Drug-placebo Differences Research Articles

APOLLOE4 Phase 3 study of oral ALZ-801/valiltramiprosate in APOE ε4/ε4 homozygotes with early Alzheimer's disease: Trial design and baseline characteristics.

The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N=325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.

P75 neurotrophin receptor modulation in mild to moderate Alzheimer disease: a randomized, placebo-controlled phase 2a trial

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug–placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16; ClinicalTrials.gov registration: NCT03069014.

A Novel Method for Deriving Adverse Event Prevalence in Randomized Controlled Trials: Potential for Improved Understanding of Benefit-Risk Ratio and Application to Drug Labels.

Adverse event (AE) data in randomized controlled trials (RCTs) allow quantification of a drug's safety risk relative to placebo and comparison across medications. The standard US label for Food and Drug Administration-approved drugs typically lists AEsby MedDRA Preferred Term that occur at ≥ 2% in drug and with greater incidence than in placebo. We suggest that the drug label can be more informative for both patients and physicians if it includes, in addition to AE incidence (percent of subjects who reported the AE out of the total subjects in treatment), the absolute prevalence (percent of subject-days spent with an AE out of the total subject-days spent in treatment) and expected duration (days required for AE incidence to be reduced by half). We also propose a new method to analyze AEs in RCTs using drug-placebo difference in AE prevalence to improve safety signal detection. AE data from six RCTs in schizophrenia were analyzed (five RCTs of the dopamine D2 receptor-based antipsychotic lurasidone and one RCT of the novel trace amine-associated receptor 1 [TAAR1] agonist ulotaront). We determined incidence, absolute prevalence, and expected duration of AEs for lurasidone and ulotaront vs respective placebo. We also calculated areas under the curve of drug-placebo difference in AE prevalence and mean percent contribution of each AE to this difference. A number of AEs with the same incidence had different absolute prevalence and expected duration. When accounting for these two parameters, AEs that did not appear in the 2% incidence tables of the drug label turned out to contribute substantially to drug tolerability.The percent contribution of a drug-related AE to the overall side effect burden increased the drug-placebo difference in AE prevalence, whereas the percent contribution of a placebo-related AE decreased such difference, revealing a continuum of risk between drug and placebo. AE prevalence curves for drug were generally greater than those for placebo. Ulotaront exhibited a small drug-placebo difference in AE prevalence curves due to a relatively low incidence and short duration of AEs in the ulotaront treatment arm as well as the emergence of disease-related AEs in the placebo arm. Reporting AE absolute prevalence and expected duration for each RCT and incorporating them in the drug label is possible, is clinically relevant, and allows standardized comparison of medications. Our new metric, the drug-placebo difference in AE prevalence, facilitates signal detection in RCTs. We piloted this metric in RCTs of several neuropsychiatric indications and drugs, offering a new way to compare AE burden and tolerability among treatments using existing clinical trial information.

Meaningful benefit and minimal clinically important difference (MCID) in Alzheimer's disease: Open peer commentary.

Approval of the anti-amyloid monoclonal antibodies has stimulated an important discussion of the value to be placed on the magnitude of slowing achieved by treatment compared to placebo. The minimal clinically important difference (MCID) was reviewed in the context of other measures and analyses that provide perspective on the meaningfulness of treatment responses. TheMCID is a clinician-anchored approach to making this determination. The MCID applies best to symptomatic therapies for which the drug-placebo difference remains constant. Disease-modifying therapies produce a progressive divergence of drug and placebo trajectories; early in the course the MCID would not be achieved, later the MCID will be achieved, and with continuing therapy the MCID will be exceeded. Clinicians are not the only stakeholders involved in determining the value proposition of slowing disease progression. Patient-reported outcomes and caregiver-related measures offer important complementary insights. Analytic approaches also widen the perspective on the observed drug-placebo differences. Risk ratios, numbers needed to treat versus number needed to harm, time-to-event analyses, and predictive benefits based on biomarkers all add depth to the discussion. Multiple stakeholder perspectives are needed to determine the importance to be attributed to the therapeutic changes observed with monoclonal antibody therapies and other emerging treatments.

A randomized controlled trial of add-on naproxen, simvastatin and their combination for the treatment of schizophrenia or schizoaffective disorder

This large randomized controlled trial examined the effect of naproxen, simvastatin or both on patients with schizophrenia. This was a large multi-center, twelve-week, randomized, double-blind, placebo-controlled, four-arm clinical trial administering naproxen, simvastatin or both to 232 subjects with schizophrenia or schizoaffective disorder. The primary outcome was change in PANSS total score. ANCOVA and mixed model analyses of the PANSS total score change showed no significant difference between naproxen and placebo (adjusted p = 0.78), simvastatin and placebo (adjusted p = 0.38) or the combination of naproxen and simvastatin compared to placebo (adjusted p = 0.72). No statistically significant drug-placebo differences were found in the PANSS subscales, CGI or BACS between all groups. There was a near significant improvement in negative symptoms (p = 0.06), and an analysis of the 5 factor PANSS factors analysis found a significant improvement in simvastatin above placebo in withdrawal (p = 0.03). These finding were not significant after correcting for multiple comparisons. A meta-analysis on changes in total PANSS scores in studies on statins in schizophrenia, including the present study together with six other studies showed a significant improvement for statins compared to placebo (Hedges’ G of -0.245 (CI= -0.403, -0.086, p = 0.002). When one outlying study which showed particularly strong effects of statins was removed, part of the effect went away. In conclusion, in this study, naproxen and simvastatin alone or in combination were not efficacious in the treatment of symptoms in schizophrenia. However, the meta-analysis of all studies of simvastatin for schizophrenia indicates further research on this topic.

Usefulness of the placebo lead-in design for clinical trials with binary outcomes.

In placebo-controlled clinical trials to develop new drugs for the treatment of psychiatric or neurological disorders, a high and sometimes greater-than-expected placebo response makes it difficult to show the superiority of an investigational drug over a corresponding placebo. To avoid such difficulty, a placebo lead-in design has been presented, but its usefulness has been open to discussion. Although the statistical properties of the placebo lead-in design are investigated in the context of continuous outcomes, whether these properties can be generalized for binary or ordinal cases remains unclear. We investigate whether the placebo lead-in design is useful in clinical trials with binary outcomes through mathematical formulae and a numerical investigation. Specifically, we compare the proportion of placebo responders, the drug-placebo difference, and the effect size between two populations: one enriched for placebo nonresponders and the other comprising the all-comers. Under positive correlation of the data between the lead-in stage and the randomized stage for both treatment groups, we mathematically show that the proportion of responders in the population enriched for placebo nonresponders is less than that in the all-comers population, and whether the placebo lead-in design increases the drug-placebo difference depends on the variances of outcomes in both treatment groups as well as the correlations of the outcomes between two stages. Further, through a numerical investigation, we show that whether the placebo lead-in design increases the effect size strongly depends on the magnitude of the correlations and their difference. If the correlation of the placebo-placebo group is much higher than that of the placebo-drug group, the placebo lead-in design is advantageous in most cases but has an impact on an estimand in placebo nonresponders. Therefore, we do not recommend using the placebo lead-in design for clinical trials with binary outcomes.

The Impact of Baseline Anxiety on Drug Placebo Separation and Drug/Placebo Response in an Acute Schizophrenia Clinical Trial-A Post-hoc Analysis.

We sought to evaluate the impact of baseline anxiety levels on drug placebo separation and drug and placebo response in acutely psychotic schizophrenic subjects. In this post-hoc analysis, modified intent-to-treat Positive and Negative Syndrome Scale data were obtained from a phase 2, multi-center, 5 week, randomized, double-blind, placebo-controlled trial of KarXT in hospitalized adults with DSM-5 schizophrenia experiencing an acute exacerbation or relapse of symptoms. We investigated the impact of anxiety on drug placebo separation and drug and placebo response in 2 ways. In the first set of analyses, we dichotomized the data based on the absence or presence of anxiety symptoms. In the second set of analyses, we categorized subjects by levels of anxiety. All analyses were conducted using generalized linear models with normal distribution and identity link function. On average, subjects entering the trial were suffering from a moderate level of anxiety. Subjects with no baseline anxiety had a significant increase in placebo response, a decrease in drug response and did not separate drugs from placebo. With increasing levels of baseline anxiety, a larger drug placebo difference was observed. Our analyses identified that absence of anxiety at baseline was associated with a loss of signal at end of treatment between drug and placebo driven by a differential effect on placebo and treatment response. The effect observed was not related to the overall baseline symptom severity and was not mediated by improvement in anxiety itself. Interpretation of the results is caveated by the retrospective nature of the analyses.

Perspectives on the success rate of current antidepressant pharmacotherapy

ABSTRACT Introduction There has been growing debate about the effectiveness of traditional antidepressants for the treatment of depression, and whether the clinical trials literature overstates the value of existing agents. Antidepressant efficacy is limited by suboptimal remission rates, lack of robust efficacy across diverse depressed subgroups, slow onset, and challenges managing tolerability. Clinicians can better navigate uncertainties in this area by recognizing patient-specific clinical and prognostic factors that influence the likelihood of antidepressant drug response. Areas covered The author summarizes pertinent literature regarding drug-placebo differences in antidepressant outcome as well as patient-specific factors that influence antidepressant drug responsivity across subtypes of depressive disorders. Expert opinion Standardized effect sizes for most monoaminergic antidepressants are relatively modest. At least one-third of treatment response derives from nonspecific (yet substantial) placebo effects, limiting the ability to compare antidepressant medication effects to that of ‘no treatment.’ Patients with high baseline depressive symptom severity are less likely to respond to placebo but may be more responsive to antidepressant pharmacotherapy than is the case in mild forms of depression. Patient satisfaction with antidepressant response must take into consideration not only efficacy for reducing symptoms but also drug tolerability/acceptability and tangible improvement in functional outcome and quality of life.

Potential beneficial effects of masupirdine (SUVN-502) on agitation/aggression and psychosis in patients with moderate Alzheimer's disease: Exploratory post hoc analyses.

The effects of masupirdine on the neuropsychiatric symptoms were explored. Masupirdine (SUVN-502) was evaluated for its effects on cognition in patients with moderate AD. The prespecified primary outcome showed no drug-placebo difference. Post hoc analyses of domains of the 12-item neuropsychiatric inventory scale were carried out. In a subgroup of patients (placebo, n=57; masupirdine 50mg, n=53; masupirdine 100mg, n=48) with baseline agitation/aggression symptoms ≥1, a statistically significant reduction in agitation/aggression scores was observed in masupirdine 50mg (95% confidence interval (CI), -1.9 to -0.5, p<0.001) and masupirdine 100mg (95% CI, -1.7 to -0.3, p=0.007) treated arms at Week 13 in comparison to placebo and the effect was sustained for trial duration of 26weeks in the masupirdine 50mg treatment arm (95% CI, -2.3 to -0.8, p<0.001). Similar observations were noted in the subgroup of patients (placebo, n=29; masupirdine 50mg, n=30; masupirdine 100mg, n=21) with baseline agitation/aggression symptoms ≥3. In the subgroup of patients (placebo, n=28; masupirdine 50mg, n=28; masupirdine 100mg, n=28) who had baseline psychosis symptoms and/or symptom emergence, a significant reduction in psychosis scores was observed in the masupirdine 50mg (Week 4: 95% CI, -2.8 to -1.4, p<0.001; Week 13: 95% CI, -3.3 to -1.3, p<0.001) and masupirdine 100mg (Week 4: 95% CI, -1.4 to 0, p=0.046; Week 13: 95% CI, -1.9 to 0.1, p=0.073) treatment arms in comparison to placebo. Further research is warranted to explore the potential beneficial effects of masupirdine on NPS.

The Use of Brexpiprazole Combined With a Stimulant in Adults With Treatment-Resistant Attention-Deficit/Hyperactivity Disorder.

This is the first controlled pharmacologic study in either adults or children with uncomplicated, treatment-resistant attention-deficit/hyperactivity disorder (ADHD). This study augmented stimulant therapy with the atypical antipsychotic brexpiprazole. The Food and Drug Administration preapproved primary outcome measure (Conners' Adult ADHD Rating Scale [CAARS]) showed no drug-placebo differences. Often studies showing no efficacy on the prestudy, defined primary outcome variable go unpublished. While this is decried, publishing studies with equivocal results remains rare. This reanalysis highlights trends in secondary measures having implications for treatment and research regarding treatment resistant ADHD. Initially, 559 stimulant-naive and 174 prior stimulant nonresponders received methylphenidate osmotic-release oral system, dexmethylphenidate hydrochloride, lisdexamfetamine, or mixed amphetamine salts. After 5 weeks, 168 stimulant-naive patients and 68 prior stimulant nonresponders who failed treatment were randomized to brexpiprazole or placebo in a 2:1 ratio while the remaining were on the stimulant. Outcome was measured with the CAARS, Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Clinical Global Impression, and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). The WRAADDS contains 2 factors: attention and emotional dysregulation. Stimulant-naive patients showed no improvement with adjunctive brexpiprazole. Prior stimulant nonresponders displayed no brexpiprazole effect on the CAARS, Montgomery-Asberg Depression Rating Scale, or Beck Depression Inventory. In contrast, the WRAADDS detected a trend in treatment benefit, primarily through emotional dysregulation symptoms. Adverse effects on brexpiprazole and placebo were equivalent. Brexpiprazole might be effective in ADHD adults who are nonresponders to 2 or more stimulants. Future trials in treatment-resistant ADHD should use a 1:1 randomization and use a measure of ADHD symptoms that includes emotional dysregulation.

Controversies in the Pharmacotherapy of Adolescent Depression.

Although fluoxetine and, in the USA, escitalopram are approved for depression in adolescence, substantial concern surrounds antidepressant use in youth. Major controversies regarding the efficacy and safety (increased suicidality) of antidepressants exist. The category of depression is very broad and overinclusive in terms of etiology, the role of psychosocial adversities severity, episodicity, presentation, and relationship with bipolarity. This heterogeneity, not fully considered in Randomized Controlled Trials (RCTs), may account for the disappointing results with respect to both the efficacy and safety. Based on the available literature, we will address the following topics: a) controversies regarding the definition of depression as a unique homogeneous condition with a unique type of pharmacological treatment; b) controversies about the interpretation of data from Randomized Controlled Trials (RCTs) on the efficacy of pharmacological treatments in adolescent depression; c) the interpretation of data regarding the safety of antidepressant treatment in adolescent depression, particularly in terms of increased suicidal risk. According to RCTs, antidepressants are minimally to moderately more effective than placebo, principally based on very high placebo responses, and only fluoxetine shows more evidence of efficacy. These differences in meta-analyses are sometimes statistically but not clinically significant. Depression is a heterogeneous condition in terms of etiology, the role of psychosocial adversities severity, episodicity, presentation, and relationship with bipolarity. This heterogeneity may partly explain the low drug-placebo difference and the high placebo response (possibly related to a high level of natural recovery of adolescent depression). In the National Institute of Mental Health (NIMH)-funded studies, including a lower number of study sites and more reliable enrollment procedures, lower placebo response rates and greater group differences between medication and placebo were found. Robust evidence supports an increased risk of emergent suicidality after starting antidepressants. A clear age effect on suicidal risk after antidepressants is supported by a comprehensive meta-analysis, showing that suicidal risk increases with decreasing age, being markedly greater in subjects aged between 18 and 25 years. However, the term suicidality is too broad, as it includes suicidal ideation, suicidal attempts, and completed suicide, with a wide range of severity and pervasiveness. If emergent suicidality should be actively and carefully explored, empirical evidence, albeit weak, suggests that combined pharmacotherapy (antidepressant and/or lithium) associated with psychotherapy may be helpful in reducing pretreatment suicidal ideation and suicidal risk. Moderate to severe depression should be treated with psychotherapy and/or fluoxetine, the bestsupported medication, and treatment-resistant adolescents should always receive combined treatment with psychotherapy. Suicidal ideation, particularly with a plan, should be actively explored before starting an antidepressant, as a reason for the closest monitoring. Emergent suicidality after starting antidepressants, as well as antidepressant-related activation, should also be closely monitored and may lead to antidepressant discontinuation. Although no response to pharmacotherapy and psychotherapy may occur in up to 40% of depressed adolescents, possible predictors or mediators of poorer response in adolescents are uncertain, and only a few studies support possible treatment strategies. Finally, studies exploring the efficacy of antidepressants in specific depression subtypes, i.e., based on prevalent psychopathological dimensions (apathy, withdrawal, impulsivity), are warranted.

Influence on study outcomes of an inpatient study by the behavior of the study staff (PINgPOng): study protocol for a randomized clinical trial

BackgroundThe placebo effect as the symptom improvement following inert treatments is a fixed component of RCTs to differentiate between specific effects of the tested pharmacological substance from other unspecific effects. The PINgPOng study was set up to analyze the influence of a study team trained to either minimize the placebo response and optimize drug-placebo differences or to maximize the placebo response to increase drug efficacy by unspecific factors on the study results of a RCT in a classical early clinical trial setting.Methods/designPINgPOng is a single-center, prospective, randomized, double-blind, placebo-controlled study in a 3-group, 2-sequence, 2-period cross-over design. The study is conducted according to the principles of ICH-GCP and the Declaration of Helsinki on the Phase I-Unit of the University Hospital Bonn. The primary endpoint is the pain intensity in the cold pressor test before and after the administration of 15 mg oxycodone or placebo. The pain intensity is compared between three study conditions: 32 healthy volunteers in each study arm will be treated either by an untrained study team (arm A), by a study team trained to maximize (arm B), or to minimize placebo responses (arm C). Neuroendocrine factors (alpha-amylase activity, salivary cortisol), characteristic traits (anxiety, depression, stress), and somatic reactions are analyzed as covariates of the pain perception.DiscussionThe PINgPOng study will allow to answer the question whether and to what extent the behavior of a trained study team (neutral vs. maximize vs. minimize placebo responses) will differentially affect placebo responses in a setting of a highly standardized early clinical trial. The results will help to control the placebo effects by education of the clinical study team and to avoid unnecessary high placebo effects in clinical development.Trial registrationGerman Clinical Trials Register DRKS00013586. Registered on December 22, 2017.

Impact of chosen cutoff on response rate differences between selective serotonin reuptake inhibitors and placebo

Response defined as a 50% reduction in the sum score of the Hamilton Depression Rating Scale (HDRS-17-sum) is often used to assess the efficacy of antidepressants. Critics have, however, argued that dichotomising ratings with a cutoff close to the median may lead to scores clustering on either side, the result being inflation of miniscule drug-placebo differences. Using pooled patient-level data sets from trials of three selective serotonin reuptake inhibitors (SSRIs) (citalopram, paroxetine and sertraline) (n = 7909), and from similar trials of duloxetine (n = 3478), we thus assessed the impact of different cutoffs on response rates. Response criteria were based on (i) HDRS-17-sum, (ii) the sum score of the HDRS-6 subscale (HDRS-6-sum) and (iii) the depressed mood item. The separation between SSRI and placebo with respect to response rates increased when HDRS-17-sum was replaced by HDRS-6-sum or depressed mood as effect parameter and was markedly dependent on SSRI dose. With the exception of extreme cutoff values, differences in response rates were largely similar regardless of where the cutoff was placed, and also not markedly changed by the exclusion of subjects close to the selected cutoff (e.g., ±10%). The observation of similar response rate differences between active drugs and placebo for different cutoffs was corroborated by the analysis of duloxetine data. In conclusion, the suggestion that using a cutoff close to the median when defining response has markedly overestimated the separation between antidepressants and placebo may be discarded.

Error-related Alpha Suppression: Scalp Topography and (Lack of) Modulation by Modafinil.

Errors in performance trigger cognitive and neural changes that are implemented to adaptively adjust to fluctuating demands. Error-related alpha suppression (ERAS)-which refers to decreased power in the alpha frequency band after an incorrect response-is thought to reflect cognitive arousal after errors. Much of this work has been correlational, however, and there are no direct investigations into its pharmacological sensitivity. In Study 1 (n = 61), we evaluated the presence and scalp distribution of ERAS in a novel flanker task specifically developed for cross-species assessments. Using this same task in Study 2 (n = 26), which had a placebo-controlled within-subject design, we evaluated the sensitivity of ERAS to placebo (0 mg), low (100 mg), and high (200 mg) doses of modafinil, a wakefulness promoting agent. Consistent with previous work, ERAS was maximal at parieto-occipital recording sites in both studies. In Study 2, modafinil did not have strong effects on ERAS (a significant Accuracy × Dose interaction emerged, but drug-placebo differences did not reach statistical significance after correction for multiple comparisons and was absent after controlling for accuracy rate). ERAS was correlated with accuracy rates in both studies. Thus, modafinil did not impact ERAS as hypothesized, and findings indicate ERAS may reflect an orienting response to infrequent events.

Commentary on: A call for better reporting of trials using surrogate primary endpoints.

Drs. Manyara, Ciani, and Taylor make the important point that randomized controlled trials (RCTs) using a primary surrogate endpoint should be more transparent in their reporting details of biomarkers in trials. They suggest a clear statement concerning use of a surrogate primary endpoint and providing information on validity and limitations of the surrogate. They announce a new project to develop SPIRIT and CONSORT extensions specific to surrogate endpoints SPIRIT-SURROGATE and CONSORT-SURROGATE. There are no fully qualified and validated surrogate biomarkers for Alzheimer's disease (AD) RCTs and none that could serve as a primary RCT endpoint. As described by the US Food and Drug Administration (FDA) a surrogate endpoint is a clinical trial endpoint used as a substitute for a direct measure of how a patient feels, functions, or survives.1 A surrogate endpoint does not measure the clinical benefit of primary interest in and of itself, but rather is expected to predict clinical benefit. Epidemiologic, therapeutic, pathophysiologic, or other scientific data provide the evidentiary basis for establishing a biomarker as a surrogate. A surrogate must change in response to multiple therapies across multiple RCTs and must explain the change in clinical outcome as well as correlate with it.2 Designation as a surrogate requires substantial statistical evidence based on trial meta-analyses.3 Robert Califf, US Commissioner of Food and Drugs, makes the point that “the single most common and serious error in the evaluation of biomarkers is the assumption that a correlation between the measured level of a biomarker and a clinical outcome means that the biomarker constitutes a valid surrogate.”2 The primary outcome of the RCTs of the aducanumab trials was the Clinical Dementia Rating–Sum of Boxes (CDR-SB; NCT02484547; NCT02477800) and the primary endpoint was the drug–placebo difference on this outcome at week 76. Accelerated approval of aducanumab was based on amyloid plaque lowering as shown by amyloid positron emission tomography (PET) considered reasonably likely to predict clinical benefit.4 Reasonably likely surrogate endpoints are supported by a strong mechanistic and/or epidemiologic rationale, but the amount of clinical data available is not sufficient to support them as a validated surrogate endpoint (defined above). Reasonably likely surrogate endpoints are used to support the FDA's Accelerated Approval program, which is intended to provide patients with serious diseases more rapid access to promising therapies.5 Accelerated approval is followed by post-marketing studies to determine whether the reasonably likely surrogate endpoint, in fact, predicts the clinical benefit. The aducanumab trials would not have been included in reporting requirements for trials using surrogate primary endpoints; their primary endpoints were drug–placebo differences on clinical measures; amyloid lowering was not a primary or a secondary endpoint and was not included in the sequential testing rank order implemented (NCT02484547; NCT024778006). I concur with Drs. Manyara, Ciani, and Taylor that biomarkers should be described in greater detail in the SPIRIT and CONSORT criteria. Using the FDA biomarker lexicon, these measures would be described as risk/susceptibility, diagnosis, monitoring, pharmacodynamic/response, predictive, prognostic, or safety biomarkers.7, 8 Candidate surrogate biomarkers or biomarkers that might be considered reasonably likely to predict clinical benefit are pharmacodynamic biomarkers. Biomarkers that have been qualified for a specific context of use in the RCT should be described in the SPIRIT and CONSORT reporting framework.9 The SPIRIT-SURROGATE and CONSORT-SURROGATE initiative is important and might be more broadly conceived as a SPIRIT-BIOMARKER and CONSORT-BIOMARKER initiatives. Another important adjustment to the SPIRIT and CONSORT criteria is to require the reporting of ethnicity and race among trial participants. These data are sometimes not collected and often omitted from clinical trial reports.10 They are critically important to assess our success in increasing the diversity of clinical trial populations. JC is supported by NIGMS grant P20GM109025; NINDS grant U01NS093334; NIA grant R01AG053798; NIA grant P20AG068053; NIA grant P30AG072959; NIA grant R35AG71476; Alzheimer’s Disease Drug Discovery Foundation (ADDF); Ted and Maria Quirk Endowment; and the Joy Chambers-Grundy Endowment. J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Karuna, Lilly, Lundbeck, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. Author disclosures are available in the supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Assessment of Negative Symptoms in Clinical Trials of Acute Schizophrenia: Test of a Novel Enrichment Strategy.

Drug trials for negative symptoms in schizophrenia select patients based on the severity and stability of negative symptoms, using criteria that are not suitable for trials of acute exacerbation of schizophrenia. Here we present a method to prognostically enrich subjects having a predefined factor structure in PANSS and apply it to the measurement of negative symptoms specifically in trials of acute schizophrenia. A vector of 1335 elements based on between- and within-item variances, covariances, and differences of PANSS items was created to calculate an index of heterogeneity and to enrich for a predetermined symptom construct in PANSS. Using prerandomization PANSS scores across N = 4876 subjects in 13 trials of acute schizophrenia, we demonstrate an ability to select for a subpopulation having the greatest amount of variance explained across the 7-items of the Marder PANSS negative symptom (MPNS) construct. Network analyses on subjects enriched for MPNS construct confirm that negative symptoms were most influential in overall psychopathology, distinct from subjects without the MPNS construct. As expected for D2 antagonists, drug-placebo differences on negative symptoms with lurasidone were not specific to the subpopulation having the MPNS construct. In contrast, the novel TAAR1 agonist ulotaront demonstrated specific improvements in negative symptoms which were greatest in the MPNS subpopulation. These results demonstrate the utility of a novel prognostic enrichment strategy that can address heterogeneity in clinical trials, where patients can be selected on the basis of a greater likelihood of having the measured symptom construct (negative symptoms) related to the disorder (schizophrenia). ClinicalTrials.gov Identifiers: NCT0296938, NCT00088634, NCT00549718, NCT00615433, NCT00790192.

Association of Single-blind Placebo Run-in Periods With the Placebo Response in Randomized Clinical Trials of Antidepressants

Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators. To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021. Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders. Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies. Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods. A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g = 1.05 [95% CI, 0.98-1.11]; I2 = 82%) than studies that did not use a PRI period (g = 1.15 [95% CI, 1.09-1.21]; I2 = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g = 1.55 [95% CI, 1.49-1.61]; I2 = 85%) than those that did use a PRI period (g = 1.42 [95% CI, 1.36-1.48]; I2 = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g = 0.33 [95% CI, 0.29-0.38]; I2 = 47% for use of a PRI period vs g = 0.34 [95% CI, 0.30-0.38]; I2 = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18). This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.

504 Assessment of the Clinical Benefits of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy

Abstract Introduction When evaluating results of randomized, placebo-controlled trials, the clinical impact of a treatment can be assessed using number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person) and effect size (magnitude of drug–placebo difference on outcome measures). Lower NNTs indicate a more robust effect; NNT &amp;lt;10 is generally considered to represent a meaningful between-treatment difference. This analysis evaluated NNTs and effect sizes for pitolisant in the treatment of excessive daytime sleepiness (EDS) and cataplexy, using data from 7- or 8-week, randomized, placebo-controlled studies. Methods Patients in both studies experienced EDS at study baseline (Epworth Sleepiness Scale [ESS] score ≥14 in HARMONY-1 and ≥12 in HARMONY-CTP); patients in HARMONY-CTP also experienced ≥3 cataplexy attacks/week. Pitolisant was titrated over a 3-week period to a maximum potential dose of 35.6 mg/day, after which the dose remained stable. End-of-treatment assessments occurred at Week 8 in HARMONY-1 and Week 7 in HARMONY-CTP. Treatment response was defined for EDS based on ESS score reduction (≥3-point decrease from baseline or final score ≤10) and for cataplexy as ≥50% reduction from baseline to stable-dose period in the weekly rate of cataplexy (WRC). NNTs were calculated as the inverse of the drug–placebo difference in response rates. Effect sizes for change from baseline in mean ESS score and WRC were calculated using Cohens’ d. Missing values were imputed using a last-observation-carried-forward approach. Results Treatment response for EDS was observed in HARMONY-1 (pitolisant, n=31; placebo, n=30) in 67.7% of pitolisant-treated versus 43.3% of placebo-treated patients (NNT=5) and in HARMONY-CTP (pitolisant, n=54, placebo, n=51) in 68.6% versus 34.0% of patients, respectively (NNT=3). In HARMONY-CTP, treatment response for cataplexy was observed in 66.7% of pitolisant-treated patients versus 25.5% of placebo-treated patients (NNT=3). Effect sizes were 0.61 (HARMONY-1) and 0.86 (HARMONY-CTP) based on ESS change scores, and 0.86 (HARMONY-CTP) based on change in WRC. Conclusion The low NNTs and large effect sizes observed in this analysis provide further evidence that pitolisant produces meaningful clinical benefits in the treatment of EDS and cataplexy in adults with narcolepsy. Support (if any) Bioprojet Pharma and Harmony Biosciences, LLC.

The Impact of Failed Antidepressant Trials on Outcomes in Children and Adolescents with Anxiety and Depression: A Systematic Review and Meta-Analysis.

Objective: To identify predictors of medication-placebo differences in double-blind placebo-controlled antidepressant trials in children and adolescents with anxiety and depression. Methods: Clinical trials in patients <18 years of age with major depressive disorder or generalized, separation or social anxiety disorders were obtained from PubMed, the Cochrane Database and clinicaltrials.gov searches from inception through 2019. Forty-nine trials (43 published and 6 unpublished) of anxiety (κ = 13) and depression (κ = 36) evaluated 19 antidepressants in 8642 child and adolescent patients; placebo and medication response rates, trial characteristics, disorder, medication class, and funding source were extracted. Antidepressant-placebo differences were examined using Bayesian hierarchical models and estimates of response were determined for trial design, disorder, and medication class variables. Using meta-regression, correlates of antidepressant-placebo difference and placebo response were examined. Results: Funding source differentiated medication-placebo differences regardless of disorder. Industry trials had larger placebo response rates (mean difference: 0.189 ± 0.066, credible interval [CrI]: 0.067 to 0.33, p = 0.0008) and smaller medication-placebo differences (-0.235 ± 0.078, CrI: -0.397 to -0.086, p = 0.005) compared with federally funded trials. However, medication response was similar for industry- and federally-funded studies (-0.046 ± 0.042, CrI: -0.130 to 0.038, p = 0.252). Conclusions: The impact of study sponsorship on trial outcome supports the assertion that industry-funded trials with high placebo response rates and small drug-placebo differences are "failed trials" and should not be described as "negative trials" or used to determine public health estimates of antidepressant efficacy in children and adolescents with anxiety and depression. Identifying the proper role and value of industry-funded trials is critical to establishing the evidence base for antidepressants in youth.

A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody

BackgroundLecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease (AD) and mild AD dementia.MethodsBAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer’s Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging.ResultsA total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (−0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly.ConclusionsBAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer’s disease is underway.Trial registrationClinical Trials.govNCT01767311.