Co-primary Efficacy Endpoints Research Articles

Comparisons and correlations of 1-month recall vs 24-hour recall in patient-reported outcomes of an exploratory, phase 2b, randomized, double-blind, placebo-controlled clinical trial of sildenafil cream, 3.6% for the treatment of female sexual arousal disorder.

Efficacy assessments in clinical trials of treatments for female sexual arousal disorder (FSAD) and other female sexual dysfunction (FSD) diagnoses rely on various patient-reported outcomes (PROs). We sought to compare 1-month recall PRO measures among participants enrolled in a clinical trial who provided these data without (test population) vs with (control population) use of an at-home, 24-hour recall electronic diary (eDiary), capturing similar data. Preplanned subset analysis as performed during a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD. Preliminary product efficacy was assessed via 1-month recall and 24-hour recall questionnaires. A subset of the participants, the Evaluation of Recall Subset [ERS] provided PROs via the 1-month recall instruments but did not provide data via the 24-hour recall eDiary. Responses to the 1-month recall instruments were compared among ERS (test) vs non-ERS (control) participants. Among the non-ERS population, correlations between 1-month and 24-hour recall endpoints were calculated. There were no significant differences in the study co-primary 1-month recall efficacy endpoints, the Arousal Sensation (AS) domain of the 28-item Sexual Function Questionnaire (SFQ28) and the Female Sexual Distress Scale - Desire, Arousal, Orgasm question 14, among ERS vs non-ERS participants during the initial 1-month no-drug run-in period or the 1-month single-blind placebo run-in period (P values > .47). Scores on these 1-month recall PROs continued to be similar after randomization for sildenafil cream (P values > .30) and placebo cream (P values > .20) assigned ERS and non-ERS participants during the 3-month double-blind dosing period. There were strong correlations between the SFQ28 AS and eDiary AS scores during the no-drug run-in (R= 0.79, P< .01) and the single-blind run-in (R= 0.73 P< .001). During the double-blind dosing period, the SFQ28 AS score continued to be highly correlated with the eDiary AS score among sildenafil cream users (R= 0.83; P< .001) and placebo cream users (R= 0.8; 2 P< .001). There was no evidence that 1-month recall PRO instruments introduce recall bias; assessing arousal sensations with 24-hour vs 1-month PRO instruments is similar and either method could be used to assess efficacy depending on study objectives. This preplanned subset analysis compared efficacy of PROs based on recall duration. While the subset was preplanned, the study was powered to detect significant differences in the primary efficacy objectives, not among this subset analyses. These data will be used in planning future efficacy assessments of sildenafil cream for FSAD. This clinical trial was registered with ClinicalTrials.gov, NCT04948151.

Efficacy and Safety of Lerodalcibep in Patients With or at High Risk of Cardiovascular Disease

Recent changes in national and international lipid guidelines for reducing cardiovascular events recommend additional drugs, greater reductions, and lower targets for low-density lipoprotein cholesterol (LDL-C) if not attained with statins. The achievement of these targets with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has not yet been evaluated in a randomized clinical trial. To evaluate the 52-week safety and efficacy of lerodalcibep, a small anti-PCSK9-binding protein, in patients with cardiovascular disease (CVD) or who are at very high or high risk of CVD and requiring addition LDL-C-lowering treatment. This was a randomized, double-blind, placebo-controlled phase 3 trial. The trial was conducted at 66 clinics in 11 countries between April 23, 2021, and November 15, 2023. Individuals 18 years and older taking maximally tolerated statin therapy with LDL-C of 70 mg/dL or greater with CVD or 100 mg/dL or greater if at high risk of CVD were included. Patients were randomized 2:1 to monthly 1.2-mL subcutaneous lerodalcibep, 300 mg, or placebo for 52 weeks. The safety analysis included all randomized patients. The co-primary efficacy end points were percent change from baseline in LDL-C at week 52 and the mean of weeks 50 and 52. Secondary efficacy outcomes included additional lipid apolipoprotein measures and achievement of guideline-recommended LDL-C targets. Of 922 randomized participants (mean [range] age, 64.5 [27-87] years; 414 [44.9%] female; mean [SD] baseline LDL-C, 116.2 [43.5] mg/dL), 811 (88%) completed the trial. The mean (SE) placebo-adjusted reduction in LDL-C with lerodalcibep by modified intention-to-treat (mITT) analysis was 56.2% (2.2%) at week 52 and 62.7% (1.9%) for the mean of weeks 50 and 52; 49.7% (2.4%) and 55.3% (2.2%) by ITT with imputation using a washout model, and 60.3% (2.3%) and 65.9% (1.9%) by per-protocol analysis at week 52 and the mean of weeks 50 and 52, respectively (P < .001 for all). With lerodalcibep, 555 of 615 participants (90%) achieved both a reduction in LDL-C of 50% or greater and recommended LDL-C targets during the study. Treatment-emergent adverse events were similar between lerodalcibep and placebo, except for injection site reactions. These occurred in 42 of 613 participants receiving lerodalcibep (6.9%) compared to 1 of 307 receiving placebo (0.3%), were graded mild or moderate, and did not result in higher discontinuation of treatment, at 26 of 613 (4.2%) and 14 of 307 (4.6%), respectively. Sporadic in vitro antidrug antibodies were detected, which had no impact on free PCSK9 or LDL-C-lowering efficacy. In this trial, lerodalcibep, a novel anti-PCSK9 small binding protein, dosed monthly and stable at ambient temperatures significantly reduced LDL-C in patients with CVD or at high risk of atherosclerotic cardiovascular disease with a safety profile similar to placebo. These results support long-term use of lerodalcibep in patients with CVD or at high risk of CVD who are unable to achieve adequate LDL-C reduction while receiving maximal tolerated statins alone. ClinicalTrials.gov Identifier: NCT04806893.

Preliminary Efficacy of Topical Sildenafil Cream for the Treatment of Female Sexual Arousal Disorder: A Randomized Controlled Trial.

To assess the efficacy of topical sildenafil cream, 3.6% among healthy premenopausal women with female sexual arousal disorder. We conducted a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream. Coprimary efficacy endpoints were the change from baseline to week 12 in the Arousal Sensation domain of the SFQ28 (Sexual Function Questionnaire) and question 14 of the FSDS-DAO (Female Sexual Distress Scale-Desire, Arousal, Orgasm). Two hundred women with female sexual arousal disorder were randomized to sildenafil cream (n=101) or placebo cream (n=99). A total of 174 participants completed the study (sildenafil 90, placebo 84). Among the intention-to-treat (ITT) population, which included women with only female sexual arousal disorder and those with female sexual arousal disorder with concomitant sexual dysfunction diagnoses or genital pain, although the sildenafil cream group demonstrated greater improvement in the SFQ28 Arousal Sensation domain scores, there were no statistically significant differences between sildenafil and placebo cream users in the coprimary and secondary efficacy endpoints. An exploratory post hoc subset of the ITT population with an enrollment diagnosis of female sexual arousal disorder with or without concomitant decreased desire randomized to sildenafil cream reported significant increases in their SFQ28 Arousal Sensation domain score (least squares mean 2.03 [SE 0.62]) compared with placebo cream (least squares mean 0.08 [SE 0.71], P =.04). This subset achieved a larger mean improvement in the SFQ28 Desire and Orgasm domain scores. This subset population also had significantly reduced sexual distress and interpersonal difficulties with sildenafil cream use as measured by FSDS-DAO questions 3, 5, and 10 (all P ≤.04). Topical sildenafil cream improved outcomes among women with female sexual arousal disorder, most significantly in those who did not have concomitant orgasmic dysfunction. In particular, in an exploratory analysis of a subset of women with female sexual arousal disorder with or without concomitant decreased desire, topical sildenafil cream increased sexual arousal sensation, desire, and orgasm and reduced sexual distress. ClinicalTrials.gov , NCT04948151.

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

(093) IMPACT OF ENROLLMENT DIAGNOSIS ON EFFICACY ENDPOINTS IN AN EXPLORATORY, PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF SILDENAFIL CREAM, 3.6% FOR THE TREATMENT OF FEMALE SEXUAL AROUSAL DISORDER

Abstract Introduction There are no FDA-approved treatments for female sexual arousal disorder (FSAD). Women with FSAD also often have co-existing secondary female sexual dysfunction (FSD) diagnoses. Objective Post-hoc subset analysis of the effect of enrollment FSD diagnoses on efficacy of Sildenafil Cream, 3.6% for treatment of FSAD. Methods Phase 2b, exploratory, randomized, placebo-controlled, double-blind study of Sildenafil Cream, 3.6% among premenopausal women with FSAD (NCT04948151). The change from baseline at week 12 in the arousal sensation (AS) domain (questions 6-9) of the 28-question sexual function questionnaire (SFQ28) was a co-primary efficacy endpoint. Changes from baseline in the mean number of satisfactory sexual experiences (SSEs) was a secondary endpoint. Exploratory efficacy endpoints included the Desire and Orgasm domains of the SFQ28. Enrollment FSD diagnoses were established during a clinical interview with independent experts. A retrospective review was performed of the clinical interviews for the intent-to-treat (ITT) population who completed the study (n=174) and enrollment diagnoses were categorized. Results Table 1 shows the breakdown of enrollment diagnoses by product group for the ITT population. Participants with FSAD and pain (n=6) were excluded. Although few women had FSAD as their sole diagnosis, when randomized to Sildenafil Cream, 3.6%, they had the largest mean increases in efficacy variables at week 12. Women with FSAD and secondary HSDD also experienced substantial benefit with Sildenafil Cream, 3.6% at week 12. Women with an enrollment diagnosis of FSAD with secondary FOD had the least benefit from Sildenafil Cream, 3.6% at week 12. Conclusions Data from this exploratory trial support the future target populations, including women with FSAD or FSAD with HSDD, will likely benefit the most from Sildenafil Cream, 3.6% treatment. Disclosure Yes, this is sponsored by industry/sponsor: Dare Bioscience and Strategic Science and Technologies LLC. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dare Bioscience and Strategic Science and Technologies LLC.

(094) MEASURES OF FEMALE SEXUAL DISTRESS IN AN EXPLORATORY, PHASE 2B, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL OF SILDENAFIL CREAM, 3.6% FOR THE TREATMENT OF FEMALE SEXUAL AROUSAL DISORDER

Abstract Introduction The diagnosis of female sexual arousal disorder (FSAD) requires that individuals experience clinically significant distress from their symptoms. Pre-trial content validity investigations were conducted by the sponsor to understand how women with FSAD best described their distress associated with this female sexual dysfunction (FSD) diagnosis. Objective Responses to the Female Sexual Distress Scale – Desire, Arousal, Orgasm (FSDS-DAO) survey among healthy premenopausal women enrolled in a Phase 2b, exploratory, randomized, placebo-controlled, double-blind study of Sildenafil Cream, 3.6% for FSAD treatment (NCT04948151). Methods After informed consent, enrollment diagnoses for each participant were established during a one-on-one clinical interview with independent experts. Baseline assessments were measured after a one-month, single-blind, placebo, run-in period. Participants were then randomized to Sildenafil Cream, 3.6% (n=101) versus Placebo (n=99) and used the investigational product (IP) as needed at home for 12 weeks, with monthly in-clinic assessments. The change from baseline at week 12 in question 14 (Q14) of the FSDS-DAO was a co-primary efficacy endpoint. All 15 FSDS-DAO questions begin with “How often did you feel, in the past 30 days” with a Likert score of 0 (Never) to 4 (Always). Results Although changes from baseline at week 12 in FSDS-DAO Q14 responses were not different among active versus placebo users in the intent-to-treat population (p=0.84) or the future target population (women with FSAD only or primary FSAD with secondary hypoactive sexual desire disorder (HSDD)) (p=0.95), responses to several FSDS-DAO questions, showed reduced sexual distress among Sildenafil Cream, 3.6% users (Table 1). While Q14 asked specifically about concerns with sexual arousal, the other 5 questions asked about generalized sexual distress, using verbiage more congruent with pre-trial content validity investigations. Post-trial psychometric validation studies selected question 5 as the most appropriate for measuring sexual distress among this population. Conclusions Data from this exploratory trial support that women with a diagnosis of FSAD only or primary FSAD with secondary HSDD experienced reduced sexual distress after receiving Sildenafil Cream, 3.6%. Disclosure Yes, this is sponsored by industry/sponsor: Dare Bioscience and Strategic Science and Technologies. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dare Bioscience and Strategic Science and Technologies.

Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam).

Benfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

Efficacy and Safety of Micronized Isotretinoin Administered Once Daily Without Food in Patients With Recalcitrant Nodular Acne.

Micronized isotretinoin 0.4 to 0.8 mg/kg/day administered in 2 divided doses with or without meals is approved for the treatment of severe nodular acne in patients aged 12 years or older. Although practitioners may suggest once-daily dosing to increase patient compliance, supporting data are limited. In this pilot study, patients aged 12 years or older with severe nodular acne (Investigator's Global Assessment [IGA] =&gt;4 and &gt;5 facial nodules) received once-daily micronized isotretinoin 0.4 to 0.8 mg/kg/day without food for 20 weeks. The coprimary efficacy endpoints were changes from baseline in nodular lesion count (NLC) and percentage of patients with a =&gt;90% reduction in NLC at week 24. Secondary endpoints included percentage of patients achieving IGA 0/1; reductions in inflammatory lesion count (ILC) and noninflammatory lesion count (NILC); adverse events (AEs); and severity of erythema, dryness, peeling, oiliness, burning, and pruritus. Analyses included all enrolled patients with the last observation carried forward. Twenty-two of 24 patients completed the study. From baseline to week 24, NLC decreased by a median (quartile [Q]1, Q3) of 6 (5, 7), all patients experienced complete clearance of nodules, 23/24 (96%) patients achieved IGA 0/1, and ILC and NILC decreased by a mean +/- standard deviation of 97.8% +/- 5.7% and 98.4% +/-&nbsp;6.2%, respectively (all P&lt;0.0001). There were small, significant, early increases in the severity of erythema, dryness, and peeling; 2 patients experienced 3 AEs considered unrelated to treatment. Once-daily micronized isotretinoin administered without food was efficacious and well tolerated in patients with severe nodular acne.&nbsp; J Drugs Dermatol. 2024;23(6):423-428.&nbsp; &nbsp;&nbsp; doi:10.36849/JDD.7863.

Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

Clinical efficacy and safety of intravenous ferric carboxymaltose for treatment of restless legs syndrome: a multicenter, randomized, placebo-controlled clinical trial.

Iron therapy is associated with improvements in restless legs syndrome (RLS). This multicenter, randomized, double-blind study evaluated the effect of intravenous ferric carboxymaltose (FCM) on RLS. A total of 209 adult patients with a baseline International RLS (IRLS) score ≥ 15 were randomized (1:1) to FCM (750 mg/15 mL) or placebo on study days 0 and 5. Ongoing RLS medication was tapered starting on Day 5, with the goal of discontinuing treatment or achieving the lowest effective dose. Co-primary efficacy endpoints were changed from baseline in IRLS total score and the proportion of patients rated as much/very much improved on the Clinical Global Impression (CGI)-investigator (CGI-I) scale at day 42 in the "As-Treated" population. The "As-Treated" population comprised 107 FCM and 101 placebo recipients; 88 (82.2%) and 68 (67.3%), respectively, completed the day 42 assessment. The IRLS score reduction was significantly greater with FCM versus placebo: least-squares mean (95% confidence interval [CI]) -8.0 (-9.5, -6.4) versus -4.8 (-6.4, -3.1); p = .0036. No significant difference was observed in the proportion of FCM (35.5%) and placebo (28.7%) recipients with a CGI-I response (odds ratio 1.37 [95% CI: 0.76, 2.47]; p = .2987). Fewer patients treated with FCM (32.7%) than placebo (59.4%) received RLS interventions between day 5 and study end (p = .0002). FCM was well tolerated. The IRLS score improved with intravenous FCM versus placebo, although the combination of both co-primary endpoints was not met. Potential methodological problems in the study design are discussed.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

(123) Preliminary Efficacy of Sildenafil Cream, 3.6% in an Exploratory, Randomized, Placebo-Controlled, Phase 2b Trial for the Treatment of Female Sexual Arousal Disorder

Abstract Introduction Female sexual arousal disorder (FSAD) is a persistent or recurrent inability to attain, or to maintain until completion of the sexual activity, an adequate lubrication-swelling response of sexual excitement that causes marked distress or interpersonal difficulty. The biologic mechanisms leading to FSAD are similar to male erectile dysfunction. Objective To test the preliminary efficacy of topical Sildenafil Cream, 3.6% among women with FSAD in a randomized, placebo-controlled, double-blind, exploratory Phase 2b study. To describe, using validated 28-day recall instruments, changes in sexual function with treatment, and to validate exploratory sexual function questionnaires in a placebo-controlled trial. Methods Healthy pre-menopausal women, aged 18-years or older and their sexual partners, if applicable, were screened and provided written informed consent. An individual clinical interview with each volunteer was conducted in order to establish that FSAD was present and was the primary sexual dysfunction concern. Women at risk of pregnancy used effective contraception during the study. Women or their partners were excluded if they had un-controlled hypertension, a history of serious cardiac events (e.g. myocardial infarction, stroke), orthostatic hypotension or other serious medical co-morbidities. The co-primary efficacy endpoints were measured by the arousal sensation domain of the sexual function questionnaire (SFQ28) and question 14 of the female sexual distress scale (FSDS). After a one-month, no drug, run-in period, and a one-month, single-blind placebo, run-in period, 200 eligible women were randomized to receive Sildenafil Cream, 3.6% (n=101) versus placebo cream (n=99). Participants applied 2 grams of the investigational product to the clitoris, vestibule, labia minora and anterior distal vagina 10 – 20 minutes prior to each partnered or un-partnered sexual experience. During the 12-week, double-blind treatment period, participants were seen monthly and completed validated, 28-day recall questionnaires. Efficacy was also measured by a 12-question Arousal Diary (AD), completed within 24 hours of each sexual experience. Results Volunteers (n=833) underwent informed consent in this ethics board (Advarra Pro 00049161) and U.S. Food and Drug Administration approved study (IND 119922), registered at ClinicalTrials.gov (#NCT04948151). There were 1131 Sildenafil and 951 placebo exposed sexual experiences recorded in the AD during the double-blind treatment period. Sildenafil Cream, 3.6% treated women had a higher proportion of satisfactory sexual events than placebo users. At 12-weeks of use, there was improvement in the co-primary endpoint of arousal sensation consistent with how women reported meaningful improvement in an exit interview at the end of the study, although this did not achieve statistical significance. Sildenafil Cream, 3.6% treated women showed improvements in pre-specified exploratory endpoints that evaluated various aspects of the sexual experience including desire (p=0.02), arousal lubrication (p = 0.059) and orgasm (p=0.066) after 8 weeks of product use. Conclusions Data from this exploratory, placebo-controlled study of topical Sildenafil Cream, 3.6% for the treatment of FSAD in healthy premenopausal women support further clinical development of this first potential treatment for FSAD. Disclosure Yes, this is sponsored by industry/sponsor: Dare Bioscience and Strategic Sciences and Technologies (SST), LLC. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Dare Bioscience and SST LLC.

Efficacy and Safety of Bacillus coagulans LBSC in Drug Induced Constipation Associated With Functional Gastrointestinal Disorder: A Double-Blind, Randomized, Interventional, Parallel, Controlled Trial a Clinical Study on Bacillus coagulans LBSC for Drug Induced Constipation Associated With FGIDs.

Active drugs and nutraceutical supplements commonly induce various gastrointestinal illnesses, and constipation is a major gastrointestinal symptom accompanied with functional gastrointestinal disorders. Drug-induced imbalance in gut microbiota may play critical role in such physiological disturbances. Probiotics have been known for resuming normal and healthy gut microbiome. To investigate the clinical efficacy and safety of Bacillus coagulans LBSC in the treatment of drug induced constipation associated with functional gastrointestinal disorder (FGID) symptoms. A prospective, interventional, randomized, double-blind, parallel, multi-arm, controlled trial with 168 patients experiencing drug induced constipation associated with FGID symptoms (DICAWFGID) screened through Rome IV criteria were randomized into 2 arms, i.e. placebo arm (n = 28) and atorvastatin, atenolol, metformin, amitriptyline, and calcium in test arm (n = 28/arm). Patients in both arms received similar dosages (1g sachet, 3 times a day) for 35 days. The occurrence of constipation using Bristol Stool Form Scale, assessment of degree of constipation on 4-point Likert scale, occurrence of hard stool and degree of stool expulsion on 3-point scale, and defecation frequency were primary endpoints. While, secondary outcomes consisted of the changes in severity of FGID symptoms, visual analogue scale and tolerance to IP, along with reports of adverse events (AEs) and severe adverse events (SAEs). There was a significant reduction in occurrence of constipation (≥98.6% and P-value <0.05) in test arm over the placebo arm. Assessment of co-primary endpoints showed significant improvements in degree of stool consistency (P-value 0.0232; CI: 0.1870, 1.1629), borderline significantly superior in degree of stool expulsion (P-value 0.0553; CI: 0.0378, -0.4939), while the other co-primary efficacy endpoints displayed considerably improved advancement (non-significant, P-value ≥0.05). The intra group analysis of symptoms at start of treatment (SOT) and end of treatment (EOT) revealed a significant reduction in scores for occurrence of constipation and degree of constipation, whereas significant improvement in the scores for degree of stool consistency and degree of stool expulsion (P-value <0.001) after the intervention period. In secondary endpoints, the processed responses clearly signified a considerable positive improvement (non-significant, P-value ≥0.05) in other symptoms of constipation associated with FGIDs as determined by the changes in the EOT-SOT score. The study data also highlighted the safety of Bacillus coagulans LBSC at the studied dose. No AEs and/or SAEs were documented during the investigation. At the studied dose, Bacillus coagulans LBSC was safe for oral consumption and effective in the management of the drug induced constipation associated with FGIDs symptoms.

Biomarker Analyses in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Treated with Crovalimab and Eculizumab: Results from the Phase III Randomized COMMODORE 2 Trial

Introduction PNH is a hematopoietic stem cell disorder characterized by hemolytic anemia, hemoglobinuria, and increased risk of thromboembolic events, and is associated with bone marrow failure. Crovalimab (crova) is a novel complement C5 inhibitor engineered with recycling technology, with a long half-life and high solubility that enables low-volume subcutaneous (SC) administration every 4 weeks (q4w). The global Phase III COMMODORE 2 study (NCT04434092) in C5 inhibitor-naive patients (pts) with PNH demonstrated non-inferiority of crova vs eculizumab (ecu) for hemolysis control, transfusion avoidance, breakthrough hemolysis, and hemoglobin stabilization, and a safety profile that was consistent between crova and ecu (Röth EHA 2023; #S181). Here we report results of the exploratory biomarker analyses in COMMODORE 2. Study Design and Methods In COMMODORE 2, C5 inhibitor-naive pts were randomized 2:1 to receive a weight-based tiered crova regimen or ecu. Regimens included loading doses, followed by maintenance dosing (crova: SC injection q4w; ecu: intravenous infusion every 2 weeks). Co-primary efficacy endpoints were proportion of pts with hemolysis control (central lactate dehydrogenase [LDH] ≤1.5×upper limit of normal [ULN]) from Week (W)5 through W25 and proportion of pts with transfusion avoidance from baseline through W25. Exploratory biomarker analyses included terminal complement activity per 50% hemolytic complement (CH50) liposome immunoassay, free hemoglobin, additional exploration of LDH levels, and flow cytometry of the PNH clone size/C3d levels. Additional descriptive analyses of hemoglobin data compared pts with and without transfusions. All biomarker data were assessed from baseline to W25. Results Data forCH50 and LDH were available for all 204 randomized pts (crova: 135; ecu: 69) and data for free hemoglobin, PNH clone size and C3d were available for 126 pts (crova: 85; ecu: 41). At baseline, mean (standard deviation [SD]) LDH levels were 7.6×ULN (3.4) in crova pts and 7.8×ULN (3.5) in ecu pts. 77% of crova pts and 74% of ecu pts had ≥1 packed red blood cell transfusion ≤12 months before screening. 39% of crova pts and 38% of ecu pts had a history of aplastic anemia; 4% and 9% had myelodysplastic syndrome, respectively. Inhibition of complement activity (per CH50) to below the lower limit of quantification was reached at W2 (first post-dose pharmacodynamic sample) in 93% and 46% of pts in the crova and ecu arms, respectively, and in 90% and 73% at W25 (post-dose) (Figure). With regards to intravascular hemolysis markers, the proportion of pts with LDH ≤1.5×ULN was 81% at W5 and 78% at W25 in crova pts, and 84% at W5 and 77% at W25 in ecu pts. Free hemoglobin, another intravascular hemolysis marker, showed a similar initial decrease from baseline in both arms; however, crova pts consistently showed numerically lower levels than ecu pts from W13 to W25. Mean (SD) increase in hemoglobin level from baseline to W25 was 1.2 g/dL (2.0) in the crova arm (baseline: 8.7 g/dL [1.4]) and 0.8 g/dL (1.9) in the ecu arm (baseline: 8.9 g/dL [1.4]). In both arms, a greater increase in mean hemoglobin level from baseline was observed in pts who achieved transfusion avoidance vs those requiring ≥1 transfusion up to W25 (crova: 1.7 g/dL [SD, 1.8; n=88] vs 0.2 g/dL [SD, 1.9; n=40]; ecu: 1.3 g/dL [SD, 1.6; n=47] vs −0.4 g/dL [SD, 2.1; n=20]). Both arms showed a similar increase from baseline to W25 in the mean (SD) percentage of C3d-positive PNH erythrocytes (crova: 0.7 [1.5] at baseline to 20.8 [19.1] at W25; ecu: 0.6 [0.9] to 22.3 [15.0]). Conclusions Treatment with crova or ecu reduced terminal complement activity effectively, with a higher proportion of crova than ecu pts having undetectable terminal complement activity. However, this did not translate into significant differences in other biomarkers (LDH and free hemoglobin) or in the clinical efficacy between crova and ecu arms. Hemoglobin levels increased in both crova and ecu arms. This improvement was more pronounced in pts not receiving a transfusion from baseline to W25; additional analysis is needed to elucidate the impact of bone marrow failure status. Similar increases in C3d level in each arm were expected, as this is a C5 inhibitor class phenomenon. Overall, biomarker data from COMMODORE 2 support the non-inferior efficacy of crova vs ecu in patients with PNH. Further analyses correlating additional biomarkers with clinical outcomes is warranted.

Randomized Double-blind Sham-controlled Trial of a Novel Silicone-filled Endoscopically Placed Device for Weight Loss

Background and AimsAlthough obesity affects over 40% of adults in the United States and is a driver of preventable chronic diseases and health care costs, most patients are left untreated. MethodsThis was a randomized, double-blind, sham-controlled trial to investigate the safety and efficacy of a novel, endoscopically placed intragastric device for weight reduction, the TransPyloric Shuttle, implanted for 1 year in 270 patients with Class I and II obesity. An additional 32 treatment patients were enrolled in an Open-Label group. The co-primary efficacy endpoints were percent total body weight loss (%TBWL) in the Treatment group compared with the Sham group and a proportion of treatment patients achieving ≥5% TBWL at 12 months. ResultsThe mean %TBWL at 12 months was 9.5% (95% CI, 8.2-10.8) in the Treatment group (n = 181) compared with 2.8% (95% CI, 1.1-4.5) in the Sham group (n = 89). In the Treatment group, 67.0% (95% CI, 59.3-74.4) of patients achieved ≥5% TBWL compared with 29.3% (95% CI, 19.3-39.4) in the Sham group. Patients in the Treatment group achieved lower blood pressure, total cholesterol, and low-density lipoprotein cholesterol compared with the Sham group. Early withdrawals occurred in 22% and 11% patients in the Treatment and Sham groups, respectively. Device- or procedure-related serious adverse events occurred in 6 patients (2.8%), and no deaths occurred. ConclusionTreatment with a novel endoscopically placed intragastric device resulted in meaningful weight loss and improvement in cardiometabolic outcomes in patients with Class I and II obesity (ClinicalTrials.gov number NCT02518685).

Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis.

Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio 0.86; 95% confidence interval 0.75-0.98; P = .029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (rate ratio 0.87; 95% confidence interval 0.75-1.01; P = .076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well tolerated. In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality.

ULIPRISTAL ACETATE VERSUS PLACEBO FOR FIBROID TREATMENT

Background: The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain. Methods: We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of &gt;100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to &gt;500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of &lt;75) and reduction of fibroid volume at week 13, after which patients could undergo surgery. Results: At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, and 19% of those receiving placebo (P&lt;0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were −21%,, and +3% (P = 0.002 for the comparison of 5 mg of ulipristal acetate with placebo. Serious adverse events occurred in one patient during treatment with 5 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo. Conclusions: Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids.

ULIPRISTAL ACETATE VERSUS PLACEBO FOR FIBROID TREATMENT

Background: The efficacy and safety of oral ulipristal acetate for the treatment of symptomatic uterine fibroids before surgery are uncertain. Methods: We randomly assigned women with symptomatic fibroids, excessive uterine bleeding (a score of &gt;100 on the pictorial blood-loss assessment chart [PBAC, an objective assessment of blood loss, in which monthly scores range from 0 to &gt;500, with higher numbers indicating more bleeding]) and anemia (hemoglobin level of ≤10.2 g per deciliter) to receive treatment for up to 13 weeks with oral ulipristal acetate at a dose of 5 mg per day (96 women) or 10 mg per day (98 women) or to receive placebo (48 women). All patients received iron supplementation. The coprimary efficacy end points were control of uterine bleeding (PBAC score of &lt;75) and reduction of fibroid volume at week 13, after which patients could undergo surgery. Results: At 13 weeks, uterine bleeding was controlled in 91% of the women receiving 5 mg of ulipristal acetate, and 19% of those receiving placebo (P&lt;0.001 for the comparison of each dose of ulipristal acetate with placebo). The rates of amenorrhea were 73%, and 6%, respectively, with amenorrhea occurring within 10 days in the majority of patients receiving ulipristal acetate. The median changes in total fibroid volume were −21%,, and +3% (P = 0.002 for the comparison of 5 mg of ulipristal acetate with placebo. Serious adverse events occurred in one patient during treatment with 5 mg of ulipristal acetate (uterine hemorrhage) and in one patient during receipt of placebo (fibroid protruding through the cervix). Headache and breast tenderness were the most common adverse events associated with ulipristal acetate but did not occur significantly more frequently than with placebo. Conclusions: Treatment with ulipristal acetate for 13 weeks effectively controlled excessive bleeding due to uterine fibroids and reduced the size of the fibroids.

Efficacy and safety of AZR-MD-001 selenium sulfide ophthalmic ointment in adults with meibomian gland dysfunction: A vehicle-controlled, randomized clinical trial

PurposeMeibomian gland dysfunction (MGD) is a chronic progressive disease with downstream effects on ocular signs and symptoms. AZR-MD-001 is a selenium sulfide ophthalmic ointment that was investigated as a potential treatment option for patients with MGD. MethodsA Phase 2, multi-center, double-masked, parallel group study was conducted across 29 sites, with 245 patients randomized 1:1:1 to AZR-MD-001 0.5%, AZR-MD-001 1.0% or vehicle applied to the lower eyelid, twice weekly. Patients were eligible for the trial if they presented with signs and symptoms of MGD. Co-primary efficacy endpoints were the changes from baseline in number of open glands (Meibomian Glands Yielding Liquid Secretion [MGYLS] score) and patient-reported ocular surface symptoms (Ocular Surface Disease Index [OSDI] total score) at Month 3. Efficacy outcomes were captured at Day 14, Month 1.5 and Month 3. Safety and tolerability were assessed for treatment-emergent adverse events (TEAEs). ResultsAZR-MD-001 0.5% (n = 82 patients) treatment resulted in significant improvements in MGYLS score, with patients experiencing an average increase from baseline of 4.2 and 2.4 open glands secreting meibum for the drug and vehicle, respectively (p < 0.001) and from baseline a mean OSDI total score improvement of 7.3 and 3.8 for the drug and vehicle, respectively (p < 0.05). Most TEAEs were mild and transient, with 3 serious adverse events (SAEs) reported with AZR-MD-001 (none related to study drug). ConclusionsCo-primary endpoints were met for AZR-MD-001 0.5% at Month 3, with a statistically significant improvement in the signs and symptoms of MGD. AZR-MD-001 was safe and well tolerated. Trial registrationClinicalTrials.gov Identifier: NCT03652051, ANZCTR Registration Number: AZ201801.

Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial.

Severe eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remains the most relapsed subtype of uncontrolled CRSwNP. CM310, a humanised anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits IL-4 and IL-13 signaling which underlying eosinophilic inflammation. This study aims to evaluate the efficacy and safety of CM310 in patients with severe ECRSwNP. A multicentre, randomised, double-blind, and placebo-controlled phase 2 clinical trial was conducted. 56 eligible adult patients with severe ECRSwNP were randomised 1:1 to receive subcutaneously either CM310 (300mg) or placebo every 2 weeks under the background therapy of mometasone furoate nasal spray (MFNS) for 16 weeks, with 8 weeks of follow-up. Coprimary endpoints included the changes from baseline in nasal polyp score (NPS) and nasal congestion score (NCS) at week 16. Key secondary endpoints included sinus Lund-Mackay CTscore, change in sinus volume occupied by disease, University of Pennsylvania Smell Identification Test score, 22-item Sino-nasal Outcome Test score, and total symptom score. Safety, pharmacodynamics, and changes in type 2 inflammation biomarkers were assessed. This study is registered with ClinicalTrials.gov, NCT04805398. Between April 6, 2021, and March 18, 2022, 27 patients respectively in both the CM310 and placebo groups completed the study. Findings suggested that CM310 improved the coprimary efficacy endpoints of decreasing nasal polyp size and alleviating nasal congestion compared with the placebo. Least squares (LS) mean differences (CM310 vs placebo) of change from baseline in NPS and NCS at week 16 were-2.1 (95% CI-2.9,-1.4; p<0.0001) and-0.9 (95%CI-1.4,-0.5; p<0.0001), respectively. Sinus CT scan revealed that Lund-Mackay CT score (LS mean difference [95%CI]-7.6, [-9.4,-5.8]; p<0.0001) and sinus volume occupied by disease (LS mean difference [95% CI]-37%, [-47%,-28%]; p<0.0001) were significantly improved with CM310 compared with placebo. In addition, CM310 significantly relieved the daily symptoms of patients with CRSwNP and improved their quality of life reflected by the improvements in the TSS (-2.6 [95% CI-3.5,-1.6]), UPSIT (10.4 [95% CI 6.8, 14.0]) and SNOT-22 score (-19.1 [95% CI-29.8,-8.5]). Compared with placebo, CM310 administration significantly reduced type 2-related biomarkers including the serum TARC and total IgE, and tissue eosinophils. The most common adverse events were upper respiratory tract infection, blood cholesterol increased, and tinnitus, but none were considered drug-related. These findings support CM310 as an effective additional treatment option to the standard of care in patients with severe ECRSwNP. KeyMed Biosciences (Chengdu) Limited.