Sequential Parallel Comparison Design Research Articles

Sexual orientation differences among men in a randomized clinical trial of extended-release naltrexone and bupropion for methamphetamine use disorder

BackgroundMethamphetamine use disorder (MethUD) disproportionately affects men who have sex exclusively with men or with men and women (collectively MSM/W), compared to men who have sex with women (MSW). This study is the first MethUD medication trial to compare treatment effect for these groups, hypothesizing that extended-release injectable naltrexone 380mg every 3 weeks plus oral extended-release bupropion 450mg daily would be less effective for MSM/W than MSW. MethodsData come from men (N = 246) in a multi-site, double-blind, randomized, placebo-controlled trial with sequential parallel comparison design. In Stage 1 (6-weeks), participants were randomized to active treatment or placebo. In Stage 2 (6-weeks), Stage 1 placebo non-responders were rerandomized. Treatment response was ≥3 methamphetamine-negative urine samples, out of four obtained at the end of Stages 1 and 2. Treatment effect was the active-versus-placebo between-group difference in the weighted average Stages 1 and 2 responses. ResultsMSM/W (n = 151) were more likely than MSW (n = 95) to be Hispanic, college-educated, and living with HIV. Adjusting for demographics, among MSM/W, response rates were 13.95 % (active treatment) and 2.78 % (placebo) in Stage 1; 23.26 % (active treatment) and 4.26 % (placebo) in Stage 2. Among MSW, response rates were 7.69 % (active treatment) and 5.80 % (placebo) in Stage 1; 3.57 % (active treatment) and 0 % (placebo) in Stage 2. Treatment effect was significantly larger for MSM/W (h = 0.1479) than MSW (h = 0.0227) (p = 0.04). ConclusionsFindings suggest efficacy of extended-release naltrexone plus bupropion for MSM/W, a population heavily burdened by MethUD. While a secondary outcome, this intriguing finding merits testing in prospective trials.

How should we design future mechanistic and/or efficacy clinical trials?

The emergence of new molecular targets, together with the development of new approaches to neuropsychiatric diseases, involving psychedelics as well as gene and cell therapies, are creating the need to improve the efficiency of mechanistic and/or efficacy clinical trials. This review article will discuss a number of issues that have hampered our ability to detect therapeutic signals, from excessive placebo/sham response rates to the imprecision of diagnostic and outcome assessments. In addition to reviewing the limitations of current efficacy and mechanistic neuropsychiatric clinical trials, this review presents some of the methodological approaches that may improve the overall performance of our neuropsychiatric trials, including the adoption of novel study designs such as the sequential parallel comparison design and independent confirmation of the appropriateness of subjects' enrollment. In addition, this review will discuss several designs that make mechanistic clinical trials more precise.

0398 Efficacy of Suvorexant for Insomnia Disorder in Patients with Poorly-Controlled Type 2 Diabetes

Abstract Introduction Sleep disturbance is a common and underappreciated feature of diabetes and sleep may contribute to glycemic control in patients with type two diabetes (T2D). We conducted a randomized placebo-controlled 3-month trial to examine the efficacy of suvorexant in improving sleep and other aspects of health in patients with suboptimally-controlled type 2 diabetes and insomnia. Methods This double-blind, randomized placebo-controlled 3-month trial was conducted using the sequential parallel comparison design (SPCD). Sixty-nine poorly-controlled T2D patients (HbA1c≥6.5) were randomized to placebo and/or suvorexant (10-20 mg). The primary outcome was subjective total sleep time (STST), and secondary outcomes were Insomnia Severity Index (ISI) score and wake time after sleep onset (WASO). Exploratory outcomes included sleep efficiency, hemoglobin A1c (HbA1c), and C-reactive protein (CRP). Exploratory analyses were conducted on relationships of sleep and diabetes outcomes. Results There were no significant improvements in STST, ISI, or WASO among patients taking suvorexant compared to those taking placebo. There were also no significant changes in any of the exploratory endpoints. Improvements in sleep were associated with improvements in both objective (i.e. HbA1c) and subjective (i.e. Diabetes Distress Scale) measures of diabetes, across treatment assignments. Conclusion Our negative findings for suvorexant efficacy for insomnia in poorly-controlled T2D may be related to inadequate sample size or due to the complex and multiple contributions to insomnia in this patient population. The associations of improved sleep with improvements in diabetes-related metrics across groups highlights the importance of identifying and treating sleeping difficulties in this population. Support (if any) This research was funded by an investigator-initiated grant from Merck Pharmaceuticals.

Naltrexone plus bupropion reduces cigarette smoking in individuals with methamphetamine use disorder: A secondary analysis from the CTN ADAPT-2 trial

IntroductionMethamphetamine (MA) use is marked by high rates of comorbid tobacco smoking, which is associated with more severe drug use and worse clinical outcomes compared to single use of either drug. Research has shown the combination of naltrexone plus oral bupropion (NTX-BUP) improves smoking cessation outcomes in non-MA-using populations. In the Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) study, NTX-BUP successfully reduced MA use. Our aim in this secondary data analysis was to examine changes in cigarette smoking among the subgroup of participants reporting comorbid tobacco use in the ADAPT-2 trial. MethodsThe multi-site ADAPT-2 study used a randomized, double blind, sequential parallel comparison design to evaluate treatment with extended-release injectable NTX (380 mg every 3 weeks) combined with once-daily oral extended-release BUP (450 mg/day) vs matching injectable and oral placebo in outpatients with moderate or severe MA use disorder. The study assessed smoking outcomes, based on self-reported timeline followback (TLFB) data, twice/week for 13 weeks. ResultsOf the 403 participants in the ADAPT-2 trial, 290 reported being current cigarette smokers (71.9 %). The study found significant differences (p's < 0.0001) for each smoking outcome indicating greater change in the proportion of nonsmoking days, number of cigarettes smoked per week, and consecutive nonsmoking days, all favoring the group receiving NTX-BUP versus placebo. ConclusionsNTX-BUP was associated with significant reductions in self-reported cigarette smoking in the context of concurrent treatment for MA use disorder. These off-target medication effects warrant prospective investigation using biochemically confirmed measures of smoking abstinence. The development of NTX-BUP as a co-addiction treatment strategy has a potential for high public health impact.

Very Low-Level Transcranial Photobiomodulation for Major Depressive Disorder: The ELATED-3 Multicenter, Randomized, Sham-Controlled Trial.

Background: Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light might represent a treatment for major depressive disorder (MDD). However, the dosimetry of administered t-PBM varies widely. We tested the efficacy of t-PBM with low irradiance, low energy per session, and low number of sessions in individuals with MDD.Methods: A 2-site, double-blind, sham-controlled study was conducted of adjunct t-PBM NIR (830 nm; continuous wave; 35.8 cm2 treatment area; 54.8 mW/cm2 irradiance; 65.8 J/cm2 fluence, 20 min/session; ~2 W total power; 2.3 kJ total energy per session), delivered to the prefrontal cortex, bilaterally, twice a week for 6 weeks, in subjects diagnosed with MDD per the DSM-IV criteria. Subjects were recruited between August 2016 and May 2018. A sequential parallel comparison design was used: 18 nonresponders to sham in phase 1 (6 weeks) were re-randomized in phase 2. The primary outcome was reduction in depression severity (Hamilton Depression Rating Scale [HDRS-17] and Quick Inventory of Depressive Symptomatology-Clinician Rating [QIDS-C] scores) from baseline. Statistical analyses used R package SPCDAnalyze2, including all subjects with ≥ 1 post-randomization evaluation.Results: Of the 54 subjects recruited, we included 49 MDD subjects in the analysis (71% female, mean ± SD age 40.8 ± 16.1 years). There were no significant differences between t-PBM and sham with respect to the change in HDRS-17 (t = -0.319, P = .751) or QIDS-C (t = -0.499, P = .620) scores. The sham effect was reasonably low.Conclusions: Mostly uncontrolled studies suggest the efficacy of t-PBM for MDD; however, its optimal dose is still to be defined. A minimal dose threshold is likely necessary, similarly to other neuromodulation techniques in MDD (electroconvulsive therapy, transcranial magnetic stimulation). We established a threshold of inefficacy of t-PBM for MDD, based on combined low irradiance, low energy per session, and low number of sessions.Trial Registration: ClinicalTrials.gov identifier: NCT02959307.

A generalized weighted combination test of treatment effect for clinical trials with a sequential parallel comparison design and binary endpoint.

To address the issue of a large placebo effect in certain therapeutic areas, rather than the application of the traditional gold standard parallel group placebo-controlled design, different versions of the sequential parallel comparison design have been advocated. In general, the design consists of two consecutive stages and three treatment groups. Stage 1 placebo nonresponders potentially form a prespecified patient subgroup for formal between-treatment comparison at the final analysis. In this research, a version of the design is considered for a binary endpoint. To fully utilize all available data, a generalized weighted combination test is proposed in case placebo has a relatively small effect for some of the study endpoints. The weighted combination of the test based on stage 1 data and the test based on stage 2 data of stage 1 placebo nonresponders suggested in the literature uses only a part of the study data and is a special case of this generalized weighted combination test. A multiple imputation approach is outlined for handling missing not at random data. Simulation is conducted to evaluate the performances of the methods and a data example is employed to illustrate the applications of the methods.

Assessing treatment benefit in the presence of placebo response using the sequential parallel comparison design.

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient's expectations for the treatment. Its presence makes the classical parallel study design suboptimal and can bias the inference. The sequential parallel comparison design (SPCD), a two-stage design where the first stage is a classical parallel study design, followed by another parallel design among placebo subjects from the first stage, was proposed to address the shortcomings of the classical design. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized subjects and the mean treatment difference in Stage II among placebo non-responders was proposed as the efficacy measure. However, by linking two possibly different populations, this weighted average lacks interpretability, and the choice of weight remains controversial. In this work, under the principal stratification framework, we propose a causal estimand for the treatment effect under each of three clinically important principal strata: Always Responders, Never Responders, and Drug-only Responders. To make the stratum treatment effect identifiable, we introduce a set of assumptions and two sensitivity parameters. By further considering the strata as latent characteristics, the sensitivity parameters can be estimated. An extensive simulation study is conducted to evaluate the operating characteristics of the proposed method. Finally, we apply our method on the ADAPT-A study data to assess the benefit of low-dose aripiprazole adjunctive to antidepressant therapy treatment.

Deuterated dextromethorphan/quinidine for agitation in Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of neurodegenerative disorder; it affects around 47 million individuals worldwide (Prince et al., 2013). AD rose from the 12th most burdensome disease in the United States in 1990 to the sixth in 2016 in terms of disability-adjusted life years (Alzheimer's Disease, Facts and Figures 2021). The burden carried by patients and their caregivers is substantially related to neuropsychiatric symptoms, notably agitation as the disease progresses. To date, there is no Food and Drug Administration (FDA)-approved treatment for agitation in AD. The American Psychiatric Association recommends pharmacotherapy in case of failure of non-pharmacological options. While antidepressants such as trazodone or citalopram can be used as first line agents, antipsychotics may be warranted in case of severe agitation. Antipsychotics carry however a black box warning regarding the increased risk of cerebrovascular events and mortality in patients with dementia. Hence, their use needs to be limited. Several agents are currently being investigated to fill the gap of finding a treatment for agitation in AD. Compounds in the pipeline include pimavanserin and brexpiprazole, both of which are antipsychotics. Newer “safer” compounds that are being studied include cannabinoid derivatives, and dextromethorphan/quinidine. Drug design is a long and expensive process. It is often associated with unexpected unfavorable tolerability and safety profile halting the development of a new product. Deuteration recently emerged as a new and cost-effective technique that aims at repurposing old medications and advancing their development in clinical trials to garner quick FDA approval. It consists of the selective replacement of hydrogen (protium) with deuterium, naturally occurring and stable isotope of hydrogen. This structural substitution increases the metabolic stability of the molecule and extends the metabolic half-life of the drug, improving its safety and tolerability (Schmidt, 2017). AVP-786 is the deuterated form of dextromethorphan/quinidine that emerges as a promising well-tolerated treatment option for agitation in AD. With two completed phase III trials investigating this compound, there is still insufficient evidence to obtain FDA approval of the deuterated form. The latest clinical evidence on dextromethorphan/quinidine and its deuterated form for this indication will be discussed herein. Dextromethorphan/quinidine or AVP-923 (Neudexta): Neudexta or AVP-923 is a compound that is FDA approved for the treatment of pseudobulbar affect, a dysfunction of emotional expression characterized by involuntary outbursts of crying or laughing disproportionate or unrelated to mood, occurring in patients with various underlying neurologic disorders including multiple sclerosis. It is composed of 20 mg of dextromethorphan and 10 mg of quinidine sulfate. Only dextromethorphan is the active component in the central nervous system. Quinidine inhibits CYP2D6 hepatic enzyme that catalyzes the metabolism of dextromethorphan. Thus, coadministration of a small dose of quinidine with dextromethorphan decreases the metabolism of the latter, leading to an increase in the concentration of free dextromethorphan by 25-fold. Free dextromethorphan will then effectively reach the brain to exert its neurological and psychiatric effects (Pope et al., 2004). In a unique 10-week phase II clinical trial (NCT0158440) in subjects with moderate to severe AD, dextromethorphan/quinidine (administered at the dose of 30/10 mg twice daily for 152 subjects) was associated with a statistically significant decrease in agitation as measured by the neuropsychiatric inventory-agitation and aggression scale, compared to placebo (127 subjects); P < 0.001. Adverse events demonstrated in this trial included falls (8.6% vs. 3.9% in placebo), diarrhea (5.9% vs. 3.1% in placebo), urinary tract infections (5.3% vs. 3.9% in placebo), and dizziness (4.6% vs. 2.4% in placebo). Serious adverse events occurred in 7.9% of those receiving dextromethorphan/quinidine compared to 4.7% of those on placebo. 11.2% of those receiving the drug discontinued the study compared to 7.1% of those receiving placebo (5.3% and 3.1% owing to adverse events, in the two groups, respectively). No significant impact on Qtc prolongation or cognition were shown. Deuterated dextromethorphan/quinidine or AVP-786: Following the successful findings in the phase II trial with AVP-923, the FDA granted a fast-track designation to the deuterated sister compound, AVP-786 (Figure 1) to be directly investigated in phase III trials for the indication of agitation in AD. Deuteration of dextromethorphan/quinidine was shown to reduce the amount of quinidine needed to reach an effective plasma concentration of free dextromethorphan, thus reducing drug-drug interaction and cardiac side effects usually associated with quinidine. Aside from the pharmacokinetic alteration, deuteration of dextromethorphan was not shown to affect the selectivity and affinity for the receptors in the brain that are implicated in the neuropsychiatric effects.Figure 1: Representation of deuterated dextromethorphan/quinidine.From left to right, deuterated dextromethorphan and quinidine chemical structures are shown. Structures are adapted from Wikimedia Public Domain.The two completed phase III trials with AVP-786 showed contradictory findings. The full dataset from both studies is not published yet in any peer-reviewed journals. According to press releases from the pharmaceutical company (Avanir Pharmaceuticals), TRIAD-1 (NCT02442765) showed statistically significant effect of the experimental drug on decreasing agitation in a sample of 410 individuals with moderate to severe AD (with one of two doses used). TRIAD-2 (NCT02442778) failed however to replicate this finding in a similar population of 522 patients (Avanir pharmaceuticals press releases). Discrepancy in the findings can be explained by differences in the study design used: Researchers in TRIAD-1 adopted the sequential parallel comparison design that involves 2 stages of randomization to drug versus placebo. The first stage randomizes more patients to placebo than to active treatment. In the second stage, placebo non-responders from stage 1 are re-randomized and included in the primary analysis. Pooled analysis of both stages maximizes the power to detect treatment differences without increasing sample size (Boessen et al., 2012). TRIAD-2 however was a conventional parallel randomized controlled trial. This study design is known to require a larger sample size to enhance the likelihood to detect a change in signal/outcome. Otherwise, both trials used the Cohen-Mansfield Agitation Inventory to assess for agitation severity as the primary outcome, whereas the initial phase II trial with dextromethorphan/quinidine used the neuropsychiatric inventory-agitation and aggression instrument. Unfortunately, without the full publication of the methods, statistical analyses, and results of TRIAD-1 and 2, the scientific community is unable to further compare the two studies and critically analyze for discrepancies. Given the mixed results, the company is planning future phase III trials with the deuterated compound, per the FDA recommendation. Surprisingly, the conventional parallel design and not the sequential parallel comparison design model will be adopted in all future trials announced by Avanir pharmaceuticals. Discussion: There are currently 7 other agents in clinical trials for this indication. Brexpiprazole (antipsychotic) at the dose of 2 mg only was associated with significant anti-agitation effect, compared to placebo (Grossberg et al., 2020). A confirmatory trial is currently in progress. Both AX-05, (a combination of dextromethorphan and bupropion) and nabilone (a cannabinoid derivative) were recently shown to have a significant anti-agitation effect in phase II trials. Phase III trials are thus planned (Cummings, 2021). Other products being investigated are lumateperone, pimavanserin, dronabinol, lithium and prazosin (Khoury et al., 2021). Designing a successful clinical trial for a medication to garner regulatory approval for treating agitation in AD remains a big challenge. Agitation is a very heterogeneous disorder, across different stages of dementia. Researchers are recommended to objectively define agitation, using the latest International Psychogeriatric Association definition, as well as using standardized tools to measure agitation in clinical trials. The Cohen-Mansfield Agitation Inventory emerges as a practical instrument given its concordance with the IPA definition for agitation. Concomitant use of psychotropic medications including cognitive enhancers need to be addressed in the statistical analysis. Innovative study designs are encouraged to minimize placebo response, in addition to using technology-based interventions to enhance treatment adherence (O’Gorman et al., 2020). From a pharmacodynamic perspective, dextromethorphan binds mainly to the sigma-1 receptors, N-methyl-D-asparate receptors, the α3β4 nicotinic acetylcholine receptors, the serotonin transporters and norepinephrine transporters. However, the exact role of these receptors in the pathophysiology of agitation is not well-understood. The neurochemical abnormalities associated with AD agitation include decreased acetylcholine and serotonin neurotransmission, leading to loss of cortical inhibition. In AD, neurofibrillary tangles (tau deposits) are seen early in the nucleus basalis of Meynert with cholinergic projections to several regions implicated in agitation including the cingulate cortex and amygdala. With the progression of the disease, there is a loss of serotoninergic neurons in the raphe and their cortical projections, notably to the frontal cortex and amygdala. Degeneration of serotonin pathways may also diminish cholinergic neurotransmission, exacerbating agitation (Rosenberg et al., 2015). The biological effects of dextromethorphan on agitation would be better elucidated by including imaging procedures with ligand binding in future planned trials. Although dextromethorphan/quinidine and its deuterated form do not share the same liabilities of antipsychotics, they are associated with a significant increased risk of falls, in addition to the risk of drug-drug interaction with medications that are metabolized by CYP2D6 such as antidepressants. Although, a small dose of quinidine is used in the deuterated form, physicians should be wary of the risk of QTc prolongation, when prescribed with other medications in poly-medicated older individuals. Conclusion: Deuterated dextromethorphan/quinidine emerges as new investigational compound for agitation in moderate to severe AD. No solid recommendation can be made for this compound at this point, with only one successful phase III trial (TRIAD-1) and without the publication of the methods, analyses, and results of the completed trials in peer-reviewed journals. Further well-designed, large, robust trials with AVP-786 are additionally needed to ascertain the efficacy and safety of this compound for this highly needed indication in neuropsychiatry.

A Test for Treatment Effects Based on the Exact Distribution of an Ordinary Least-Square Estimator in Sequential Parallel Comparison Design

Sequential parallel comparison design (SPCD) is used to deal with high placebo response when evaluating treatment effects in clinical trials. Several analysis methods assuming a continuous variable have been proposed within the SPCD framework. In particular, statistical tests using an ordinal least-square (OLS) estimator of an overall treatment effect have been discussed. These tests are usually adequate because the test statistic is asymptotically distributed as a normal distribution from the central limit theorem. However, the exact distribution of the OLS estimator has not been derived and the comprehensive performance of the test statistics is unknown. In this work, we derived the exact distribution of the OLS estimator and constructed a test based on the derived distribution within the SPCD framework. The performances (Type I error rate and power) of the test were compared with those of tests based on an asymptotic distribution (asymptotic tests). The Type I error rate of the exact test was well controlled, whereas that of the asymptotic method tended to deviate from the significance level. The results show that the power of the exact test is almost equivalent to that of the asymptotic tests.

AVP-786 as a promising treatment option for Alzheimer’s Disease including agitation

ABSTRACT Introduction To date, there is no FDA-approved treatment for agitation in Alzheimer’s disease (AD). Medications currently used off-label have modest clinical efficacy and serious side effects. Areas covered The authors review the pharmacology, mechanism of action, pharmacokinetics, efficacy, safety and tolerability data of AVP-786, for the treatment of agitation in AD. Expert opinion AVP-786, the deuterated form of dextromethorphan/quinidine (AVP-923) which is an approved treatment for Pseudo-Bulbar Affect, emerges as a promising and safe treatment for agitation in AD. Deuteration is an innovative technology that accelerates drug development by conducting faster and less costly clinical trials. No phase II trial was conducted with AVP-786 for the treatment of agitation in AD; the decision to expedite the development of this drug was based on a successful phase II study with AVP-923. Phase III trials with AVP-786 (TRIAD-1 and TRIAD-2) showed mixed findings probably due to the difference in study design. Future phase III studies should use innovative study designs such as the Sequential Parallel Comparison Design to mitigate high placebo response, and the Cohen-Mansfield Agitation Inventory for agitation assessment. They should also include positron emission tomography studies to assess occupancy of various receptors in the brain after AVP-786 is administered.

Bupropion and Naltrexone in Methamphetamine Use Disorder

BackgroundThe use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.MethodsWe conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone–bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone–bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.ResultsA total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone–bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone–bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone–bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone–bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone–bupropion during the trial.ConclusionsAmong adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.)

Repeated Measures Analysis of the Sequential Parallel Comparison Design With Normal Responses

For the sequential parallel comparison design with normally distributed outcomes and rerandomization at the start of phase 2, we propose fitting separate repeated measures models for the two phases. We show analytically the asymptotic independence between the treatment effect estimators in the two phases. We recommend prespecification of the weights for combining the treatment effects in the two phases and use of the t reference distribution with the Welch–Satterthwaite degrees of freedom for testing the overall treatment effect when the sample size is small. We use simulation studies to demonstrate that the proposed method controls Type I error and has proper coverage of 95% confidence intervals.

Double-blind, placebo-controlled, proof-of-concept trial of a kappa-selective opioid receptor antagonist augmentation in treatment-resistant depression.

Kappa-opioid antagonism may possess antidepressant properties. We assessed, in a proof-of-concept pilot trial among patients with major depressive disorder with inadequate response to antidepressants, the efficacy of adjunctive CERC-501 (formerly LY2456302), a kappaselective opioid receptor antagonist. In a Sequential Parallel Comparison Design study, patients were pre-randomized to: a) 10 mg/d of CERC-501 for 6 days, b) 20 mg/d of CERC-501 for 6 days, c) placebo for 3 days followed by 10 mg/d of CERC- 501 for 3 days, d) placebo for 3 days followed by 20 mg/d of CERC-501 for 3 days, or e) placebo for 6 days. The study was terminated early by the National Institute of Mental Health due to slow enrollment (N = 8). The weighted mean difference of changes (drug vs placebo) in the 6-item Hamilton Depression Rating Scale (HAMD-6) (primary outcome measure) (1.28), Montgomery-Åsberg Depression Rating Scale (MADRS) (2.33), Perceived Stress Scale (1.01), Symptoms of Depression Questionnaire (9.17), Positive Affect Scale (PAS) (6.39), Symptom Questionnaire (SQ) Depression scale (2.94), SQ Anger- Hostility scale (1.67), and Patient-Reported Outcomes Measurement Information System Satisfaction with Participation in Discretionary Social Activities (4.67) scores were all numerically but not statistically greater for CERC-501 than for placebo. Although the small sample size limits the ability to draw conclusions, results suggest that CERC-501 may have antidepressant effects. Additional studies are necessary to further explore these effects of CERC-501.

Power calculations for the sequential parallel comparison design with continuous outcomes

ABSTRACT In the sequential parallel comparison design (SPCD) in stage 1, placebo subjects are randomized between placebo and an experimental therapy. In stage 2, stage 1 placebo non-responders are re-randomized between placebo and an experimental therapy. We give the formula for power/sample size calculations for two test statistics for the SPCD. The first one omits the correlation between the estimated treatment effects from the two stages, and the second one does not. We discuss how to construct a confidence interval for the weighted average of the treatment effects that has proper coverage.

Sequential parallel comparison design with two coprimary endpoints.

A placebo-controlled randomized clinical trial is required to demonstrate that an experimental treatment is superior to its corresponding placebo on multiple coprimary endpoints. This is particularly true in the field of neurology. In fact, clinical trials for neurological disorders need to show the superiority of an experimental treatment over a placebo in two coprimary endpoints. Unfortunately, these trials often fail to detect a true treatment effect for the experimental treatment versus the placebo owing to an unexpectedly high placebo response rate. Sequential parallel comparison design (SPCD) can be used to address this problem. However, the SPCD has not yet been discussed in relation to clinical trials with coprimary endpoints. In this article, our aim was to develop a hypothesis-testing method and a method for calculating the corresponding sample size for the SPCD with two coprimary endpoints. In a simulation, we show that the proposed hypothesis-testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy. In addition, the usefulness of our methods is confirmed by returning to an SPCD trial with a single primary endpoint of Alzheimer disease-related agitation.

P.032 A phase-2, double-blind, placebo-controlled, sequential parallel comparison design study of efficacy and safety of adjunctive pimavanserin in major depressive disorder

The controllability and observability of a glucose insulin system is checked for the Sturis–Tolic model and its modified form for a type 1 diabetic patient. This technique plays a vital role in the development of a fully automatic artificial pancreas and stabilizes the control loop system for the glucose insulin pump. It would be important for helping type 1 diabetic patients to control their disease. We treated the Sturis–Tolic model for a healthy person and modified this model for a type 1 diabetic patient to check the linear controllability and observability. The Lyapunov equation is used to check the stability analysis of the model, which yields that the modified model is stable. We show the numerical simulation of the model for type 1 diabetes mellitus for the controllability and observability matrix according to different initial conditions on state vector. These models can be used to simulate a glucose insulin system for the treatment of type 1 diabetes.

Notes on power comparison between the sequential parallel comparison and other commonly-used designs

Because one excludes in the sequential parallel comparison design (SPCD) both placebo responders and patients assigned to the experimental treatment in period 1 from comparison in period 2, test procedures for the SPCD may lose efficiency. Assuming a random effects logistic regression model, we evaluate the loss of efficiency by comparing power of the SPCD with those for the parallel groups design with repeated measurements (PGDRM), simple crossover design (SCD), and parallel group design (PGD). Based on Monte Carlo simulations, we find that the increase in efficiency of the SPCD by use of the PGDRM and SCD can be significant, especially when the variation of responses between patients is large. The SPCD can be, however, of use if the relative treatment effect on placebo non-responders is of our primary interest.

Randomization-based analysis of covariance for inference in the sequential parallel comparison design

ABSTRACTThe sequential parallel comparison design (SPCD), with sequence groups P:P, P:T, and T:T, together with the exclusion of the second-period information from placebo responders in the first period, can serve usefully for studies with highly favorable placebo response, for example, psychiatric clinical trials. This paper presents a methodology for the first-period treatment difference in the overall population and the second-period treatment difference in the placebo nonresponders for the first period, as well as other available sources of information that could be of potential interest. Without any assumptions, a hypothesis testing method is proposed based on the randomization distribution of comparisons using the covariance structure for the randomized population under the null hypothesis to control type I error. Randomization-based analysis of covariance (ANCOVA) is introduced to adjust for baseline and for the observations that serve as baselines for the second period. Related methods are proposed for the study population as a simple random sample of an almost infinite population. The statistical properties of the proposed methods are described with simulation studies; and the use of the methods is illustrated for an example based on the data from the ADAPT-A clinical trial.

Statistical inference problems in sequential parallel comparison design

ABSTRACTThe sequential parallel comparison designhas recently been considered to solve the problem with high placebo response and the required sample size in the psychiatric clinical trials. One feature with this design is that a difference between the placebo group and the drug group may also arise in the variance–covariance structure of the clinical outcome. Provided the heterogeneity of the second moment, the treatment effect estimation at the second stage can be biased for the entire randomized patient population that includes patient responders. Our work presented here aims at how the coverage probability of the interval estimation of treatment effect performs under the unstructured variance–covariance matrix. The interaction between the truncation after the first stage and the heterogeneity of the second moment causes a substantial coverage probability problem. The type I error probability may not be controlled under the weak null due to this bias. This bias can also cause spurious power evaluation under an alternative hypothesis. The coverage probability of the ordinary least square statistic is shown in different scenarios.

Rejoinder to “Statistical inference problems in sequential parallel comparison designs”

ABSTRACTIn this rejoinder the authors stipulate further for two challenging issues. First, if placebo non-responders are selected simply by their response meeting a threshold, this selection may have misclassification error and consequently the treatment effect estimate may be biased, regardless of whether the estimand at the second stage is the treatment effect in the entire population or placebo non-responders. Secondly, the weak null hypothesis considered in our article Statistical Inference Problems in Sequential Parallel Comparison Design (2019) is that the expected treatment effects in placebo non-responders and in the entire set of patients entering the trial are both zero, in contrast to the strong null hypothesis that the statistical distribution of the response variable is equal in the compared treatments. The impact of violating the assumption of equal moments other than the mean parameter on statistical operating characteristics in estimation and testing of treatment effect can be substantial. As an example, the ordinary least squares based test detects a treatment difference even if the expected treatment effects in placebo non-responders and the entire population are both zero.