scholarly journals 1174. Phase 2 STRIVE Clinical Trial of Rezafungin for Treatment of Candidemia and/or Invasive Candidiasis Demonstrates Consistent Trough Concentrations Across Diverse Patient Populations

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S612-S613
Author(s):  
Shawn Flanagan ◽  
Christopher M Rubino ◽  
Taylor Sandison
Keyword(s):  
Body Weight ◽  
Invasive Candidiasis ◽  
Fungal Infections ◽  
Standard Of Care ◽  
Geographic Region ◽  
Continuous Variables ◽  
Phase 2 ◽  
Double Blind ◽  
Wide Range ◽  
Diverse Patient Populations

Abstract Background Rezafungin is a novel echinocandin antifungal in development for treatment as well as prevention (prophylaxis) of invasive fungal infections. STRIVE (NCT02734862) is a global, randomized, double-blind, placebo-controlled, Phase 2 trial evaluating safety and efficacy of IV rezafungin once weekly (QWk) for treatment of candidemia and/or invasive candidiasis compared with standard-of-care (IV caspofungin once daily with optional oral stepdown). Here we report pharmacokinetic (PK) data from the completed STRIVE trial analyzed by patient demographics at baseline. Methods Rezafungin Day 8 trough (Cmin) concentrations from patients treated with rezafungin were summarized categorically by race (black or white), sex (male or female), and geographic region (North America [NA], or Europe [EU]), or plotted versus continuous variables of age, body weight, body mass index (BMI), and body surface area (BSA). As the first dose of rezafungin was 400 mg for all rezafungin-treated patients, data from both dose groups (Group 1: 400 mg QWk; Group 2: 400 mg in Week 1 followed by 200 mg QWk) were combined in this analysis. Results Rezafungin mean Cmin (SD) values were 1.8 (0.7) and 2.3 (1.2) in black and white patients, 1.9 (1.0) and 2.6 (1.2) in males and females, and 1.9 (0.6) and 2.4 (1.3) in patients from NA and EU. There were small differences in point estimates between the groups, but there was a great deal of overlap and the differences are not expected to be clinically meaningful (Figure). Similarly, no trends in Cmin values were observed across a range of ages (20-80 years), weights (~40-155 kg), BMI (~15-65 kg/m2), and BSA (~1.4-2.4 m2). Figure Conclusion No meaningful differences in rezafungin Cmin values were observed in patients grouped by sex, race, or geographic region, or across a wide range of patient factors, including age and body weight and size. These findings indicate that a single rezafungin dose regimen can be expected to provide consistent PK across diverse patient populations. Disclosures Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Christopher M. Rubino, PharMD, Institute for Clinical Pharmacodynamics, Inc. (Employee)Spero Therapeutics (Grant/Research Support) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

scholarly journals Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis

Neurology ◽  
2019 ◽  
Vol 92 (23) ◽  
pp. e2661-e2673 ◽  
Author(s):  
James F. Howard ◽  
Vera Bril ◽  
Ted M. Burns ◽  
Renato Mantegazza ◽  
Malgorzata Bilinska ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myasthenia Gravis ◽  
Vital Signs ◽  
Standard Of Care ◽  
Placebo Treatment ◽  
Phase 2 ◽  
Double Blind ◽  
Severity Scores ◽  
Quality Of Life Scale ◽  
Life Scale

ObjectiveTo investigate safety and explore efficacy of efgartigimod (ARGX-113), an anti-neonatal Fc receptor immunoglobulin G1 Fc fragment, in patients with generalized myasthenia gravis (gMG) with a history of anti-acetylcholine receptor (AChR) autoantibodies, who were on stable standard-of-care myasthenia gravis (MG) treatment.MethodsA phase 2, exploratory, randomized, double-blind, placebo-controlled, 15-center study is described. Eligible patients were randomly assigned (1:1) to receive 4 doses over a 3-week period of either 10 mg/kg IV efgartigimod or matched placebo combined with their standard-of-care therapy. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy (change from baseline to week 11 of Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Composite disease severity scores, and of the revised 15-item Myasthenia Gravis Quality of Life scale), pharmacokinetics, pharmacodynamics, and immunogenicity.ResultsOf the 35 screened patients, 24 were enrolled and randomized: 12 received efgartigimod and 12 placebo. Efgartigimod was well-tolerated in all patients, with no serious or severe adverse events reported, no relevant changes in vital signs or ECG findings observed, and no difference in adverse events between efgartigimod and placebo treatment. All patients treated with efgartigimod showed a rapid decrease in total immunoglobulin G (IgG) and anti-AChR autoantibody levels, and assessment using all 4 efficacy scales consistently demonstrated that 75% showed a rapid and long-lasting disease improvement.ConclusionsEfgartigimod was safe and well-tolerated. The correlation between reduction of levels of pathogenic IgG autoantibodies and disease improvement suggests that reducing pathogenic autoantibodies with efgartigimod may offer an innovative approach to treat MG.Classification of evidenceThis study provides Class I evidence that efgartigimod is safe and well-tolerated in patients with gMG.

scholarly journals Rezafungin versus Caspofungin in a Phase 2, Randomized, Double-Blind Study for the Treatment of Candidemia and Invasive Candidiasis- The STRIVE Trial

2020 ◽  
Author(s):  
George R Thompson ◽  
Alex Soriano ◽  
Athanasios Skoutelis ◽  
Jose A Vazquez ◽  
Patrick M Honore ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Double Blind Study ◽  
Phase 2 ◽  
Double Blind ◽  
Once Daily ◽  
Secondary Endpoints ◽  
Intent To Treat ◽  
Cure Rates ◽  
Treat Population

Abstract Background Rezafungin (RZF) is a novel echinocandin exhibiting distinctive pharmacokinetics/pharmacodynamics. STRIVE was a phase 2, double-blind, randomized trial designed to compare the safety and efficacy of RZF once weekly (QWk) to caspofungin (CAS) once daily for treatment of candidemia and/or invasive candidiasis (IC). Methods Adults with systemic signs and mycological confirmation of candidemia and/or IC were randomized to RZF 400 mg QWk (400 mg), RZF 400 mg on week 1 then 200 mg QWk (400/200 mg), or CAS 70 mg as a loading dose followed by 50 mg daily for ≤ 4 weeks. Efficacy assessments included overall cure (resolution of signs of candidemia/IC + mycological eradication) at day 14 (primary endpoint), investigator-assessed clinical response at day 14, and 30-day all-cause mortality (ACM) (secondary endpoints), and time to negative blood culture. Safety was evaluated by adverse events and ACM through follow-up. Results Of 207 patients enrolled, 183 were in the microbiological intent-to-treat population (~21% IC). Overall cure rates were 60.5% (46/76) for RZF 400 mg, 76.1% (35/46) for RZF 400/200 mg, and 67.2% (41/61) for CAS; investigator-assessed clinical cure rates were 69.7% (53/76), 80.4% (37/46), and 70.5% (43/61), respectively. 30-day ACM was 15.8% for RZF 400 mg, 4.4% for RZF 400/200 mg, and 13.1% for CAS. Candidemia was cleared in 19.5 and 22.8 hours in RZF and CAS patients, respectively. No concerning safety trends were observed; ACM through follow-up was 15.2% (21/138) for RZF and 18.8% (13/69) for CAS. Conclusions RZF was safe and efficacious in the treatment of candidemia and/or IC.

A randomized, double-blind, phase (Ph) III study of the irinotecan-based chemotherapy FOLFIRI plus ramucirumab (RAM) or placebo (PL) in patients (pts) with metastatic colorectal carcinoma (mCRC) progressive during or following first-line therapy with bevacizumab (BEV), oxaliplatin (OXALI), and a fluoropyrimidine (FP) (RAISE) (NCT01183780).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3634-TPS3634 ◽  
Author(s):  
Axel Grothey ◽  
Josep Tabernero ◽  
Philippe Rougier ◽  
Shaila Ballal ◽  
Heidi Crane ◽  
...  
Keyword(s):  
Performance Status ◽  
Geographic Region ◽  
Blood Collection ◽  
Vegf Receptor ◽  
Antitumor Effects ◽  
Ecog Performance Status ◽  
Human Colon Cancer ◽  
Double Blind ◽  
Line Therapy ◽  
Wide Range

TPS3634 Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in CRC. RAM is a fully human IgG1 monoclonal antibody that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In a preclinical study, antiangiogenic and antitumor effects were observed when DC101, an antibody that targets murine VEGFR-2, was administered to mice bearing human colon cancer xenografts. Antitumor activity for RAM has been demonstrated in a Ph I study in pts with solid tumors over a wide range of RAM dose levels and in a Ph II study with RAM + mFOLFOX-6 as 1st-line therapy in pts with mCRC. Methods: This ongoing, randomized, double-blind, placebo-controlled Ph III study includes mCRC pts with measurable or nonmeasurable disease and ECOG performance status of 0-1 who have experienced disease progression during or within 6 months following 1st-line therapy with BEV, OXALI, and any FP. Randomization is stratified by geographic region, KRAS status, and time to progression after initiation of 1st-line therapy. Pts are randomized 1:1 to either RAM 8 mg/kg or PL every 14 days. Pts in both arms receive FOLFIRI (irinotecan: 180 mg/m2, folinic acid: 400 mg/m2, 5-fluorouracil: 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46-48 hours). The primary endpoint is overall survival (OS). The sample-size estimate assumes 85% power to detect at least a 2.5-month median OS difference (HR = 0.8) between treatment arms with a 1-sided alpha of 0.025. Secondary endpoints include progression-free survival, tumor response, safety, pharmacokinetics, immunogenicity, and correlations between biomarkers and clinical outcome. CRC tissue and blood collection is mandatory for biomarker analyses. As of 05 January 2012, 238 of 1050 planned pts have been enrolled from 100 sites in North America, South America, Europe, Asia, and Australia.

Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4013-4013
Author(s):  
Yelena Y. Janjigian ◽  
Akihito Kawazoe ◽  
Patricio Eduardo Yanez ◽  
Suxia Luo ◽  
Sara Lonardi ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Standard Of Care ◽  
Geographic Region ◽  
Phase 3 ◽  
Two Phase ◽  
Double Blind ◽  
End Points ◽  
New Treatment ◽  
Ecog Ps

4013 Background: Trastuzumab (tras) plus chemotherapy (chemo) is standard-of-care (SOC) 1L therapy for HER2+ metastatic G/GEJ cancer. In two phase 2 studies, tras, chemo, and pembrolizumab (pembro) in combination showed promising efficacy and manageable safety. The ongoing global, randomized, double-blind, placebo-controlled phase 3 KEYNOTE-811 study is assessing whether adding pembro to SOC improves efficacy vs SOC alone for HER2+ metastatic G/GEJ cancer (NCT03615326). Methods: Eligible patients (pts) with previously untreated, unresectable or metastatic HER2+ G/GEJ cancer and ECOG PS 0 or 1 are randomized 1:1 to pembro 200 mg IV Q3W or placebo IV Q3W. All pts receive tras and investigator’s choice of 5-fluorouracil and cisplatin (FP) or capecitabine and oxaliplatin (CAPOX). Treatment is given up to 2 y or until intolerable toxicity or PD. Dual primary end points are PFS per RECIST v1.1 by blinded, independent central review (BICR) and OS. Secondary end points are ORR and DOR per RECIST v1.1 by BICR and safety. Planned enrollment in the global cohort is 692 pts; accrual is almost complete. The protocol-specified first interim analysis (IA1) was to occur when the first 260 pts enrolled had ≥8.5 mo of follow-up and tested whether pembro + SOC significantly improved ORR; the superiority boundary was P = 0.002. The ORR difference was calculated using the Miettinen and Nurminen method stratified by the randomization stratification factors of geographic region, PD-L1 status, and chemo choice. Efficacy is presented for the first 264 pts enrolled. Safety is presented for all treated pts enrolled as of Jun 17, 2020. Results: Among the first 264 pts enrolled, 133 were randomized to pembro + SOC, 131 to placebo + SOC; 0.8% had MSI-H tumors, CAPOX was chosen for 87.1%, and median study follow-up was 12.0 mo (range, 8.5-19.4). Confirmed ORR (95% CI) was 74.4% (66.2-81.6) for pembro + SOC vs 51.9% (43.0-60.7) for placebo + SOC (difference, 22.7 percentage points [95% CI, 11.2-33.7], P = 0.00006); CR rate was 11.3% vs 3.1% and DCR (95% CI) was 96.2% (91.4-98.8) vs 89.3 (82.7-94.0). Median (range) DOR was 10.6 mo (1.1+ to 16.5+) for pembro + SOC vs 9.5 mo (1.4+ to 15.4+) for placebo + SOC; KM estimates of DOR ≥6 mo and ≥9 mo were 70.3% vs 61.4% and 58.4% vs 51.1%. As of data cutoff, 433/434 enrolled pts were treated (217/217 pembro + SOC, 216/217 placebo + SOC). AEs were grade 3-5 in 57.1% of pts with pembro + SOC vs 57.4% with placebo + SOC, led to death in 3.2% vs 4.6%, and led to discontinuation of any drug in 24.4% vs 25.9%. Conclusions: Adding pembro to tras and chemo resulted in a substantial, statistically significant increase in ORR versus trastuzumab and chemo alone as 1L therapy for HER2+ metastatic G/GEJ cancer; responses were durable and safety was manageable. These initial data support pembro plus tras and chemo as a potential new treatment option for this population. Clinical trial information: NCT03615326.

scholarly journals A Phase 2, Randomized, Double-Blind, Multicenter Trial To Evaluate the Safety and Efficacy of Three Dosing Regimens of Isavuconazole Compared with Fluconazole in Patients with Uncomplicated Esophageal Candidiasis

2015 ◽  
Vol 59 (3) ◽  
pp. 1671-1679 ◽  
Author(s):  
J. Viljoen ◽  
N. Azie ◽  
A.-H. Schmitt-Hoffmann ◽  
M. Ghannoum
Keyword(s):  
Fungal Infections ◽  
Clinical Success ◽  
Multicenter Trial ◽  
Primary Treatment ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Once Daily ◽  
Esophageal Candidiasis ◽  
Dosing Regimens

ABSTRACTEsophageal candidiasis is a frequent cause of morbidity in immunocompromised patients. Isavuconazole is a novel, broad-spectrum antifungal developed for the treatment of opportunistic fungal infections. This phase 2 trial compared the efficacy and safety of three oral dosing regimens of isavuconazole with an oral fluconazole regimen in the primary treatment of uncomplicated esophageal candidiasis. The isavuconazole regimens were as follows: 200 mg on day 1 and then 50 mg once daily (arm A), 400 mg on day 1 and then 400 mg once-weekly (arm B), and 400 mg on day 1 and then 100 mg once daily (arm C). Patients in arm D received fluconazole at 200 mg on day 1 and then 100 mg once daily. The minimum treatment duration was 14 days. The primary endpoint was the rate of endoscopically confirmed clinical response at end of therapy. Safety and tolerability were also assessed. Efficacy was evaluated in 153 of 160 enrolled patients. Overall, 146 (95.4%) achieved endoscopically confirmed clinical success. Each of the isavuconazole regimens was shown to be not inferior to fluconazole, i.e., arm A versus D, −0.5% (95% confidence interval [CI] −10.0 to 9.4), arm B versus D, 3.5% (95% CI, −5.6 to 12.7), and arm C versus D, −0.2% (95% CI, −9.8 to 9.4). The frequency of adverse events was similar in arm A (n= 22; 55%), arm B (n= 18; 45%), and arm D (n= 22; 58%), but higher in arm C (n= 29; 71%). In summary, efficacy and safety of once-daily and once-weekly isavuconazole were comparable with once-daily fluconazole in the primary treatment of uncomplicated esophageal candidiasis.

scholarly journals Design and rationale of a randomized, double-blind, placebo-controlled, Phase 2/3 study to evaluate the safety and efficacy of dociparstat sodium (DSTAT) in adults with acute lung injury associated with severe COVID-19

2020 ◽  
Author(s):  
Joseph A. Lasky ◽  
Jyotsna Fuloria ◽  
Marion E. Morrison ◽  
Randall Lanier ◽  
Odin Naderer ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Critical Care ◽  
Standard Of Care ◽  
Bleeding Complications ◽  
Continuous Measure ◽  
Phase 2 ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Double Blind Placebo ◽  
Critical Care Units

Abstract Background: The COVID-19 Global Pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure, threaten to overrun hospital critical care units globally. New agents that can address the hyperinflammatory “cytokine storm” and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, including the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding complications compared to commercially available forms of heparin. Methods: This study is a randomized, double-blind, placebo-controlled, Phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care versus placebo, in adults with COVID-19 who require hospitalization and supplemental oxygen therapy. The Phase 2 portion will enroll 12 participants in each of two dose escalating cohorts, to confirm the safety of DSTAT in this population. Following a data monitoring committee review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, the Phase 3 portion of the study will enroll approximately 450 participants randomized 1:1 to DSTAT or placebo. The primary endpoint, agreed on by the US FDA, is the proportion of participants who survive and do not require mechanical ventilation through day 28. Discussion: Advances in standard of care regimens and the recent emergency use authorization of remdesivir and positive data with dexamethasone, has likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement of NIAID score will be essential to provide a more continuous measure of drug effect on recovery. Additional analysis of other endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble RAGE, D-dimer) will be performed at the conclusion of Phase 2 to further define the effect of DSTAT in patients hospitalized with COVID-19 infection. Trial Registration: ClinicalTrials.gov identifier NCT04389840, Registered 13 May 2020, https://clinicaltrials.gov/ct2/keydates/NCT04389840

scholarly journals Clinical trial design in phase 2 and 3 trials for pulmonary hypertension

2020 ◽  
Vol 10 (4) ◽  
pp. 204589402094149
Author(s):  
Sylvia Nikkho ◽  
Peter Fernandes ◽  
R. James White ◽  
Chunqin (CQ) Deng ◽  
Harrison W. Farber ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pulmonary Hypertension ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Phase 2 ◽  
Innovative Drug ◽  
Double Blind ◽  
Future Design ◽  
Wide Range ◽  
Double Blind Design

This article on clinical trial design incorporates the broad experience of members of the Pulmonary Vascular Research Institute’s (PVRI) Innovative Drug Development Initiative (IDDI) as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. It is increasingly clear that the design of phase 2 and 3 trials in pulmonary hypertension will have to diversify from the traditional randomised double-blind design, given the anticipated need to trial novel therapeutic approaches in the immediate future. This article reviews a wide range of differing approaches and places these into context within the field of pulmonary hypertension.

scholarly journals Design and rationale of a randomized, double-blind, placebo-controlled, Phase 2/3 study evaluating dociparstat in acute lung injury associated with severe COVID-19

2020 ◽  
Author(s):  
Joseph A. Lasky ◽  
Jyotsna Fuloria ◽  
Marion E. Morrison ◽  
Randall Lanier ◽  
Odin Naderer ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Critical Care ◽  
Standard Of Care ◽  
Supplemental Oxygen ◽  
Phase 2 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Critical Care Units ◽  
Soluble Rage ◽  
Novel Coronavirus

Abstract Introduction: The COVID-19 Global Pandemic caused by the novel coronavirus, SARS-CoV-2, and the consequent morbidity and mortality attributable to progressive hypoxemia and subsequent respiratory failure, threaten to overrun hospital critical care units globally. New agents that address the hyperinflammatory “cytokine storm” and hypercoagulable pathology seen in these patients may be a promising approach to treat patients, minimize hospital stays, and ensure hospital wards and critical care units are able to operate effectively. Dociparstat sodium (DSTAT) is a glycosaminoglycan derivative of heparin with robust anti-inflammatory properties, with the potential to address underlying causes of coagulation disorders with substantially reduced risk of bleeding compared to commercially available heparin. Methods: This study is a randomized, double-blind, placebo-controlled, Phase 2/3 trial to determine the safety and efficacy of DSTAT added to standard of care, in hospitalized adults with COVID-19 who require supplemental oxygen. Phase 2 will enroll 12 participants in each of two dose escalating cohorts, to confirm the safety of DSTAT in this population. Following review of the data, an additional 50 participants will be enrolled. Contingent upon positive results, Phase 3 will enroll approximately 450 participants randomized to DSTAT or placebo. The primary endpoint is the proportion of participants who survive and do not require mechanical ventilation through day 28. Discussion: Advances in standard of care, recent emergency use authorizations, and positive data with dexamethasone, has likely contributed to an increasing proportion of patients who are surviving without the need for mechanical ventilation. Therefore, examining the time to improvement in the NIAID score will be essential to provide a measure of drug effect on recovery. Analysis of additional endpoints, including supportive biomarkers (e.g., IL-6, HMGB1, soluble-RAGE, D-dimer) will be performed to further define the effect of DSTAT in patients with COVID-19 infection. Trial Registration: ClinicalTrials.gov identifier NCT04389840, Registered 13 May 2020, https://clinicaltrials.gov/ct2/keydates/NCT04389840

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