Loge: Consultancies; CdlL is a consultant to UCB Pharma, Brussels, Belgium. U. Massow: Other; UM is an employee of UCB Pharma. V. Taieb: Other; VT is employee of UCB Pharma. H. Marzo-Ortega: Grants/research support; HMO has received grants/research support from Janssen, Novartis and UCB Pharma. Other; HMO has received honoraria and/or consultancy and/or speaker fees from Abbvie, Biogen, Celgene, Janssen, Eli-Lilly, Moonlake, Novartis, Pfizer and UCB Pharma. K. Gaffney: Consultancies; KG has received honoraria or consultancy fees from Novartis, AbbVie, UCB Pharma, Eli Lilly and Pfizer. Shareholder/stock ownership; KG is a shareholder of Rheumatology Events. Member of speakers’ bureau; KG has paticipated in speaker's bureau for Novartis, UCB Pharma, AbbVie and Eli Lilly. Grants/research support; KG has received grants/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Norvartis, Eli Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received meeting expenses from AbbVie, Eli Lilly, Roche, Novartis, Pfizer and UCB Pharma.

335 Improvement in sleep quality, anxiety and depression in adults with moderate-to-severe atopic dermatitis with dupilumab treatment

Abstract Sleep disturbance is considered one of the most prevalent symptoms of atopic dermatitis (AD), and is associated with daytime sleepiness, anxiety and depression. In previous phase 3 trials, dupilumab treatment demonstrated significant improvement in objective AD signs and severity of symptoms, including sleep disturbance and mental health symptoms. To investigate the effect of dupilumab for up to 24 weeks on sleep quality, daytime sleepiness, anxiety and depression, using data from the DUPISTAD (NCT04033367) study. The randomized, phase 4 DUPISTAD study, was divided into two 12-week periods: an initial double-blind placebo-controlled period, and a subsequent 12-week open-label extension (OLE) period. The 24-week study enrolled adult patients with moderate-to-severe AD (Eczema Area and Severity Index score ≥12, Peak Pruritus Numeric Rating Scale [NRS] score ≥3, Sleep Disturbance NRS average score ≥5) who showed an inadequate response to topical treatments. These patients were randomized 2 : 1 to dupilumab 300 mg every 2 weeks (q2w) for both the double-blind and OLE periods or placebo for the initial double-blind period, followed by dupilumab 300 mg q2w for the OLE period. The use of concomitant topical corticosteroids was permitted as needed by both groups throughout the study. Endpoints included mean change from baseline to week 24 for Patient-Reported Outcome Measures Information System (PROMIS) Sleep T-score (standardized score ranging from 30 [best] to 80 [worst], with a mean of 50), Epworth Sleepiness Scale (ESS; scored 0–24; higher values indicate increased daytime sleepiness), and Hospital Anxiety and Depression Scale (HADS; scored 0–21; higher values indicate a worse outcome). Throughout the study, patients also completed a Sleep Diary, recording the NRS of restfulness upon waking up (scored 0–10; lower values indicate a worse outcome). Statistical comparisons were not performed on the data collected during the OLE observation period. A total of 188 patients were enrolled in the study: 127 received continuous dupilumab (dupilumab–dupilumab group) and 61 received placebo to week 12 and then dupilumab to week 24 (placebo–dupilumab group). Baseline demographics and disease characteristics were well balanced. Improvement from baseline in sleep quality, daytime sleepiness, anxiety and depression was observed at week 24 in both groups, as illustrated by the mean change from baseline in PROMIS Sleep T-scores (−12.5 in the dupilumab–dupilumab group and −11.7 in the placebo–dupilumab group), ESS scores (−4.6 in the dupilumab–dupilumab group and −3.7 in the placebo–dupilumab group), HADS anxiety scores (−3.8 in the dupilumab–dupilumab group and −4.4 in the placebo–dupilumab group), HADS depression scores (−4.4 in the dupilumab–dupilumab group and −3.4 in the placebo–dupilumab group), and the NRS of restfulness upon a waking-up item of the Sleep Diary (+3.3 in the dupilumab–dupilumab group and +3.4 in the placebo–dupilumab group). The improvement achieved by the placebo–dupilumab group converged with that of the dupilumab–dupilumab group during the OLE period, as shown by the mean change from week 12 to week 24 in PROMIS Sleep T-score (−3.8), ESS score (−1.9), HADS anxiety score (−1.6), HADS depression score (−0.9) and NRS of restfulness upon a waking-up item of the Sleep Diary (+1.5). The safety profile of dupilumab was consistent with the known safety profile. Dupilumab provided sustained improvement through 24 weeks in patient-reported measures of sleep, daytime sleepiness, anxiety, and depression in adult patients with moderate-to-severe AD. Patients who were switched from placebo to dupilumab at week 12 showed rapid improvement in these parameters after the switch, eventually matching the improvement achieved by patients who received dupilumab from baseline through week 24.

MP07-09 12-MONTH ANALYSIS OF ILLUMINATE-A, A PHASE 3 STUDY OF LUMASIRAN: SUSTAINED OXALATE LOWERING AND KIDNEY STONE EVENT RATES IN PRIMARY HYPEROXALURIA TYPE 1

MP07-09 12-MONTH ANALYSIS OF ILLUMINATE-A, A PHASE 3 STUDY OF LUMASIRAN: SUSTAINED OXALATE LOWERING AND KIDNEY STONE EVENT RATES IN PRIMARY HYPEROXALURIA TYPE 1

Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study.

This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient’s current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with pulmonary arterial hypertension. Patients received tadalafil 20 mg or 40 mg based on their weight (heavy-weight: ≥40 kg; middle-weight: ≥25 to <40 kg) or placebo orally once daily for 24 weeks. Primary endpoint was change from baseline in six-minute walk distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results showed that patient demographics and baseline characteristics (N = 35; tadalafil = 17; placebo = 18) were comparable between treatment groups; median age was 14.2 years (6.2–17.9 years) and majority (71.4%, n = 25) of patients were in the heavy-weight cohort. Least square mean (standard error) changes from baseline in six-minute walk distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 (20.41) vs 36.60 (20.78) meters; placebo-adjusted mean difference (standard deviation) 23.88 (29.11)). Safety of tadalafil treatment was as expected without any new safety concerns. During study Period 1, two patients (one in each group) discontinued due to investigator’s reported clinical worsening, and no deaths were reported. In conclusion, the statistical significance testing was not performed between the treatment groups due to low sample size; however, the study results show positive trend in improvement in non-invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with pulmonary arterial hypertension. Safety of tadalafil treatment was as expected without any new safety signals.

Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.

SAFETY RESULTS FROM 3 LONG-TERM VALBENAZINE STUDIES IN YOUNGER AND OLDER ADULTS WITH TARDIVE DYSKINESIA

Introduction Older age is a significant risk factor for developing tardive dyskinesia (TD). Valbenazine, a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved to treat TD in adults, regardless of age. We report a comparison of the long-term safety and tolerability of once-daily valbenazine in adults with TD aged ≥55 vs. Methods Data were pooled from two phase 3 studies, KINECT 3 (NCT02274558: valbenazine 40 or 80 mg, 6-week double-blind placebo-controlled period, 42-week double-blind extension) and KINECT 4 (NCT02405091: valbenazine 40 or 80 mg, 48-week open-label treatment). KINECT 3/4 study completers could enroll in a subsequent rollover study (NCT02736955: valbenazine 40 or 80 mg, additional ≤72-week open-label treatment or until valbenazine became commercially available). For safety analyses, participants were categorized by age (older, ≥55y; younger, Results Analyses included 383 KINECT 3/4 participants (≥55y=239; 0.05); serious TEAE (10.1% vs. 9.8%; P>0.05); and discontinuation due to TEAE (3.7% vs. 9.8%; P>0.05). The most common TEAE was somnolence among older participants (4.6%) and cough among younger participants (9.8%). During both KINECT 3/4 and the rollover study, no clinically important changes in vital signs or ECGs were found in either age subgroup, and most participants (>90%) had no worsening in C-SSRS scores from baseline. Conclusions In older (≥55y) and younger ( 1 year of once-daily valbenazine for TD, TEAEs and other safety outcomes were consistent with previous long-term analyses. These results confirm that valbenazine is generally safe and well-tolerated in all adults with TD. This research was funded by This research was fully funded by Neurocrine Biosciences, Inc.

L-theanine in the adjunctive treatment of generalized anxiety disorder: A double-blind, randomised, placebo-controlled trial

Partial or non-response to antidepressants in Generalized Anxiety Disorder (GAD) is common in clinical settings, and adjunctive biological interventions may be required. Adjunctive herbal and nutraceutical treatments are a novel and promising treatment option. L-theanine is a non-protein amino acid derived most-commonly from tea (Camellia sinensis) leaves, which may be beneficial in the treatment of anxiety and sleep disturbance as suggested by preliminary evidence. We conducted a 10-week study (consisting of an 8-week double-blind placebo-controlled period, and 1-week pre-study and 2-week post-study single-blinded observational periods) involving 46 participants with a DSM-5 diagnosis of GAD. Participants received adjunctive L-theanine (450–900 mg) or matching placebo with their current stable antidepressant treatment, and were assessed on anxiety, sleep quality, and cognition outcomes. Results revealed that adjunctive L-theanine did not outperform placebo for anxiety reduction on the HAMA (p = 0.73) nor insomnia severity on the Insomnia Severity Index (ISI; p = 0.35). However, LT treated participants reported greater self-reported sleep satisfaction than placebo (ISI item 4; p = 0.015). Further, a separation in favour of L-theanine was noted on the ISI in those with non-clinical levels of insomnia symptoms (ISI ≤ 14; p = 0.007). No significant cognitive effects (trail making time and the modified emotional Stroop) were revealed. While this preliminary study did not support the efficacy of L-theanine in the treatment of anxiety symptoms in GAD, further studies to explore the application of L-theanine in sleep disturbance are warranted.

Atomoxetine in Autism Spectrum Disorder: No Effects on Social Functioning; Some Beneficial Effects on Stereotyped Behaviors, Inappropriate Speech, and Fear of Change

Abstract Objective: The objective of this study was to investigate the short-term treatment effects of atomoxetine on autism spectrum disorder (ASD) symptoms in children and adolescents with both ASD and attention-deficit/hyperactivity disorder (ADHD). A total of 97 patients 6-17 years of age, with ASD and ADHD, were treated with 1.2 mg/kg/day of atomoxetine during an 8 week double-blind placebo-controlled period. Here, we investigated effects on two parent-based secondary outcome measures, the Aberrant Behavior Checklist (ABC) and the Children's Social Behavior Questionnaire (CSBQ). After 8 weeks of double-blind treatment, atomoxetine administration was associated with significant treatment effects on the ABC subscales Hyperactivity, Inappropriate Speech, and Stereotypic Behavior, and on the CSBQ subscale Fear for Changes. Our study results indicate no beneficial effects of atomoxetine on social functioning. However, atomoxetine may ameliorate restricted and stereotyped behaviors and communication. This study has been registered in ClinicalTrials.gov ( www.clinicaltrials.gov ) under registration number NCT00380692.

Long-Term Treatment with Atomoxetine for Attention-Deficit/Hyperactivity Disorder Symptoms in Children and Adolescents with Autism Spectrum Disorder: An Open-Label Extension Study

The efficacy and tolerability of long-term treatment with atomoxetine for symptoms of attention-deficit/hyperactivity disorder (ADHD) in children with autism spectrum disorder (ASD) has not been established. In this study, 88 patients 6-17 years of age, with ADHD and ASD, were treated with 1.2 mg/kg/day atomoxetine for 20 weeks as follow-up of an 8 week double-blind placebo-controlled period. Primary endpoint was the ADHD Rating Scale (ADHD-RS). After 8 weeks of initial treatment, the mean total, inattention, and hyperactivity-impulsivity ADHD-RS further decreased significantly from 34.9 to 27.0 for the total ADHD-RS, from 18.3 to 14.5 for the ADHD-RS inattention subscale, and from 16.5 to 12.6 for the hyperactivity-impulsivity subscale. Adverse events were mild and tended to diminish over time during continued treatment, especially regarding nausea and fatigue. There were no serious adverse events. The results of the present analysis suggest that continued treatment with atomoxetine up to 28 weeks further improve ADHD symptoms in children and adolescents with ASD, while adverse events tend to subside. Future studies investigating the long-term efficacy of atomoxetine in children and adolescents with ASD should be randomized and placebo controlled. This study has been registered in ClinicalTrials.gov ( www.clinicaltrials.gov ) under registration number NCT00380692.

The Tertatolol International Multicenter Study (T.I.M.S.): Predicting Factors of an Efficient Therapy

The Tertatolol International Multicenter Study (T.I.M.S.) was aimed at assessing the efficacy and tolerability of 5 mg tertatolol (T) once daily over a one year period and at finding, among the clinical variables before treatment, parameters predicting a successful single beta-blocking therapy. The study was carried out in 230 patients (96 men, 134 women, mean age +/- standard error of the mean: (51.5 +/- 0.7 years) suffering from uncomplicated mild to moderate hypertension. After a one-month placebo run-in period (M0-M1) and a one-month double-blind placebo-controlled period (M1-M2), 213 patients entered and 166 completed the one-year open period (M2-M14). A diuretic (D) was added if blood pressure (BP) was inadequately controlled with the single therapy. After one year, 88.5% of patients were controlled (sitting diastolic BP less than or equal to 90 mm Hg): 56.3% on single therapy (T) and 32.2% on dual therapy (T + D), respectively. Statistical analysis performed on the controlled subjects showed that patients who were controlled with T alone had an initially lower standing diastolic BP and a higher standing heart rate, were younger and had a lower sitting systolic BP than those controlled with T + D. Using such discriminant parameters which are predictors, 83.5% patients (single therapy group) and 49% patients (dual therapy group) were classified in the therapeutic group to which they really belonged. This study confirms the antihypertensive efficacy of tertatolol, and highlights relevant parameters for a successful single beta-blocker therapy in clinical practice.

Lyell, Green, Hilgard, and the Mississippi Valley loess

<h3>Objective</h3> To assess long-term (2 years) effects of bimagrumab in participants with sporadic inclusion body myositis (sIBM). <h3>Methods</h3> Participants (aged 36–85 years) who completed the core study (RESILIENT [Efficacy and Safety of Bimagrumab/BYM338 at 52 Weeks on Physical Function, Muscle Strength, Mobility in sIBM Patients]) were invited to join an extension study. Individuals continued on the same treatment as in the core study (10 mg/kg, 3 mg/kg, 1 mg/kg bimagrumab or matching placebo administered as IV infusions every 4 weeks). The co–primary outcome measures were 6-minute walk distance (6MWD) and safety. <h3>Results</h3> Between November 2015 and February 2017, 211 participants entered double-blind placebo-controlled period of the extension study. Mean change in 6MWD from baseline was highly variable across treatment groups, but indicated progressive deterioration from weeks 24–104 in all treatment groups. Overall, 91.0% (n = 142) of participants in the pooled bimagrumab group and 89.1% (n = 49) in the placebo group had ≥1 treatment-emergent adverse event (AE). Falls were slightly higher in the bimagrumab 3 mg/kg group vs 10 mg/kg, 1 mg/kg, and placebo groups (69.2% [n = 36 of 52] vs 56.6% [n = 30 of 53], 58.8% [n = 30 of 51], and 61.8% [n = 34 of 55], respectively). The most frequently reported AEs in the pooled bimagrumab group were diarrhea 14.7% (n = 23), involuntary muscle contractions 9.6% (n = 15), and rash 5.1% (n = 8). Incidence of serious AEs was comparable between the pooled bimagrumab and the placebo group (18.6% [n = 29] vs 14.5% [n = 8], respectively). <h3>Conclusion</h3> Extended treatment with bimagrumab up to 2 years produced a good safety profile and was well-tolerated, but did not provide clinical benefits in terms of improvement in mobility. The extension study was terminated early due to core study not meeting its primary endpoint. <h3>Clinical Trial Registration</h3> Clinicaltrials.gov identifier NCT02573467. <h3>Classification of Evidence</h3> This study provides Class IV evidence that for patients with sIBM, long-term treatment with bimagrumab was safe, well-tolerated, and did not provide meaningful functional benefit. The study is rated Class IV because of the open-label design of extension treatment period 2.