Wide brick tunnel randomization - an unequal allocation procedure that limits the imbalance in treatment totals.

In open-label studies, partial predictability of permuted block randomization provides potential for selection bias. To lessen the selection bias in two-arm studies with equal allocation, a number of allocation procedures that limit the imbalance in treatment totals at a pre-specified level but do not require the exact balance at the ends of the blocks were developed. In studies with unequal allocation, however, the task of designing a randomization procedure that sets a pre-specified limit on imbalance in group totals is not resolved. Existing allocation procedures either do not preserve the allocation ratio at every allocation or do not include all allocation sequences that comply with the pre-specified imbalance threshold. Kuznetsova and Tymofyeyev described the brick tunnel randomization for studies with unequal allocation that preserves the allocation ratio at every step and, in the two-arm case, includes all sequences that satisfy the smallest possible imbalance threshold. This article introduces wide brick tunnel randomization for studies with unequal allocation that allows all allocation sequences with imbalance not exceeding any pre-specified threshold while preserving the allocation ratio at every step. In open-label studies, allowing a larger imbalance in treatment totals lowers selection bias because of the predictability of treatment assignments. The applications of the technique in two-arm and multi-arm open-label studies with unequal allocation are described.

Hierarchical dynamic allocation procedures based on modified Zelen's approach in multiregional studies with unequal allocation.

Morrissey, McEntegart, and Lang (2010) showed that in multicenter studies with equal allocation to several treatment arms, the modified Zelen's approach provides excellent within-center and across-study balance in treatment assignments. In this article, hierarchical balancing procedures for equal allocation to more than two arms (with some elements different from earlier versions) and their unequal allocation expansions that incorporate modified Zelen's approach at the center level are described. The balancing properties of the described procedures for a case study of a multiregional clinical trial with 1:2 allocation where balance within regions as well as in other covariates is required are examined through simulations.

Shift in re-randomization distribution with conditional randomization test.

Proschan, Brittain, and Kammerman made a very interesting observation that for some examples of the unequal allocation minimization, the mean of the unconditional randomization distribution is shifted away from 0. Kuznetsova and Tymofyeyev linked this phenomenon to the variations in the allocation ratio from allocation to allocation in the examples considered in the paper by Proschan et al. and advocated the use of unequal allocation procedures that preserve the allocation ratio at every step. In this paper, we show that the shift phenomenon extends to very common settings: using conditional randomization test in a study with equal allocation. This phenomenon has the same cause: variations in the allocation ratio among the allocation sequences in the conditional reference set, not previously noted. We consider two kinds of conditional randomization tests. The first kind is the often used randomization test that conditions on the treatment group totals; we describe the variations in the conditional allocation ratio with this test on examples of permuted block randomization and biased coin randomization. The second kind is the randomization test proposed by Zheng and Zelen for a multicenter trial with permuted block central allocation that conditions on the within-center treatment totals. On the basis of the sequence of conditional allocation ratios, we derive the value of the shift in the conditional randomization distribution for specific vector of responses and the expected value of the shift when responses are independent identically distributed random variables. We discuss the asymptotic behavior of the shift for the two types of tests.

Preserving the allocation ratio at every allocation with biased coin randomization and minimization in studies with unequal allocation.

The demand for unequal allocation in clinical trials is growing. Most commonly, the unequal allocation is achieved through permuted block randomization. However, other allocation procedures might be required to better approximate the allocation ratio in small samples, reduce the selection bias in open-label studies, or balance on baseline covariates. When these allocation procedures are generalized to unequal allocation, special care is to be taken to preserve the allocation ratio at every allocation step. This paper offers a way to expand the biased coin randomization to unequal allocation that preserves the allocation ratio at every allocation. The suggested expansion works with biased coin randomization that balances only on treatment group totals and with covariate-adaptive procedures that use a random biased coin element at every allocation. Balancing properties of the allocation ratio preserving biased coin randomization and minimization are described through simulations. It is demonstrated that these procedures are asymptotically protected against the shift in the rerandomization distribution identified for some examples of minimization with 1:2 allocation. The asymptotic shift in the rerandomization distribution of the difference in treatment means for an arbitrary unequal allocation procedure is explicitly derived in the paper.

Two-stage designs for Phase 2 dose-finding trials.

We propose a Bayesian adaptive two-stage design for the efficient estimation of the maximum dose or the minimum effective dose in a dose-finding trial. The new design allocates subjects in stage two according to the posterior distribution of the target dose location. Simulations show that the proposed two-stage design is superior to equal allocation and to a two-stage strategy where only one dose is left in the second stage.

Brick tunnel randomization for unequal allocation to two or more treatment groups.

Studies with unequal allocation to two or more treatment groups often require a large block size for permuted block allocation. This could present a problem in small studies, multi-center studies, or adaptive design dose-finding studies. In this paper, an allocation procedure, which generalizes the maximal procedure by Berger, Ivanova, and Knoll to the case of K≥2 treatment groups and any allocation ratio, is offered. Brick tunnel (BT) randomization requires the allocation path drawn in the k-dimensional space to stay close to the allocation ray that corresponds to the targeted allocation ratio. Specifically, it requires the allocation path to be confined to the set of the k-dimensional unitary cubes that are pierced by the allocation ray (the 'brick tunnel'). The important property of the BT randomization is that the transition probabilities at each node within the tunnel are defined in such a way that the unconditional allocation ratio is the same for every allocation step. This property is not necessarily met by other allocation procedures that implement unequal allocation.

Optimal response-adaptive randomized designs for multi-armed survival trials.

We considered design issues for multiple treatment arms in survival intervention trials and used optimal design theory to allocate patients adaptively in such trials. We proposed three types of optimal designs: one ensures that we have the most precise estimates of the treatment effects, another guarantees that we have the minimal sample size subject to user-specified allocation ratio assignments among treatment arms, and the third ensures that the design has minimal total hazard for the cohort. The latter two types of optimal designs are also subject to user-specified power constraints for testing contrasts among treatment effects. The operating characteristics of these optimal designs along with balanced designs are compared theoretically and by simulation, including their robustness properties with respect to model misspecifications. Our results show that the proposed optimal designs are frequently unbalanced and that they are generally more efficient and more ethical than the popular balanced designs. We also apply our response-adaptive allocation strategy to redesign a three-arm head and neck cancer trial and make comparisons.

Treatment Response With Esketamine Nasal Spray Plus an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Evidence of Early Response: A Pooled Post Hoc Analysis of the TRANSFORM Studies.

Objective: To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder (DSM-5) and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment.Methods: The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Åsberg Depression Rating Scale total score at day 2 or days 2 and 8. Response rates at day 28 were determined among those not meeting early response criteria.Results: 518 patients in the analysis had day 28 observations (ESK + AD, n = 310; AD + PBO, n = 208). A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]). In day 2 nonresponders, 54.9% vs 44.3% (ESK + AD vs AD + PBO, respectively) achieved response at day 28 (P < .01). Similarly, among day 2 and 8 nonresponders, 52.1% vs 42.4% achieved response by day 28 (P = .01). In nonresponders at day 2 and at days 2 and 8, the odds ratio for a response at day 28 was 1.61 (95% CI, 1.09-2.40) with ESK + AD versus 1.56 (95% CI, 1.04-2.35) with AD + PBO.Conclusions: Patients with TRD without a demonstrated response within the first week of treatment may still derive benefit from a full 4-week induction course of esketamine nasal spray.Trial Registration: ClinicalTrials.gov identifiers NCT02417064 and NCT02418585.

Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease: A Truncated Randomized Phase 2b/3 Clinical Trial.

Importance: Atabecestat, a nonselective oral ß-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). Objective: To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. Interventions: Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). Main Outcomes and Measures: Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. Results: Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups. Conclusions and Relevance: Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02569398.

A phase I randomized, placebo-controlled, dose-exploration study of single-dose inhaled montelukast in patients with chronic asthma.

BACKGROUND: The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast. METHODS: Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15-65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 µg, and doses of 50, 100, and 500 µg could be used if needed based on a prespecified dose-response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV1) over the first 4 hours after administration, calculated as a time-weighted average (ΔFEV1 [0-4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast. RESULTS: Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 µg (0.13 L; p ≤ .001), 250 µg (0.10 L; p < .01), and 1000 µg (0.12 L; p ≤ .001) had significantly greater ΔFEV1 (0-4 hours). At 24 hours postdose, inhaled montelukast 100 µg (0.10 L) and 1000 µg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p < .05 vs. montelukast). Montelukast 1000 µg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. -0.05 L), whereas montelukast 100 µg provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for ΔFEV1 (0-90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported. CONCLUSIONS: Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.

EEG power spectra response to a 4-h phase advance and gaboxadol treatment in 822 men and women.

STUDY OBJECTIVE: To explore the effect of gaboxadol on NREM EEG in transient insomnia using power spectral analysis and evaluate the response between men and women. METHODS: This was a randomized, double-blind, 3-way, parallel-group transient insomnia study in 22 sleep laboratories. After a baseline night (N1), subjects underwent a 4-h phase-advance of their habitual sleep time the following night (N2). Healthy subjects aged 18-64 y were given single-blind placebo on N1 followed by double-blind treatment on N2 (gaboxadol 10 mg [n = 271], 15 mg [n = 274], or placebo [n = 277]) RESULTS: At baseline, women showed significantly greater values in low frequency activity (< 10 Hz) and in high spindle/low beta frequency activity (14-18 Hz) compared to men. During the phase advance (placebo N2-baseline N1), there was a significant increase in power within the high spindle/low beta frequency range (15-17 Hz) and a significant reduction in beta activity (20-32 Hz), which was greater in women than men. Gaboxadol induced a significant (dose-related) increase in low frequencies (< 8 Hz) and a significant (dose-related) decrease within the alpha/spindle range (11-12 Hz). The effect was dependent upon sex, with a greater magnitude of effect observed in women than men. CONCLUSION: Gaboxadol shows a characteristic NREM EEG spectral profile in a model of transient insomnia. Men and women show clear differences in NREM EEG activity at baseline, to gaboxadol treatment and to phase-shifts in habitual sleep/wake times. The exact mechanisms underlying the sex differences remain unclear, but sex is an important variable in studies evaluating sleep and gaboxadol. TRIAL REGISTRY INFORMATION: TRIAL REGISTRY: www.clinicaltrials.gov, study identifier: NCT00102167.

Impact of Her-2 Neu overexpression on outcome of elderly women treated with wide local excision and breast irradiation for early stage breast cancer: an exploratory analysis.

OBJECTIVE: The purpose of this study was to investigate the prognostic significance of Her-2 neu status in elderly patients managed with breast conservation strategy for stage I-II breast cancer. METHODS: We conducted an IRB approved retrospective review of 153 women age 70 and older with stage I-II breast cancer, managed with wide local excision and breast radiation between January 1997 and December 2002. The subset of 106 patients had a known Her-2 neu status and was analyzed for primary patient and tumor characteristics. These characteristics were correlated with cause specific survival (CSS), overall survival (OS), and combined nodal and distant failure (NDF). Her-2 neu positivity was confirmed with FISH HercepTestTM. Statistical tests included Cox regression, contingency table and Kaplan-Meier analysis. RESULTS: Median follow-up was 55 months and patient's median age was 76. Twenty two percent of patients were Her-2 neu positive and 78% were Her-2 neu negative. Her-2 neu positivity was significantly associated with high histologic grade (P = 0.008), T2 stage (P = 0.001) and positive axillary lymph nodes (P = 0.02) among 73 patients who had surgical assessment of axilla. Overall, only 15 patients (14%) received chemotherapy. There were no recurrences in the breast. Her-2 neu positivity predicted for NDF and CSS on multivariate analysis. Projected 5-year freedom from NDF was 70% for Her-2 neu positive and 97% for Her-2 neu negative patients (P < 0.01, log-rank). CSS was 86% for Her-2 neu positive and 98% for Her-2 neu negative patients (P < 0.01, log-rank). OS was no different between Her-2 neu positive and Her-2 neu negative patients (80% versus 85%, P = 0.25). CONCLUSIONS: Her-2 neu amplification predicts development of NDF and negatively influences CSS, but not local control or OS in elderly patients treated with breast conservation. Similar to the trend in younger patients, Her-2 neu positivity may be used in the future to consider more aggressive treatment strategies in elderly patients.