Weeks Of Open-label Treatment Research Articles

Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.

To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.

Effects of Rimegepant 75 mg on Monthly Migraine Days: a 52-Week, Open-Label Extension Study (P10-12.010)

Effects of Rimegepant 75 mg on Monthly Migraine Days: a 52-Week, Open-Label Extension Study (P10-12.010)

Efficacy and Safety of Calcipotriene/Betamethasone Dipropionate Foam in the Treatment of Psoriasis in Skin of Color.

There is a paucity of data on usage of topical medications in patients with darker phototypes. This single-center, randomized, double-blinded, vehicle-controlled clinical study investigated the efficacy of a combination calcipotriene/betamethasone dipropionate (Cal/BD) aerosol foam 0.005%/0.064% in the treatment of psoriasis vulgaris in Fitzpatrick skin types IV to VI. 25 adult subjects were randomized 4:1 to Cal/BD foam or foam vehicle once daily for 4 weeks followed by 4 weeks of open label treatment. From week 4 to week 8, subjects randomized to Cal/BD foam once daily switched to Cal/BD foam twice weekly for 4 weeks, while those randomized to vehicle applied Cal/BD foam once daily. At week 4, 4/19 (21%) of Cal/BD foam patients achieved clear/almost clear Investigator Global Assessment (IGA) status with ≥2 grade improvement compared with 0/5 (0%) of vehicle patients (P=0.54). 12/19 (63%) of Cal/BD foam patients achieved a 50% reduction in Psoriasis Area and Severity Index (PASI 50) at week 4, compared with 0/5 (0%) of vehicle patients (P=0.04). Mean changes in melanin index at week 4 indicate a trend toward increased pigmentation in Cal/BD foam patients and decreased pigmentation in foam vehicle patients (P=0.30). All adverse events were mild and deemed unrelated to treatment by the investigators. The sample size was small and underpowered to detect statistically significant changes in most endpoints. Cal/BD foam was safe and well tolerated in plaque psoriasis patients with skin of color. Larger studies involving skin of color populations with psoriasis are warranted. Pigmentary changes (hyper- and hypopigmentation) in lesional skin were observed. J Drugs Dermatol. 2023;22(2): 165-173.doi:10.36849/JDD.6910.

Effects of adjunctive brexpiprazole on sleep-wake and circadian parameters in youth with depressive disorders: study protocol for a clinical trial

IntroductionSleep-wake and circadian disturbance is a key feature of mood disorders with a potential causal role and particular relevance to young people. Brexpiprazole is a second-generation antipsychotic medication with demonstrated...

Dorzagliatin in drug-naïve patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Improving glucose sensitivity remains an unmet medical need in treating type 2 diabetes (T2D). Dorzagliatin is a dual-acting, orally bioavailable glucokinase activator that enhances glucokinase activity in a glucose-dependent manner, improves glucose-stimulated insulin secretion and demonstrates effects on glycemic control in patients with T2D. We report the findings of a randomized, double-blind, placebo-controlled phase 3 clinical trial to evaluate the efficacy and safety of dorzagliatin in patients with T2D. Eligible drug-naïve patients with T2D (n = 463) were randomly assigned to the dorzagliatin or placebo group at a ratio of 2:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin from baseline to week 24. Safety was assessed throughout the trial. At week 24, the least-squares mean change in glycated hemoglobin from baseline (95% confidence interval) was -1.07% (-1.19%, -0.95%) in the dorzagliatin group and -0.50% (-0.68%, -0.32%) in the placebo group (estimated treatment difference, -0.57%; 95% confidence interval: -0.79%, -0.36%; P < 0.001). The incidence of adverse events was similar between the two groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin group. In summary, dorzagliatin improved glycemic control in drug-naïve patients with T2D and showed a good tolerability and safety profile.

Dorzagliatin add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 3 trial

Metformin, the first-line therapy for type 2 diabetes (T2D), decreases hepatic glucose production and reduces fasting plasma glucose levels. Dorzagliatin, a dual-acting orally bioavailable glucokinase activator targeting both the pancreas and liver glucokinase, decreases postprandial glucose in patients with T2D. In this randomized, double-blind, placebo-controlled phase 3 trial, the efficacy and safety of dorzagliatin as an add-on therapy to metformin were assessed in patients with T2D who had inadequate glycemic control using metformin alone. Eligible patients with T2D (n = 767) were randomly assigned to receive dorzagliatin or placebo (1:1 ratio) as an add-on to metformin (1,500 mg per day) for 24 weeks of double-blind treatment, followed by 28 weeks of open-label treatment with dorzagliatin for all patients. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) levels from baseline to week 24, and safety was assessed throughout the trial. At week 24, the least-squares mean change from baseline in HbA1c (95% confidence interval (CI)) was −1.02% (−1.11, −0.93) in the dorzagliatin group and −0.36% (−0.45, −0.26) in the placebo group (estimated treatment difference, −0.66%; 95% CI: −0.79, −0.53; P < 0.0001). The incidence of adverse events was similar between groups. There were no severe hypoglycemia events or drug-related serious adverse events in the dorzagliatin and metformin combined therapy group. In patients with T2D who experienced inadequate glycemic control with metformin alone, dorzagliatin resulted in effective glycemic control with good tolerability and safety profile (NCT03141073).

Efficacy of second-line dolutegravir plus 2 nucleoside reverse transcriptase inhibitors by baseline nucleoside reverse transcriptase inhibitor resistance and nucleoside reverse transcriptase inhibitor use in the DAWNING study

Background In the DAWNING study, dolutegravir + 2 nucleoside reverse transcriptase inhibitors (NRTIs) demonstrated superior efficacy at Week 48 and a favourable safety profile compared with lopinavir/ritonavir + 2 NRTIs in adults with HIV-1 failing first-line therapy of a non-nucleoside reverse transcriptase inhibitor + 2 NRTIs. Methods Participants at 58 centres in 13 countries were randomised (1:1) to 52 weeks of open-label treatment with dolutegravir or lopinavir/ritonavir combined with 2 investigator-selected NRTIs, including at least one fully active NRTI based on screening resistance testing. The primary endpoint was the proportion of participants achieving HIV-1 RNA &lt;50 copies/ml at Week 48 (Snapshot algorithm). Post-hoc efficacy analyses were performed based on baseline NRTI resistance profile and second-line NRTI use. Results Of 624 participants randomised and treated, 499 (80%) received &lt;2 active NRTIs at Baseline. NRTI resistance was present in 561 participants (90%). Among participants receiving lamivudine or emtricitabine in the presence of M184V/I, 85% (187/220) of participants on dolutegravir versus 72% (152/210) on lopinavir/ritonavir had HIV-1 RNA &lt;50 copies/ml at Week 48 (difference, 12.6%; 95% CI: 4.9–20.3%). High responses were also observed in the dolutegravir group, when zidovudine or tenofovir disoproxil fumarate were included in the background regimen in the presence of thymidine analogue mutations or K65R, respectively; however, participant numbers in these subgroups were small. Conclusions Response rates were high in participants receiving dolutegravir + 2 NRTIs as second-line treatment regardless of pre-existing resistance to one of the NRTIs, including in participants using lamivudine or emtricitabine in the presence of M184V/I.

Durability of the Clinical Benefit of Droxidopa for Neurogenic Orthostatic Hypotension During 12 Weeks of Open-Label Treatment.

IntroductionDroxidopa is approved to treat neurogenic orthostatic hypotension (nOH) symptoms in patients with autonomic failure based on short-term clinical trial data. Additional data on the long-term efficacy of droxidopa are needed. We have evaluated the 12-week efficacy and tolerability of droxidopa in patients with nOH in an open-label period of an ongoing phase 4 study .MethodsPatients received 12 weeks of open-label treatment with an individually optimized droxidopa dose (100–600 mg, 3 times daily) as identified during a preceding titration period. Patient-reported outcomes included the Orthostatic Hypotension Symptom Assessment (OHSA), Orthostatic Hypotension Daily Activity Scale (OHDAS), and clinician- and patient-rated Clinical Global Impression–Severity (CGI-S) scales. Supine blood pressure (BP) and adverse events (AEs) were recorded.ResultsData from 114 patients enrolled into the 12-week open-label period were available for analyses. After 12 weeks of droxidopa treatment, patients reported significant (P < 0.0001) improvements from baseline in OHSA and OHDAS composite and individual item scores and on clinician and patient CGI-S scores. Mean ± SD supine systolic and diastolic BP at week 12 increased by 15.5 ± 22.9 and 7.8 ± 11.7 mmHg from baseline, respectively (P < 0.0001 for both). The most frequently reported AEs were falls (17%), headache (13%), and dizziness (9%); one (0.9%) patient reported an AE of supine hypertension.ConclusionDuring 12 weeks of open-label treatment, droxidopa was associated with significant improvement from baseline in nOH symptoms and activities of daily living. No clinically important changes in supine hypertension or AEs of concern were observed. These results support the efficacy of droxidopa beyond 2 weeks of treatment. Trial RegistrationNCT02586623.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00317-5.

WITHDRAWN: EFFICACY, SAFETY, AND TOLERABILITY OF OMILANCOR IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF PATIENTS WITH ULCERATIVE COLITIS.

Omilancor is an oral, once-daily, gut-restricted, small molecule, first-in-class therapeutic for Crohn's disease (CD) and ulcerative colitis (UC) that targets the novel LANCL2 pathway. Through LANCL2 activation, omilancor increases the suppressive capacity of regulatory immune cells, including regulatory CD4+ T cells (Tregs), locally within the intestinal mucosa. In a Phase I study in normal healthy volunteers no changes in AEs or trends in safety laboratory trends were observed up to daily oral doses of 7500 mg/day. In a Phase 2, proof of concept, double blind, parallel-group study, adult patients with Mayo Clinic scores (MCS) of 4 - 10 and endoscopic subscores of 2 or more were randomly assigned to groups given omilancor 440 mg QD (n=66), omilancor 880 mg QD (n=66) or placebo (n=66) for 12 weeks. The primary endpoint was clinical remission after 12 weeks as defined by rectal bleeding (RB) equal to 0, stool frequency (SF) equal to 0 or 1 and endoscopic appearance (MES) equal to 0 or 1. A modified intent to treat (mITT) population was defined by patients with RB > 0, histological activity and elevated fecal calprotectin (FCP) at baseline. Secondary endpoints included histological remission as defined by a Geboes score < 3.1 with absence of neutrophils in the lamina propria, endoscopic remission as defined by a MES < 2, normalization of FCP and pharmacokinetics (PK) of omilancor in stool, tissue and plasma. Oral omilancor was well tolerated with no trends in AE profile observed and most AEs of mild severity and no dose-limiting toxicities. In the mITT population, clinical remission was induced in 30.4% of omilancor treated patients relative to 3.7% of patients given placebo (Δ = 26.7, p = 0.01), thereby meeting the primary endpoint. Endoscopic remission was induced in 41.7% of patients treated with omilancor relative to 18.6% of patients given placebo (Δ = 23.1, p = 0.07). Histological remission was induced in 41.7% of patients treated with omilancor relative to 22.2% of patients given placebo (Δ = 19.5, p = 0.14). In patients with elevated baseline FCP, normalization occurred in 43.8% of the omilancor 880 mg group and 40.6% of the omilancor 440 mg group relative to 21.4% of the placebo group after 2 weeks (p = 0.048). PK analysis validated a gut-restricted profile with stable drug levels in stool over the 12-week treatment period and penetration into colonic biopsy tissue with limited systemic exposure. Reduction of patient reported outcomes occurred during the OLE with nearly 90% of patients reaching SF ≤ 1 and RB = 0 after 36 weeks of open-label treatment. Once a day oral dosing with omilancor was well-tolerated and induced clinical remission in a Phase II mild to moderate UC population. A Phase II study in CD and a Phase III program in UC (PACIFY) were initiated in 2021 and are currently recruiting.

WITHDRAWN: EFFICACY, SAFETY, AND TOLERABILITY OF OMILANCOR IN A PHASE 2 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF PATIENTS WITH ULCERATIVE COLITIS

Omilancor is an oral, once-daily, gut-restricted, small molecule, first-in-class therapeutic for Crohn’s disease (CD) and ulcerative colitis (UC) that targets the novel LANCL2 pathway. Through LANCL2 activation, omilancor increases the suppressive capacity of regulatory immune cells, including regulatory CD4+ T cells (Tregs), locally within the intestinal mucosa. In a Phase I study in normal healthy volunteers no changes in AEs or trends in safety laboratory trends were observed up to daily oral doses of 7500 mg/day. In a Phase 2, proof of concept, double blind, parallel-group study, adult patients with Mayo Clinic scores (MCS) of 4 – 10 and endoscopic subscores of 2 or more were randomly assigned to groups given omilancor 440 mg QD (n=66), omilancor 880 mg QD (n=66) or placebo (n=66) for 12 weeks. The primary endpoint was clinical remission after 12 weeks as defined by rectal bleeding (RB) equal to 0, stool frequency (SF) equal to 0 or 1 and endoscopic appearance (MES) equal to 0 or 1. A modified intent to treat (mITT) population was defined by patients with RB > 0, histological activity and elevated fecal calprotectin (FCP) at baseline. Secondary endpoints included histological remission as defined by a Geboes score < 3.1 with absence of neutrophils in the lamina propria, endoscopic remission as defined by a MES < 2, normalization of FCP and pharmacokinetics (PK) of omilancor in stool, tissue and plasma. Oral omilancor was well tolerated with no trends in AE profile observed and most AEs of mild severity and no dose-limiting toxicities. In the mITT population, clinical remission was induced in 30.4% of omilancor treated patients relative to 3.7% of patients given placebo (Δ = 26.7, p = 0.01), thereby meeting the primary endpoint. Endoscopic remission was induced in 41.7% of patients treated with omilancor relative to 18.6% of patients given placebo (Δ = 23.1, p = 0.07). Histological remission was induced in 41.7% of patients treated with omilancor relative to 22.2% of patients given placebo (Δ = 19.5, p = 0.14). In patients with elevated baseline FCP, normalization occurred in 43.8% of the omilancor 880 mg group and 40.6% of the omilancor 440 mg group relative to 21.4% of the placebo group after 2 weeks (p = 0.048). PK analysis validated a gut-restricted profile with stable drug levels in stool over the 12-week treatment period and penetration into colonic biopsy tissue with limited systemic exposure. Reduction of patient reported outcomes occurred during the OLE with nearly 90% of patients reaching SF ≤ 1 and RB = 0 after 36 weeks of open-label treatment. Once a day oral dosing with omilancor was well-tolerated and induced clinical remission in a Phase II mild to moderate UC population. A Phase II study in CD and a Phase III program in UC (PACIFY) were initiated in 2021 and are currently recruiting.

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...

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.

Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials

The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity. These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960. Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials. Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency. Rhythm Pharmaceuticals.

Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response

The current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial. Children aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of≥25%, whereas nonresponders (NR) had<25% reduction posttreatment. Assessments included weekly behavioral ratings and pre-/posttreatment cognitive EEG measures. The final sample was 25 RESP and 26 NR comprising 34 male and 17 female children, with a mean (SD) age of 10.3 (1.4) years. Baseline measures that significantly differentiated RESP from NR included: lower working memory, lower spelling and mathematics achievement, deficits on behavioral ratings of executive function (BRIEF), and lower resting state EEG power in the right frontal (F4) region (all p values<.05). Compared to NRs, responders showed significantly increased right frontal EEG power with TNS treatment, which was predictive of improved executive functions and ADHD symptomatology (β= 0.65, p< .001). When EEG findings and behavior were modeled together, the area under the curve (AUC) for BRIEF Working Memory scale was 0.83 (p= .003), indicating moderate prediction of treatment response. Children with ADHD who have executive dysfunction are more likely to be TNS responders and show modulation of right frontal brain activity, improved/normalized executive functions, and ADHD symptom reduction. Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov; NCT02155608.

Exhalation delivery system with fluticasone improves quality of life and health status: pooled analysis of phase 3 trials NAVIGATE I and II

BackgroundChronic rhinosinusitis with or without nasal polyps (CRSwNP/CRSsNP) seriously impairs health‐related quality of life (HRQoL). This analysis describes the impact of the exhalation delivery system with fluticasone (EDS‐FLU) on HRQoL, assessed by the 36‐item Short‐Form Health Survey version 2 (SF‐36v2), and on utilities, assessed via the Short‐Form 6‐Dimension (SF‐6D), in patients with CRSwNP.MethodsPost hoc analysis of pooled randomized clinical trial data (NAVIGATE I and II; N = 643) to examine change from baseline in SF‐36v2 and SF‐6D at end‐of‐double‐blind (EODB: 16 weeks) and end‐of‐open‐label (EOOL: 24 weeks; following 8 weeks of open‐label treatment) for EDS‐FLU vs placebo (EDS‐PBO). Baseline characteristics predictive of change in SF‐36 and SF‐6D scores were assessed.ResultsMean baseline SF‐36v2 scores were below population norms. At EODB, mean improvement was greater for all SF‐36v2 domain and component scores with EDS‐FLU (range: 2.9 [physical functioning] to 5.11 [bodily pain {BP}]) vs EDS‐PBO (range: 0.81 [mental health] to 2.87 [BP]) (each comparison p < 0.01); physical and mental component score improvements within the EDS‐FLU group exceeded the minimal clinically important difference (MCID). Clinically meaningful and statistically significant improvements in SF‐6D utility scores were seen in EDS‐FLU–treated patients compared to EDS‐PBO–treated patients (0.058 vs 0.023, respectively, p < 0.001). At EOOL, SF‐36v2 and SF‐6D mean scores were at or above population norms, with clinically meaningful and statistically significant improvements from baseline.ConclusionIn this pooled analysis of 2 large pivotal EDS‐FLU trials, health domain and health utilities improvements were significantly greater with EDS‐FLU than EDS‐PBO and were comparable to population norms.

Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream

Atopic dermatitis (AD) is a highly pruritic chronic inflammatory skin disorder. Ruxolitinib, a selective inhibitor of Janus kinase 1 and Janus kinase 2, potently suppresses cytokine signaling involved in AD pathogenesis. We sought to evaluate the efficacy and safety of ruxolitinib (RUX) cream in adults with AD. In this phase 2 study (NCT03011892), 307 adult patients with AD, an Investigator's Global Assessment score of 2 or 3 (mild or moderate), and 3% to 20% affected body surface area were equally randomized for 8 weeks of double-blind treatment to RUX (1.5% twice daily [BID], 1.5% once daily [QD], 0.5% QD, 0.15% QD), vehicle, or triamcinolone cream (0.1% BID for 4 weeks, then vehicle for 4 weeks). Subsequently, patients could apply 1.5% RUX BID for 4 additional weeks of open-label treatment. The primary end point was the comparison between 1.5% RUX cream BID and vehicle in mean percentage change from baseline in Eczema Area and Severity Index at week 4. All RUX regimens demonstrated therapeutic benefit at week 4; 1.5% BID provided the greatest improvement in Eczema Area and Severity Index (71.6% vs 15.5%; P< .0001) and Investigator's Global Assessment responses (38.0% vs 7.7%; P< .001) versus vehicle. Rapid reductions in the itch numerical rating scale score occurred within 36 hours (1.5% BID vs vehicle, ‒1.8 vs ‒0.2; P< .0001) and were sustained through 12 weeks. Patients who transitioned to 1.5% RUX BID improved in all measures. RUX was not associated with clinically significant application-site reactions. RUX cream provided rapid and sustained improvements in AD symptoms and was well tolerated.

A randomized, double-blind, 6-week prospective pilot study on the efficacy and safety of dose escalation in non-remitters in comparison to those of the standard dose of escitalopram for major depressive disorder

BackgroundEscalating doses of selective serotonin reuptake inhibitors are often used to treat patients with a suboptimal response to the standard dose. This study assessed the efficacy and safety of dose escalation of escitalopram, up to 30 mg, in non-remitters with major depressive disorder (MDD) after treatment with the standard dose. MethodWe recruited 98 patients with MDD (aged 18–65 years). After 4 weeks of open-label treatment with 10–20 mg of escitalopram per day, non-remitters [Montgomery–Åsberg Depression Rating Scale (MADRS) score > 10] were randomized 1:1 for double-blind treatment with either escitalopram (30 mg per day) or escitalopram (20 mg per day) plus placebo for 6 weeks. The primary efficacy outcome was a change in the total MADRS score. ResultsAfter 4 weeks of open-label treatment, 12 patients achieved remission, and 36 dropped out, leaving 50 non-remitters, of whom 44 (88%) completed the double-blind study. The primary outcome measure, the least-squares mean (standard error) change in the total MADRS score at week 6 was significantly different (p = 0.046) between the groups [−8.0 (1.2) in the placebo dose-escalation and −11.8 (1.2) in the escitalopram dose-escalation]. The dose escalation of escitalopram was well tolerated. However, the response and remission rates and quality of life showed no significant differences. LimitationsSmall sample size and short follow-up period ConclusionThis study suggests that dose escalation of escitalopram up to 30 mg per day may be beneficial for the treatment of depressive symptoms in non-remitters after standard (10–20 mg/day) treatment.

Safety and Tolerability of Omalizumab: A Randomized Clinical Trial of Humanized Anti-IgE Monoclonal Antibody in Systemic Lupus Erythematosus.

Autoreactive IgE antibodies have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesize that omalizumab, a monoclonal antibody binding IgE, may improve SLE activity by reducing type I interferon (IFN) production by hampering plasmacytoid dendritic cells and basophil activation. This study was undertaken to assess the safety, tolerability, and clinical efficacy of omalizumab in mild to moderate SLE. Sixteen subjects with SLE and a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of ≥4 and elevated autoreactive IgE antibody levels were randomized to receive omalizumab or placebo (2:1) for 16 weeks, followed by 16 weeks of open-label treatment and a 4-week washout period. The SLEDAI-2K score, British Isles Lupus Assessment Group index (BILAG 2004) score, and physician's global assessment of disease activity were recorded at each visit. The type I IFN-induced gene signature was determined using quantitative polymerase chain reaction. Omalizumab was well tolerated with no allergic reactions, and mostly mild adverse events comparable to those experienced with placebo treatment. SLEDAI-2K scores improved in the omalizumab group compared to the placebo group at week 16 (P = 0.038), as well as during the open-label phase in subjects initially receiving placebo (P = 0.02). No worsening in BILAG scores or the physician's global assessment was detected. There was a trend toward a reduction in IFN gene signature in subjects treated with omalizumab (P = 0.11), especially in subjects with a high baseline IFN signature (P = 0.052). Our findings indicate that omalizumab is well tolerated in SLE and is associated with improvement in disease activity. Larger randomized clinical trials will be needed to assess the efficacy of omalizumab in patients with SLE.

Efficacy of Budesonide Orodispersible Tablets as Induction Therapy for Eosinophilic Esophagitis in a Randomized Placebo-Controlled Trial

Swallowed topical-acting corticosteroids are recommended as first-line therapy for eosinophilic esophagitis (EoE). Asthma medications not optimized for esophageal delivery are sometimes effective, although given off-label. We performed a randomized, placebo-controlled trial to assess the effectiveness and tolerability of a budesonide orodispersible tablet (BOT), which allows the drug to be delivered to the esophagus in adults with active EoE. We performed a double-blind, parallel study of 88 adults with active EoE in Europe. Patients were randomly assigned to groups that received BOT (1 mg twice daily; n= 59) or placebo (n= 29) for 6 weeks. The primary end point was complete remission, based on clinical and histologic factors, including dysphagia and odynophagia severity ≤2 on a scale of 0-10 on each of the 7 days before the end of the double-blind phase and a peak eosinophil count <5 eosinophils/high power field. Patients who did not achieve complete remission at the end of the 6-week double-blind phase were offered 6 weeks of open-label treatment with BOT (1 mg twice daily). At 6 weeks, 58% of patients given BOT were in complete remission compared with no patients given placebo (P < .0001). The secondary end point of histologic remission was achieved by93% of patients given BOT vs no patients given placebo (P<.0001). After 12 weeks, 85% of patients had achieved remission. Six-week and 12-week BOT administration were safe and well tolerated; 5% of patients who received BOT developed symptomatic, mild candida, which was easily treated with an oral antifungal agent. In a randomized trial of adults with active EoE, we found that budesonide oral tabletswere significantly more effective thanplacebo in inducingclinical and histologic remission. Eudra-CT number 2014-001485-99; ClinicalTrials.gov ID NCT02434029.

Relationship between work functioning and self-reported cognitive complaints in patients with major depressive disorder treated with desvenlafaxine

Patients with major depressive disorder (MDD) often report that cognitive difficulties, such as memory problems or poor concentration, interfere with their work functioning. We examined the association between self-reported cognitive complaints and work functioning in employed patients with MDD treated with desvenlafaxine. A sample of 36 adult outpatients with MDD completed subjective cognition (British Columbia Cognitive Complaints Inventory [BC-CCI]) and functioning scales (Sheehan Disability Scale [SDS]; Lam Employment Absence and Productivity Scale [LEAPS]; and Health and Work Performance Questionnaire [HPQ]) before and after 8 weeks of open-label treatment with flexibly-dosed desvenlafaxine (50–100 mg/day). Multiple regression analyses were used to assess the relationship between subjective cognitive measures and work functioning scales. Patients showed significant improvements in clinical, cognitive, and work functioning measures following treatment with desvenlafaxine. A predictive association was found between the BC-CCI and both the SDS and LEAPS, but not with the HPQ, when adjusted for depression severity. Self-report cognitive questionnaires can provide useful information to monitor changes in cognitive functioning over time and to predict improvement in work functioning outcomes.