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.

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.

Impact of Patient Subgroups on the Efficacy and Safety of Methylnaltrexone for Opioid-Induced Constipation in Patients with Advanced Illness.

Purpose: We evaluated the impact of baseline patient characteristics on safety and efficacy of methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, in patients with advanced illness with opioid-induced constipation (OIC). Patients and Methods: This analysis pooled data from 2 randomized, double-blind, placebo-controlled studies (study 302: NCT00402038; study 4000: NCT00672477) in patients with advanced illness, including cancer, and OIC. Patients were randomized to receive subcutaneous methylnaltrexone (study 302: 0.15 mg/kg; study 4000: 8 or 12 mg based on weight) or placebo every other day for 2 weeks. The proportions of patients achieving rescue-free laxation within 4 or 24 hours after the first dose of study drug were assessed in patient subgroups stratified by baseline age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, laxative type, and opioid requirement. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Overall, 363 patients were included in this analysis (methylnaltrexone, 178; placebo, 185). Mean (SD) age was 66.3 (13.7) years and 48.5% were men overall. A significantly greater proportion of patients receiving methylnaltrexone versus placebo achieved rescue-free laxation within 4 hours (111/178 [62.4%] vs 31/185 [16.8%]; P<0.0001) and 24 hours (135/178 [75.8%] vs 81/185 [43.8%]; P<0.0001) of the first dose. These trends were consistent across all subgroups. Most patients experienced ≥1 TEAE in the overall population (methylnaltrexone, 82.1%; placebo, 76.2%), which remained consistent when stratified by baseline characteristics. More than half of TEAEs were gastrointestinal in nature. Abdominal pain was more common in patients receiving methylnaltrexone than placebo across baseline characteristic subgroups. Conclusion: Methylnaltrexone treatment was superior to placebo in achieving rescue-free laxation within 4 and 24 hours after the first dose, irrespective of patients' cancer status, baseline ECOG performance status, or baseline opioid or laxative use. The methylnaltrexone safety profile remained consistent across baseline characteristic subgroups.

Methylnaltrexone Treatment for Opioid-Induced Constipation in Patients with and without Cancer: Effect of Initial Dose.

Purpose: Opioid-induced constipation (OIC) is a common side effect of opioid therapy. Methylnaltrexone (MNTX) is a selective, peripherally acting µ-opioid receptor antagonist, with demonstrated efficacy in treating OIC. We pooled results from MNTX clinical trials to compare responses to an initial dose in patients with chronic cancer and noncancer pain. Patients and Methods: This post hoc analysis used pooled data from 3 randomized, placebo-controlled studies of MNTX in patients with advanced illness with OIC. Assessments included the proportions of patients achieving rescue-free laxation (RFL) within 4 and 24 hours of the first study drug dose, time to RFL, current and worst pain intensity, and adverse events, stratified by the presence/absence of cancer. Results: A total of 355 patients with cancer (MNTX n = 198, placebo n = 157) and 163 without active cancer (MNTX n = 83; placebo n = 80) were included. More patients treated with MNTX compared with those who received placebo achieved an RFL within 4 (cancer: MNTX, 61.1% vs placebo,15.3%, p<0.0001; noncancer: MNTX, 62.2% vs placebo, 17.5%, p<0.0001) and 24 hours (cancer: MNTX, 71.2% vs placebo, 41.4%, p<0.0001; noncancer: MNTX, 74.4% vs placebo, 37.5%, p<0.0001) of the initial dose. Cumulative RFL response rates within 4 hours of the first, second, or third dose of study drug were also higher in MNTX-treated patients. The estimated time to RFL was shorter among those who received MNTX and similar in cancer and noncancer patients. Mean pain scores declined similarly in all groups. The most common adverse events in both cancer and noncancer patients were abdominal pain, flatulence, and nausea. Conclusion: After the first dose, MNTX rapidly induced a laxation response in the majority of both cancer and noncancer patients with advanced illness. Opioid-induced analgesia was not compromised, and adverse events were primarily gastrointestinal in nature. Methylnaltrexone is a well-tolerated and effective treatment for OIC in both cancer and noncancer patients.

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.

Influencia del estado nutricional en el desarrollo psicomotor infantil: una revisión sistemática / The influence of nutritional status on child psychomotor development: a systematic review

Fundamentos: La desnutrición infantil es una problemática que se desenvuelve con gran preponderancia en el mundo, una situación que genera preocupación, debido a que la infancia es la etapa donde se comienzan a establecer diferentes procesos que determinan el desarrollo del aprendizaje cognitivo y emocional de losinfantes. El propósito de este trabajo fue estudiar la influencia que tiene el estado nutricional en el desarrollo psicomotor infantil en Latinoamérica durante el periodo (2008-2022). Métodos: Se empleó una metodología Prisma 2020, mediante la cual se realizó una búsqueda literaria en diferentes bases de datos, considerando criterios de inclusión y exclusión relacionados a la temática de estudio. A partir de ello, se obtuvo un muestreo final de 21 artículos, material que fue analizado de manera objetiva e interdependiente a través del programa Microsoft Excel 2019. Resultados: Dichos resultados determinaron que la mayoría de estudios evidencian una influencia directa entre el estado nutricional y el desarrollo psicomotor, en donde existe una alta tasa de casos de desnutrición global y severa, así como una prevalencia por problemas de sobrepeso. Una situación que termina afectando el aprendizaje del desarrollo infantil en las áreas de coordinación, lenguaje y cognición. Conclusiones: La desnutrición infantil es una temática de gran prevalencia en América Latina, en especial en la población que presenta bajos ingresos económicos y educacionales, motivos por los cuales se debe seguir trabajando y fortaleciendo los programas sociales dedicados a mermar esta problemática. (AU)

Background: Child malnutrition is a problem that develops with great preponderance in the world, a situation that generates concern, because childhood is the stage where different processes that determine the development of cognitive and emotional learning of infants begin to be established. The purpose of this work was to study the influence of nutritional status on child psychomotor development in Latin America during the period (2008-2022).Methods: A Prisma 2020 methodology was used, through which a literary search was carried out in different databases, considering inclusion and exclusion criteria related to the subject of study. From this, a final sampling of 21 articles was obtained, material that was analyzed objectively and interdependently through the Microsoft Excel program 2019. Results: These results determined that most studies show a direct influence between nutritional status and psychomotor development, where there is a high rate of cases of global and severe malnutrition, as well as a prevalence of overweight problems. A situation that ends up affecting the learning of child development in the areas of coordination, language and cognition. Conclusions: Child undernutrition is a highly prevalent issue in Latin America, especially in the populationwith low economic and educational income, which is why it is necessary to continue working and strengthening social programs dedicated to reducing this problem. (AU)

Subcutaneous Methylnaltrexone as Treatment for Opioid-Induced Constipation in Patients with Advanced Cancer and Noncancer Illnesses: A Post Hoc Analysis of Two Clinical Trials.

Purpose: To evaluate the efficacy and safety of subcutaneous (SC) methylnaltrexone for opioid-induced constipation (OIC) in patients with and without active cancer. Patients and Methods: We analyzed two randomized, double-blind, placebo-controlled, Phase 3/4 trials (NCT00402038, NCT00672477). Patients received SC methylnaltrexone (study 302, 0.15 mg/kg; study 4000, 8 mg or 12 mg based on body weight) or placebo every other day for 2 weeks. Patients were stratified by cancer status. Primary efficacy endpoints included proportion of patients achieving rescue-free laxation (RFL); secondary endpoints included time to RFL, pain intensity scores, and safety/tolerability. Trial results were evaluated separately. Results: The safety population (patients receiving ≥1 study drug dose) included 364 patients (study 302, n=134; study 4000, n=230). Study 302 had 78 patients with active cancer (methylnaltrexone, n=37; placebo, n=41) and 56 without cancer (methylnaltrexone, n=26; placebo, n=30); study 4000 had 152 patients with active cancer (methylnaltrexone, n=79; placebo, n=73) and 78 without cancer (methylnaltrexone, n=37; placebo, n=41). A significantly greater proportion of patients treated with methylnaltrexone achieved a laxation response within 4 hours after at least 2 of the first 4 doses versus placebo, dosed by body weight (cancer, 54.1% [methylnaltrexone] vs 7.3% [placebo], P<0.0001; noncancer, 48.0% vs 10.0%; P<0.005) or given as a weight-adjusted fixed dose (cancer, 59.5% vs 6.8%; noncancer, 70.3% vs 14.6%; P<0.0001 each). With fixed-dose methylnaltrexone, average time to RFL for patients with and without cancer was <1 hour of the first dose; with methylnaltrexone dosed by body weight, the first RFL occurred in <4 and <7 hours of treatment in patients with and without cancer, respectively. No significant differences were found in pain scores. SC methylnaltrexone was well tolerated at all doses in all patient cohorts. Conclusion: SC methylnaltrexone was efficacious in inducing rapid RFL and safe among patients with and without active cancer suffering from OIC.

A Randomized, Double-Blind, Parallel Design Thorough QT Study With a Nested Crossover to Compare the Cardiac Safety of Amiselimod With Placebo and Positive Control in Healthy Volunteers.

This double-blind study evaluated the cardiac safety of amiselimod. Healthy adults (n = 190) were randomized (2:1:1) to receive (1) oral placebo (day -1), followed by oral amiselimod (days 1-26), which was upwardly titrated from 0.4 to 1.6 mg once daily to achieve steady-state concentrations comparable with 0.4 (therapeutic) and 0.8 mg (supratherapeutic) once daily, and placebo (day 27); (2) placebo (day -1), oral moxifloxacin 400 mg (day 1; positive control), followed by placebo (days 1-27); or (3) placebo (days -1 to 26), followed by moxifloxacin 400 mg (day 27). No participant had a corrected QT interval by Fredericia (QTcF) >500 milliseconds or a change from baseline (dQTcF) >60 milliseconds. The upper limits of the 90%CIs for the differences in least-squares mean difference in dQTcF between amiselimod and placebo on days 13 and 26 were <10 milliseconds. Area under the concentration-time curve from 0 to 23.5 hours after dosing and maximum plasma concentration of amiselimod and amiselimod-P (active metabolite) at steady-state concentrations for the 0.8-mg dose on day 26 were approximately double that observed with the 0.4-mg dose on day 13. All adverse events were mild to moderate in severity, and no deaths occurred. Amiselimod did not have any clinically relevant effect on the QTcF interval.

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.

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).

Ribavirin aerosol in hospitalized adults with respiratory distress and COVID-19: An open-label trial.

There is an unmet medical need for effective treatments for hospitalized patients with coronavirus disease 2019 (COVID-19). Ribavirin is a broad-spectrum antiviral with demonstrated in vitro activity against multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This trial evaluated the potential of ribavirin inhalation solution (ribavirin aerosol) to reduce COVID-19 disease severity in adults with confirmed SARS-CoV-2 infection and a diagnosis of respiratory distress. This phase I, multicenter, open-label, nonrandomized trial was conducted from February 2021 through August 2021. Patients received ribavirin aerosol (100 mg/ml for 30 min or 50 mg/ml for 60 min) twice daily for up to 6 days. The primary end point was change from baseline in clinical status severity, rated on a 7-point scale (1 [death]; 7 [not hospitalized; no limitations on activities]), at day 7 (or end-of-treatment/early termination) and day 30 (follow-up). Fifty-one patients were treated with ribavirin aerosol (mean age, 51.5 years; 78.4% men); mean number of doses was 9.7 (range, 1-12). Improvement of ≥1 level in clinical status severity was observed in 31.4% (16/51) and 78.4% (40/51) of patients at end-of-treatment and day 30, respectively. Of 21 patients who required a ventilator, 16 (76.2%) were able to discontinue ventilator use. Five patients (9.8%) died between end-of-treatment and day 30. Three patients (5.9%) discontinued study treatment due to adverse events. No deaths were considered related to study treatment. These data provide preliminary evidence that ribavirin aerosol may be an efficacious treatment for respiratory distress in adults with COVID-19.

A randomized, placebo-controlled study to evaluate safety and pharmacokinetics of inhaled ribavirin.

Ribavirin is an inosine monophosphate dehydrogenase inhibitor. Studies suggest ribavirin aerosol could be a safe and efficacious treatment option in the fight against coronaviruses. However, current treatment is long (12-18 h per day, 3-7 days), limiting clinical utility. A reduction in treatment time would reduce treatment burden. We aimed to evaluate safety and pharmacokinetics (PK) of four, single-dose regimens of ribavirin aerosol in healthy volunteers. Thirty-two subjects were randomized, to four cohorts of aerosolized ribavirin (active) or placebo. Cohort 1 received 50 mg/ml ribavirin/placebo (10 ml total volume); cohort 2, 50 mg/ml ribavirin/placebo (20 ml total volume); cohort 3, 100 mg/ml ribavirin/placebo (10 ml total volume); and cohort 4, 100 mg/ml ribavirin/placebo (20 ml total volume). Intense safety monitoring and PK sampling took place on days 1, 2, 3, and 40. Subjects were (mean ± SD, active vs. placebo) aged 57 ± 4.5 vs. 60 ± 2.5 years; 83% vs. 88% were female; and 75% vs. 50% were Caucasian. Some 12.5% (3/24) and 25% (2/8) experienced at least one treatment-emergent adverse event (TEAE) (two moderate; five mild) in the active and placebo groups, respectively. No clinically significant safety concerns were reported. Mean maximum observed concentration (Cmax ) and area under the curve (AUC) values were higher in cohort 4, whereas cohorts 2 and 3 showed similar PK values. Ribavirin absorption reached Cmax within 2 h across cohorts. Four single-dose regimens of ribavirin aerosol demonstrated systemic exposure with minimal systemic effects. Results support continued clinical development of ribavirin aerosol as a treatment option in patients with coronaviruses.

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.

Subcutaneous Methylnaltrexone for Treatment of Opioid-Induced Constipation in Cancer versus Noncancer Patients: An Analysis of Efficacy and Safety Variables from Two Studies.

PURPOSE: Methylnaltrexone inhibits opioid-induced constipation (OIC) by binding to peripheral µ-opioid receptors without impacting central opioid receptor mediated analgesia. This analysis compared methylnaltrexone efficacy and safety among advanced illness patients with and without active cancer and OIC. PATIENTS AND METHODS: This post hoc analysis included two multicenter, randomized, double-blind, placebo-controlled studies in adults with advanced illness and OIC who received subcutaneous methylnaltrexone. Efficacy endpoints included the proportion of patients achieving rescue-free laxation (RFL), time to RFL, weekly laxations within 24 hours after dosing, rescue laxative use, and pain scores. Adverse events were monitored for safety. RESULTS: After pooling, 178 patients received methylnaltrexone (n = 116 with cancer) and 185 received placebo (n = 114 with cancer). Median baseline daily opioid morphine equivalents (mg/d) were higher in cancer (methylnaltrexone: 180; placebo: 188) versus noncancer patients (methylnaltrexone: 120; placebo: 80). The proportions of patients achieving RFL within 4 hours after ≥2 of the first 4 doses were significantly greater with methylnaltrexone (cancer: 56.9%; noncancer: 58.1%) versus placebo (cancer: 5.3%; noncancer: 11.3%; P < 0.0001). The median time to laxation within 24 hours after the first methylnaltrexone dose was significantly shorter in cancer and noncancer patients versus placebo (cancer: 0.96 vs 22.53 hours, P < 0.0001; noncancer: 1.25 vs >24 hours, P = 0.0002). The mean number of weekly laxations within 24 hours after dosing by week 2 was significantly higher in methylnaltrexone- vs placebo-treated cancer and noncancer patients (cancer: 7.9 vs 4.9, P < 0.0001; noncancer: 8.4 vs 5.0, P < 0.0001). Methylnaltrexone reduced rescue laxative use without impacting pain scores. Consistent with previous data, methylnaltrexone was well tolerated in cancer and noncancer patients, and the AE profile did not suggest symptoms of opioid withdrawal. CONCLUSION: Methylnaltrexone reduced RFL time in advanced-illness patients with and without active cancer, while maintaining pain control with opioid treatment despite higher baseline opioid use among cancer patients.

Ribavirin Aerosol in the Treatment of SARS-CoV-2: A Case Series.

Ribavirin is an inosine monophosphate dehydrogenase inhibitor with demonstrated activity against coronaviruses, including SARS-CoV-2. Five hospitalized patients with COVID-19 (confirmed by positive tests for SARS-CoV-2) received treatment with ribavirin for inhalation solution (ribavirin aerosol) as part of a compassionate use program. Patients included four men and one woman, with an age range of 29-72 years. Patients were managed according to international and Italian treatment guidelines for COVID-19. In addition, therapy with ribavirin aerosol 100 mg/mL was administered for 30 min twice daily for 6 days (i.e., 12 doses) in all patients. In order to address concerns about a possible increase in viral dispersal with the use of a nebulizer, healthcare providers remained outside the patient room during ribavirin aerosol administration. Pretreatment chest computed tomography (CT) scans showed pseudonodular areas of parenchymal thickening in the upper right lobe with associated ground glass opacities, multiple areas of parenchymal consolidation in both lower lobes with associated ground glass opacities, bilateral parenchymal thickening and multiple associated ground glass areas, or focal ground glass areas in the upper lobes bilaterally, which were almost completely resolved (three patients) or moderately cleared (one patient) on imaging at the end of ribavirin treatment. For a fifth patient, CT scans showed a stable pulmonary picture at the end of ribavirin treatment. No adverse reactions to ribavirin treatment were observed in any of the five patients. All patients recovered fully, and nasopharyngeal swabs obtained after hospital discharge tested negative for SARS-CoV-2. Ribavirin aerosol appears to be efficacious in the treatment of patients with COVID-19. A controlled trial of ribavirin aerosol is ongoing and will provide additional data across a broader patient population.

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.

Attrition of methylnaltrexone treatment-emergent adverse events in patients with chronic noncancer pain and opioid-induced constipation: a post hoc pooled analysis of two clinical trials.

Background: Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of treatment-emergent adverse events (TEAEs) after the first or second dose of methylnaltrexone or placebo. Methods: This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone (150, 300, or 450 mg daily), or placebo. TEAEs, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose (i.e., RFBM responders) were assessed. Associations between TEAE frequencies and RFBM response were also evaluated. Results: The analysis included 1263 adult patients with chronic noncancer pain. TEAE rates declined from treatment day 1 to 2 (methylnaltrexone: 16.2%-5.3%; placebo: 6.6%-5.4%). Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal TEAEs on day 1. No associations between RFBM response and the frequency of TEAEs were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed. Conclusions: Early-onset TEAEs following methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids.

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.

Malignancy Rates in Brodalumab Clinical Studies for Psoriasis.

BACKGROUND: Brodalumab is a fully human anti-interleukin-17 receptor A monoclonal antibody efficacious for the treatment of adults with moderate-to-severe plaque psoriasis. OBJECTIVE: This study summarizes malignancy rates in psoriasis clinical studies of brodalumab. METHODS: Data were pooled from one phase II study and three large, multicenter, phase III randomized studies of brodalumab for the treatment of psoriasis, including two studies with randomization to brodalumab, ustekinumab, or placebo. Data from the 52-week (brodalumab and ustekinumab) and long-term (brodalumab) pools were summarized as exposure-adjusted or follow-up time-adjusted event rates per 100 patient-years (PY). RESULTS: Exposure-adjusted event rates per 100 PY at 52 weeks were lower with brodalumab (n = 4019; 3446 total PY of exposure) than with ustekinumab (n = 613; 495 total PY of exposure), including adjudicated malignancies (0.9 vs 2.6) and Surveillance, Epidemiology, and End Results (SEER)-adjudicated malignancies (0.3 vs 0.4). The exposure-adjusted event rate of adjudicated malignancies in the brodalumab group remained stable in the long-term analysis (0.9 [82 events]). CONCLUSIONS: Rates of malignancy among brodalumab-treated patients with psoriasis were generally low. TRIAL REGISTRY: ClinicalTrials.gov identifier NCT00975637; NCT01101100; NCT01708590 (AMAGINE-1); NCT01708603 (AMAGINE-2); NCT01708629 (AMAGINE-3).

Subcutaneous methylnaltrexone for opioid-induced constipation in advanced-illness patients with or without active cancer.

Aim: To evaluate methylnaltrexone for opioid-induced constipation in patients with and without cancer. Methods: This post hoc analysis comprises two Phase III, multicenter, double-blind, randomized studies of advanced-illness patients who received methylnaltrexone subcutaneous injection or placebo. Results: Significantly more patients treated with methylnaltrexone than placebo experienced laxation within 4 (cancer = 55.5 vs 15.5%; noncancer = 55.6 vs 12.8%) and 24 (cancer = 64.7 vs 29.8%; noncancer = 64.4 vs 30.8%) h after the first dose (p < 0.01 vs placebo). Regardless of cancer status, methylnaltrexone reduced median time to laxation and improved constipation relief without impacting opioid analgesia or withdrawal symptoms. Conclusion: Methylnaltrexone provided significant improvements in opioid-induced constipation over placebo in advanced-illness patients with and without cancer. Clinical trial registration numbers: study 301: NCT00401362; study 302: NCT00402038.