Double-blind Placebo-controlled Phase Research Articles

Healthcare Workers (HCWs) and non-HCWs reaction to Bacillus Calmette-Guérin (BCG) in the BATTLE trial

ObjectivesHealthcare workers (HCWs) may have different response to Bacillus Calmette-Guérin (BCG) vaccination due to previous occupational exposure to Mycobacterium particles. We report subgroup analysis of the BATTLE trial, comparing BCG effects in HCWs vs non-HCWs. This was a secondary analysis of a trial. MethodsThe BATTLE trial was a double-blind placebo-controlled phase III clinical trial that investigated BCG revaccinating adults who were recently infected with SARS-CoV-2 virus. BCG and placebo recipients were sub-grouped based on regular occupational contact with patients into HCWs (48 BCG and 50 placebo) and non-HCWs (124 BCG and 134 placebo). Weekly COVID-19 symptom progression and injection site reactions were compared between subgroups on weeks one, two, three, and six follow-ups. ResultsHCWs were more likely to complain of itching on the injection site early after injection (OR = 2.5, p = 0.049). They developed peeling and crusting on the site of injection faster than non-HCWs (during the second week, p = 0.033 and 0.040, OR = 3.3 and 2.7, respectively). HCWs were also more likely to maintain their papule or develop a late onset pustule during later weeks (weeks four and six, p = 0.024 and 0.006, OR = 2.2 and 8.6, respectively). In terms of COVID-19 symptom progression, recovery from anosmia was more likely in the non-HCWs who received BCG (week six, pHolm’s corrected = 0.002, OR = 3.3). ConclusionHCWs’ local reaction to BCG injection was slightly more rapid and more intense, possibly due to their occupational exposure. BCG may also ameliorate COVID-19 induced inflammation and anosmia in non-HCWs but not HCWs. Therefore, HCWs might be less likely to benefit from BCG vaccination. ClinicalTrials.gov register number NCT04369794.

Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer

ObjectiveTo determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer. MethodsThe placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30). ResultsAfter 38 months’ median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66–1.06; p = 0.13); median OS was not estimable with atezolizumab versus 49.2 months with placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78–1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed ≥10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother. ConclusionsIncorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients.ClinicalTrials.gov registration: NCT03038100.

Retrospective observational study on the use of acetyl-l-carnitine in ALS

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case–control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46–3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10–0.71). For ALSFRS-R, a mean slope of − 1.0 was observed in treated subjects compared to − 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Successful treatment with avacopan (CCX168) in a pediatric patient with C3 glomerulonephritis.

C3 glomerulonephritis (C3GN) is a subtype of C3 glomerulopathy (C3G), characterized by dysregulation of the alternative pathway of complement and by dominant C3 by immunofluorescence on the kidney biopsy. There is no approved treatment for patients with C3G. Immunosuppressive drugs as well as biologics have been used with limited success. In recent decades, substantial advances in the understanding of the complement system have led to the development of new complement inhibitors. Avacopan (CCX168) is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a, one of the most potent pro-inflammatory mediators of the complement system. We describe a child with biopsy-proven C3GN treated with avacopan. She was enrolled in the ACCOLADE double-blind placebo-controlled Phase 2 study (NCT03301467), where during the first 26weeks she was randomized to receivean avacopan-matching placebo orally twice daily, while in the following 26weeks, the study was open-label and she received avacopan. After a wash-out period, she was restarted on avacopan through an expanded access program. In this case, use of avacopan in a pediatric patient with C3GN was safe and well tolerated. On avacopan, the patient was able to discontinue mycophenolate mofetil (MMF) while maintaining remission.

A randomized phase II clinical trial of talazoparib maintenance therapy in patients with triple-negative breast cancer who showed platinum-sensitivity on first- or second-line platinum-based chemotherapy: KCSG BR21-10.

TPS1132 Background: A potent PARP inhibitor, talazoparib, demonstrated superior clinical activity compared to standard chemotherapy in germline BRCA1/2-mutant advanced breast cancer patients. However, the role of talazoparib treatment in BRCA1/2 wild-type triple-negative breast cancer (TNBC) patients remains undefined, although high incidence of homologous recombination deficiency (HRD) is one of the major characteristics of the TNBC. Previous studies indicated clinical responsiveness to platinum agents is a useful surrogate for HRD that may predict favorable PARP inhibitor response. Here, we present a phase II study to test talazoparib maintenance therapy in germline BRCA1/2 mutation unselected advanced TNBC patients after platinum-based chemotherapy. Methods: The KCSG BR21-10 study (NCT04755868) is a randomized double-blind placebo-controlled phase II clinical trial of talazoparib maintenance therapy in metastatic TNBC patients whose tumor showed platinum-sensitivity to first- or second-line platinum-based chemotherapy. The criteria for platinum-sensitivity were set as follows: remaining complete response (CR), partial response (PR), or stable disease (SD) after 6 to 9 tri-weekly doses or 18 to 27 weekly doses of platinum-based chemotherapy. The eligible TNBC patients are enrolled to the trial after completion of platinum-based therapy and 1:1 randomized to receive talazoparib (once daily 1.0 mg) or placebo maintenance therapy. The patient with any germline BRCA1/2 mutation status is eligible, and randomization stratification factors include line of platinum-based chemotherapy, response to platinum-based chemotherapy, and germline BRCA1/2 mutation status. The talazoparib/placebo maintenance treatment is initiated within 8 weeks after the last platinum chemotherapy. At the time of progression of disease, unblinding can be performed and patients in placebo arm may be eligible for crossover to talazoparib single treatment. The primary endpoint is progression-free survival (PFS) after randomization by RECIST 1.1, and the key secondary endpoints are overall survival, PFS2, objective response rate, adverse events by CTCAE 5.0 criteria, and quality of life. We also planned exploratory study to find predictive biomarker by tumor tissue and blood analysis. The median PFS from the randomization is expected to be 3 months in the placebo maintenance arm and we expect that talazoparib maintenance will improve PFS with hazard ratio of 0.65. It is predicted that a total of 206 patients (103 patients in each arm) are required with the α of 0.05 and power of 0.8 (1-β) by two-sided test, considering monthly 3% dropout rate. Currently, 23 of planned 206 patients have been enrolled. Clinical trial information: NCT04755868 .

N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study

BackgroundNiemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code “IB1001-301”) for the chronic treatment of symptoms in adult and pediatric patients with NPC.MethodsThis multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments.DiscussionPre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders.Trial registrationsThe trial (IB1001-301) has been registered at www.clinicaltrials.gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021–005356-10). Registered on 20 December 2021.

Acetyl-L-Leucine for Niemann-Pick type C: A Multinational Double-blind Randomized Placebo-controlled Crossover Study (P14-11.001)

<h3>Objective:</h3> To assess the clinical efficacy (symptomatic and long-term) of N-acetyl-L-Leucine on symptoms of ataxia, functioning, and quality of life for patients with NPC. To evaluate the safety and tolerability of N-acetyl-L-leucine at 4 g/day in patients with NPC aged ≥4 years and older. Extension Phase Only: Characterize the pharmacokinetics of N-acetyl-L-leucine in NPC patients. <h3>Background:</h3> Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded Phase IIb clinical trial. <h3>Design/Methods:</h3> This multinational double-blind randomized placebo-controlled crossover Phase III study enrolls patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites (NCT05163288). Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. The Parent Study is followed by the 1-year Extension Phase. <h3>Results:</h3> The clinical trial has been initiated in July 2022. Twenty-one patients have been screened, 15 patients have been recruited. Approximately 53 patients will be enrolled, 46 patients will be analyzed according to the Intention to Treat (ITT). <h3>Conclusions:</h3> Given the lack of global symptomatic or disease-modifying therapies for NPC and other lysosomal diseases there is an urgent need for effective and well-tolerated drug treatments. This clinical trial was designed through a collaboration between National Regulatory Agencies, leading Clinical Experts, Patient Organizations, and the industry Sponsor. <b>Disclosure:</b> Dr. Bremova-Ertl has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Intrabio. The institution of Dr. Bremova-Ertl has received research support from InnoSuisse. Dr. Bremova-Ertl has received research support from Baasch-Medicus. Ms. Fields has received personal compensation for serving as an employee of IntraBio. Ms. Fields has stock in IntraBio. Ms. Fields has received intellectual property interests from a discovery or technology relating to health care. Dr. Martakis has nothing to disclose. Dr. Strupp has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for IntraBio. Dr. Strupp has received personal compensation in the range of $0-$499 for serving as a Consultant for AurisMedical. Dr. Strupp has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Dr. Strupp has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers. Dr. Strupp has stock in IntraBio.

Increasing Ecopipam Exposure Improves Yale Global Tic Severity Scale-Total Tic Scores (YGTSS-TTS) in Children and Adolescents with Tourette Syndrome (TS): Results from a Population Pharmacokinetic (popPK) Model-Based Simulation Using D1AMOND Trial Data (P5-9.007)

<h3>Objective:</h3> To develop popPK and exposure-response (E-R) models to characterize the relationship between ecopipam concentrations and efficacy as well as safety in children and adolescents (ages 6 to &lt;18 years) with TS. <h3>Background:</h3> Ecopipam is a first-in-class selective dopamine-1 receptor antagonist in development for TS. Results from the 12-week randomized, double-blind placebo-controlled phase 2b D1AMOND trial demonstrated 2 mg/kg/day ecopipam significantly reduced motor and phonic tics (YGTSS-TTS) and was well-tolerated. Understanding the PK of ecopipam and its active metabolite, the intrinsic/extrinsic factors affecting variability, and the relationships between exposure and efficacy/safety in TS are key to perform model-based simulations to ensure the optimal dose in TS. <h3>Design/Methods:</h3> In D1AMOND, a responder was defined as a ≥25% improvement in YGTSS-TTS. Logistic regression modeling was used to determine the relationship between responder status and exposure (area-under-the-curve, AUC) of ecopipam and its active metabolite (E+M) in children and adolescents with TS. <h3>Results:</h3> The steady-state (E+M) AUC exposure predicted clinical YGTSS-TTS responders at week 12. A 2-compartment model with first-order absorption and elimination described plasma concentration-time data for ecopipam and a 1-compartment model with first order elimination described the active metabolite concentration-time data. The final logistic regression model was based on the combined steady-state AUC for E+M as a univariate predictor for a clinical responder. The odds of ≥25% improvement in YGTSS-TTS increased near linearly by 6.8% for each 100 unit increase in E+M steady-state AUC. E-R modeling of safety parameters was not performed as there were not enough adverse events in the study to model. <h3>Conclusions:</h3> These data demonstrate a positive relationship between ecopipam exposure and efficacy in pediatric patients with TS. This study validates the D1AMOND trial ecopipam dosing and informed the posology for a confirmatory Phase 3 trial, currently recruiting patients. <b>Disclosure:</b> Dr. Freidy has received personal compensation for serving as an employee of Allucent. Dr. Pene Dumitrescu has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Allucent. Dr. Pene Dumitrescu has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for TEVA Pharmaceutics. Dr. Pene Dumitrescu has stock in GlaxoSmithkline. Dr. Schmith has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Emalex Biosciences. Dr. Schmith has received research support from Emalex BIosciences. The institution of Dr. Gilbert has received research support from NIMH. The institution of Dr. Gilbert has received research support from Emalex. The institution of Dr. Gilbert has received research support from Erydel. The institution of Dr. Gilbert has received research support from PTC Therapeutics. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Medical Second Opinion Expert with Teldoc/Advanced Medical. Dr. Gilbert has received personal compensation in the range of $5,000-$9,999 for serving as a Medical Expert with Department of Health and Human Services/Vaccine Injury Compensation Program. Atul Mahableshwarkar has received personal compensation for serving as an employee of Emalex Biosciences. Atul Mahableshwarkar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ecor1 Capital. Atul Mahableshwarkar has stock in Johnson &amp; Johnson. Dr. Dubow has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Paragon Biosciences. Dr. Dubow has stock in Avadel Pharmaceuticals. Dr. Cunniff has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Cunniff has stock in Harmony Biosciences. Dr. Cunniff has stock in Emalex Biosciences. Mr. Kim has received personal compensation for serving as an employee of Emalex Biosciences. Mrs. Miller has received personal compensation for serving as an employee of Emalex Biosciences. Mrs. Miller has stock in Emalex Biosciences. Dr. Wanaski has received personal compensation for serving as an employee of Paragon Biosciences. Dr. Wanaski has stock in Paragon Biosciences.

PD11-09 PROSPECTIVE RANDOMIZED TREATMENT OF ERECTILE DYSFUNCTION AFTER RADICAL PROSTATECTOMY WITH AUTOLOGOUS ADIPOSE-DERIVED REGENERATIVE CELLS

You have accessJournal of UrologyCME1 Apr 2023PD11-09 PROSPECTIVE RANDOMIZED TREATMENT OF ERECTILE DYSFUNCTION AFTER RADICAL PROSTATECTOMY WITH AUTOLOGOUS ADIPOSE-DERIVED REGENERATIVE CELLS Sabrina Toft Hansen, Sabrina Hansen, Charlotte Harken Jensen, Ditte Caroline Andersen, Per Damkier, Jens Ahm Sørensen, and Lars Lund Sabrina Toft HansenSabrina Toft Hansen More articles by this author , Sabrina HansenSabrina Hansen More articles by this author , Charlotte Harken JensenCharlotte Harken Jensen More articles by this author , Ditte Caroline AndersenDitte Caroline Andersen More articles by this author , Per DamkierPer Damkier More articles by this author , Jens Ahm SørensenJens Ahm Sørensen More articles by this author , and Lars LundLars Lund More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003251.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We have previously reported safety and preliminary efficacy outcomes from a phase 1 clinical trial using autologous adipose-derived regenerative cells (ADRCs) to treat erectile dysfunction (ED) in 21 men after radical prostatectomy (RP). To further evaluate the effectiveness of the stem cell intervention, we here performed a randomized double-blind placebo-controlled phase 2 trial. METHODS: The trial was approved by The Danish National Committee on Health Research Ethics (60915) and included 70 men (58-67 years) with normal erectile function (EF) before robotic-assisted RP, and undetectable PSA levels at inclusion. Patients were randomized (35:35) to placebo or ADRC treatment using REDCap. The trial's primary endpoint was changes in EF using the International Index of Erectile Function 5 (IIEF-5) and Erection Hardness Score (EHS) questionnaires as an online survey at baseline, 1, 3, 6, and 12 months after treatment. The secondary endpoint was an objective measure of nocturnal erection at baseline and 6 months after treatment using RigiScan® that besides the frequency-, registers tumescence- (TAU) and rigidity (RAU) of erections at the base and tip of the penis during sleep. As a normal reference, RigiScan® -values from men of similar age and no ED were used. All 70 participants underwent liposuction of 200-360 ml from the abdominal subcutis and ADRCs were isolated using a Cytori Celution® System. Immediately after isolation, the patient received an injection into each corpus cavernosum of 2 ml with either Ringer`s lactate or ADRCs. RESULTS: The two groups were similar regarding age and comorbidity. Patient-reported outcome measures showed no statistical difference between groups in either the IIEF-5 or EHS scores at baseline, 1, 3, 6, or 12 months. RigiScan® evaluation following method validation and reference setting, showed that for each of the four RAU/TAU parameters, more patients in the treatment group had a response beneficial effect compared to the placebo group with tip TAU being significantly higher (46% vs 11%; p=0.0097). We observed that the probability for improvement in EF remained higher in the treatment group independent of the time between surgery and treatment. No severe adverse events related to the treatment were reported during the follow-up period. CONCLUSIONS: In conclusion, ADRCs had no measurable effect on IIEF-5 and EHS scores in this study. ADRCs injected into the corpora cavernosum had some effect as evaluated by Rigiscan®, which suggest a potential for ADRC in subgroups of patients despite negative clinical findings in this study. Source of Funding: Innovation Found Denmark © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e335 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sabrina Toft Hansen More articles by this author Sabrina Hansen More articles by this author Charlotte Harken Jensen More articles by this author Ditte Caroline Andersen More articles by this author Per Damkier More articles by this author Jens Ahm Sørensen More articles by this author Lars Lund More articles by this author Expand All Advertisement PDF downloadLoading ...

Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials.

Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13. To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Patients who responded to lebrikizumab 250 mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250 mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period. After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity. After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data.

Abstract OT3-26-01: CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER)

Abstract Background: The PI3K/AKT/mTOR pathway is a rational target in the metastatic disease setting for hormone receptor positive breast cancer based on preclinical and clinical data demonstrating that pathway inhibition improves outcome (Baselga 2012, Andre 2019, Jones 2019). Combining fulvestrant and AKT inhibition demonstrated efficacy in pts with HR+aBC (Howell 2022). Ipatasertib is a potent, highly selective, small-molecule inhibitor of three isoforms of serine/threonine kinase AKT. We hypothesize that Ipatasertib plus fulvestrant will improve PFS compared to fulvestrant in the second line setting post disease progression on aromatase inhibitor (AI) + CDK 4/6 inhibitor therapy. Methods: MA40 is a double blind, placebo-controlled trial in patients with hormone receptor positive, HER2-negative breast cancer with prior progression on AI plus CDK4/6 inhibitor therapy. Patients are randomized to fulvestrant/ipatasertib 400 mg po days 1-21 every 28 day or fulvestrant/placebo. The primary objective is to compare Progression Free Survival (PFS) between arms (RECIST 1.1, investigator assessed). Secondary objectives include comparisons between arms: PIK3CA/AKT1/PTEN altered cohort and non-altered cohorts; PFS by Blinded Central Radiology Review (all enrolled patients, PIK3CA/AKT1/PTEN altered and non-altered cohorts), Response rate; Duration of Response; Clinical Benefit Rate; Overall Survival; Time to Commencement of Subsequent Line of Systemic Therapy or Death; Safety and Tolerability (CTCAE version 5.0); QOL (EORTC QLQ-C30, NCI PRO-CTCAE); Economic Evaluation, (healthcare utilization and health utilities(EQ-5D-5L)). Statistical Design: Allocation 1:1 balanced for: PIK3CA/PTEN/AKT1 mutation status (ctDNA analysis using FoundationOne®Liquid Platform) (altered vs wildtype/unknown); prior treatment duration with CDK4/6 inhibitor (&amp;lt; 6 months vs &amp;gt; 6 months) and centre. Sample size is 250 to detect a benefit in PFS with the addition of ipatasertib. Eligibility Criteria: Histologically and/or cytologically confirmed ER positive and HER-2 negative breast cancer by local assessment that is advanced; postmenopausal status; clinical and/or radiographic progression during treatment with or within 28 days after discontinuation of first line of treatment with a CDK 4/6 inhibitor and an AI; only one prior line of chemotherapy in the advanced setting. Conduct to Date: Enrollment is ongoing. Supported by Hoffmann-La Roche Limited, CCS Citation Format: Stephen K. Chia, David W. Cescon, Andrew D. Redfern, Danielle Rodin, Christine Simmons, Jean-Pierre Ayoub, Haji Ibrahim Chalchal, Daniel Rayson, Moira Rushton-Marovac, Tracey Hay, Lisa Gallinaro, Bingshu Chen, Wendy Parulekar. CCTG MA40: DOUBLE-BLIND PLACEBO CONTROLLED PHASE III TRIAL OF FULVESTRANT AND IPATASERTIB FOR ADVANCED HER-2 NEGATIVE AND ESTROGEN RECEPTOR POSITIVE (ER+) BREAST CANCER POST FIRST LINE CDK 4/6 AND AROMATASE INHIBITOR THERAPY (FINER) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-26-01.

Safety and immunogenicity of the group B streptococcus vaccine AlpN in a placebo-controlled double-blind phase 1 trial

Group B streptococcus (GBS) is a leading cause of life-threatening neonatal infections and subsets of adverse pregnancy outcomes. Essentially all GBS strains possess one allele of the alpha-like protein (Alp) family. A maternal GBS vaccine, consisting of the fused N-terminal domains of the Alps αC and Rib (GBS-NN), was recently demonstrated to be safe and immunogenic in healthy adult women. To enhance antibody responses to all clinically relevant Alps, a second-generation vaccine has been developed (AlpN), also containing the N-terminal domain of Alp1 and the one shared by Alp2 and Alp3. In this study, the safety and immunogenicity of AlpN is assessed in a randomized, double-blind, placebo-controlled, and parallel-group phase I study, involving 60 healthy non-pregnant women. AlpN is well tolerated and elicits similarly robust and persistent antibody responses against all four Alp-N-terminal domains, resulting in enhanced opsonophagocytic killing of all Alp serotypes covered by the vaccine.

INTEGRATE IIa: A randomised, double-blind, phase III study of regorafenib versus placebo in refractory advanced gastro-oesophageal cancer (AGOC)—A study led by the Australasian Gastro-intestinal Trials Group (AGITG).

LBA294 Background: AGOC has limited options after second-line therapy. Regorafenib (Rego), an oral multi-targeted tyrosine kinase inhibitor (TKI) targeting angiogenic, stromal and oncogenic receptor TKs, prolonged progression free survival (PFS) versus placebo (PBO) across all regions/subgroups in the INTEGRATE phase 2 randomised trial (JCO 2016 43(23):2728-2735). INTEGRATE IIa was designed to examine if Rego improves overall survival (OS). Methods: Double-blind placebo-controlled phase 3 trial comparing Rego + best supportive care (BSC) vs PBO + BSC using 2:1 randomisation, stratified by tumour location (GO junction vs gastric), geographic region (Asia vs rest of world), prior VEGF inhibitors (Y/N). Eligibility criteria: histologically/cytologically confirmed AGOC, evaluable metastatic/locally advanced disease, failure/intolerance of ≥ 2 prior lines of therapy with a platinum agent + fluoropyrimidine. Primary objective: OS in the whole study population. OS among Asian sub-population is a key secondary objective. Target of at least 221 events from 250 patients provides 80% power to detect an OS hazard ratio (HR) of 0.67. Pooled OS analysis incorporating INTEGRATE phase 2 data is also planned. Secondary endpoints include PFS, objective response rate, safety and quality of life. Results: 251 patients enrolled (Oct16 - Sep21) from 5 countries:157 from Asia (Korea, Taiwan, Japan);169 Rego and 82 PBO. After 238 events, median OS (in months) for Rego vs PBO was 4.5 vs 4.0 (HR 0.70 [95%CI: 0.53 to 0.92]; p = 0.011) in the whole study population, with a 12 mo survival of 19% vs 6%. Median PFS was 1.8 v 1.6 (HR = 0.52; [95%CI: 0.40-0.69]; p = &lt; .0001). After pre-planned adjustment for multiplicity, there were no statistically significant differences across regions (Asia versus non-Asia) or other pre-specified subgroups. Pooled analysis median OS was 5.0 v 4.1 (HR 0.69 [95% CI:0.56 to 0.87]; p = 0.001). Rego toxicity was similar to previously reported. Conclusions: Rego improves survival compared with PBO in advanced refractory AGOC, offering a new treatment option. This result creates a therapeutic platform for combination studies. INTEGRATE IIb is an ongoing international randomised Phase 3 trial in pre-treated patients with AGOC comparing Rego + nivolumab to standard chemotherapy (NCT0487936). Clinical trial information: NCT02773524 .

338 Laboratory safety from a 16-week phase 3 study of dupilumab in patients aged 6 months to 5 years with moderate-to-severe atopic dermatitis

Abstract Many systemic therapies used for moderate-to-severe atopic dermatitis (AD) have immunosuppressive properties and necessitate laboratory screening and monitoring, adding to the treatment burden. Previous dupilumab studies in adults, adolescents and children aged 6–11 years with moderate-to-severe AD showed no clinically meaningful adverse changes in laboratory parameters. Here we evaluate hematology and chemistry laboratory safety data for dupilumab-treated children aged 6 months to 5 years with moderate-to-severe atopic dermatitis. Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (NCT03346434 part B), a randomized, double-blind placebo-controlled phase 3 study. 162 patients were randomized to either dupilumab 200/300 mg every 4 weeks (q4w; N = 83; baseline weight ≥5 &amp;lt;15 kg: 200 mg; ≥15 to &amp;lt;30 kg: 300 mg) or placebo (N = 79) for 16 weeks. From Day –14, all patients initiated standardized treatment with low-potency topical corticosteroids. Laboratory data was collected at baseline, weeks 4 and 16. At baseline, mean (SD) counts of hematology parameters were similar in both treatment groups: haemoglobin (dupilumab: 129.4 gL−1 [12]; placebo: 127.2 gL−1 [11.4]), lymphocyte (dupilumab: 4.6 × 109 L−1 [1.8]; placebo: 4.5 × 109 L−1 [1.7]), basophil (dupilumab: 0.07 × 109 L−1 [0.03]; placebo: 0.07 × 109 L−1 [0.04]), platelet (dupilumab: 397.7 × 109 L−1 [103.2]; placebo: 385.6 × 109 L−1 [112.9]) and eosinophils (dupilumab: 1.1 × 109 L−1 [0.7]; placebo: 1.1 × 109 L−1 [0.7]). Mean (SD) haemoglobin count in the dupilumab (128.4 × gL−1 [11]) and placebo groups (128.2 × gL−1 [11.2]), lymphocyte count in the dupilumab (4.20 × 109 L−1 [2.06]) and placebo groups (4.29 × 109 L−1 [1.52]) and basophil count in the dupilumab (0.07 × 109 L−1 [0.04]) and placebo groups (0.06 × 109 L−1 [0.03]) remained with the normal reference range for this population at week 16. The mean change (SD) in platelet count at week 16 was −16.3 × 109 L−1 (78.5) in the dupilumab group and +17.4 × 109 L−1 (106.6) in the placebo group. In the dupilumab treatment group, the mean eosinophil count increased at week 4 (mean change from baseline [SD]; + 0.48 × 109 L−1 [1.8]) and trended downward by week 16 (+0.31 × 109 L−1 [1.4]) while minimal changes were noted in the placebo group at week 4 (0.1 × 109 L−1 [0.7]) and week 16 (−0.2 × 109 L−1 [0.7]). The values for creatine kinase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, albumin and protein at week 16 remained within the normal reference range in all treatment groups. Two patients in the dupilumab 200/300 mg q4w arm of this study reported treatment-emergent adverse events of severe and moderate eosinophilia. Neither event was associated with clinical symptoms nor led to the discontinuation of the study treatment. No clinically meaningful changes in hematology and chemistry parameters in children aged 6 months to 5 years with moderate-to-severe AD were seen with 16 weeks of dupilumab treatment. These data demonstrate that, as with adults, adolescents and older children, routine laboratory monitoring is unnecessary in this younger population. Dupilumab was generally well tolerated with an acceptable safety profile.

329 Efficacy and safety of dupilumab treatment with concomitant topical corticosteroids in children aged 6 months to 5 years with severe atopic dermatitis

Abstract There are limited approved systemic treatment options for children with atopic dermatitis (AD). Dupilumab is now approved in the United States for patients 6 months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies. European Medicines Agency is evaluating the use of dupilumab in children aged 6 months through 5 years with severe AD only. To report the efficacy and safety of dupilumab in the subgroup of children aged 6 months to 5 years with severe AD (IGA score = 4) at baseline in the LIBERTY AD PRESCHOOL trial (NCT03346434 part B). Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (part B), a randomized, double-blind placebo-controlled phase 3 study. Patients were randomized to either dupilumab 200/300 mg every 4 weeks (200 mg if baseline weight 5 to &amp;lt;15 kg, 300 mg if 15 to &amp;lt;30 kg) or placebo for 16 weeks. All patients initiated standardized treatment with low-potency topical corticosteroids (TCS) from day –14. This analysis reports efficacy and quality-of-life endpoints including a 75% reduction from baseline in the Eczema Area and Severity Index (EASI-75), Peak-Pruritus Numerical Rating Scale (PP-NRS), Children’s Dermatology Life Quality Index (CDLQI, for children aged 4 to &amp;lt;6 years), and Infant’s Dermatitis Quality Of Life (IDQOL, for children &amp;lt;4 years) in children with severe AD. Of the total trial population of 162 patients with moderate-to-severe AD, 125 patients with severe AD at baseline were randomized: 63 to the dupilumab + TCS treatment group and 62 to the placebo + TCS treatment group. Baseline demographics were similar. Mean (SD) baseline disease characteristics were also similar between the dupilumab and placebo groups: EASI (38.8 [13.7] vs. 35.4 [12]), body surface area (63.1% [21] vs. 58.9% [21.4]), weekly average PP-NRS (7.6 [1.4] vs. 7.6 [1.6]), CDLQI (17.5 [5.5] vs. 17.8 [6.4]) and IDQOL (18.4 [5.1] vs. 17.4 [5.4]). Dupilumab treatment resulted in a rapid and significant increase in the proportion of patients achieving EASI-75 compared with placebo treatment by week 4 (27% vs. 4.8%; P = 0.0009). By week 16, this improvement was further increased compared with the placebo group (46% vs. 7%; P &amp;lt; 0.0001). At week 16, dupilumab-treated patients had a significantly greater percent reduction from baseline in PP-NRS compared with the placebo group (LS mean (SE)–41.8 [5.4] vs. 0.5 [5.4]; P &amp;lt; 0.0001). Dupilumab also resulted in significant improvement in quality-of-life outcomes compared with placebo (LS mean [SE]) change from baseline to week 16 in CDLQI (−9.1 [1.1] vs. −2.6 [1.2]; P &amp;lt; 0.0001); IDQOL (−9.1 [1.3] vs. −0.6 [1.1]; P &amp;lt; 0.0001). Treatment-emergent adverse events (TEAEs) were reported in 42 (66.7%) patients in the dupilumab group and 45 (73.8%) patients in the placebo group. Most TEAEs were mild to moderate and deemed unrelated to the study drug by the investigator. The most common TEAE was atopic dermatitis in both the dupilumab group (10 [15.9%]) and placebo group (16 [26.2%]). Additionally, TEAEs in the conjunctivitis cluster were reported by 4 (6.4%) patients in the dupilumab group and none in the placebo group. In the placebo group, 3 (4.9%) serious adverse events were reported. No dupilumab-related adverse events were serious or led to treatment discontinuation. Dupilumab significantly improved AD signs, symptoms, and quality of life in children aged 6 months to 5 years with severe AD. The safety profile was consistent with that previously seen in adults, adolescents, and children aged &amp;gt; 6 years of age.

Pathogenetic therapy of cognitive impairment: results of a multicenter placebo-controlled clinical trial of the efficacy and safety of Miladean

Evaluation of the efficacy and safety of the use of the drug Miladean in the treatment of patients with cognitive disorders (CDs) of vascular genesis. In during the double-blind multicenter prospective randomized placebo-controlled phase III clinical trial, 300 patients with CDs and chronic cerebral ischemia were randomized into 3 groups: group 1 (n=100) received Miladean (daily dose: memantine 10 mg + melatonin 6 mg), group 2 (n=101) - memantine (10 mg/day), group 3 - placebo (n=99) for 8 weeks. The dynamics of the overall score (the primary criterion of effectiveness) and the proportion of patients with improvement on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog), the dynamics of visual-spatial orientation disorders (Benton test), sleep quality (Pittsburgh Sleep Quality Index scale) and the safety of therapy were evaluated. Miladean demonstrated efficacy in the treatment of CDs: a statistically and clinically significant decrease in the overall score on the ADAS-Sod scale was shown (by 6.1 versus 4.7 and 3.5 points in the 2nd (p=0.009) and 3rd (p<0.05) groups) and an increase in the proportion of patients (96.9%) with clinically and statistically a significant improvement compared to the 2nd and 3rd groups (p=0.019 and p<0.001 respectively). Miladean significantly improved the performance in the Benton test (1.20±1.66 vs. 0.64±1.69 points in group 3, p=0.026) and sleep quality (84.7% of patients with CDs), compared to placebo (63.9%) and memantine (64.3%) (p=0.002 in both cases). Miladean was well tolerated, there were no cases of interaction with basic therapy drugs. The combination of many different pathogenetic effects of Miladean suggests that it has the ability to slow down the rate of progression of CDs and stabilize the condition of patients. The unique combination of active substances in Miladean has been proven to be effective and safe in the treatment of patients with CDs.

Vivacity MG Phase 3 Study: Clinical Trial of Nipocalimab Administered to Adults With Generalized Myasthenia Gravis

Objective We describe Vivacity-MG3. our pivotal Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics (PK), and Pharmacodynamics (PD) of Nipocalimab Administered to Adults With gMG (NCT04951622). Background Nipocalimab is a high affinity, fully human, aglycosylated, effectorless IgG1 anti FcRn monoclonal antibody that targets the neonatal Fc receptor (FcRn) with high affinity, thereby lowering IgG pathogenic antibodies in autoimmune disease. Data from Vivacity-MG, a Phase 2 randomized placebo-controlled study of nipocalimab in adult generalized myasthenia gravis (gMG), demonstrated safety, tolerability, and efficacy of nipocalimab (clinicaltrials.gov NCT03772587). Design/Methods This global study will enroll approximately 180 participants with gMG, aged 18 and older, with an insufficient clinical response to ongoing, stable standard-of-care therapy, as reflected by a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of &gt;/= to 6 at screening and baseline, and a Myasthenia Gravis Foundation of America (MGFA) Class of IIa/b–IVa/b at screening. The study will consist of a screening period of up to 4 weeks, a 24-week double-blind placebo-controlled phase where participants will be randomly assigned in a 1:1 ratio to receive either placebo or nipocalimab intravenously every two weeks, and an open label extension phase of variable duration. The primary outcome is the average change in MG-ADL score from baseline to weeks 22, 23 and 24 of the double-blind placebo-controlled phase. Results Study enrollment began in July 2021 and is ongoing. Conclusions The ongoing Vivacity MG Phase 3 study will assess the efficacy, safety, and PK/PD of Nipocalimab in adult gMG.

Study Protocol for a Randomized Double-blind Placebo-controlled Phase 2 Clinical Trial to Assess Anti-inflammatory Effect of Colchicine (DRC3633) in Mild to Moderately Severe COVID‒19 Patients (DRC-06C)

Study Protocol for a Randomized Double-blind Placebo-controlled Phase 2 Clinical Trial to Assess Anti-inflammatory Effect of Colchicine (DRC3633) in Mild to Moderately Severe COVID‒19 Patients (DRC-06C)

Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women

Objective This study aimed to determine the effects of estetrol (E4) on hemostasis, lipids, carbohydrate metabolism and bone turnover in postmenopausal women. Methods This study was a multicenter, randomized, double-blind placebo-controlled phase 2 trial. Participants (n = 180, age 43–64 years) received E4 2.5 mg, 5 mg, 10 mg and 15 mg or placebo once daily for 12 weeks. Changes from baseline at week 12 were evaluated versus placebo for hemostasis parameters, sex hormone binding globulin (SHBG), lipids, carbohydrate metabolism and bone markers. Results Changes for hemostasis parameters were minimal with a small increase only in the normalized activated protein C sensitivity ratio in the E4 15 mg group versus placebo. SHBG increased in the E4 5 mg, 10 mg and 15 mg groups versus placebo. High-density lipoprotein cholesterol increased in all E4 groups; changes were not consistent for other lipids. Significant decreases versus placebo were seen for insulin resistance (E4 10 mg group), hemoglobin A1c (E4 15 mg group) and type 1 collagen C-terminal telopeptide (E4 10 mg and 15 mg groups). Small decreases in osteocalcin in the E4 5 mg, 10 mg and 15 mg groups were significant versus the increase observed in placebo. Conclusion E4 had limited impact on hemostasis and potentially beneficial effects on lipids, carbohydrate metabolism and bone turnover.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: The REALIZE study.

BackgroundA tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs.MethodsThis randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion).ResultsForty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group.DiscussionThis is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies.Clinical Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).