Open-label Treatment Research Articles

#12: The Safety and antibody kinetics of COVID-19 Convalescent Plasma for the Treatment of Moderate to Severe Cases of SARS-CoV-2 Infection in Pediatric Patients

Abstract Introduction A novel Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified as the pathogen responsible for a serious, life threatening respiratory infection (COVID-19) initially reported in Wuhan, China which rapidly spread worldwide resulting in global pandemic. Multiple immunological and pharmacological therapies have been evaluated with variable results. Convalescent plasma has been used in previous outbreaks such as Influenza 1918 and 2009, Ebola, MERS and SARS with good efficacy and safety reported. There have been multiple large reports on the safety of COVID-19 convalescent plasma (CCP) for the treatment of this serious infection in the adults; controversy has ensued regarding its efficacy. Pediatric data on CCP use are limited. Methods We conducted a prospective, open label treatment trial using CCP (10 ml/kg up to 1 unit) for the treatment of COVID-19 in pediatric patients with moderate to severe disease or high risk for serious illness. Safety and antibody kinetics and outcome data were collected. Results Eighteen moderate to severe COVID19 pediatric patients were enrolled and received CCP early in their illness (median days of symptoms XX). We observed no infusion related adverse events, no hematological or metabolic adverse events were noted during the hospitalization and at 3 weeks after infusion follow up. Sixteen patients demonstrated significant clinical improvement by day seven post infusion, as measured by the WHO eight-category ordinal severity scale for COVID-19. Presence of SARS-COV-2 anti-nucleocapsid IgG was demonstrated in all CCP specimens, a significant increase in antibodies was demonstrated in CCP recipients 24 hours after receiving CCP. Sustained high levels of anti- SARS-COV-2 anti-nucleocapsid IgG was demonstrated at 7- and 21-days post-transfusion. A transient IgM response not associated with CCP was noted. Eleven (61.1%) patients were discharge to home by day 7 post CCP infusion. One patient remained on invasive ventilatory support 21 days after CCP infusion and was eventually discharged to an intermediate care facility, one patient died retrospectively confirmed to have been brain death before receiving CCP. Conclusion We conclude that CCP was well tolerated in pediatric patients. CCP resulted in rapid increase of antibodies and sustained levels 21 days after infusion suggesting that CCP did not interfere with patients own immune response. More data are necessary to establish efficacy of this intervention in children, but our patients clinical course suggests benefit of CCP. Pediatric patients with moderate to severe COVID-19 may benefit of CCP when used early in the course of illness in conjunction with other immunological or antiviral interventions as needed.

Open-label placebo treatment to improve relaxation training effects in healthy psychology students: a randomized controlled trial

Placebos, that are administered with deception, can reduce stress and increase relaxation. The present study investigated an open-label placebo (OLP) to improve the effects of Progressive Muscle Relaxation (PMR) training. A total of 160 psychology students were randomly assigned to a 14-day PMR course with or without daily OLP treatment. The placebo was administered along with an explanation of placebo effects and the verbal suggestion that the OLP activates the body’s natural relaxation response. The relaxation instructions for home practice were delivered via a smartphone app, which was also used for the evaluation of the exercises. The participants of the OLP group completed more PMR exercises (M = 9.75) than the group without a placebo (M = 8.15). The two groups did not differ in reported exercise-related changes in relaxation level. On average, the OLP group rated the effects of the placebo as very low and was characterized by a higher drop-out rate compared to the group without OLP. Some participants experienced the OLP as negative. In conclusion, factors that influence the acceptance of OLP treatment require further investigation.

Impact of a 12-week open-label placebo treatment on headache days in episodic and chronic migraine: a study protocol for a parallel-group, multicentre, randomised controlled trial

IntroductionMigraine is the most common neurological disorder and one of the major causes of years lived with disability. Its treatment (especially of chronic forms) is often challenging and accompanied with...

Efficacy and safety of tofacitinib modified-release 11 mg once daily plus methotrexate in adult patients with rheumatoid arthritis: 24-week open-label phase results from a phase 3b/4 methotrexate withdrawal non-inferiority study (ORAL Shift)

ObjectivesTo report the efficacy, safety and patient-reported outcome measures (PROs) of tofacitinib modified-release 11 mg once daily plus methotrexate in patients with rheumatoid arthritis (RA) from the open-label phase of...

Effect of a Multi-Layer, Extended-Release Methylphenidate Formulation (PRC-063) on Sleep in Adults with ADHD: A Randomized, Double-Blind, Forced-Dose, Placebo-Controlled Trial Followed by a 6-month Open-Label Extension.

BackgroundThe effects of stimulant treatment on sleep in adults with attention-deficit/hyperactivity disorder (ADHD) are complex and varied, with some individuals experiencing worsening of sleep but others experiencing improvement.MethodsData from previously reported trials of the clinical efficacy and safety of the long-acting methylphenidate formulation PRC-063 (Adhansia XR® in the USA; Foquest® in Canada) in adults with ADHD were used to evaluate patient-reported sleep outcomes, as captured using the Pittsburgh Sleep Quality Index (PSQI) and adverse events of insomnia. The trials comprised 4 weeks of randomized, forced-dose PRC-063 treatment at a dose of 0 (placebo), 25, 45, 70, or 100 mg/day followed by an optional 6 months of open-label PRC-063 treatment at an individually optimized dose of 25–100 mg/day.ResultsAt the end of double-blind treatment, PRC-063 (all doses combined; N = 297) showed no significant difference versus placebo (N = 78) in least squares mean change in global PSQI score from baseline (− 0.7 vs. − 1.3; P = 0.0972) or in scores for each of the seven subscales of the PSQI. For patients enrolled in the open-label extension (N = 184), mean ± standard deviation global PSQI score improved from 7.8 ± 3.55 at the end of double-blind treatment to 5.8 ± 3.11 at 1 month and 5.4 ± 3.21 at 6 months (P < 0.0001). A greater proportion of patients were good sleepers (global PSQI score ≤ 5) at the end of the open-label extension (57.3%) than at baseline (20.9%) or at the end of double-blind treatment (26.0%). In a logistic regression analysis, baseline global PSQI score (odds ratio 1.491; P < 0.0001), but not randomized study treatment (P = 0.1428), was a significant predictor of poor sleep (global PSQI score > 5) at the end of double-blind treatment. Adverse event rates for insomnia (15.8 vs. 3.8%) and initial insomnia (6.1 vs. 1.3%) during double-blind treatment were higher for PRC-063 (all doses combined) than for placebo. Two patients receiving PRC-063 in the double-blind study and one patient in the open-label study were withdrawn because of insomnia adverse events.ConclusionsOur findings indicate that, on average, PRC-063 had no significant impact on overall sleep quality in adults with ADHD. Although insomnia was observed as an adverse event, when sleep was measured over time as an outcome in its own right for patients receiving dose-optimized PRC-063 open-label, more patients showed improvement in sleep than deterioration.ClinicalTrials.gov IdentiferNCT02139124 and NCT02168127.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00814-z.

FC 034SAFETY AND EFFICACY OF INTRAVENOUS BELIMUMAB IN PATIENTS WITH LUPUS NEPHRITIS: A 6-MONTH OPEN-LABEL EXTENSION

Abstract Background and Aims Lupus nephritis (LN) is the most common severe manifestation of systemic lupus erythematosus (SLE), occurring in up to 40% of patients (pts) with SLE over their disease course, and resulting in 10–20% of pts progressing to end-stage kidney disease.1-3 The BLISS-LN (GSK Study BEL114054; NCT01639339) study demonstrated that the addition of intravenous (IV) belimumab (BEL) to standard therapy (ST) in pts with active LN significantly improved renal responses over 2 years compared with ST alone.4 Here we present additional safety and efficacy data from the 6-month open-label (OL) extension phase of BLISS-LN. Method In this OL phase, eligible completers of the Phase 3 BLISS-LN study (those who received BEL or placebo [PBO] through Week 100 and completed Week 104 assessments) received BEL 10 mg/kg IV plus ST every 28 days for 24 weeks. Endpoints at OL Week 28 included: safety; Primary Efficacy Renal Response (PERR; defined as urine protein:creatinine ratio [uPCR] ≤0.7; eGFR no more than 20% below OL baseline value or ≥60 ml/min/1.73m2; no rescue therapy); Complete Renal Response (CRR; defined as uPCR &amp;lt;0.5; eGFR no more than 10% below OL baseline value or ≥90 ml/min/1.73m2; no rescue therapy); uPCR; eGFR; the proportion of pts with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score &amp;lt;4; Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI); and corticosteroid use. Analyses were based on observed data and summarised relative to the OL baseline (last available value measured prior to dosing on or before the date of the first OL treatment dose). Results Of 257 pts (57.4 % of pts in BLISS-LN double-blind [DB] study) screened and enrolled, 255 pts were treated (safety population: 123 pts switched from PBO to BEL; 132 pts remained on BEL). In total, 254 pts were included in the efficacy analyses (PBO to BEL: 122 pts; BEL to BEL: 132 pts). Mean (standard deviation) age was 35.9 (10.3) years. In total, 3.5% of pts withdrew from the OL phase, mainly due to adverse events (AE; 2.0%). Overall, 168/255 (65.9%) pts experienced ≥1 AE (76/123 [61.8%] PBO to BEL pts; 92/132 [69.7%] BEL to BEL pts); 49/255 (19.2%) pts had ≥1 treatment-related AE (25/123 [20.3%] PBO to BEL pts; 24/132 [18.2% ] BEL to BEL pts); 15/255 (5.9%) pts had ≥1 serious AE (5/123 [4.1%] PBO to BEL pts; 10/132 [7.6%] BEL to BEL pts); and 1 death was reported in the PBO to BEL group. The proportion of patients achieving PERR and CRR increased from OL baseline to OL Week 28 in both groups (Table). The median (interquartile range [IQR]) for uPCR and eGFR were maintained from OL baseline through to OL Week 28 (Table). The proportion of SLEDAI score &amp;lt;4 responders in BEL to BEL group tended to increase from OL baseline to OL Week 28, and decrease in the PBO to BEL group (Table). SDI worsening (change &amp;gt;0) was experienced by 7 (2.9%) pts (4 [3.3%] PBO to BEL; 3 [2.5%] BEL to BEL) compared with OL baseline. There was no appreciable change in the number of patients receiving average daily prednisone-equivalent doses of ≤5 mg or ≤7.5 mg from OL baseline to OL Week 28 (Table). Conclusion BEL was well tolerated as an add-on to ST, with no new safety signals. Efficacy among pts with LN randomised to BEL during the DB phase was maintained during the OL phase. Study funding GSK. Editorial assistance (GSK-funded): Olga Conn, PhD, Fishawack Indicia Ltd., part of Fishawack Health, UK.

Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder

BackgroundSulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD.MethodsWe conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3–12 years, with ASD over 36 weeks. Twenty-eight were assigned SF and 29 received placebo (PL). Clinical effects, safety and tolerability of SF were measured as were biomarkers to elucidate mechanisms of action of SF in ASD.ResultsData from 22 children taking SF and 23 on PL were analyzed. Treatment effects on the primary outcome measure, the Ohio Autism Clinical Impressions Scale (OACIS), in the general level of autism were not significant between SF and PL groups at 7 and 15 weeks. The effect sizes on the OACIS were non-statistically significant but positive, suggesting a possible trend toward greater improvement in those on treatment with SF (Cohen’s d 0.21; 95% CI − 0.46, 0.88 and 0.10; 95% CI − 0.52, 0.72, respectively). Both groups improved in all subscales when on SF during the open-label phase. Caregiver ratings on secondary outcome measures improved significantly on the Aberrant Behavior Checklist (ABC) at 15 weeks (Cohen’s d − 0.96; 95% CI − 1.73, − 0.15), but not on the Social Responsiveness Scale-2 (SRS-2). Ratings on the ABC and SRS-2 improved with a non-randomized analysis of the length of exposure to SF, compared to the pre-treatment baseline (p < 0.001). There were significant changes with SF compared to PL in biomarkers of glutathione redox status, mitochondrial respiration, inflammatory markers and heat shock proteins. Clinical laboratory studies confirmed product safety. SF was very well tolerated and side effects of treatment, none serious, included rare insomnia, irritability and intolerance of the taste and smell.LimitationsThe sample size was limited to 45 children with ASD and we did not impute missing data. We were unable to document significant changes in clinical assessments during clinical visits in those taking SF compared to PL. The clinical results were confounded by placebo effects during the open-label phase.ConclusionsSF led to small yet non-statistically significant changes in the total and all subscale scores of the primary outcome measure, while for secondary outcome measures, caregivers’ assessments of children taking SF showed statistically significant improvements compared to those taking PL on the ABC but not the SRS-2. Clinical effects of SF were less notable in children compared to our previous trial of a SF-rich preparation in young men with ASD. Several of the effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures.Trial registration: This study was prospectively registered at clinicaltrials.gov (NCT02561481) on September 28, 2015. Funding was provided by the U.S. Department of Defense.

When Can We Rely on Real-World Evidence to Evaluate New Medical Treatments?

Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real‐world evidence (RWE) in the evaluation of new treatments or products. The RWE label has been used to refer to a variety of departures from the methods of traditional randomized controlled trials. Recognizing this complexity and potential confusion, the National Academies of Science, Engineering, and Medicine convened a series of workshops to clarify and address questions regarding the use of RWE to evaluate new medical treatments. Those workshops identified three specific dimensions in which RWE studies might differ from traditional clinical trials: use of real‐world data (data extracted from health system records or data captured by mobile devices), delivery of real‐world treatment (open‐label treatments delivered in community settings by community practitioners), and real‐world treatment assignment (including nonrandomized comparisons and variations on random assignment such as before‐after or stepped‐wedge designs). For any RWE study, decisions regarding each of these dimensions depends on the specific research question, characteristics of the potential study settings, and characteristics of the settings where study results would be applied.

POS0655 LONG-TERM SAFETY AND EFFICACY OF UPADACITINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS: 3-YEAR RESULTS FROM THE SELECT-EARLY STUDY

Background:Upadacitinib (UPA), an oral Janus kinase inhibitor, demonstrated significant improvements in signs, symptoms, and structural inhibition as monotherapy (mono) vs methotrexate (MTX) in MTX-naïve patients (pts) with rheumatoid arthritis (RA) through 48 weeks (wks).1Objectives:To report the efficacy and safety of UPA vs MTX mono up to 156 wks in pts with RA from the ongoing long-term extension (LTE) of the SELECT-EARLY trial.Methods:During the 48-wk double-blind study period, pts were randomized to UPA 15 or 30 mg once daily (QD) or MTX (titrated to 20 mg/wk by Wk 8). At Wk 26, pts who did not achieve Clinical Disease Activity Index (CDAI) remission (≤2.8) and had &lt;20% improvement from baseline in tender or swollen joint count received blinded rescue therapy (addition of MTX for UPA groups and UPA 15 or 30 mg for MTX group). In the LTE, pts received open-label treatment once the last pt reached Wk 48. Efficacy assessments up to Wk 156 were summarized by randomized group and included American College of Rheumatology (ACR) responses, remission and low disease activity (LDA) measures, and change in modified Total Sharp Score (mTSS; up to 96 wks). Treatment-emergent adverse events (AEs) per 100 pt-years (PY) for pts on continuous mono were summarized through 156 wks. Non-responder imputation was used for binary endpoints for missing data and when pts received rescue therapy or prematurely discontinued the study drug.Results:Of 945 pts randomized and treated, 775 entered the LTE on study drug (including 57 rescued pts; MTX, 33; UPA 15 mg, 17; UPA 30 mg, 7). Overall, 161 (21%) pts discontinued during the LTE. At Wk 156, higher proportions of pts randomized to UPA achieved a 20/50/70% improvement in ACR response (ACR20/50/70), LDA, and remission vs MTX (Figure 1). Change from baseline in mTSS at Wk 96 favored UPA vs MTX (data not shown). Most AEs were numerically more frequent with UPA 30 mg. The overall rate of serious infection was numerically higher with UPA vs MTX (Table 1). Herpes zoster (HZ), neutropenia, non-melanoma skin cancer (NMSC), and creatine phosphokinase (CPK) elevation were more frequent with UPA vs MTX. Two active tuberculosis (TB) events were reported in each UPA arm; 3 adjudicated gastrointestinal (GI) perforation events were observed in the UPA 30 mg arm. Adjudicated major adverse cardiovascular events (MACEs) or venous thromboembolic events (VTEs) were comparable across treatment arms.Conclusion:UPA monotherapy showed sustained clinically meaningful responses including remission vs MTX through Wk 156 but higher rates of several AEs, including HZ, neutropenia, and CPK elevations; no new safety risks were observed compared with previous results.1,2

POS0689 A 6-MONTH OPEN-LABEL EXTENSION STUDY OF THE SAFETY AND EFFICACY OF INTRAVENOUS BELIMUMAB IN PATIENTS WITH LUPUS NEPHRITIS

Background:BLISS-LN (GSK Study BEL114054; NCT01639339), the largest lupus nephritis (LN) study to date, showed that intravenous (IV) belimumab (BEL) + standard therapy (ST) improved outcomes compared with ST alone in patients (pts) with active LN.1Objectives:To assess additional safety and efficacy data of BEL + ST in pts with LN in a 6-month open-label (OL) phase beyond 2 years of double-blind (DB) treatment in BLISS-LN.Methods:In this OL phase, eligible completers of the DB phase received monthly BEL 10 mg/kg IV + ST for 6 months. Endpoints: safety; Primary Efficacy Renal Response (PERR; uPCR ≤0.7; eGFR no worse than 20% below OL baseline eGFR or ≥60 ml/min/1.73 m2; no prohibited medications) and Complete Renal Response (CRR; uPCR &lt;0.5; eGFR no worse than 10% below OL baseline eGFR or ≥90 ml/min/1.73 m2; no prohibited medications) at OL Week 28; proportion of pts with SLEDAI score &lt;4; corticosteroid use; biomarkers. Analyses were based on observed data and summarised relative to the OL baseline (last value measured prior to the first dose of OL treatment).Results:We enrolled 257 pts (57.4% of pts in BEL114054) and treated 255 pts. All treated pts were included in the safety population (123 pts switched from placebo [PBO] to BEL; 132 pts remained on BEL). Efficacy was assessed in the safety population, excluding 1 pt due to non-compliance (mITT population; PBO to BEL: 122 pts; BEL to BEL: 132 pts). 96.5% of pts completed the OL phase; 3.5% withdrew, mainly due to adverse events (AE; 2.0%).Overall, 168/255 (65.9%) pts had ≥1 AE (76/123 [61.8%] PBO to BEL pts; 92/132 [69.7%] BEL to BEL pts); 15/255 (5.9%) pts had ≥1 serious AE (5/123 [4.1%] PBO to BEL pts; 10/132 [7.6%] BEL to BEL pts); 1 (0.8%) pt died in the PBO to BEL group.Proportions of PERR and CRR responders increased from OL baseline to OL Week 28 (Table 1. below)Proportions of pts who attained SLEDAI scores &lt;4 increased from OL baseline to OL Week 28 in the BEL to BEL group and decreased in the PBO to BEL group. Among pts receiving average daily prednisone-equivalent doses of ≤5 mg or ≤7.5 mg dose was maintained from OL baseline to OL Week 28 (Table 1. below)In pts with autoantibodies at OL baseline, anti-dsDNA and anti-C1q levels decreased from OL baseline to OL Week 28 in both groups. Among pts with low C3/C4 levels at OL baseline, C3/C4 levels increased from OL baseline to OL Week 28 in both groups (Table 1. below)Conclusion:In this OL phase of BLISS-LN, proportions of PERR and CRR responders increased in both the BEL-naïve and BEL-experienced groups; and no new safety signals were observed. Improvements in biomarker levels were observed, especially in pts who switched from PBO to BEL.Funding:GSK.

495 Efficacy of Lower-Sodium Oxybate on Idiopathic Hypersomnia, Measured by the Idiopathic Hypersomnia Severity Scale

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder with no approved treatment, characterized by excessive daytime sleepiness, prolonged sleep time, and sleep inertia. The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses severity of IH symptoms, including symptoms related to night/inertia (component I) and day/performance (component II). Individual IHSS items measure symptom frequency, intensity, and consequences using 3- or 4-point Likert scales, yielding a total score (range, 0–50), comprising component I (range, 0–16) and component II (range, 0–34). Higher scores indicate worse symptoms. In a recent clinical trial of the efficacy and safety of lower-sodium oxybate (LXB; Xywav™) for the treatment of IH, the IHSS was a key efficacy measure. Methods Eligible participants 18–75 years of age with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week stable-dose period (SDP). Participants were randomized to placebo or continued LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The IHSS was completed at baseline, during OLTTOP (weeks 1, 4, and 8), and at the end of OLTTOP, SDP, and DBRWP. Change in IHSS total score from SDP to DBRWP was a key secondary endpoint. Results The efficacy population included 115 participants (mean±SD age, 41±14 years; 71% female). At baseline and the end of SDP, respectively, mean±SD IHSS scores were 31.6±8.3 and 15.3±8.5 for total score, 10.3±3.6 and 5.4±2.8 for component I (night/inertia), and 21.2±5.8 and 9.9±6.5 for component II (day/performance). Worsening from SDP to DBRWP was observed in patients randomized to placebo compared with LXB in IHSS total scores (estimated median difference [95% CI], −12.0 [−15.0, −8.0]; significant P&amp;lt;0.0001), component I scores (LS mean difference [95% CI], −3.9 [−4.9, −2.9]; nominal P&amp;lt;0.0001), and component II scores (LS mean difference [95% CI], −7.8 [−9.6, −5.9]; nominal P&amp;lt;0.0001). Results on all individual IHSS items reflected an improvement with LXB treatment over time during OLTTOP, which remained consistent during SDP. Conclusion These results support the efficacy of LXB for the treatment of IH symptoms, as assessed with the IHSS. Support (if any) Jazz Pharmaceuticals

500 Correlation of the Idiopathic Hypersomnia Severity Scale With Other Measures of Sleep Parameters in a Phase 3 Trial

Abstract Introduction The Idiopathic Hypersomnia Severity Scale (IHSS) is a 14-item, self-reported questionnaire that assesses core Idiopathic Hypersomnia (IH) symptom severity. The relationship between IHSS scores and other IH symptom measures, such as the Epworth Sleepiness Scale (ESS; measures daytime sleepiness), sleep inertia visual analog scale (VAS-SI; measures sleep inertia), and Patient Global Impression of Change (PGIc; measures patients’ self-assessed change in symptoms), has not been established. This post hoc analysis analyzed correlations between the IHSS and ESS, VAS-SI, and PGIc using data from a clinical trial (NCT03533114) evaluating lower-sodium oxybate (LXB; Xywav™) for the treatment of IH. Methods During a clinical trial, the IHSS (0–50 score range) and ESS (0–24 score range) were completed at baseline; the IHSS, ESS, and PGIc (ordinal, 7 categories) were completed during an open-label treatment titration and optimization period (OLTTOP), after the OLTTOP, after a stable-dose period (SDP), and after a double-blind, randomized withdrawal period (DBRWP). The VAS-SI (0–100 score range) was completed during screening, SDP, and DBRWP. Correlation coefficients (rs) for IHSS vs ESS and VAS-SI were estimated from the within-subject variance matrix using a repeated-measures linear mixed model (LMM). The correlation between changes in IHSS score and PGIc was assessed using a Kruskal-Wallis test. Results IHSS scores correlated positively with ESS scores (rs [95% CI], 0.77 [0.73, 0.81]) and VAS-SI scores (0.69 [0.63, 0.75]). IHSS total score change was correlated with PGIc rank (chi-square with 6 degrees of freedom = 595.8, nominal P&amp;lt;0.001). The LMM showed that a 3-point change in ESS score corresponded to an average 3.99-point change in IHSS score; a 10-point change in VAS-SI score corresponded to an average 3-point change in IHSS score. Participants very much improved in the PGIc had a −12.13 (95% CI: −13.23, −11.04) expected change in IHSS score. Participants much improved in the PGIc had a −8.39 (95% CI: −9.30, −7.48) expected change in IHSS score. Conclusion IHSS scores or score changes strongly correlated with individual instruments assessing excessive daytime sleepiness, sleep inertia, and self-reported global symptoms, suggesting that the IHSS is a reliable, comprehensive measure of these symptoms of IH. Support (if any) Jazz Pharmaceuticals

The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design

BackgroundA phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier: NCT03746522). MethodsIt was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m2 (in those aged ≥16 years) or a weight >97th percentile (in those aged 6–15 years) are included. Participants are initially randomized in a 1:1 ratio to receive setmelanotide or placebo for 14 weeks (period 1). Following period 1, all participants receive 38 weeks of open-label treatment with setmelanotide (period 2). In each treatment period, setmelanotide is administered at 3 mg once a day following completion of dose escalation. The primary endpoint is the proportion of participants aged ≥12 years achieving a clinically meaningful reduction from baseline (≥10%) in body weight after ~52 weeks (eg, following period 2). Safety and tolerability are assessed by frequency of adverse events. ConclusionsThis pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome. Submission categoryStudy Design, Statistical Design, Study Protocols.

487 Effect of Lower-Sodium Oxybate on Sleep Inertia in Idiopathic Hypersomnia in a Double-Blind, Randomized Withdrawal Study

Abstract Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness. A common feature is sleep inertia, which is prolonged difficulty waking up accompanied by confusion, disorientation, poor motor coordination, and repeated returns to sleep. Sleep inertia is burdensome to patients, resulting in missed work or school, and patients may be dependent on others to wake them. No treatment is currently approved for IH. The efficacy and safety of lower-sodium oxybate (LXB; Xywav™), a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®), was evaluated in a phase 3 study (NCT03533114) in adults with IH. We focus here on the drug effect on sleep inertia. Methods Eligible participants aged 18–75 years with IH began LXB treatment with an open-label treatment titration and optimization period (OLTTOP; 10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP). Participants were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale score. The visual analog scale for sleep inertia (VAS-SI) was included as an exploratory endpoint. The VAS-SI, administered daily during the last 2 weeks of screening before baseline, SDP, and DBRWP, is a self-reported retrospective measure of difficulty awakening each morning using a 100-mm line with anchors 0 (very easy) and 100 (very difficult). Results The safety population included 154 participants (mean±SD age, 40±14 years; 68% female); modified intent-to-treat population, n=115. VAS-SI scores gradually decreased from week 2 of screening (mean±SD, 56.6±25.1) to week 2 of SDP (29.0±20.8). During week 2 of DBRWP, VAS-SI scores worsened in participants randomized to placebo (n=59) compared with maintenance of improvement in participants continuing LXB treatment (n=56); LS mean difference (95% CI) in change from SDP, −22.2 (−29.7, −14.8); P&amp;lt;0.0001 (nominal). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion Sleep inertia improved with LXB treatment and significant differences were seen between placebo and LXB after DBRWP. The overall safety profile in participants with IH is consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals, Inc

When Are Treatment Blinding and Treatment Standardization Necessary in Real-World Clinical Trials?

Concerns regarding both the limited generalizability and the slow pace of traditional randomized trials have led to calls for greater use of real‐world evidence in the evaluation of new treatments or products. Real‐world clinical trials or pragmatic trials often differ from traditional clinical trials in the use of open‐label or nonblinded treatments delivered by real‐world clinicians in community practice settings. Blinding and standardization of treatment may sometimes be necessary for internal validity, but they may also obscure or distort meaningful differences between treatments. When investigators consider whether blinding of clinicians, patients, or assessors is necessary, we suggest they consider several specific questions: Will clinicians, patients, and assessors have expectations or preferences regarding benefits or adverse effects? How might those expectations affect treatment uptake, treatment adherence, or assessment of outcomes? Will expectations differ in the settings where trial results will be applied? How would blinding of treatment reduce biases? How would blinding obscure true differences between treatments? How would procedures necessary for blinding reduce acceptability or increase risk of trial participation? When investigators consider how strictly treatments should be standardized, we suggest they consider several specific questions: How would treatment effectiveness or safety vary according to clinician experience or expertise? What level of experience or expertise is available in potential trial settings and settings where trial results would be applied? Is some level of standardization necessary for valid inference? Considering any special vulnerabilities of the study population, is some level of standardization necessary to assure participant safety?

Lurasidone in adolescents with schizophrenia: Sustained remission and recovery during 2 years of open-label treatment

IntroductionCompared with adult onset, early onset schizophrenia is typically characterized by greater illness severity and less favorable prognosis.ObjectivesTo evaluate the proportion of adolescent patients with schizophrenia who achieved sustained remission and recovery during 2 years of treatment with lurasidone.MethodsPatients aged 13-17 years with a DSM-IV-TR diagnosis of schizophrenia, and a Positive and Negative Symptom Scale (PANSS) total score ≥70 and &lt;120, were randomized to 6 weeks of double-blind (DB), fixed-dose treatment with lurasidone (37 or 74 mg/d) or placebo. Patients who completed 6 weeks of DB treatment were eligible to enroll in a 2-year, open-label (OL), flexible dose extension study of lurasidone (18.5-74 mg/d). Criteria for sustained remission, were the 6-month consensus criteria summarized by Andreasen (Am J Psych 2005;162:441-9). Criteria for sustained recovery consisted of meeting sustained remission criteria with a Children’s Global Assessment Scale (CGAS) score ≥70 for at least 6-months indicating no clinically significant functional impairment.ResultsA total of 271 patients completed the 6-week DB study and entered the extension study, and 186 (68.6%) and 156 (57.6%) completed 52 weeks and 104 weeks of treatment, respectively. During OL treatment with lurasidone, 52.8% met sustained remission criteria, with a Kaplan-Meier (KM) estimate of 64.1 weeks for median time to sustained remission; and 28.8% met sustained recovery criteria, KM estimate of 104.6 weeks for median time to sustained recovery.ConclusionsFor adolescents with schizophrenia, treatment with lurasidone was associated with high rates of sustained remission and sustained recovery over a two-year period.DisclosureEmployee of Sunovion Pharmaceuticals Inc. The study summarized in this Abstract was supported by funding from Sunovion Pharmaceuticals Inc

Safety and Effectiveness of SEP−363856 in Schizophrenia: Results of a 6-Month, Open-Label Extension Study

SEP-363856 is a novel psychotropic agent without dopamine D2 receptor occupancy. Although its mechanism of action has not been fully elucidated, preclinical data suggest that agonism at trace amine receptor 1 (TAAR1) and the serotonin 5-H1A receptor contributes to its efficacy. In a double-blind (DB), placebo-controlled study, SEP-363856 demonstrated significant efficacy in the treatment of an exacerbation of schizophrenia (Koblan et al, NEJM 2020; 82:1497-1506). We present results of a 6-month extension study whose aim was to evaluate the safety and effectiveness of longer-term treatment with SEP-363856. Patients with an acute exacerbation of schizophrenia who completed a 4-week, DB, placebo-controlled, flexible-dose (50 or 75 mg) study of SEP-363856 were given the option to enroll in an extension study in which they were treated, open-label (OL), with flexible doses (25/50/75 mg/d) of SEP-363856 for 26-weeks. The primary outcomes were safety measures; effectiveness outcomes were secondary and included the PANSS total score and the Brief Negative Symptom Scale (BNSS) total score. A total of 193 patients completed the 4-week DB study, and 156 (80.8%) were dosed in the OL extension study and received at least one dose of SEP-363856 (safety population). Study completer rate was 66.9%; reasons for discontinuation consisted of adverse event (11.5%), withdrawal of consent (10.2%), lack of efficacy (5.1%), and other (6.4%). 15 patients experienced an SAE: schizophrenia (n=11); acute psychosis (N=1); uterine hemorrhage and suicidal ideation (N=1 each); there were no deaths in the study. Individual AEs with an incidence =2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). On movement scales, minimal mean change from OL-baseline to Week 26 occurred on the Barnes total score (-0.1), AIMS total score (0.0) and SAS score (-0.1). Mean month 6 change from DB baseline in weight was -0.3 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, one patient had an increase in QTcF =60 msec; no patients had a QTcF interval =480 msec. Treatment with SEP-363856 was associated with significant improvement from OL baseline to week 26 in PANSS total score (-22.6) and BNSS total score (-11.3). Treatment with SEP-363856 was associated with continued improvement from open-label baseline in the PANSS total (-22.6) and BNSS total (-11.3) scores. The most frequently reported adverse events (= 5%) were schizophrenia, headache, insomnia and anxiety. SEP-363856 had minimal effects on weight, lipids, glycemic indices, prolactin, and was associated with minimal risk of extrapyramidal symptom. Sunovion Pharmaceuticals Inc.

Pharmacokinetics and pharmacodynamics of ampreloxetine, a novel, selective norepinephrine reuptake inhibitor, in symptomatic neurogenic orthostatic hypotension

PurposeAmpreloxetine is a novel, selective, long-acting norepinephrine reuptake (NET) inhibitor being investigated as a once-daily oral treatment for symptomatic neurogenic orthostatic hypotension (nOH) in patients with autonomic synucleinopathies. The purpose of this study was to characterize the pharmacokinetic and pharmacodynamic profiles of ampreloxetine in this target population.MethodsPatients with nOH were enrolled in a multicenter, phase II clinical trial of ampreloxetine (NCT02705755). They received escalating doses over 5 days in the clinical research unit, followed by 20 weeks of open-label treatment and then a 4-week withdrawal. As neurochemical biomarkers of NET inhibition, we assayed plasma concentrations of norepinephrine (NE) and its main intraneuronal metabolite 3,4-dihydroxyphenylglycol (DHPG) pre- and post-ampreloxetine.ResultsThirty-four patients with nOH were enrolled. Plasma ampreloxetine concentrations increased with repeated escalating doses, with peak concentrations observed 6–9 h post-drug administration. The median ampreloxetine dose in the 20-week treatment phase was 10 mg once daily. Plasma ampreloxetine concentrations reached steady state by 2 weeks, with stable plasma levels over 24 h. No influence of age or renal function on ampreloxetine plasma concentrations was observed. On treatment, compared to baseline, plasma NE significantly increased by 71% (p < 0.005), plasma DHPG significantly declined by 22% (p < 0.05), and the NE:DHPG ratio significantly increased (p < 0.001).ConclusionsPersistent elevation of plasma NE levels accompanied by reduced DHPG levels after ampreloxetine suggests reduced neuronal reuptake and metabolism of NE in postganglionic efferent sympathetic neurons. The findings are consistent with long-lasting NET inhibition, which may increase vasoconstrictor tone, supporting once-daily ampreloxetine dosing in patients with nOH.

Validation of the McIntyre And Rosenblat Rapid Response Scale (MARRRS) in Adults with Treatment-Resistant Depression Receiving Intravenous Ketamine Treatment

Background: Depression severity and efficacy measurement scales employed for rapid-acting treatments (e.g., ketamine) were initially validated in adults receiving conventional monoamine-based antidepressants. The emergence of rapid-acting antidepressants in psychiatry provides the impetus for outcome measures that have been validated as sensitive to change with rapid-acting treatments. Herein, we provide results validating the McIntyre and Rosenblat Rapid Response Scale (MARRRS).Methods: Adults with treatment-resistant depression (TRD) receiving intravenous (IV) ketamine had depressive symptoms measured with the 16-Item Quick Inventory Depressive Symptoms Self-Report (QIDS-SR-16) and MARRRS at baseline and as a repeated measure across an acute course of four infusions. The MARRRS is a self-report measure assessing depressive symptoms during the past 72 hours.Results: Sixty-four patients (Mage = 45.4 ± 13.5) were included. The MARRRS had a high internal consistency across acute infusions as determined by Cronbach's alpha (0.84 to 0.94). There was significant convergent validity between the QIDS-SR-16 and MARRRS total scores across infusions (rs(292) = .87, p < .001); the MARRRS was also sensitive to change (rs(49) = .70, p < .001). Exploratory factor analysis revealed that MARRRS items loaded onto two factors (i.e., dysphoria and psychic anxiety) accounting for 63.4% of the total variance.Limitations: Heterogenous sample of adults with TRD receiving open-label treatment without placebo comparison.Conclusion: The MARRRS is a brief validated self-report metric of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. Measuring outcomes with the MARRRS informs treatment progress and facilitates treatment decisions in persons receiving the rapid-acting antidepressant ketamine. Studies of other rapid-acting antidepressants should incorporate outcome measures that are validated as sensitive to change with rapid-acting antidepressants.

Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine.

ObjectiveTo assess long‐term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients.BackgroundPreviously published results from the double‐blind treatment phase (DBTP) of a phase 2 clinical study have demonstrated the efficacy and safety of erenumab in Japanese patients with EM.MethodsPatients completing the 24‐week placebo‐controlled DBTP could continue into the 76‐week open‐label treatment phase (OLTP), receiving erenumab 70 mg or 140 mg subcutaneously once monthly. The initial dose in the OLTP was erenumab 70 mg monthly, which was later changed to 140 mg. After study completion, the following were assessed: change from baseline in monthly migraine days (MMD), change from baseline in monthly acute migraine‐specific medication days (MSMD), percentage of patients achieving ≥50% and ≥75% reduction in MMD, change from baseline in the 6‐item Headache Impact Test (HIT‐6™) score, and safety (exposure‐adjusted patient‐incidence of adverse events [AEs], calculated as number of patients per 100 patient‐years).ResultsOf 475 patients enrolled in the DBTP, 459 (96.6%) continued in the OLTP. The mean (SD) MMD was 7.9 (2.3) at baseline with the overall change from baseline at week 100 of –2.9 (4.1) days. The monthly acute MSMD was 5.7 (2.8) at baseline with change from baseline at week 100 of −1.7 (3.7) days. The proportion of patients who achieved ≥50% and ≥75% reduction in MMD from baseline at week 100 was 177/398 (44.5%) and 94/398 (23.6%), respectively. The HIT‐6™ score was 58.4 (5.4) at baseline with a change of −6.4 (8.2) at week 100. The exposure‐adjusted patient‐incidence of AEs during the OLTP was 207.1/100 patient‐years for the combined erenumab group, similar to that observed for either erenumab (271.0/100 patient‐years) or placebo (257.3/100 patient‐years) during the DBTP, and no new safety signals were detected during the OLTP.ConclusionLong‐term erenumab treatment in Japanese patients with EM demonstrated sustained efficacy for up to 2 years, with a safety profile similar to previous studies, supporting erenumab as a potential new therapy for EM prevention in Japan.