Safety of baricitinib for the treatment of atopic dermatitis over a median of 1.6 years and up to 3.9 years of treatment: an updated integrated analysis of eight clinical trials.

BACKGROUND: Baricitinib, a selective Janus kinase (JAK)1/JAK2 inhibitor, is approved for treatment of moderate-to-severe atopic dermatitis (AD) in adults. OBJECTIVES: We report integrated baricitinib safety data in patients with up to 3.9-years exposure. METHODS: Three datasets from the integrated AD clinical trial program were analyzed: placebo-controlled, 2-mg-4-mg extended, and All-bari. Data cutoffs were up to 21-December-2021 for long-term extension studies. Proportions of patients with events and incidence rates (IR)/100 patient years (PY) at risk were calculated. RESULTS: 2636 patients received baricitinib for 4628.4 PY. Discontinuation due to adverse events was low (IR = 3.4). IRs in All-bari were: serious adverse events, 5.2; infection, 67.2 (any infection), 6.7 (herpes simplex), 2.8 (herpes zoster), and 0.3 (opportunistic infections). Adverse events of special interest in All-bari included seven patients with positively adjudicated major adverse cardiovascular events (MACE) (IR = 0.15), three pulmonary emboli (PE) (IR = 0.06), 14 malignancies excluding nonmelanoma skin cancer (IR = 0.3), one gastrointestinal perforation (IR = 0.02), and four deaths (IR = 0.1). No deep vein thromboses (DVT) or tuberculosis were reported. CONCLUSION: In this analysis, baricitinib maintained a similar safety profile to earlier analyses with no new safety signals. Rates of MACE, DVT/PE, malignancies, and serious infections were within ranges of background rates in patients with AD. CLINICALTRIALS.GOV: NCT02576938 (JAHG), NCT03334396 (JAHL; BREEZE-AD1), NCT03334422 (JAHM; BREEZE-AD2), NCT03334435 (JAHN; BREEZE-AD3), NCT03428100 (JAIN; BREEZE-AD4), NCT03435081 (JAIW; BREEZE-AD5), NCT03559270 (JAIX; BREEZE-AD6), NCT03733301 (JAIY; BREEZE-AD7).

Efficacy and safety of mirikizumab in psoriasis: results from a 52-week, double-blind, placebo-controlled, randomized withdrawal, phase III trial (OASIS-1).

BACKGROUND: Interleukin-23 inhibitors are effective and safe for treating moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the efficacy and safety of mirikizumab in adult patients with moderate-to-severe plaque psoriasis through 52 weeks in a phase III randomized controlled trial. METHODS: OASIS-1 (NCT03482011) was a double-blind, placebo-controlled, randomized withdrawal, phase III trial. Patients (n = 530, randomized 4 : 1) received subcutaneous mirikizumab 250 mg or placebo every 4 weeks (Q4W) through week 16. Coprimary endpoints were superiority of mirikizumab vs. placebo on static Physician's Global Assessment (sPGA; score of 0 or 1 with ≥ 2-point improvement) and ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90, responders) at week 16. Mirikizumab responders were rerandomized (1 : 1 : 1) to mirikizumab 250 mg every 8 weeks (Q8W), mirikizumab 125 mg Q8W, or placebo Q8W through week 52. Secondary endpoints were evaluated at weeks 16 and 52. Safety was monitored in all patients. RESULTS: All primary and key secondary endpoints were met. At week 16, sPGA(0,1) responses were significantly greater with mirikizumab (293 of 423, 69·3%) than placebo (seven of 107, 6·5%) (P < 0·001). PASI 90 response was also greater with mirikizumab (272 of 423, 64·3%) than placebo (seven of 107, 6·5%) (P < 0·001). Significantly more patients in the mirikizumab arms achieved PASI 75 and PASI 100 (mirikizumab 349, 82·5% and 137, 32·4%; placebo 10, 9·3% and 1, 0·9%, respectively; all P < 0·001). At week 52, PASI 90, PASI 100 and sPGA(0,1) responses were mirikizumab 250Q4W/placeboQ8W (N = 91; 19%, 10%, 18%), mirikizumab 250Q4W/125Q8W (N = 90; 86%, 59%, 86%) and mirikizumab 250Q4W/250Q8W (N = 91; 86%, 60%, 82%; all P < 0·001), respectively. Rates of serious adverse events were similar across treatments (induction: mirikizumab 1·2% vs. placebo 1·9%; maintenance: mirikizumab 250Q4W/125Q8W 1%, mirikizumab 250Q4W/250Q8W 3% vs. placebo 3%). No deaths occurred. CONCLUSIONS: Mirikizumab was superior to placebo at week 16 and maintained efficacy through week 52, with no new safety signals. What is already known about this topic? Interleukin (IL)-23 is a key cytokine in the pathogenesis of psoriasis. Drugs targeting the p19 subunit of IL-23 have recently been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis. Patients with moderate-to-severe plaque psoriasis achieved significantly greater improvements in skin measures and patient-reported quality-of-life measures after 16 weeks when treated every 8 weeks with mirikizumab compared with placebo in a phase II clinical trial. What does this study add? Compared with placebo, mirikizumab demonstrated high levels of efficacy at week 16 in a large phase III trial; safety profiles were similar between the mirikizumab and placebo arms. After week 16, patients maintained on doses of mirikizumab 250 mg every 8 weeks (Q8W) or 125 mg Q8W showed similar efficacy and favourable safety profiles over 52 weeks, whereas patients switched to placebo gradually lost efficacy over time.

Disease Burden and Patient-Reported Outcomes Among Ulcerative Colitis Patients According to Therapy at Enrollment Into CorEvitas' Inflammatory Bowel Disease Registry.

Background: To evaluate disease burden and patient-reported outcomes (PROs) of ulcerative colitis (UC) patients at enrollment into CorEvitas' Inflammatory Bowel Disease Registry by therapy class. Methods: Between May 3, 2017 and September 3, 2019, 773 UC registry patients were categorized by therapy class at enrollment: patients on 5-aminosalicylic acids (5-ASAs) only (n = 290), and patients on biologics/Janus kinase inhibitors (JAKi) alone or in combination with 5-ASAs or immunosuppressant therapies (BIO/JAKi) (n = 315). To quantify between group differences, the mean/proportional differences and corresponding 95% CIs were calculated. Results: Among 605 UC patients at enrollment, BIO/JAKi patients were younger (44.1 vs. 50.9 years) more were female (58.0% vs. 49.7%), had lower remission (45.4% vs. 60.0%), had more moderate/severe disease (16.5% vs. 7.1%), experienced less proctitis (10.5% vs. 22.1%), but more pancolitis (54.6% vs. 34.1%), more corticosteroid experience (70.8% vs. 44.5%), previous biologic experience (1 prior: 21.6% vs. 2.4%; 2+ prior: 12.1% vs. 0.3%), and shorter duration of current UC therapy (1.6 vs. 3.5 years) than 5-ASAs patients. BIO/JAKi patients had higher current employment than 5-ASAs patients (70.7% vs. 62.4%) and higher mean Work Productivity and Activity Impairment (WPAI) domains for absenteeism (7.3 vs. 2.8) and activity impairment (22.0 vs. 17.5). Conclusions: Among UC patients in a real-world setting, BIO/JAKi patients had less remission, more moderate-to-severe disease, and worse PROs than 5-ASAs patients. These results suggest that despite increased therapeutic options, patients with UC currently being treated with biologics or JAKi may still experience disease burden and continued unmet needs.

Real-World Treatment Sequences and Outcomes Among Patients With Non-Small Cell Lung Cancer (RESOUNDS) in the United States: Study Protocol.

BACKGROUND: Survival outcomes are related to treatment choices in a line of therapy and to treatment sequences across all lines of therapy. OBJECTIVE: The Real-World Treatment Sequences and Outcomes among Patients with NSCLC (RESOUNDS) study is designed to (1) evaluate treatment sequences used for patients who receive at least two lines of therapy for non-small cell lung cancer (NSCLC) in the United States and (2) evaluate patient outcomes in terms of progression-free and overall survival related to treatment sequencing. Additional objectives include the evaluation of symptoms, comorbidities, and health care resource utilization and costs. METHODS: Patients will be censored at loss to follow-up due to leaving the health plan or reaching the end of the study period. RESULTS: This study is ongoing. CONCLUSIONS: The RESOUNDS cohort study is a novel approach to building a comprehensive dataset that mimics a prospective observational study using linked patient-level data from four real-world data sources. This study will provide timely information on the sequencing of treatments for patients with NSCLC.

Time to onset of clinically meaningful improvement with tadalafil 5 mg once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled from 4 pivotal, double-blind, placebo controlled studies.

PURPOSE: Tadalafil once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia consistently shows statistically significant I-PSS improvements. However, physicians and patients wish to know whether tadalafil provides rapid, clinically meaningful improvement in lower urinary tract symptoms. In this post hoc analysis we integrated results from 4 placebo controlled studies to determine the duration of tadalafil once daily required to achieve clinically meaningful improvement. MATERIALS AND METHODS: We performed post hoc analysis of data integrated from 4 double-blind studies of tadalafil 5 mg and placebo once daily in 742 and 735 men, respectively, 45 years old or older with total I-PSS 13 or greater. Two clinically meaningful improvement categories were assessed, including 1) 3-point or greater baseline to end point total I-PSS improvement and 2) 25% or greater baseline to end point total I-PSS improvement. I-PSS was assessed at weeks 4, 8 and 12 in all studies, week 1 in 2 and week 2 in 1. Results in men treated with tadalafil who showed clinically meaningful improvement (responders) were further examined to determine the earliest time to clinically meaningful improvement. RESULTS: Of 742 tadalafil treated patients 513 (69.1%) and 444 (59.8%) demonstrated category 1 and 2 clinically meaningful improvement, respectively, at the study end point. Of 234 category 1 responders with week 1 assessments 140 (59.8%) achieved clinically meaningful improvement by week 1 and 407 of the total of 513 category 1 responders (79.3%) showed it by week 4. Of the 205 category 2 responders with week 1 assessments 103 (50.2%) achieved clinically meaningful improvement by week 1 while 322 of the 444 category 2 responders (72.5%) did so by week 4. CONCLUSIONS: Tadalafil 5 mg once daily led to clinically meaningful improvement in approximately two-thirds of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. More than half of this group of tadalafil treated responders achieved clinically meaningful improvement after 1 week of therapy and more than 70% did so within 4 weeks.

Treatment satisfaction with tadalafil or tamsulosin vs placebo in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH): results from a randomised, placebo-controlled study.

OBJECTIVES: To assess treatment satisfaction with tadalafil or tamsulosin vs placebo in a 12-week, randomised, double-blind study of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). PATIENTS AND METHODS: After a 4-week placebo lead-in period, men aged ≥45 years with an International Prostate Symptom Score (IPSS) of ≥13 and a maximum urinary flow rate of ≥4 to ≤15 mL/s received placebo (172 men), tadalafil 5 mg (171), or tamsulosin 0.4 mg (168) once daily for 12 weeks. Treatment Satisfaction Scale-BPH (TSS-BPH) responses were assessed based on median treatment differences using the van Elteren test. RESULTS: Overall treatment satisfaction was greater for tadalafil vs placebo (P = 0.005), based on greater satisfaction with efficacy (P = 0.003); neither overall treatment satisfaction nor satisfaction with efficacy was greater for tamsulosin vs placebo (P ≥ 0.409). For individual questions, 66.5% of men rated tadalafil treatment as 'effective/very effective' (Question 1, Q1) vs placebo (P = 0.011), 72.6% would 'definitely/probably recommend their treatment' (Q3; P = 0.043), 71.8% were generally 'very satisfied/satisfied with their medication' (Q8; P < 0.003), and 65.0% would 'definitely/probably continue therapy' (Q10; P = 0.035). With tamsulosin, differences vs placebo were not statistically significant. Subgroup analyses of overall TSS-BPH by baseline age (≤65/>65 years), history of erectile dysfunction (yes/no), LUTS/BPH severity (IPSS

Nonresponders, partial responders, and complete responders to PDE5 inhibitors therapy according to IIEF criteria: validation of an anchor-based treatment responder classification.

INTRODUCTION: Despite widespread use of the International Index of Erectile Function (IIEF) in erectile dysfunction (ED) research, there are no published criteria for classifying ED treatment responders in clinical trials or patient management settings. A new classification for treatment response in men with ED has been developed and validated in a large clinical trial database. AIM: The study aims to test discriminant and convergent validity of the responder classification and examine the role of covariates. METHOD: Treatment assignment was used to test discriminant validity. The diary-based Sexual Encounter Profile (SEP) question ("Did your erection last long enough for you to have successful intercourse?") and Global Assessment Question (GAQ) ("Has the treatment you have been taking over the past study interval improved your erections?") were used to evaluate convergent validity. Chi-square and Cochran-Armitage trend tests were used to examine outcome associations. Logistic regression was used to further assess the relationship of outcomes controlling for covariates. MAIN OUTCOME MEASURE: The classification measure was developed and validated in a database from 17 clinical trials in 3,252 men with ED randomized to placebo or tadalafil. The treatment responder is defined as complete (erectile function [EF] ≥ 26); partial (EF < 26; met minimal clinically important difference [MCID] criteria); or nonresponder following treatment (EF < 26; did not meet MCID). RESULTS: The new responder definition performed consistently well in all prespecified tests of validity. Eighty-nine percent of subjects classified as complete responders were in the treatment group, and the responder definition was associated with changes on the SEP and GAQ measures, respectively (SEP odds ratio [OR] = 14, 95% confidence intervals [CI] 11-17; GAQ OR = 50, 95% CI 39-88; complete vs. nonresponders). CONCLUSIONS: We developed and validated a novel method of defining an ED treatment responder based on multiple IIEF criteria and using other measures (SEP, GAQ) for validation. The results have implications for understanding results of clinical trials in ED, and in monitoring response to treatment in the clinic.

The role of initial success rates and other factors in determining reliability of outcomes of phosphodiesterase inhibitor therapy for erectile dysfunction: a pooled analysis of 17 placebo-controlled trials of tadalafil for use as needed.

INTRODUCTION: Reliability of successful outcomes in men with erectile dysfunction (ED) on phosphodiesterase type 5 inhibitors is an important aspect of patient management. AIMS: We examined reliability of successful outcomes in a large integrated dataset of randomized tadalafil trials. MAIN OUTCOME MEASURES: Success rates, time to success, subsequent success after first success, and probability of success were analyzed based on Sexual Encounter Profile questions 2 and 3. METHODS: Data from 3,254 ED patients treated with tadalafil 10 mg (N = 510), 20 mg (N = 1,772), or placebo (N = 972) were pooled from 17 placebo-controlled studies. RESULTS: Tadalafil patients had significantly higher first-attempt success rates vs. placebo. This effect was consistent across most subgroups; however, patients with severe ED experienced a greater response to tadalafil than patients with mild-moderate ED. Approximately 80% of patients achieved successful penile insertion within two attempts with either tadalafil dose and successful intercourse within eight attempts for tadalafil 10 mg and four attempts for tadalafil 20 mg. However, approximately 70% of tadalafil-treated patients achieved successful intercourse even by the second attempt. Subsequent success rates were higher for patients with first-attempt success (81.5% for 10 mg and 86.1% for 20 mg vs. 66.2% for placebo, P < 0.001) vs. patients with later initial success (53.2% for 10 mg and 56.4% for 20 mg vs. 39.9% for placebo, P < 0.001). Among patients treated with tadalafil, intercourse success rates at early attempts were similar to rates at later attempts (i.e., attempts 5 and 10 vs. 25), although insertion success rates were significantly lower earlier in treatment. CONCLUSIONS: The findings affirm the reliability of successful outcomes with tadalafil treatment and that first-attempt success is a critical factor affecting subsequent outcomes. The results further show that even among men who did not succeed on first attempt, a substantial proportion will have successful outcomes if treatment is maintained.

Estimated risk of invasive breast cancer in postmenopausal women with and without family history of the disease.

OBJECTIVE: To characterize the estimated risk of invasive breast cancer (IBC) in postmenopausal women without a family history of breast cancer (FHBC), baseline risk scores were calculated using the Breast Cancer Risk Assessment tool. We also analyzed the incidence rates of IBC stratified by FHBC. METHODS: For the Continuing Outcomes Relevant to Evista (CORE) study population (n = 3,991; excluding women ≥86 y of age or with a history of ductal carcinoma in situ or lobular carcinoma in situ), the prevalence of risk factors to the overall IBC risk was calculated. To evaluate IBC incidence rates, the placebo arm of the CORE trial (n = 1,275) was pooled with the placebo arm of the Raloxifene Use for the Heart trial (n = 5,047; total of 6,322 women). RESULTS: Common risk factors in the CORE population were age 65 years or older (78.4%) and menarche at 12 years or younger (29.4%). Incidence rates of IBC in the CORE plus Raloxifene Use for the Heart trial placebo populations correlated with IBC risk estimates; incidence rates were higher as risk scores increased. Of those who developed IBC, 65% (60/92) had scores between 1% and 2% and did not have FHBC; nearly half (43%; 40/92) had risk scores below the high-risk cutoff of 1.66%. CONCLUSIONS: A significant portion of women who develop IBC do not have a family history of the disease. FHBC is important in assessing IBC risk; however, other relevant risk factors, together with FHBC and results from a validated tool risk assessment tool, should be jointly considered to develop a complete assessment of women's IBC risk.

First fractures among postmenopausal women with osteoporosis.

After the occurrence of the first fracture, osteoporosis is no longer a "silent" disease, and the patient's risk for future fracture is increased several fold. We assessed the location of first osteoporotic fractures among women with osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a fracture outcomes study of postmenopausal women with osteoporosis. All subjects received supplements containing 500 mg elemental calcium and 400-600 IU vitamin D. We assessed the location of first fractures among women with osteoporosis and no previous fractures at baseline from the placebo group of this trial after 3 years of follow-up. Prespecified fracture sites included vertebral fractures and nonvertebral fractures as defined in the MORE study protocol. Among 875 women (mean age, 64.5 +/- 7.4 years) with no prevalent vertebral or nonvertebral fractures, 9% experienced their first fracture event during the trial. Fractures of radius and spine each occurred in 3% of patients. Fractures at other individual sites included ankle (0.6%), metatarsal (0.6%), humerus (0.5%), rib (0.5%), patella (0.3%), leg (0.2%), hip (0.2%), and clavicle (0.1%). These data suggest that for postmenopausal women with osteoporosis but no previous fractures, skeletal care should include a focus on preventing spine and radius fractures.

Benefits and risks of raloxifene by vertebral fracture status.

OBJECTIVE: Women without versus those with vertebral fracture may have different benefits and risks during raloxifene treatment. Our objective was to compare the effects of raloxifene to decrease risk for vertebral fracture and invasive breast cancer with its effect to increase risk for venous thromboembolism in postmenopausal women without or with baseline vertebral fracture. RESEARCH DESIGN AND METHODS: The Multiple Outcomes of Raloxifene Evaluation trial included postmenopausal women with osteoporosis randomized to placebo, raloxifene 60 mg/day, or raloxifene 120 mg/day for 4 years. The protocol specified subgroups based on whether or not patients had a vertebral fracture at baseline. Absolute differences between placebo and raloxifene 60 mg/day (the approved dose) for endpoints in these groups were defined as the incidence in the raloxifene group minus the incidence in the placebo group. RESULTS: Raloxifene decreased the incidence of vertebral fracture and invasive breast cancer while increasing the incidence of venous thromboembolism. All treatment by vertebral fracture status interaction p-values were greater than 0.13, indicating that the effect of raloxifene on these outcomes was not significantly different between patients without versus those with vertebral fractures. In women without baseline vertebral fracture, absolute risk differences between the raloxifene and placebo group included vertebral fracture -2.83%, invasive breast cancer -1.21%, and venous thromboembolism +0.28%. In women with baseline vertebral fracture, absolute risk differences between raloxifene and placebo group included vertebral fracture -8.21%, invasive breast cancer -0.75% and venous thromboembolism +0.91%. The analysis had limited power to test whether raloxifene had a significantly different effect on venous thromboembolism in women without versus those with a vertebral fracture. CONCLUSIONS: In women without and in those with vertebral fractures at baseline, the effects of raloxifene to decrease vertebral fracture and invasive breast cancer were greater than its effects to increase venous thromboembolism.