Dosing of Rifaximin Soluble Solid Dispersion Tablets in Adults With Cirrhosis: 2 Randomized, Placebo-controlled Trials.

BACKGROUND & AIMS: Cirrhosis-related complications are a major burden. Rifaximin soluble solid dispersion (SSD) tablets (immediate-release [IR]; sustained extended-release [SER]) were designed to increase rifaximin water solubility. These analyses evaluate dosing for prevention of cirrhosis complication-related hospitalizations/mortality and overt hepatic encephalopathy (OHE) treatment. METHODS: Two phase II, randomized, double-blind, placebo-controlled trials were conducted. Trial 1: outpatients with early decompensated cirrhosis randomized to placebo or rifaximin SSD once-nightly: IR 40 or 80 mg, SER 40 or 80 mg, or IR 80 mg plus SER 80 mg, for 24 weeks. Trial 2: inpatients with OHE randomized to lactulose plus placebo or rifaximin SSD: IR 40 mg once or twice daily or SER 80 mg once or twice daily for ≤14 days. Primary efficacy endpoint: time to cirrhosis complication-related hospitalization/all-cause mortality (Trial 1) or time to OHE resolution (Trial 2). RESULTS: In Trial 1 (n = 516), no significant difference in time to cirrhosis complication-related hospitalization/all-cause mortality vs placebo. In a post hoc analysis, time to all-cause hospitalization/all-cause mortality was improved with IR 40 mg vs placebo (15.4% [12/78] vs 27.7% [26/94]; P = .03). A Trial 2 prespecified interim analysis (n = 71) showed lactulose plus rifaximin SSD IR 40 mg bid significantly reduced median time to OHE resolution (21.1 hours) vs lactulose plus placebo (62.7 hours; P = .02). Trial 2 was subsequently terminated. CONCLUSION: Rifaximin SSD IR 40 mg may reduce hospitalizations in patients with cirrhosis and shorten duration of OHE during hospitalization-considered a negative finding, yet also hypothesis-generating. (ClinicalTrials.govNCT01904409; NCT03515044).

Reductions in All-Cause Mortality Associated with the Use of Methylnaltrexone for Opioid-Induced Bowel Disorders: A Pooled Analysis.

OBJECTIVE: Preclinical and clinical studies suggest that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients with cancer and noncancer pain. Methylnaltrexone, a selective, peripherally acting µ-opioid receptor antagonist, has demonstrated efficacy for the treatment of opioid-induced constipation. This retrospective analysis of 12 randomized, double-blind, placebo-controlled studies of methylnaltrexone evaluated the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain. METHODS: The risk of all-cause mortality within 30 days after the last dose of study medication during the double-blind phase was compared between methylnaltrexone and placebo groups. The data were further stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnoses. RESULTS: Pooled data included 2,526 methylnaltrexone-treated patients of which 33 died, and 1,192 placebo-treated patients of which 35 died. The mortality rate was 17.8 deaths/100 person-years of exposure in the methylnaltrexone group and 49.5 deaths/100 person-years of exposure for the placebo group. The all-cause mortality risk was significantly lower among patients receiving methylnaltrexone compared with placebo (hazard ratio: 0.399, 95% confidence interval: 0.25, 0.64; P = .0002), corresponding to a 60% risk reduction. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer or chronic diagnoses. Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender. CONCLUSIONS: Methylnaltrexone reduced all-cause mortality vs placebo treatment across multiple trials, suggesting methylnaltrexone may confer survival benefits in patients with opioid-induced bowel disorders taking opioids for cancer-related or chronic noncancer pain.

Cumulative Laxation Response with Methylnaltrexone: Implications for Hospitalized Patients with Advanced Illness and Opioid-Induced Constipation.

Background: Opioid-induced constipation (OIC) may increase the risk of fecal impaction and mortality in patients with advanced illness. Methylnaltrexone (MNTX) is efficacious for OIC. Objective: The purpose of this analysis was to evaluate cumulative rescue-free laxation response with repeat MNTX dosing in patients with advanced illness who were refractory to current laxative regimens and to assess the influence, if any, of poor functional status on response to MNTX treatment. Methods: This analysis included pooled data from patients with advanced illness and established OIC who were on a stable opioid regimen in a pivotal, randomized, placebo (PBO)-controlled clinical trial (study 302 [NCT00402038]) or a randomized, PBO-controlled Food and Drug Administration-required postmarketing study (study 4000 [NCT00672477]). Patients in study 302 received subcutaneous MNTX 0.15 mg/kg or PBO every other day, whereas those in study 4000 received MNTX 8 mg (body weight ≥38 to <62 kg), MNTX 12 mg (body weight ≥62 kg), or PBO every other day. Outcomes included cumulative rescue-free laxation rates at 4- and 24-hours postdose for the first 3 doses of study drug and time to rescue-free laxation. To assess if functional status influenced treatment outcomes, we performed a secondary analysis on the outcomes stratified by baseline World Health Organization/Eastern Cooperative Oncology Group performance status, pain scores, and safety. Results: One hundred eighty-five patients received PBO and 179 patients received MNTX. The median age was 66.0 years, 51.5% were women, 56.5% had a baseline World Health Organization/Eastern Cooperative Oncology Group performance status score >2, and 63.4% had a primary diagnosis of cancer. Cumulative rescue-free laxation rates were significantly higher with MNTX than PBO 4- and 24-hours after doses 1, 2, and 3 (P < 0.0001), and between-treatment comparisons remained significant (P < 0.0001) regardless of performance status. The estimated time to first rescue-free laxation was shorter for patients receiving MNTX versus PBO. No new safety signals were identified. Conclusions: Repeated use of MNTX represents a safe and effective treatment for OIC in patients with advanced illness regardless of baseline performance status. ClinicalTrials.gov identifier: NCT00672477. (Curr Ther Res Clin Exp. 2023; 84:XXX-XXX)© 2023 Elsevier HS Journals, Inc.

First-Dose Efficacy of Methylnaltrexone in Patients with Severe Medical Illness and Opioid-Induced Constipation: A Pooled Analysis.

BACKGROUND: Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist indicated for the treatment of OIC. OBJECTIVE: To assess the safety and efficacy of a single methylnaltrexone dose. METHODS: Results were pooled from three randomized, placebo-controlled methylnaltrexone (MNTX) studies in opioid-treated patients with advanced illness and OIC, despite treatment with conventional laxatives. Baseline assessments included demographics, disease/treatment characteristics, and functional levels. Efficacy endpoints included rescue-free laxation (RFL) rates within 4 and 24 h, time to first RFL, pain score change, and adverse events (AEs) after a single MNTX dose or placebo. RESULTS: The analysis included 281 patients receiving MNTX and 237 receiving placebo. Mean age was 66.2 years for MNTX and 65.8 for placebo; ∼50% were men. The most frequent primary diagnosis was cancer (MNTX = 70.5%; placebo = 66.2%) and most (∼98%) were receiving at least one laxative at baseline. RFL occurred in 61.4% vs. 16.0%, and 72.1% vs. 40.1% MNTX vs. placebo patients, within 4 and 24 h of the initial dose, respectively. Relative to placebo, MNTX use reduced the time to first RFL, with most MNTX-treated patients achieving RFL within 2 h. Baseline and posttreatment pain scores were similar (p = 0.9556 vs. placebo for current and worst pain change from baseline), demonstrating that MNTX did not negatively affect opioid analgesia. Most AEs were gastrointestinal related and dissipated by the second dose. CONCLUSIONS: Methylnaltrexone provides early RFL without compromising analgesia in patients receiving chronic opioid therapy.

P029 Pharmacokinetic/Pharmacodynamic Analysis of Amiselimod, a Selective Sphingosine 1-Phosphate Receptor Modulator, in Healthy Subjects: Results From a Phase 1 Study.

BACKGROUND: Amiselimod is a selective sphingosine 1-phosphate receptor modulator in development for inflammatory bowel disease. It is converted to its active metabolite, amiselimod phosphate (amiselimod-P), and has a long half-life and slow accumulation to steady state. We evaluated a multiple-dose titration regimen to determine the plasma pharmacokinetic (PK) profile of amiselimod and amiselimod-P at steady state for the 0.4 mg QD therapeutic dose on day 13 and for the 0.8 mg QD supratherapeutic dose on day 26. We also investigated the pharmacodynamic (PD) effect of amiselimod on absolute lymphocyte counts (ALCs). METHODS: A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design assessed amiselimod and amiselimod-P. Healthy adults received a single dose of placebo followed by oral amiselimod, which was upwardly titrated in doses ranging from 0.4 to 1.6 mg QD to rapidly achieve steady-state concentrations for the 0.4 mg QD and 0.8 mg QD doses within a 28-day treatment period. The PK parameters of amiselimod and amiselimod-P (on days 1, 13 and 26) included the geometric mean (geometric coefficient of variation percentage [CV%]) maximum plasma concentration (Cmax), median (minimum, maximum) time to Cmax (Tmax), geometric mean (geometric CV%) area under the concentration-time curve (AUC) from time 0 to the last measurable concentration, and geometric mean (geometric CV%) AUC from time 0 to 23.5 hours post dose (AUC0-23.5). Multidose PD were evaluated by changes in ALCs. RESULTS: The PK population included 95 amiselimod-treated participants and the PD population included 190 participants who received amiselimod or placebo. On day 13, the steady-state AUC and Cmax for amiselimod 0.4 mg QD increased by 10-fold for amiselimod and by 4-fold for amiselimod-P compared with day 1. On day 26, the steady-state AUC0-23.5 and Cmax for amiselimod 0.8 mg QD increased by 1.9-fold for amiselimod and by 1.8-fold for amiselimod-P compared with day 13. The median Tmax of plasma amiselimod and amiselimod-P were similar on all 3 days and were reached at 11 to 12 hours post dose for amiselimod and at 10 hours post dose for amiselimod-P. The mean ALCs for amiselimod exhibited a gradual decrease from pre-dose (1.681 × 103/uL) to a nadir of 0.424 × 103/uL on day 27. CONCLUSION: The abbreviated amiselimod dosing titration regimen reached steady state within 14 days for the therapeutic 0.4 mg QD regimen and within 26 days for the supratherapeutic 0.8 mg QD regimen; expected decreases in ALCs were observed following amiselimod.

The influence of brain metastases on the central nervous system effects of methylnaltrexone: a post hoc analysis of 3 randomized, double-blind studies.

PURPOSE: Peripherally acting µ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor®) are indicated for the treatment of opioid-induced constipation (OIC). The structural properties unique to MNTX restrict it from traversing the blood-brain barrier (BBB); however, the BBB may become more permeable in patients with brain metastases. We investigated whether the presence of brain metastases in cancer patients compromises the central effects of opioids among patients receiving MNTX for OIC. METHODS: This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms. RESULTS: Among 356 cancer patients in the pooled population, 47 (MNTX n = 27; placebo n = 20) had brain metastases and 309 (MNTX n = 172; placebo n = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, p = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal. CONCLUSION: Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.

PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open-label single-arm phase 2 study.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody-drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti-PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA-positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate-specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. METHODS: A total of 119 (84 chemotherapy-experienced and 35 chemotherapy-naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. RESULTS: PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy-naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy-naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy-naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy-experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy-naïve group had partial responses. The most common treatment-related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. CONCLUSIONS: PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment-related AEs included neutropenia and neuropathy.

Immunogenicity and skin clearance recapture in clinical studies of brodalumab.

BACKGROUND: Antidrug antibodies (ADAs) may change pharmacokinetic or pharmacodynamic profiles of biologic therapies, potentially decreasing efficacy. OBJECTIVE: To evaluate the potential effects of brodalumab immunogenicity on safety, efficacy, and retreatment. METHODS: Data from 1 phase 2 and 3 phase 3 studies of brodalumab in psoriasis were analyzed. RESULTS: Overall, 2.7% of patients had positive test results for binding ADAs after receiving brodalumab; ADAs were transient in 1.4% of patients, and there were no neutralizing ADAs. Among ADA-positive patients, 60.0% (3/5) achieved a static physician's global assessment score of 0 or 1 at week 12 in the group receiving the brodalumab 210 mg every 2 weeks, compared with 79.1% (1131/1429) of ADA-negative patients. All patients (100%) who experienced return of disease and were retreated with brodalumab 210 mg every 2 weeks (none were ADA positive) achieved at least a 75% improvement in Psoriasis Area And Severity Index, ≥90% of whom regained response by week 8 of retreatment. Hypersensitivity reactions were less frequent with brodalumab than with placebo. Injection site reactions occurred in 1.8% of patients treated with brodalumab versus 2% of patients treated with ustekinumab. LIMITATIONS: Retreatment could be assessed in only 1 phase 3 brodalumab study. CONCLUSION: Brodalumab compares favorably with other biologics in terms of immunogenicity and high rates of efficacy recapture upon retreatment.

Phase 1 study of PSMA ADC, an antibody-drug conjugate targeting prostate-specific membrane antigen, in chemotherapy-refractory prostate cancer.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is a well-characterized target that is overexpressed selectively on prostate cancer cells. PSMA antibody-drug conjugate (ADC) is a fully human IgG1 monoclonal antibody conjugated to the microtubule disrupting agent monomethyl auristatin E (MMAE), which is designed to specifically bind PSMA-positive cells, internalize, and then release its cytotoxic payload into the cells. PSMA ADC has demonstrated potent and selective antitumor activity in preclinical models of advanced prostate cancer. A Phase 1 study was conducted to assess the safety, pharmacokinetics, and preliminary antitumor effects of PSMA ADC in subjects with treatment-refractory prostate cancer. METHODS: In this first-in-man dose-escalation study, PSMA ADC was administered by intravenous infusion every three weeks to subjects with progressive metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with docetaxel chemotherapy. The primary endpoint was to establish a maximum tolerated dose (MTD). The study also examined the pharmacokinetics of the study drug, total antibody, and free MMAE. Antitumor effects were assessed by measuring changes in serum prostate-specific antigen (PSA), circulating tumor cells (CTCs), and radiologic imaging. RESULTS: Fifty-two subjects were administered doses ranging from 0.4 to 2.8 mg/kg. Subjects had a median of two prior chemotherapy regimens and prior treatment with abiraterone and/or enzalutamide. Neutropenia and peripheral neuropathy were identified as important first-cycle and late dose-limiting toxicities, respectively. The dose of 2.5 mg/kg was determined to be the MTD. Pharmacokinetics were approximately dose-proportional with minimal drug accumulation. Reductions in PSA and CTCs in subjects treated with doses of ≥1.8 mg/kg were durable and often concurrent. CONCLUSIONS: In an extensively pretreated mCRPC population, PSMA ADC demonstrated acceptable toxicity. Antitumor activity was observed over dose ranges up to and including 2.5 mg/kg. The observed anti-tumor activity supported further evaluation of this novel agent for the treatment of advanced metastatic prostate cancer.

Efficacy, Safety, and Tolerability of a Halobetasol 0.01% /Tazarotene 0.045% Fixed Combination in the Treatment of Severe Localized Plaque Psoriasis: Post Hoc Analysis of Two Phase III Randomized Controlled Trials

Background: The use of topical therapy is a key component in the management of almost all psoriasis patients. Topicals are considered first-line therapy for mild disease and are having an increasing role in moderate or severe psoriasis as an integral part of combination therapy. Halobetasol has been shown be effective in moderate or severe localized plaque psoriasis, and tazarotene affords important effects on epidermal hyperproliferation that may be important in more severe disease. Objective: To investigate the efficacy, safety and tolerability of a once-daily application of a fixed combination halobetasol propionate 0.01% and tazarotene 0.045% (HP/TAZ) lotion in comparison with its vehicle in patients with severe localized plaque psoriasis (as defined by an Investigator Global Assessment (IGA) of 4 and Body Surface Area (BSA) of 3%-12%. Methods: Post hoc analysis of two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies. Sixty-two patients with severe localized psoriasis (mean BSA 7.4) randomized (2:1) to receive HP/TAZ lotion or vehicle, once-daily for 8 weeks, with a 4-week posttreatment follow-up. Efficacy assessments included treatment success (defined as at least a 2-grade improvement from baseline in the IGA score and a score of 'clear' or 'almost clear'), impact on individual signs of psoriasis (erythema, plaque elevation, and scaling) at the target lesion, BSA, reduction in mean baseline IGAxBSA and achievement of a clinically meaningful response (number of patients who achieved at least a 75% improvement in IGAxBSA). Safety and treatment emergent adverse events (TEAEs) were evaluated throughout. Results: By week 8, 34.8% of patients were treatment successes compared with 0.0% on vehicle (P=0.004). HP/TAZ lotion was also significantly superior in reducing psoriasis signs and symptoms and improving BSA. At week 8, 47.4% (erythema), 66.4% (plaque elevation), and 65.4% (scaling) subjects achieved at least a 2-grade improvement, compared with 14.0% (P=0.016), 14.8% (P<0.001) and 14.7% (P<0.001) respectively with vehicle. Patients treated with HP/TAZ lotion achieved a 32.8% reduction in baseline mean BSA, compared with a 39.6% increase with vehicle (P=0.013). HP/TAZ lotion achieved a statistically significant superior reduction in mean IGAxBSA compared to vehicle from week 2 (P<0.001 versus vehicle). By week 8, almost half of the patients treated with HP/TAZ lotion achieved a clinically meaningful response (IGAxBSA-75) and a 52.9% reduction in mean IGAxBSA score compared with a 17.5% increase in those patients treated with vehicle (P<0.001). One patient (2.6%) treated with HP/TAZ lotion discontinued due to AE. Most frequently reported treatment related AEs were application site pain (7.9%), contact dermatitis (5.3%) and pruritus (5.3%). Conclusions: HP/TAZ lotion provides significantly greater efficacy than vehicle that is both rapid and sustained, in patients with severe localized plaque psoriasis, with good tolerability and safety over 8 weeks' once-daily use. J Drugs Dermatol. 2019;18(10):1012-1018.

Psychiatric adverse events during treatment with brodalumab: Analysis of psoriasis clinical trials.

BACKGROUND: Individuals with psoriasis are at increased risk for psychiatric comorbidities, including suicidal ideation and behavior (SIB). OBJECTIVE: To distinguish between the underlying risk and potential for treatment-induced psychiatric adverse events in patients with psoriasis being treated with brodalumab, a fully human anti-interleukin 17 receptor A monoclonal antibody. METHODS: Data were evaluated from a placebo-controlled, phase 2 clinical trial; the open-label, long-term extension of the phase 2 clinical trial; and three phase 3, randomized, double-blind, controlled clinical trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3) and their open-label, long-term extensions of patients with moderate-to-severe psoriasis. RESULTS: The analysis included 4464 patients with 9161.8 patient-years of brodalumab exposure. The follow-up time-adjusted incidence rates of SIB events were comparable between the brodalumab and ustekinumab groups throughout the 52-week controlled phases (0.20 vs 0.60 per 100 patient-years). In the brodalumab group, 4 completed suicides were reported, 1 of which was later adjudicated as indeterminate; all patients had underlying psychiatric disorders or stressors. LIMITATIONS: There was no comparator arm past week 52. Controlled study periods were not powered to detect differences in rare events such as suicide. CONCLUSIONS: Comparison with controls and the timing of events do not indicate a causal relationship between SIB and brodalumab treatment.

Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-to-severe plaque psoriasis: Results of 2 phase 3 randomized controlled trials.

BACKGROUND: Topical corticosteroids are the mainstay of psoriasis treatment, with long-term safety considerations limiting their use. Combining them with tazarotene may optimize their efficacy and minimize safety and tolerability concerns. OBJECTIVE: To investigate the safety and efficacy of halobetasol propionate 0.01% plus tazarotene 0.045% (HP/TAZ) lotion in moderate-to-severe plaque psoriasis. METHODS: Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N = 418) were conducted. Subjects were randomized (2:1) to HP/TAZ lotion or vehicle once daily for 8 weeks with a 4-week follow-up. The primary efficacy assessment end point was treatment success (at least a 2-grade improvement from baseline in Investigator's Global Assessment score and a score of clear or almost clear). Safety and treatment-emergent adverse events were evaluated throughout. RESULTS: HP/TAZ lotion demonstrated statistically significant superiority over vehicle within as few as 2 weeks. By week 8, 35.8% (study 1) and 45.3% (study 2) of subjects were treatment successes compared with 7.0% and 12.5% of those treated with vehicle (P < .001). HP/TAZ lotion was also superior in reducing signs and symptoms of psoriasis and body surface area affected by psoriasis. The most frequently reported treatment-related adverse events were contact dermatitis (6.3%), application site pain (2.6%), and pruritus (2.2%). LIMITATIONS: Studies did not include subjects with more than 12% of their body surface area affected by psoriasis. CONCLUSIONS: HP/TAZ lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, with no safety concerns.

Safety and Efficacy of a Once-Daily Halobetasol Propionate 0.01% Lotion in the Treatment of Moderate-to-Severe Plaque Psoriasis: Results of Two Phase 3 Randomized Controlled Trials.

BACKGROUND: Topical corticosteroids (TCS) are the mainstay of psoriasis treatment; long-term safety concerns limiting consecutive use of potent TCS to 2-4 weeks. OBJECTIVE: Investigate safety and efficacy of halobetasol propionate 0.01% lotion in moderate-to-severe plaque psoriasis. METHODS: Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N=430). Subjects randomized (2:1) to halobetasol propionate 0.01% lotion or vehicle once-daily for 8 weeks, 4-week posttreatment follow-up. Primary efficacy assessment: treatment success (at least a 2-grade improvement from baseline in Investigator Global Assessment [IGA] score and 'clear' or 'almost clear') at week 8. Safety and treatment emergent adverse events (AEs) evaluated throughout. RESULTS: Halobetasol propionate 0.01% lotion demonstrated statistically significant superiority over vehicle as early as week 2. By week 8, 36.5% (Study 1) and 38.4% (Study 2) of subjects were treatment successes compared with 8.1% and 12.0% on vehicle (P less than 0.001). Halobetasol propionate 0.01% lotion was also superior in reducing psoriasis signs and symptoms, body surface area (BSA), and improving quality of life. Halobetasol propionate 0.01% lotion was well-tolerated with no treatment-related AEs greater than 1%. LIMITATIONS: Study did not include subjects with BSA greater than 12. CONCLUSIONS: Halobetasol propionate 0.01% lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, without the safety concerns of a longer treatment course. J Drugs Dermatol. 2018;17(10):1062-1069.

Safety and Efficacy of a Fixed Combination Halobetasol and Tazarotene Lotion in the Treatment of Moderate-to-Severe Plaque Psoriasis: A Pooled Analysis of Two Phase 3 Studies.

BACKGROUND: Topical corticosteroids (TCS) are the mainstay of psoriasis treatment. Safety concerns may limit use. Combination with tazarotene may optimize efficacy and minimize safety and tolerability concerns. OBJECTIVE: Investigate safety and efficacy of halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion in moderate-to-severe plaque psoriasis. METHODS: Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies (N=418). Subjects randomized (2:1) to HP/TAZ lotion or vehicle once-daily for 8 weeks, 4-week follow-up. Primary efficacy assessment: treatment success (at least a 2-grade improvement from baseline in IGA score and 'clear' or 'almost clear'). Safety and treatment emergent AEs evaluated throughout. RESULTS: HP/TAZ lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P equals 0.002). By week 8, 40.6% of subjects were treatment successes compared with 9.9% on vehicle (P less than 0.001). A third of subjects remained treatment successes post-treatment. HP/TAZ lotion was also superior in reducing psoriasis signs and symptoms, and Body Surface Area (BSA) involvement. Most frequently reported treatment related AEs were contact dermatitis (6.3%), application site pain (2.6%), and pruritus (2.2%). LIMITATIONS: No data were collected beyond the 4-week follow-up. CONCLUSIONS: HP/TAZ lotion provides synergistic efficacy that is both rapid and sustained, with good tolerability and safety over 8 weeks use. J Drugs Dermatol. 2018;17(8):855-861.

Long-Term Safety and Efficacy of Subcutaneous Methylnaltrexone in Patients with Opioid-Induced Constipation and Chronic Noncancer Pain: A Phase 3, Open-Label Trial.

OBJECTIVE: Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, alleviates opioid-induced constipation. Understanding its long-term safety and efficacy profile in patients with chronic noncancer pain is warranted given the persistence of opioid-induced constipation. METHODS.: In this phase 3, multicenter, open-label trial, adults with chronic noncancer pain (N = 1034) received subcutaneous methylnaltrexone 12 mg once daily for 48 weeks. RESULTS: The most common adverse events were gastrointestinal related (e.g., abdominal pain, diarrhea, nausea) and were mild to moderate in intensity. Only 15.2% of patients discontinued because of an adverse event. Serious cardiac-related adverse events occurred in nine patients. Of the seven instances of major adverse coronary events reported, three were adjudicated after external review; all instances occurred in patients with cardiovascular risk factors. Methylnaltrexone elicited a bowel movement within four hours in 34.1% of the injections throughout the 48-week treatment period. CONCLUSIONS: Change from baseline in mean weekly bowel movement rate, Bowel Movement Straining Scale score, Bristol Stool Scale score, and mean percentage of patients with complete evacuation from baseline to week 48 were significantly improved ( P < 0.001 for all). Long-term subcutaneous methylnaltrexone was well tolerated, with no new safety concerns, and provided consistent opioid-induced constipation relief in patients with chronic noncancer pain.

Randomized, Double-Blind Trial of Oral Methylnaltrexone for the Treatment of Opioid-Induced Constipation in Patients with Chronic Noncancer Pain.

BACKGROUND: Subcutaneous methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, improves opioid-induced constipation (OIC) in patients with chronic noncancer pain. An oral methylnaltrexone formulation has been developed. METHODS: In this phase 3, double-blind trial, adults with chronic noncancer pain receiving opioid doses of ≥ 50 mg/day oral morphine equivalents with OIC were randomly assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by as-needed dosing for 8 weeks. Patients who had ≥ 3 rescue-free bowel movements (RFBMs)/week, with an increase of ≥ 1 RFBM/week from baseline for ≥ 3 of 4 weeks during the QD period, were responders. RESULTS: Overall, 803 patients were included in the analyses. A significantly greater percentage of patients had an increase in mean percentage of dosing days resulting in an RFBM within 4 hours of dosing during weeks 1 through 4 (QD period; primary endpoint) with methylnaltrexone (300 mg/day [24.6%; P = 0.002] and 450 mg/day [27.4%; P < 0.0001]) vs. placebo (18.2%). The percentage of responders (49.3% for 300 mg [P = 0.03] and 51.5% for 450 mg [P = 0.005] vs. 38.3% with placebo) and change from baseline in mean number of weekly RFBMs (difference vs. placebo, 0.5 for 300 mg [P = 0.03] and 0.5 for 450 mg [P = 0.02]) was significantly greater with methylnaltrexone 300 and 450 mg/day vs. placebo during the QD period. All dosages of oral methylnaltrexone were well tolerated. CONCLUSIONS: Oral methylnaltrexone was efficacious and well tolerated for OIC in patients with chronic noncancer pain, particularly the 450-mg dose.

Untangling the relatedness among correlations, part I: Nonparametric approaches to inter-subject correlation analysis at the group level.

FMRI data acquisition under naturalistic and continuous stimuli (e.g., watching a video or listening to music) has become popular recently due to the fact that it entails less manipulation and more realistic/complex contexts involved in the task, compared to the conventional task-based experimental designs. The synchronization or response similarities among subjects are typically measured through inter-subject correlation (ISC) between any pair of subjects. At the group level, summarizing the collection of ISC values is complicated by their intercorrelations, which necessarily lead to the violation of independence assumed in typical parametric approaches such as Student's t-test. Nonparametric methods, such as bootstrapping and permutation testing, have previously been adopted for testing purposes by resampling the time series of each subject, but the quantitative validity of these specific approaches in terms of controllability of false positive rate (FPR) has never been explored before. Here we survey the methods of ISC group analysis that have been employed in the literature, and discuss the issues involved in those methods. We then propose less computationally intensive nonparametric methods that can be performed at the group level (for both one- and two-sample analyses), as compared to the popular method of circularly shifting the EPI time series at the individual level. As part of the new approaches, subject-wise (SW) resampling is adopted instead of element-wise (EW) resampling, so that exchangeability and independence assumptions are satisfied, and the patterned correlation structure among the ISC values can be more accurately captured. We examine the FPR controllability and power achievement of all the methods through simulations, as well as their performance when applied to a real experimental dataset.

Dermal Granuloma Annulare After SARS-CoV-2 Vaccination: A Rare Complication.

Granuloma annulare (GA) is an inflammatory granulomatous skin disease of unknown etiology that is self-limiting in nature. However, it is hypothesized that trauma, medications, malignancy, viral infections, different vaccines, and hypersensitivity reactions can trigger the formation of GA. Only three cases of post-SARS-CoV-2 vaccination-related GA have been reported so far. Here, we report the fourth documented case of post-SARS-CoV-2 vaccination-related generalized GA.

Clinico-Virological Outcomes and Mutational Profile of SARS-CoV-2 in Adults Treated with Ribavirin Aerosol for COVID-19 Pneumonia.

The emergence of new SARS-CoV-2 variants can affect vaccine efficacy, laboratory diagnosis and the therapies already available, triggering interest in the search for antiviral agents for SARS-CoV-2 infections. Ribavirin (RBV) is a broad-spectrum antiviral with demonstrated in vitro activity against multiple viruses, including SARS-CoV-2. This retrospective study evaluated the dynamics and viral clearance of SARS-CoV-2 in hospitalised adult participants (PTs) with COVID-19 pneumonia who received an RBV aerosol within a compassionate use study. The impact of RBV on the clinical outcome and the mutational profile of SARS-CoV-2 was also assessed. The median RNA values measured in nine PTs included in this study decreased from baseline to discharge (at BL, threshold cycle (Ct) = 22.4, IQR 19.84-5.07; at discharge, Ct = 27.92, IQR 26.43-36.11), with a significant decline in the Ct value evaluated by Friedman rank ANOVA analysis, p = 0.032. Seven out of nine PTs experienced a clinical improvement, while two PTs deceased during hospitalisation. In PTs with a favourable outcome, the virus clearance rate at discharge was 28.6%. The cumulative clearance rate was 71.4% within 14 days from discharge. A mutational pattern after RBV was detected in three out of five PTs in whom whole-genome sequencing was available. Our findings suggest that RBV limits SARS-CoV-2 replication, possibly resulting in a favourable clinical outcome. Ribavirin may also contribute to the mutational spectrum of SARS-CoV-2.