scholarly journals Dealing with competing risks in clinical trials: How to choose the primary efficacy analysis?

2018 ◽  
Vol 37 (19) ◽  
pp. 2787-2796
Author(s):  
James F. Troendle ◽  
Eric S. Leifer ◽  
Lauren Kunz
Keyword(s):  
Clinical Trials ◽  
Competing Risks ◽  
Primary Efficacy ◽  
Efficacy Analysis ◽  
Primary Efficacy Analysis

A Randomized Double-Blind Placebo-Controlled Study on Nadroparin for Prophylaxis of Thromboembolic Events in Cancer Patients Receiving Chemotherapy: The PROTECHT Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 6-6 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Gualberto Gussoni ◽  
Carlo Bianchini ◽  
Melina Verso ◽  
Maurizio Tonato
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Interim Analysis ◽  
P Value ◽  
Thromboembolic Events ◽  
Primary Efficacy ◽  
Double Blind ◽  
Thromboembolic Risk ◽  
Efficacy Analysis ◽  
Primary Efficacy Analysis

Abstract Background: Patients receiving chemotherapy (CHT) for cancer are at increased risk for thromboembolic events but clinical trials are required before any recommendations can be made about the use of antithrombotic prophylaxis in these patients. Patients and methods: A placebo-controlled, double-blind, multicenter, clinical outcome-based study (PROTECHT) was designed to evaluate the efficacy of the low molecular weight heparin nadroparin for prophylaxis of thromboembolic events in cancer patients receiving CHT. Patients with metastatic or locally advanced lung, breast, gastrointestinal (stomach, colon, rectum, pancreas), ovary or head and neck cancer with an ECOG performance status ≤2 were included in the study. Patients on adjuvant or neo-adjuvant CHT were excluded from the study. Eligible patients were randomized in a 2:1 ratio to receive subcutaneous injections of nadroparin, 3,800 anti-Xa IU once daily, or placebo. Treatment was started on the day of initiation of CHT (the first cycle or a new course) and planned for the overall duration of CHT or up to a maximum of 4 months. The primary study end-point was the composite of clinically overt venous or arterial thromboembolic events (deep vein thrombosis of the lower and upper limbs, visceral and cerebral venous thrombosis, pulmonary embolism, acute myocardial infarction, ischemic stroke, acute peripheral arterial thromboembolism, unexplained death of possible thromboembolic origin). Major bleeding was the main safety outcome measure. All study outcome events were evaluated by an independent Adjudication Committee unaware of treatment allocation. The results of one interim analysis of efficacy and two interim analyses of safety were reviewed by an independent Data and Safety Board. In the primary efficacy analysis the p value was adjusted for the interim analysis of efficacy. Results: The two treatment study groups were well balanced for demographic characteristics, cancer site and staging, CHT regimen and thromboembolic risk factors. The average study treatment duration was 90.3±41.2 and 93.9±39.8 days in the nadroparin and placebo groups, respectively. Overall, 1166 patients were randomized and 1150 received at least one dose of the study treatment (primary efficacy analysis and safety population). Cancer distribution was as follows: lung 279 patients (24.3%), colon 235 (20.4%), breast 165 (14.3%), ovary 143 (12.4%), stomach 98 (8.5%), rectum 87 (7.6%), pancreas 53 (4.6%), head and neck 36 (3.1%) and other 54 (4.7%). Sixteen of the 769 patients treated with nadroparin (2.1%) and 15 of the 381 patients treated with placebo (3.9%) had a thromboembolic event (interim-adjusted p value = 0.033, relative risk reduction 47.2%, NNT = 53.8). Venous thromboembolism accounted for 11 events in both the nadroparin and placebo patients. Fifteen of the thromboembolic events occurred in patients with lung cancer (4.0% and 8.8% in nadroparin and placebo patients, respectively; NNT = 22.7). Pancreatic cancer was associated with an overall rate of thromboembolic events of 7.5%. Five patients in the nadroparin group (0.7%) and none in the placebo group suffered a major bleeding (p= 0.177, NNH = 153.8). The incidence of minor bleeding was similar in the two treatment groups: 77 events in 57 patients (7.4%) and 38 events in 30 patients (7.9%) for nadroparin or placebo respectively. Conclusions: We conclude that nadroparin reduces the incidence of thromboembolic events in cancer patients receiving CHT. Future confirmatory studies should be focused on patients at high thromboembolic risk such as those with lung and pancreatic cancer.

scholarly journals Two Currently Recruiting Randomized Phase III Trials: COMMODORE 1 and 2 Evaluating Crovalimab Vs Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Current Anti-Complement Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4313-4313
Author(s):  
Austin G. Kulasekararaj ◽  
Antonio Risitano ◽  
Alexander Roeth ◽  
Guangsheng He ◽  
Jeffrey Pu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Phase Iii ◽  
Primary Efficacy ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Efficacy Analysis ◽  
To Receive ◽  
Primary Efficacy Analysis

Abstract Background Crovalimab is a novel anti-complement C5 antibody currently being studied as a treatment for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disease associated with hemolytic anemia and thrombosis. Treatment with approved C5 inhibitors eculizumab or ravulizumab is effective, but can be limited by breakthrough hemolysis due to unsustained C5 inhibition, inadequate efficacy in patients with C5 mutational variants, and the requirement of regular intravenous infusions. Crovalimab is unique in that its properties allow for subcutaneous injections once every 4 weeks (Q4W) that can be self-administered. Additionally, crovalimab binds to C5 mutational variants. Promising results were obtained in the Phase I/II COMPOSER trial (NCT03157635; Röth et al, Blood. 2020) conducted in patients with PNH, with or without prior anti-C5 treatment. The efficacy and safety of crovalimab vs eculizumab will be evaluated in two Phase III, randomized, open-label trials in patients with PNH, with or without current complement C5 inhibition. Study Design and Methods COMMODORE 1 (NCT04432584) will enroll patients who are currently receiving complement C5 inhibitor therapy. This trial is divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years can be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive eculizumab intravenous maintenance dosing from Day 1, Q2W for a total of 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab based on percentage change in lactate dehydrogenase levels from baseline, averaged over weeks 21, 23, and 25. Secondary efficacy objectives are to determine the proportion of patients who experience breakthrough hemolysis, achieve transfusion avoidance or hemoglobin stabilization, as well as determine mean change in fatigue according to the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire from baseline to Week 25. Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. COMMODORE 2 (NCT04434092) will enroll patients not currently treated with C5 complement inhibitors. This trial is also divided into two parts (Figure). Patients aged ≥ 18 years will be randomized 2:1 to receive either crovalimab (Arm A) or eculizumab (Arm B) and will contribute to the primary efficacy analysis. Patients aged < 18 years will be enrolled in an exploratory descriptive arm (Arm C). Arm A and C patients will receive crovalimab loading and subsequent subcutaneous Q4W maintenance dosing from Week 5. Arm B patients will receive induction doses of eculizumab intravenously QW for 4 weeks followed by maintenance dosing Q2W up to 24 weeks. Patients in Arm A and Arm C can continue to receive crovalimab, and patients in Arm B can switch to crovalimab, after 24 weeks of treatment, as determined by the treating physician. The primary efficacy objective is to determine the non-inferiority of crovalimab vs eculizumab, based on the proportion of patients who 1) achieve transfusion avoidance from baseline to Week 25 and 2) with hemolysis control from Week 5-25 (co-primary efficacy endpoints). Safety and tolerability of crovalimab vs eculizumab will also be evaluated along with pharmacokinetic, immunogenicity, biomarker, and health status utility objectives. Figure 1 Figure 1. Disclosures Kulasekararaj: F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Akari: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support. Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA Pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Jazz: Other: Lecture fees, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Roeth: Novartis: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Kira: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. He: LongBio Pharma: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd.: Consultancy. Pu: University of Arizona: Current Employment; Pennsylvania State University: Patents & Royalties; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Wright: Genentech, Inc.: Current Employment. Appius: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment. Sreckovic: F. Hoffmann-La Roche Ltd.: Current Employment. Stanzel: F. Hoffmann-La Roche Ltd.: Current Employment, Current equity holder in publicly-traded company. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Nishimura: Apellis: Consultancy; Novartis: Consultancy; Chugai: Consultancy; Sanofi: Consultancy; Alexion: Consultancy; Roche: Consultancy; Biocryst: Consultancy.

A phase 2 study of tislelizumab monotherapy in patients with previously treated, locally advanced unresectable ormetastatic microsatellite instability-high/mismatch repair deficient solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2569-2569
Author(s):  
Jian Li ◽  
Ye Xu ◽  
Aimin Zang ◽  
Yunong Gao ◽  
Quanli Gao ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Locally Advanced ◽  
Primary Efficacy ◽  
Phase 2 ◽  
Efficacy Analysis ◽  
Phase 2 Study ◽  
Previously Treated ◽  
Grade 3 ◽  
Tumor Types ◽  
Primary Efficacy Analysis

2569 Background: Tislelizumab is an anti-programmed cell death protein 1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. In early phase clinical studies, tislelizumab monotherapy was generally well tolerated and had antitumor activity in patients (pts) with solid tumors, including microsatellite instability-high (MSI-H) or mismatch-repair-deficient (dMMR) solid tumors such as colorectal cancer (CRC). Methods: This single-arm, multicenter, open-label, phase 2 study evaluated the efficacy and safety of tislelizumab monotherapy in adult Chinese pts with previously treated, locally advanced, unresectable or metastatic histologically confirmed MSI-H/dMMR solid tumors by central lab. Pts received tislelizumab 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. Radiological imaging was performed at 9 weeks then every 6 weeks for the first year of therapy and every 12 weeks thereafter. The primary efficacy analysis set was all pts who received any dose of tislelizumab with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed overall response rate (ORR; RECIST v1.1). Secondary endpoints included duration of response (DoR) and disease control rate. Using a binomial exact test, the null hypothesis of ORR=10% (historical rate) was rejected if 1-sided p≤0.025. Results: Between Sep 2018-Aug 2020, 80 pts were enrolled (median age 53 years; range 19-81 years) and 74 were included in the primary efficacy analysis set. At median study follow-up of 11.78 months, ORR by IRC was 45.9% (n=34/74; 95% CI 34.3, 57.9) in all tumor types (1-sided p<0.0001), including 4 complete responses (CR) and 30 partial responses (PR). Observed ORR by IRC was 39.1% (n=18/46; 95% CI 25.1, 54.6) in CRC pts and 57.1% (n=16/28; 95% CI 37.2, 75.5) in non-CRC pts. Of 74 pts, 53 (71.6%) had disease control and 39 (52.7%) achieved CR, PR or durable stable disease by IRC ≥24 weeks. Median DoR by IRC has not been reached; no disease progression was reported in the 34 responders (CR+PR), with 33 responders still on treatment (12-month DoR rate=100%). Treatment-emergent adverse events (TEAEs) ≥Grade 3 occurred in 47.5% (n=38/80) pts, of which 21.3% (n=17/80) were lab abnormalities. Immune-mediated TEAEs ≥Grade 3 were 5% (n=4/80). Conclusions: Tislelizumab achieved statistical significance and demonstrated clinically meaningful improvement in ORR in pts with previously treated locally advanced unresectable or metastatic MSI-H or dMMR solid tumors. Treatment effect was consistent and durable across tumor types and endpoints. Tislelizumab was generally well tolerated and no new safety signals were identified. The data support tislelizumab as a new treatment option in this population. Clinical trial information: NCT03736889.

Defibrotide (DF) in the Treatment of Severe Hepatic Veno-Occlusive Disease (VOD) with Multi-Organ Failure (MOF) Following Stem Cell Transplantation (SCT): Results of a Phase 3 Study Utilizing a Historical Control.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 654-654 ◽  
Author(s):  
Paul Richardson ◽  
Marcie Tomblyn ◽  
Nancy Kernan ◽  
Joel A. Brochstein ◽  
Shin Mineishi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Interim Analysis ◽  
Research Funding ◽  
Historical Control ◽  
Primary Efficacy ◽  
Phase 3 ◽  
Advisory Committees ◽  
Efficacy Analysis ◽  
Independent Expert ◽  
Primary Efficacy Analysis

Abstract Abstract 654 Background: Phase 2 clinical trials of DF in the treatment of severe VOD/MOF have demonstrated a complete response (CR) in 36-46% of patients (pts) with encouraging overall survival and tolerability (Richardson Blood 2002; Richardson ASH 2006). Given the life-threatening nature of VOD/MOF, a trial randomizing pts to placebo or best supportive care was considered but rejected. A phase 3 trial, comparing DF in the treatment of VOD/MOF post-SCT to a contemporaneous historical control (HC) was therefore performed. The HC was created using a sequential review of medical charts starting 6 months prior to use of DF at each center. Methods: Eligible pts met Baltimore VOD criteria by D+21 (total bilirubin ≥ 2.0 mg/dL with ≥ 2 of the following: hepatomegaly, ascites or 5% weight gain) and either renal and/or pulmonary failure by D+28. Exclusion criteria: severe GvHD involving liver or gut; clinically significant bleeding; or need for >1 pressors to maintain BP. As this is a non-randomized study, the primary efficacy analysis compared CR by D+100, adjusted by quintiles of propensity score based on 4 stratification variables, at an overall two-sided 0.01 significance level (Koch et al,1989). CR was defined as bilirubin < 2 mg/dL + resolution of MOF; stratification variables were allogeneic/autologous SCT, adult/pediatric, 1 or 2+ SCTs, and ventilator/dialysis dependence. A secondary endpoint was mortality at D+100. DF was given at 6.25 mg/kg IV q6h; treatment duration was recommended for at least 21d. To create the HC, 35 centers sequentially reviewed up to 266 cases. To determine HC eligibility, the Medical Review Committee (MRC, composed of 2 independent expert hematologists) assessed all pts who met VOD criteria with MOF. The MRC were provided data for each pt (a redacted medical chart or pt narrative, depending on the privacy laws for each center) only up to the date on which the pt met inclusion criteria. The MRC remained blinded to outcome data at all times. One interim analysis was planned. Results: For the HC, 6821 medical charts were screened, identifying 123 pts with features consistent with VOD in a setting of renal and/or pulmonary dysfunction that were reviewed for eligibility by the MRC. The MRC selected 32 cases as having an unequivocal diagnosis of VOD whose MOF was secondary to VOD, who met all protocol entry criteria; for all eligible pts, a confounding diagnosis of GvHD was ruled out. In the DF-treated group, 102 pts were enrolled. Following the interim analysis (comparing 61 DF pts to 32 HC pts), the DMC recommended an increase in HC sample size to 51 pts; given the large number of medical charts already reviewed, this was not considered feasible. In the final analysis (comparing 102 DF pts to 32 HC pts), the 2 groups were balanced regarding stratification variables. Baseline demographics (DF vs HC pts): median age 21 vs 18 yrs (43% and 44% pediatric); 63% vs 53% male, 88% vs 84% allogeneic SCT; 13% vs 3% with prior SCT; and 38% vs 38% ventilator/dialysis dependent. Median time post-SCT to VOD diagnosis was 13 and 11 days. Acute leukemia was the underlying diagnosis in 44% and 47%. Median duration of DF therapy was 22 days (range 1-60 days), with a median daily dose of 19 mg/kg/d. For the primary efficacy analysis, D+100 CR rate equaled 24% vs 9% (99%CI difference in CR rate: -1–35%; 95%CI difference in CR rate: 3–30%); p=0.015. D+100 mortality rate equaled 62% vs 75% (95%CI difference in rate -32–3%); p=0.051 by stratified log-rank. Consistent with prior studies, DF in children resulted in higher CR compared with HC (CR 36% vs 7%; p=0.04). Use of DF was associated with improved outcome in less sick pts (D+100 CR for pts without ventilator dependence equaled 40% vs 9%; p=0.051 and for pts without dialysis dependence equaled 34% vs 9 %; p=0.027). For pts receiving autologous SCT (n=12 and 5 pts in DF and HC arms), DF was associated with markedly improved CR (75% vs 0%, p=0.005). Hemorrhagic adverse events (any grade) were similar between the two groups (65% vs 69%); 18% of DF pts experienced a drug-related toxicity that led to discontinuation. D+100 CR strongly correlated with D+100 survival in both DF and HC groups (p<0.0001, p=0.0016). Conclusions: DF improves CR by D+100 in pts with severe VOD/MOF post-SCT with a p value < 0.05. In addition, there was a trend towards improved D+100 survival in this critically ill population. DF-associated toxicities are consistent with prior studies, supporting the observation that DF is generally well tolerated. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Grupp:Gentium: Research Funding. Martin:Gentium: Research Funding. Corbacioglu:Gentium: Consultancy, Research Funding. Holler:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment. Soiffer:Gentium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Efficacy Analysis in Clinical Trials an Update

2019 ◽  
Author(s):  
Ton J. Cleophas ◽  
Aeilko H. Zwinderman
Keyword(s):  
Clinical Trials ◽  
Efficacy Analysis

scholarly journals S246. THE EFFECT OF INCORRECT SCALE ADMINISTRATION ON DATA QUALITY IN SCHIZOPHRENIA CLINICAL TRIALS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S132-S132
Author(s):  
Alan Kott ◽  
David Daniel
Keyword(s):  
Clinical Trials ◽  
Clinical Global Impression ◽  
Primary Outcome Measure ◽  
Primary Efficacy ◽  
Double Blind ◽  
Clinical Global Impression Scale ◽  
Primary Efficacy Outcome ◽  
Pooled Data ◽  
Efficacy Outcome ◽  
Time Stamps

Abstract Background The availability of date and time stamps of interview start times on eCOA systems permits monitoring and documentation of the order of administration of scales and instruments at each visit. The Clinical Global Impression Scale (CGI) is a holistic instrument that synthesizes all information available from the subject, caregivers, medical notes, etc. and is therefore typically required to be rated last at a particular visit. In the current retrospective analysis of double blind eCOA collected schizophrenia data pooled from multiple clinical trials we assessed the percent of visits where CGI was not administered last among other efficacy assessments. Additionally we assessed whether the inappropriate administration order of Clinical Global Impression Scale was associated with discrepancies in the data and change from baseline between the CGI and the primary efficacy outcome. Methods Available eCOA data were pooled from schizophrenia double blind, placebo controlled clinical trials. Within the data, we identified those visits where the CGI was not administered last among other efficacy assessments (inappropriate administration order). Within each trial we identified as discordant those data where the actual primary efficacy score or its change from baseline differed by at least two standard deviations from the expected score after linear regression. For this procedure the CGI- S score used as a predictor and the primary efficacy outcome as dependent variable. Logistic regression was then used on pooled data to explore whether the incorrect order of CGI administration increased the odds of discordant ratings between the CGI and primary outcome measure. Results The dataset consisted of 5,784 paired ratings of the CGI and the primary efficacy outcome. Among these, a total of 4,628 visits allowed to calculate change from baseline. Inappropriate order of CGI administration was identified in a total of 443 visits (7.7% of all visits). Discrepancies between CGI-S and the primary efficacy outcome were identified in 292 visits (5.1% of data) and discrepancies between change from baseline in CGI-S and in the primary efficacy outcome were observed in 249 cases (5.3% of data). The presence of incorrectly administered CGI increased the odds of raw score discrepancy 1.6x (95%CI 1.1–2.4), and the odds of discrepancy in change from baseline 1.8x (95%CI 1.2–2.7), both significant with p &lt;0.01. Discussion Our data indicate a relatively large percent of visits suffer from an incorrect scale administration order. We have previously explored a number of sources of possible noise in schizophrenia clinical trials. Current analyses identified a significant effect of incorrect scale administration on the presence of between scale discordances. Such findings indicate that order of CGI administration should be mandated in schizophrenia clinical trials and enforced by eCOA platforms. Additionally, violations to correct scale administration should be monitored through analytic programs and acted upon in case of repeated occurrences at the rater or site level.

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