Single Interim Research Articles

609TiP - The Idea (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: a Prospective Pooled Non-Inferiority Analysis of > 11,500 Patients from 6 Phase III Trials of Adjuvant Therapy Duration with Folfox (Folfox4 or Mfolfox6) or Xelox (3 Vs. 6 Months) for Stage III Colon Cancer

ABSTRACT Background: The IDEA collaboration was established to prospectively pool and analyse data from 6 randomized trials to answer whether 3-months of oxaliplatin-based adjuvant therapy (FOLFOX4/modified FOLFOX6 or XELOX) is non-inferior to the current standard 6-month treatment in pts with stage III colon cancer, with a primary endpoint of 3 years disease-free survival. A 3 month duration of oxaliplatin-based adjuvant therapy would provide substantial advantages in toxicity, cost, and patient convenience. Design: Members of the IDEA have agreed to pool data from their individual trials (SCOT-UK led with accrual from Australia, Denmark, Spain, Sweden & New Zealand, final accrual 4027 pts; TOSCA-Italy, final 2436 pts; GERCOR/PRODIGE-France, final 2000 pts; CALGB/SWOG-US/Canada, current accrual 1600 pts; ACHIEVE-Japan, final 1200 pts; HORG-Greece, current 600 pts) to allow a definitive analysis. IDEA members prospectively agreed on eligibility criteria, treatment administration, primary endpoints, and statistical analysis plan. May 1, 2014 total IDEA accrual exceeds 11,500 pts. This sample size will provide 3390 DFS events to provide 90% power to declare non-inferiority, based on an expected 3 year DFS rate in the control group of 72%, with a one-sided alpha of 0.025 if the true DFS HR is 1.12. A single pooled interim analysis, conducted by an external Data Monitoring Board (DMB), is prospectively specified when 50% of planned DFS events have been observed; this analysis occurred in May 2014 and the DMB recommended the trial continue per protocol with no modifications. Disclosure: T. Yoshino: Research funding provided by Yakult Honsha. All other authors have declared no conflicts of interest.

Exploring the statistical and clinical impact of two interim analyses on the Phase II design with option for direct assignment

PurposeThe primary goal of Phase II clinical trials is to understand better a treatment's safety and efficacy to inform a Phase III go/no-go decision. Many Phase II designs have been proposed, incorporating randomization, interim analyses, adaptation, and patient selection. The Phase II design with an option for direct assignment (i.e. stop randomization and assign all patients to the experimental arm based on a single interim analysis (IA) at 50% accrual) was recently proposed [An et al., 2012]. We discuss this design in the context of existing designs, and extend it from a single-IA to a two-IA design. MethodsWe compared the statistical properties and clinical relevance of the direct assignment design with two IA (DAD-2) versus a balanced randomized design with two IA (BRD-2) and a direct assignment design with one IA (DAD-1), over a range of response rate ratios (2.0–3.0). ResultsThe DAD-2 has minimal loss in power (<2.2%) and minimal increase in T1ER (<1.6%) compared to a BRD-2. As many as 80% more patients were treated with experimental vs. control in the DAD-2 than with the BRD-2 (experimental vs. control ratio: 1.8 vs. 1.0), and as many as 64% more in the DAD-2 than with the DAD-1 (1.8 vs. 1.1). We illustrate the DAD-2 using a case study in lung cancer. ConclusionIn the spectrum of Phase II designs, the direct assignment design, especially with two IA, provides a middle ground with desirable statistical properties and likely appeal to both clinicians and patients.

Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study.

LBA1^ Background: Enzalutamide, an orally administered androgen receptor inhibitor, improved overall survival (OS) in men with mCRPC who had received prior docetaxel therapy (Scher et al, NEJM 367:13, 2012). This study examined whether enzalutamide could prolong OS and radiographic progression-free survival (rPFS) in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC. Methods: In this randomized, double-blind, placebo-controlled, multinational phase 3 study (NCT01212991), chemotherapy-naive patients with mCRPC were stratified by site and randomized 1:1 to enzalutamide 160 mg/day or placebo. OS and rPFS were co-primary endpoints and analyzed for the intent-to-treat population. Planned sample size was 1,680 with 765 deaths to achieve 80% power to detect a target OS hazard ratio (HR) of 0.815 with a type I error rate of 0.049 and a single interim analysis at 516 (67%) deaths. The co-primary endpoint of rPFS had sufficient power to detect a target HR of 0.57 and a type I error rate of 0.001 with a minimum of 410 events. Results: A total of 1,717 men were randomized (1,715 treated) between September 2010 and September 2012. The interim analysis at 539 deaths showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (OS: HR 0.70; 95% CI: 0.59-0.83; P&lt; 0.0001) and an 81% reduction in risk of radiographic progression or death (rPFS: HR 0.19; 95% CI: 0.15-0.23; P&lt; 0.0001). At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died. Estimated median OS was 32.4 months (mo) (95% CI, 31.5–upper limit not yet reached [NYR]) in the enzalutamide arm vs 30.2 mo (95% CI, 28–upper limit NYR) in the placebo arm. Median rPFS was NYR (95% CI: 13.8–upper limit NYR) in the enzalutamide arm vs 3.9 mo (95% CI: 3.7-5.4) in the placebo arm. Seizure events were reported in two patients. The Independent Data Monitoring Committee considered the benefit-risk ratio to favor enzalutamide and recommended stopping the study and crossing placebo patients to enzalutamide. Secondary endpoints and safety analysis will be presented. Conclusions: Treatment with enzalutamide significantly improves OS and rPFS in men with chemotherapy-naive mCRPC. Clinical trial information: NCT01212991.

Routine Intraoperative Transesophageal Echocardiography: Impact on Intraoperative Surgical Decision Making, a Single Center Interim Analysis

ABSTRACTTransesophageal echocardiography (TEE) has become an important part of armamentarium for anesthesiologists in the management of patients undergoing cardiac surgery. Many studies have demonstrated the safety and utility of TEE in cardiac surgery. With advances in hardware and software, easy availability of resources for learning and optimal understanding of image generation and interpretation, many new findings crop up in the operating room (OR) which may have been missed in preoperative transthoracic echocardiography (TTE), leading to necessary changes in planned surgical procedure. In our retrospective analysis of 726 cases in which TEE was performed over the last 1 year, changes in decision was made in 65 (8.9%) of cases. This included 42 unanticipated findings prior to cardiopulmonary bypass and 23 new findings after CPB, requiring revision in 15 cases. With the increasing use and further impending advances of TEE, the number of cases in which surgical decision will be altered may increase in near future.How to cite this articleBadamali AK, Madhavan JS, Ghuman BPS, Subash S, Raj R, Mishra A, Mishra A, Arya VK, Kumar B, Jayant A, Shyam KST, Rana SS, Singh H, Mishra A, Kuthe S, Mahajan S, Prasad S, Mathew S, Arora I, Puri GD. Routine Intraoperative Transesophageal Echocardiography: Impact on Intraoperative Surgical Decision Making, a Single Center Interim Analysis. J Perioper Echocardiogr 2013;1(1):16-20.

CA184-043: A randomized, double-blind, phase III trial comparing ipilimumab versus placebo following a single dose of radiotherapy (RT) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior treatment with docetaxel (D).

TPS4689 Background: Ipilimumab (Ipi), a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Ipi has shown antitumor effects in prostate cancer model systems and clinical activity (via prostate-specific antigen [PSA] declines and RECIST response) in Phase 1/2 investigations in CRPC, with a side effect profile reflective of its mechanism of action. Preclinical data suggest that RT given prior to CTLA-4 blockade may increase antitumor activity. Methods: In this study, pts with CRPC who have progressed during or after D are randomized 1:1 to receive either a single dose of bone-directed RT followed by Ipi 10mg/kg, or RT followed by placebo. Within 2 days of RT administration (up to 5 lesions at 8 Gy on a single day) patients receive their initial dose of Ipi/placebo; Ipi/placebo is then given every 3 weeks for a total of 4 doses. Eligible pts may continue to receive blinded study drug every 12 weeks until they meet treatment stopping criteria, withdraw consent, are lost to follow-up, or study closure. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival, pain response, and safety. The study is designed to detect a 3.8 month difference (HR=0.76) in median OS with 90% power and 0.05 2-sided type one error. The enrollment goal is 800 randomized patients, with a single interim analysis for superiority of OS planned at 435 events at approximately 33 months from first patient first visit (ClinicalTrials.gov identifier: NCT00861614). [Table: see text] [Table: see text]

A Bayesian approach for unplanned sample sizes in phase II cancer clinical trials

Phase II cancer clinical trials commonly employ two-stage designs that incorporate a single interim analysis for lack of efficacy and are designed to achieve specified frequentist properties. The requirement to examine the outcome at a prespecified sample size (SS) can be problematic, because the attained SS often differs from the planned SS. We propose to address unplanned SSs achieved at either stage by means of a Bayesian approach that approximately preserves the original design's properties. Our approach translates the rejection rule of the original frequentist design into equivalent statements about the posterior distribution of the response rate and applies this Bayesian criterion to the analysis with any realized SS. The results demonstrate that our approach approximately maintains operating characteristics of the original frequentist design including type I and type II error rates, probability of early termination, and expected SS under the null hypothesis. Designs attained under this approach may not satisfy target limits for type I error rate and power. Our method offers a coherent analysis plan when the attained SS at either stage deviates from that specified in the original design. The price of its flexibility, in terms of erosion of the desired frequentist properties, is modest.

Functional Dyspepsia Treatment Trial (FDTT): A double-blind, randomized, placebo-controlled trial of antidepressants in functional dyspepsia, evaluating symptoms, psychopathology, pathophysiology and pharmacogenetics

BackgroundFunctional dyspepsia (FD) is a common problem affecting up to 10–25% of individuals. FD accounts for significant health care costs and affects quality of life but has no definitive treatment. ObjectivesThe Functional Dyspepsia Treatment Trial (FDTT) aims to test whether treatment with an antidepressant (amitriptyline or escitalopram) leads to improvement of symptoms in patients with moderate to severe FD. DesignThe FDTT is an international multicenter, parallel group, randomized, double-blind, placebo-controlled trial to evaluate whether 12weeks of treatment with escitalopram or amitriptyline improves FD symptoms compared to treatment with placebo. Secondly, it is hypothesized that acceleration of solid gastric emptying, reduction of postprandial satiation, and enhanced gastric volume change with a meal will be significant positive predictors of short- and long-term outcomes for those on antidepressants vs. placebo. The third aim is to examine whether polymorphisms of GNβ3 and serotonin reuptake transporter influence treatment outcomes in FD patients receiving a tricyclic antidepressant, selective serotonin reuptake inhibitor therapy, or placebo. MethodsThe FDTT enrollment began in 2006 and is scheduled to randomize 400 patients by the end of 2012 to receive an antidepressant or placebo for 12weeks, with a 6-month post-treatment follow-up. The study incorporates multiple validated questionnaires, physiological testing, and specific genetic evaluations. The protocol was approved by participating centers' Institutional Review Boards and an independent Data Safety Monitoring Board was established for monitoring to ensure patient safety and a single interim review of the data in December 2010 (ClinicalTrials.gov number NCT00248651).

Longer Time to the Start of Continuation Therapy Is Associated with Improved Survival In High Risk Pediatric Acute Lymphoblastic Leukemia (ALL): A Report From the Children's Oncology Group (COG)

AbstractAbstract 3223 Background:Delays in treatment are common in pediatric ALL and may occur more often in high risk ALL (HR-ALL). Delays during maintenance therapy have adverse impact on survival, but the significance of delays prior to maintenance is unknown (Schmiegelow, et al, American Journal of Pediatric Hematology Oncology 1990 and Dibenedetto et al, Pediatric Hematology Oncology 1994). We studied the effect of delays in therapy prior to maintenance by analyzing data from two HR-ALL clinical trials, CCG1961 and POG9906. The objective was to determine the association between time to maintenance (TTM) from starting induction therapy and event-free survival (EFS) in children with high-risk ALL. Methods:CCG1961 enrolled 2078 patients from September 1996 to May 2002 with B- and T-lineage ALL with high-risk features, defined as those aged 1–9 years with initial white blood cell count (WBC) ≥ 50,000/μl, any patient aged ≥ 10 years and ≤ 21 years, and those with central nervous system (CNS) leukemia or overt testicular leukemia. Rapid early responders (RERs), those with < 25% blasts in the bone marrow on day 7 of therapy, were randomized to receive standard or augmented BFM therapy with either a single interim maintenance and delayed intensification phase (SDI) or two interim maintenance and delayed intensification (DDI) courses as outlined in Table 1. Slow early responders (SERs) were randomized to augmented BFM with DDI with either doxorubicin or idarubicin and cyclophosphamide in the DI courses. POG9906 enrolled 276 patients from March 2000 to April 2003 with high-risk B-precursor ALL, defined as all patients with CNS disease, testicular disease, MLL rearrangement, age ≥ 16 years, or WBC ≥ 100K. In addition, it included selected patients aged 12–15 with high-risk disease based on the Shuster criteria for age and initial WBC. Patients with favorable cytogenetic features (ETV6-RUNX1 fusion or trisomy of chromosomes 4 and 10) were excluded unless they had CNS or testicular leukemia. Patients were treated with augmented BFM with DDI. Patients who made it to start of maintenance are included in this report. TTM was calculated as time from start induction until start of maintenance therapy. Expected TTM for those with B-lineage ALL is shown in Table 1. TTM was dichotomized by plotting the Akaike information criterion (AIC) versus all possible cutoff values of TTM and identifying the cut-point which best discriminated between groups who did and did not fail. The identified threshold was then examined as a predictor of EFS using the Kaplan Meier method and log rank test. The outcomes were 5-year EFS for CCG1961 and 4-year EFS for POG9906. Results:Among the B-lineage patients, longer TTM was significantly associated with improved EFS in CCG1961 Std BFM DI and SER Aug BFM Doxo arms, as well as on POG 9906. For example, in Std BFM DI, 5-year EFS was 83% in those with longer TTM and 71.9% in those with shorter TTM (P=.036). Among the T lineage cohort enrolled on CCG1961, similar results were seen with longer TTM being significantly associated with improved EFS in Std BFM DDI and SER Aug BFM Ida, and a trend toward improved EFS with longer TTM in each of the other arms. Conclusions:These data suggest that longer TTM may be associated with superior EFS in pediatric high-risk ALL. Multiple factors may contribute to this association. For instance, pharmacogenetic differences resulting in more treatment toxicity and delays may also be associated with more potent anti-leukemic effects, or patients with infectious complications may have an endogenous immune response that also has an anti-leukemia effect. Further research is needed to validate the association between TTM and EFS and to characterize the timing and causes of these delays in protocol therapy. Disclosures:No relevant conflicts of interest to declare.

Abstract LB-291: Translational studies of the dual mTOR-PI3K inhibitor SF1126

Abstract LB-291: Translational studies of the dual mTOR-PI3K inhibitor SF1126

Two‐Stage Group Sequential Robust Tests in Family‐Based Association Studies: Controlling Type I Error

In family-based association studies, an optimal test statistic with asymptotic normal distribution is available when the underlying genetic model is known (e.g., recessive, additive, multiplicative, or dominant). In practice, however, genetic models for many complex diseases are usually unknown. Using a single test statistic optimal for one genetic model may lose substantial power when the model is mis-specified. When a family of genetic models is scientifically plausible, the maximum of several tests, each optimal for a specific genetic model, is robust against the model mis-specification. This robust test is preferred over a single optimal test. Recently, cost-effective group sequential approaches have been introduced to genetic studies. The group sequential approach allows interim analyses and has been applied to many test statistics, but not to the maximum statistic. When the group sequential method is applied, type I error should be controlled. We propose and compare several approaches of controlling type I error rates when group sequential analysis is conducted with the maximum test for family-based candidate-gene association studies. For a two-stage group sequential robust procedure with a single interim analysis, two critical values for the maximum tests are provided based on a given alpha spending function to control the desired overall type I error.

Bortezomib, Pegylated-Lyposomal-Doxorubicin and Dexamethasone Followed by Melphalan 100 mg/m2 in Elderly Newly Diagnosed Patients: An Interim Analysis.

Bortezomib has been evaluated as induction regimen to improve cyto-reduction before autologous stem cell transplant. Combinations including bortezomib, doxorubicin and dexamethasone have shown encouraging results. Melphalan at 100 mg/m2 has been suggested as reduced-intensity conditioning regimen for elderly patients. In this prospective multicenter phase II study, bortezomib, pegylated-liposomal-doxorubicin and dexamethasone (PAD) followed by tandem melphalan 100 mg/m2 has been investigated in newly diagnosed patients aged 65–75 years. The induction regimen included four 21-day PAD cycles (bortezomib 1.3 mg/m2 days 1, 4, 8, 11, pegylated-liposomal-doxorubicin 30 mg/m2 day 4 and dexamethasone 40 mg days 1–4, 8–11, and 15–18 for cycle 1 and days 1–4 for cycles 2–4). Cyclophosphamide (3 g/m2) plus G-CSF were used to harvest stem cells. Patients were then conditioned with tandem melphalan 100 mg/m2 followed by stem cell infusion. A single interim analysis has been planned. Sixty-five patients have been enrolled in the study and 37 completed the induction cycles. Median age was 69 years; median β2-microglobulin 3 mg/L; median albumin 4.1 g/L; chromosome 13q deletion was detected by FISH in 35% of patients. After the 4 courses of PAD 97.1% of patients achieved at least a partial response (PR), 50% at least a very good partial response (VGPR), 11.8% an immunofixation negative complete remission (CR). After tandem melphalan 100 mg/m2, all patients achieved at least a PR, 80% at least a VGPR and 30% an immunofixation negative CR. After 4 cycles of PAD, grade 3–4 hematologic events were thrombocytopenia (13.5%) and neutropenia (8.1%); more frequent grade 3–4 non-hematologic toxicities were peripheral neuropathy (21.6%) and infections (10.8%). One early toxic death was reported (central nervous system bleeding) and two patients had to discontinue therapy due to pneumonia and HBV reactivation. Eighty-two percent of patients achieved successful stem cell harvest (>4 CD34+ cells/Kg). PAD is an effective induction approach, it may improve autologous transplant results in selected elderly patients. Updated results of the interim analysis will be presented at the meeting.

Multicenter Radial Artery Patency Study (RAPS): Study Design

The use of an internal thoracic artery rather than a saphenous vein graft for left anterior descending coronary artery bypass is associated with improved long-term outcome. Hence, expanded use of arterial conduits for other coronary targets has been advocated. The radial artery possesses a number of anatomic features that are technically advantageous compared with other arterial conduits. This study will determine the relative patency of the radial artery compared to the saphenous vein for right and circumflex coronary bypass. Patients with graftable multivessel coronary disease and an estimated left ventricular ejection fraction ⩾ 35% undergoing nonemergent primary isolated coronary bypass surgery are eligible. The right and circumflex vessels must have high-grade lesions (⩾ 70% diameter stenosis), with target segments of reasonable quality ⩾ 1.5 mm in diameter. Patients serve as their own controls. The radial artery is randomly allocated to bypass the right or circumflex territory and a saphenous vein is used for the nonradial site. An internal thoracic artery is used for the left anterior descending coronary artery in all cases. Randomization is stratified by center. The primary study endpoint is graft patency as determined by angiography, 8–12 months postoperatively. The relative patency of the radial artery compared with the saphenous vein will be determined using McNemar's test. A sample size of 464 patients will provide 80% power for a two-tailed test (α = 0.05) for a 40% relative reduction in the rate of distal anastomotic occlusion from 12% in the saphenous vein to 7.2% in the radial arteries assuming a 20% within-patient correlation. A single interim analysis will be performed following completion of 232 angiograms. To allow for lack of follow-up angiography in up to 20% of enrolled patients, we plan to randomize a total of 560 patients. It is also our intention to assess the long-term patency (5–10 years) of radial artery relative to saphenous vein grafts in follow-up studies. Three hundred patients were recruited from 12 Canadian, university-affiliated sites from November 1996 until February 1999, of which 128 patients have undergone follow-up angiography. Approximately 80% of those who have been followed for more than 1 year have undergone follow-up angiography. This trial will determine the 8–12 month patency of the radial artery relative to the saphenous vein for non–left anterior descending coronary bypass using a novel study design which helps control for potential bias from individual patient and vessel factors. Positive results would support the use of the radial artery in particular, and multiple arterial grafts in general. Control Clin Trials 2000;21:397–413

Design Considerations in Crossover Trials with a Single Interim Analysis and Serial Patient Entry

A two-stage sequential design is presented to facilitate a single interim analysis in crossover trials with serial patient entry. The interim analysis is based on a linear statistic that combines data from individuals observed for only one treatment period with data from those observed for both periods (Cook, R. J., 1995, Biometrics 51, 932-945). The final analysis is based on the usual test statistic used in crossover trials. The size of this procedure is controlled by partitioning the experimental type I error rate over the two analyses and deriving the appropriate critical values. We investigate the design implications of adopting this procedure over the usual analysis for crossover trials by examining the necessary sample size inflation factors to maintain power, and indicate the expected savings in terms of the number of responses required. Data from a study designed to compare two antiemetic therapies for previously untreated chemotherapy patients (Osaba, D., et al., 1986, Clinical and Investigative Medicine 9, 225-231) are used to illustrate the procedure.

Interim Analyses in 2 x 2 Crossover Trials

A method is presented for performing interim analyses in long term 2 x 2 crossover trials with serial patient entry. The analyses are based on a linear statistic that combines data from individuals observed for one treatment period with data from individuals observed for both periods. The coefficients in this linear combination can be chosen quite arbitrarily, but we focus on variance-based weights to maximize power for tests regarding direct treatment effects. The type I error rate of this procedure is controlled by utilizing the joint distribution of the linear statistics over analysis stages. Methods for performing power and sample size calculations are indicated. A two-stage sequential design involving simultaneous patient entry and a single between-period interim analysis is considered in detail. The power and average number of measurements required for this design are compared to those of the usual crossover trial. The results indicate that, while there is minimal loss in power relative to the usual crossover design in the absence of differential carry-over effects, the proposed design can have substantially greater power when differential carry-over effects are present. The two-stage crossover design can also lead to more economical studies in terms of the expected number of measurements required, due to the potential for early stopping. Attention is directed toward normally distributed responses.

Sample size determination using an interim analysis.

Interim analyses are often employed to terminate comparative clinical trials for ethical or economic reasons when the evidence indicates that one treatment is superior to the other. Here an interim analysis is proposed for the situation where a one-sided test is to be performed. The proposed interim analysis consists of a one-sided test to terminate the clinical trial if it appears that the null hypothesis of interest is true. By noting that incorporation of a single interim analysis is similar to the two-stage procedure used for constructing a test procedure with power independent of the unknown variance, it also includes estimation of the variance, which can be used to control the power of the test if the trial is not terminated. Various properties of this two-stage procedure and derivation of the constants needed for its implementation are presented.

Comparison of a two-stage and three-stage interim-analysis procedure.

A statistical model for combining p values from multiple tests of significance is used to define rejection and acceptance regions for two-stage and three-stage sampling plans. Type I error rates, power, frequencies of early termination decisions, and expected sample sizes are compared. Both the two-stage and three-stage procedures provide appropriate protection against Type I errors. The two-stage sampling plan with its single interim analysis entails minimal loss in power and provides substantial reduction in expected sample size as compared with a conventional single end-of-study test of significance for which power is in the adequate range. The three-stage sampling plan with its two interim analyses introduces somewhat greater reduction in power, but it compensates with greater reduction in expected sample size. Either interim-analysis strategy is more efficient than a single end-of-study analysis in terms of power per unit of sample size.

The Acute Infarction Ramipril Efficacy (AIRE) Study

The rationale, design, organization, and outcome definitions of the Acute Infarction Ramipril Efficacy (AIRE) Study are described prospectively. A total of 2,000 patients (1,000 per treatment group) will be recruited to this multicenter, multinational, double-blind, randomized, placebo-controlled study investigating the effect of oral treatment with ramipril (2.5 or 5 mg twice daily) on the total mortality of survivors of an acute myocardial infarction (AMI) with early clinical evidence of heart failure. Secondary outcomes of the study include progression to severe/resistant heart failure (at which time the patient will be withdrawn from the study treatment), reinfarction, and stroke. Treatment will be initiated in hospital between day 3 and day 10 following AMI, and follow-up continued for an average of 15 months and a minimum of 6 months. The study data will be analyzed on an intention-to-treat basis: a single formal interim analysis will be conducted after 175 deaths. An Independent Adjudicating Panel will act as the overall ethical supervisory body for the study and will retain the randomization code. An International Steering Committee will be responsible for the clinical definitions of the secondary study outcomes, and will regularly review progress of the study. We believe that early treatment with ramipril may reduce the total mortality of patients surviving an AMI with clinical evidence of heart failure.

A one-sided interim analysis with binary outcomes

Wieand and Therneau (Controlled Clin Trials 8:20–28, 1987) proposed a technique for conducting a clinical trial to test the equality of response rates for two treatments using a one-sided test with an option of terminating the trial at the single interim analysis if it appears that the test treatment will offer no improvement over the control treatment. Chi, Bristol, and Castellana (Stat Med 5:387–392, 1986) considered a clinical trial with the same option when the treatments are compared with respect to the means of variables with normal distributions with a common known variance. Here a decision rule similar to the one proposed in the latter is employed for the problem examined in the former. This decision rule, a generalization of the one proposed by Wieand and Therneau, consists of a one-sided test at the final analysis with a one-sided test at the interim analysis, which is performed in the direction opposite to the one at the final analysis. It is shown that the proposed generalization may result in desirable properties regarding the probability of stopping the trial at the interim analysis in some situations.

Prospective randomised trial of endoscopic sclerotherapy versus oesophageal staple transection for acute variceal bleeding. Single interim analysis

Prospective randomised trial of endoscopic sclerotherapy versus oesophageal staple transection for acute variceal bleeding. Single interim analysis

Prospective randomised trial of chronic sclerotherapy for prevention of variceal rebleeding, with use of the same protocol to treat rebleeding in all patients. Single interim analysis

Prospective randomised trial of chronic sclerotherapy for prevention of variceal rebleeding, with use of the same protocol to treat rebleeding in all patients. Single interim analysis