Objective stated in the publication

“To evaluate the efficacy and safety of LB-102 in acute schizophrenia.” (opens the source at this quote in a new tab)

Primary, secondary, and exploratory objectives in the protocol

“To determine whether LB-102 administered to patients with acutely exacerbated schizophrenia demonstrates antipsychotic efficacy, as determined by a change from Baseline on the PANSS total score, compared to placebo.” (opens the source at this quote in a new tab)
“To evaluate the safety and tolerability of LB-102 in patients with acutely exacerbated schizophrenia.” (opens the source at this quote in a new tab)
“To assess the effect of LB-102 on PANSS subscale and Marder Factor scores in patients with acutely exacerbated schizophrenia.” (opens the source at this quote in a new tab)
“To explore the effect of LB-102 on Cogstate test score” (opens the source at this quote in a new tab)

Registered study purpose

“This is a Phase 2, randomized, double-blind, placebo-controlled, multi-center inpatient study to evaluate the efficacy and safety of LB-102 in adult patients diagnosed with acutely exacerbated schizophrenia.” (opens the source at this quote in a new tab)
“The secondary objectives of the study are to evaluate improvement in CGI-S, safety and tolerability, and pharmacokinetics.” (opens the source at this quote in a new tab)

Study dates in the registry

Milestone	Registry record
Study start (actual)	“2023-11-29”
Primary completion (actual)	“2024-12-04”
Study completion (actual)	“2024-12-04”
First posted	“2023-12-21”
Results first posted	“2025-10-22”

Sites and conduct period reported in the publication

“conducted at 25 inpatient sites in the US between December 2023 and August 2024” (opens the source at this quote in a new tab)

Registered locations

“This study has 25 locations” (opens the source at this quote in a new tab)

Study centers and contract research organization in the protocol

“This study will be conducted in up to 25 study centers, with up to 25 Investigators, located in the US. Worldwide Clinical Trials, a contract research organization, will oversee operational aspects of this study on behalf of LB Pharmaceuticals Inc, the Sponsor of the study.” (opens the source at this quote in a new tab)

Topline results announcement date

“The topline results from the trial were announced in January 2025.” (opens the source at this quote in a new tab)

Phase 2 randomized, double-blind, placebo-controlled, fixed-dose design

“This Phase 2 randomized, double-blinded, placebo-controlled, fixed dose, multicenter clinical study is designed to evaluate the efficacy, safety, tolerability, and PK of LB-102 50 mg QD, LB-102 75 mg QD, and LB-102 100 mg QD versus placebo in patients diagnosed with schizophrenia having an acute exacerbation of psychosis.” (opens the source at this quote in a new tab)

Study periods

“Trial participation lasted approximately 8 weeks and included an inpatient screening period of up to 14 days, 28-day inpatient treatment period, an inpatient stabilization period, and an outpatient final safety follow-up approximately 2 weeks after completion of the treatment period.” (opens the source at this quote in a new tab)

Randomization, allocation ratio, and blinding

“Eligible participants were randomized according to a computer-generated randomization schedule using a site-based block size of 4.” (opens the source at this quote in a new tab)
“The randomization ratio was 3:3:3:1 to oral once-daily placebo; LB-102 50 mg; LB-102 75 mg; or LB-102 100 mg, with a smaller sample planned in the arm receiving 100 mg.” (opens the source at this quote in a new tab)
“Randomization was fully blinded, with assignments concealed from participants, trial personnel, investigators, sponsor, contract research organization, and clinical site teams.” (opens the source at this quote in a new tab)

Registry design fields

Field	Registry record
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Masking	“Quadruple”
Phase	“Phase 2”

Sponsor rationale for the smaller exploratory 100 mg arm

“Based on previous results, we believed that there was a potential for the 100 mg dose to result in receptor occupancy above 80%. As a result, we chose to limit the number of participants enrolled at this dose level while maintaining enough patients to provide insight into the therapeutic potential of this dose.” (opens the source at this quote in a new tab)
“The 100 mg dose cohort was exploratory and was intended to characterize safety at the higher dose. However, we analyzed the 100 mg cohort with the same statistical rigor, including sensitivity analyses, applied to the 50 and 75 mg cohorts.” (opens the source at this quote in a new tab)

Protocol rationale for the 4-week duration, fixed doses, and inpatient setting

“A 4-week double-blind Treatment Period is of adequate length to determine whether an antipsychotic effect has been demonstrated. Since efficacy in schizophrenia is dependent on both treatment duration and dose, a fixed dose approach represents the optimal study design to evaluate efficacy. To facilitate enrollment of acutely ill patients and optimize treatment compliance, a 4-week inpatient hospitalization is required following the initial screening phase.” (opens the source at this quote in a new tab)

Protocol dose rationale

“Based on the mechanism of action of LB-102 at dopamine D2 and 5HT7 receptors, data from animal models, and PET dopamine RO data, it is hypothesized that LB-102 will have antipsychotic effects at doses ranging from 50 mg/day to 100 mg/day.” (opens the source at this quote in a new tab)

Central review of ratings

“PANSS and MINI screening assessments, as well as PANSS assessments at baseline and week 4, were reviewed by an independent central reviewer.” (opens the source at this quote in a new tab)

Measures intended to limit placebo response

“We included a number of measures in this Phase 2 trial to reduce the risk of an elevated placebo rate including consistent, frequent, and close engagement with clinical sites, the use of a third-party vendor to help identify and exclude professional patients from the trial, and a centralized review of PANSS ratings to ensure consistency and quality control throughout the trial.” (opens the source at this quote in a new tab)

“The PANSS Rater will read the PCRS before administering the PANSS at each study visit.” (opens the source at this quote in a new tab)

Safety oversight, individual stopping criteria, and interim analysis

“A Safety Review Committee (SRC) will be established to review available safety data; details are included in the safety data plan.” (opens the source at this quote in a new tab)
“Dosing of an individual patient will cease if any of the following criteria are met:” (opens the source at this quote in a new tab)
“An increase in QTcF to >500 msec for male and female patients.” (opens the source at this quote in a new tab)
“An increase in QTcF of >60 msec over Baseline.” (opens the source at this quote in a new tab)
“No interim analysis is planned for this study.” (opens the source at this quote in a new tab)

Pharmacokinetic sampling subset

“PK analyses will include the first 60 patients randomized in the study regardless of cohort.” (opens the source at this quote in a new tab)

Sponsor statement on the regulatory role of the trial

“Based on the design of this clinical trial, the results discussed below, and positive feedback from FDA as part of our end-of-Phase 2 interaction, we believe this Phase 2 trial may serve as one of two adequate well-controlled clinical trials of LB-102 required for approval.” (opens the source at this quote in a new tab)

Key inclusion criteria

Criterion	Quoted registry text
Age and diagnosis	“Male and female patients 18 to 55 years of age inclusive at the time of informed consent with a diagnosis of schizophrenia as defined by DSM-5 criteria and confirmed by the MINI 7.0.2”
Body mass index	“Body mass index (BMI) must be ≥18 and ≤40 kg/m2.”
PANSS total score	“Total PANSS score between 80 and 120, inclusive, and”
PANSS positive items	“Score of ≥4 (moderate or greater) for ≥2 of the following Positive Scale (P) items: Item 1 (P1; delusions), Item 2 (P2; conceptual disorganization), Item 3 (P3; hallucinatory behavior), Item 6 (P6; suspiciousness/persecution), and”
CGI-S	“CGI-S score ≥4 (moderately to severely ill).”
Prior antipsychotic response	“Have received previous antipsychotic treatment (dose and duration as per the label) and who showed a previous good response to such antipsychotic treatment (other than clozapine) in the last 12 months, according to the Investigator's opinion.”
Relapse history	“Have history of relapse and/or exacerbation of symptoms when they were not receiving antipsychotic treatment.”
Hospitalization	“Must be willing to be hospitalized for the duration of the inpatient period of the study.”
Living situation	“Have stable living environment when not in a hospital.”

Acute exacerbation window and antipsychotic-free interval

“At screening, participants were required to need hospitalization, or continued hospitalization, for a current acute exacerbation of psychotic symptoms, with symptom onset less than or equal to 6 weeks prior; if already an inpatient at screening, the participant must have been hospitalized for onset less than or equal to 2 weeks for the current exacerbation.” (opens the source at this quote in a new tab)
“Participants must have been free from antipsychotic treatment for 2 or more weeks (or ≥5 times the treatment half-life) before baseline assessment.” (opens the source at this quote in a new tab)

Key exclusion criteria: psychiatric history and illness course

“Patients who presented with a first episode of schizophrenia.” (opens the source at this quote in a new tab)
“Improvement of ≥20% in total PANSS score between the Screening and Baseline assessments.” (opens the source at this quote in a new tab)
“History of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (dose and duration as per the label) or required clozapine within the last 12 months.” (opens the source at this quote in a new tab)
“Current DSM-5 Axis I diagnosis other than schizophrenia.” (opens the source at this quote in a new tab)
“Patients who met DSM-5 criteria for substance abuse or dependence within the past 1 year.” (opens the source at this quote in a new tab)
“Patients with clinically significant tardive dyskinesia.” (opens the source at this quote in a new tab)
“Prisoners or patients who were compulsorily detained (involuntarily hospitalized) for treatment of either a psychiatric or physical illness or have been in the last 6 months prior to the Screening Visit” (opens the source at this quote in a new tab)

Exclusion of recently diagnosed schizophrenia

“Patients who presented with a first episode of schizophrenia based on the clinical judgment of the Investigator and patients with diagnosed schizophrenia equal to or less than a year.” (opens the source at this quote in a new tab)

Key exclusion criteria: medical conditions and laboratory values

“Patients with insulin-dependent diabetes mellitus (i.e., any patient using insulin) are excluded.” (opens the source at this quote in a new tab)
“Patients with known ischemic heart disease or any history of myocardial infarction, congestive heart failure.” (opens the source at this quote in a new tab)
“Patients with epilepsy or a history of seizures.” (opens the source at this quote in a new tab)
“AST and ALT >2 × upper limit of normal (ULN)” (opens the source at this quote in a new tab)
“HbA1c ≥7.0%” (opens the source at this quote in a new tab)
“Patients with a history of neuroleptic malignant syndrome.” (opens the source at this quote in a new tab)

Electrocardiographic exclusion threshold

“Interval between Q and T wave corrected for heart rate using Fridericia’s formula (QTcF) interval >450 msec for males and females” (opens the source at this quote in a new tab)

Rescreening

“Participants were able to be rescreened on a case-by-case basis with approval of the sponsor and medical monitor.” (opens the source at this quote in a new tab)

Treatment arms

Arm	Quoted registry description
LB-102 50 mg once daily	“Oral LB-102: 50 mg (n ~ 105)”
LB-102 75 mg once daily	“Oral LB-102: 75 mg (n ~ 105)”
LB-102 100 mg once daily	“Oral LB-102: 100 mg (n ~ 35)”
Placebo	“Matched placebo tablets”

Dosing frequency, duration, and titration

“LB-102 will be dosed orally once a day.” (opens the source at this quote in a new tab)
“The duration of treatment of the study is 28 days (4 weeks).” (opens the source at this quote in a new tab)

“All patients started at the planned dose level without titration.” (opens the source at this quote in a new tab)

Tablet strength, matched placebo, and supervised administration

“LB-102 and placebo will be administered as visually matched tablets for the treatment of adult patients with an acute exacerbation of schizophrenia. LB-102 tablets are 50 mg in strength. The placebo tablets will match the 50-mg tablets in appearance.” (opens the source at this quote in a new tab)
“Administration of study drug will be supervised by study personnel to ensure compliance.” (opens the source at this quote in a new tab)

Discontinuation of prior psychotropic medication

“Starting on the first day of the screening phase, after written informed consent for the study has been provided, all antipsychotic or other psychotropic medications will be stopped with clinically appropriate titration down as per the Investigator’s clinical judgment.” (opens the source at this quote in a new tab)

Permitted concomitant psychotropic medication

“Psychotropic medications are prohibited except for lorazepam as needed for agitation, restlessness, irritability, or hostility; zolpidem, zaleplon, or eszopiclone for insomnia; diphenhydramine or benztropine for EPS; and propranolol for akathisia.” (opens the source at this quote in a new tab)

Medication and study period	Dose permitted
Lorazepam, screening phase through day 7	“Maximum of 6 mg/day”
Lorazepam, day 8 through day 14	“Maximum of 4 mg/day”
Lorazepam, day 15 through day 28	“Maximum of 2 mg/day”
Benztropine, screening phase through day 28	“Maximum 4 mg/day”
Propranolol, screening phase through day 28	“Maximum of 40 mg/day”

Post-treatment stabilization on standard antipsychotic medication

“an inpatient Stabilization Period of up to 5 days (during which patients will be stabilized on standard antipsychotic medication)” (opens the source at this quote in a new tab)

Concomitant medication use during the trial by treatment arm

No evidence found.

Primary endpoint and the sponsor's stated rationale

“The primary end point was change from baseline to week 4 in PANSS total score.” (opens the source at this quote in a new tab)

“The scale utilized for the primary study endpoint, Positive and Negative Syndrome Scale (PANSS) is validated and widely used in this patient population.” (opens the source at this quote in a new tab)

PANSS structure and scoring range

“The PANSS rating is composed of 7 positive symptom scales, 7 negative system scales, and 16 general psychopathology symptom scales. Patients are scored from 1 to 7 on each symptom scale. The total score of the PANSS is a minimum of 30 and a maximum of 210.” (opens the source at this quote in a new tab)
“A decrease in PANSS total score correlates with an improvement in schizophrenia symptoms whereas a higher PANSS total value represents a worse outcome” (opens the source at this quote in a new tab)

“The PANSS consists of 3 subscales containing a total of 30 symptom constructs. For each symptom construct, severity is rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms.” (opens the source at this quote in a new tab)
“The PANSS will be administered using the clinician rated semi-structured interview via the SCI-PANSS.” (opens the source at this quote in a new tab)

Development and validation of the PANSS

“Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology.” (opens the source at this quote in a new tab)
“Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.” (opens the source at this quote in a new tab)

European Medicines Agency guidance on the primary efficacy measure

“To support an indication for the treatment of schizophrenia, efficacy on a broad range of schizophrenia symptoms, as captured by the total score on instruments such as the PANSS or BPRS, has to be demonstrated in short-term studies (see section 4.4.3.1.) and maintenance of treatment effectiveness has to be shown in at least one long term study (see section 4.4.4.).” (opens the source at this quote in a new tab)
“The primary efficacy measure should be a composite measure of the symptoms of schizophrenia. For this, the widely accepted measurement scales are the PANSS (Positive and Negative Symptom Scale) and BPRS (Brief Psychiatric Rating Scale), which are still considered to be reliable and validated.” (opens the source at this quote in a new tab)
“Primary efficacy measure(s) should be presented as the numerical change in schizophrenia symptom score from baseline to study endpoint (final measurement). The results should be discussed not only in terms of statistical significance but also in terms of clinical relevance.” (opens the source at this quote in a new tab)

PANSS total score as the primary efficacy measure in FDA-approved labeling for xanomeline and trospium chloride

“The primary efficacy measure was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 5.” (opens the source at this quote in a new tab)
“The PANSS is a 30-item scale that measures symptoms of schizophrenia. Each item is rated by a clinician on a seven-point scale. A score of 1 indicates the absence of symptoms, and a score of 7 indicates extremely severe symptoms. The PANSS total score may range from 30 to 210 with higher scores reflecting greater overall symptom severity.” (opens the source at this quote in a new tab)

FDA guidance document specific to efficacy endpoints in schizophrenia trials

No evidence found.

Clinical meaning of PANSS total scores and percentage reductions

“Being considered "mildly ill" according to the CGI approximately corresponded to a PANSS total score of 58, "moderately ill" to a PANSS of 75, "markedly ill" to a PANSS of 95 and severely ill to a PANSS of 116.” (opens the source at this quote in a new tab)
“To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively. The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%.” (opens the source at this quote in a new tab)

Absolute PANSS change corresponding to minimal clinical improvement

“An absolute reduction of the BPRS/PANSS by approximately 10/15 points corresponded to a CGI change of 'minimally improved' and to a change of the CGI severity score by one severity step.” (opens the source at this quote in a new tab)
“Less severely ill patients required less BPRS/PANSS total score reduction to achieve the same CGI-improvement score than more severely ill patients.” (opens the source at this quote in a new tab)

Responder thresholds recommended for acute schizophrenia trials

“In short term trials in patients with acute/exacerbated symptoms at least a 30% reduction on the total PANSS score compared to baseline is generally considered to be clinically relevant and can be accepted as a definition of responder.” (opens the source at this quote in a new tab)

“When the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS) are used for definitions of response, a cut-off of at least 50% reduction of the baseline score should be used for acutely ill, non-refractory patients and a cut-off of at least 25% reduction for refractory patients.” (opens the source at this quote in a new tab)

Correction of percentage change for the 30-point minimum score

“All 30 items range from 1 to 7 leading to a minimum total score of 30, implying that the PANSS is an interval scale. For such interval scales straightforward calculation of relative changes is not appropriate.” (opens the source at this quote in a new tab)
“This systematic literature research shows that the majority of authors (62%) actually appear to use incorrect calculations.” (opens the source at this quote in a new tab)

“In the prespecified analysis, PANSS total score was derived from the standard item rating scale (1-7, total score range: 30-210). In the post hoc analysis, item scores were rescaled (0-6; total score range: 0-180) to adjust for the mathematical floor effect.” (opens the source at this quote in a new tab)

Placebo response trends in acute schizophrenia trials: FDA analysis of new drug applications

“the mean placebo response (change from baseline in PANSS score) increased from -6.4 to -10.5” (opens the source at this quote in a new tab)
“In North American trials, placebo response increased from -4.3 (pre-2009) to -8.5 (post-2009), and treatment effect decreased from -9.0 (pre-2009) to -3.4 (post-2009).” (opens the source at this quote in a new tab)
“Baseline disease severity remained similar in the pre- and post-2009 time periods, with PANSS scores ranging between 85 and 100.” (opens the source at this quote in a new tab)

Placebo response trends in acute schizophrenia trials: meta-analyses

“The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38.” (opens the source at this quote in a new tab)
“However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes.” (opens the source at this quote in a new tab)

“The average treatment change associated with placebo treatment in antipsychotic trials rose since 1960, while the change associated with medication treatment decreased.” (opens the source at this quote in a new tab)

Secondary efficacy endpoints

“Secondary end points included changes from baseline to week 4 in CGI-S, PANSS Positive Symptoms subscale, PANSS Negative Symptoms subscale, and PANSS Marder factor scores” (opens the source at this quote in a new tab)
“CGI-S responder rate (ie, proportion of participants with a score of 1 [normal], 2 [borderline ill], or 3 [mildly ill])” (opens the source at this quote in a new tab)
“greater than or equal to 20% PANSS responder rate (ie, proportion of participants with ≥20% reduction from baseline in PANSS total score; using the original item scores [range, 1-7]) at week 4” (opens the source at this quote in a new tab)
“Post hoc analyses evaluated the greater than or equal to 20% PANSS responder rate using a floor adjustment (ie, item scores rescaled from 1-7 to 0-6), to provide context for indirect comparisons with prior data.” (opens the source at this quote in a new tab)

Clinical Global Impressions-Severity of Illness scale

“The Clinical Global Impressions-Severity (CGI-S) rates illness severity on a scale from 1 to 7 and has been shown to correlate with PANSS.” (opens the source at this quote in a new tab)
“The scoring is for the CGI-S:1-normal, not at all ill, 2-Borderline mentally ill, 3-Mildly ill, 4-Moderately ill, 5-Markedly ill, 6-Severely ill, and 7-Extremely ill.” (opens the source at this quote in a new tab)

“Clinical global impression (CGI) data should also be presented, both CGI-severity and CGI-improvement.” (opens the source at this quote in a new tab)

PANSS Marder factor scores

“PANSS Marder is a way to group the 30 individual items of the PANSS into five broader categories or dimensions. This factor structure is widely used in clinical trials and research to assess and analyze symptoms of schizophrenia.” (opens the source at this quote in a new tab)

Negative symptom measurement in regulatory guidance

“Satisfactory reliability and validity has been demonstrated for the negative symptoms subscale of the PANSS and for the SANS (Scale for the Assessment of Negative Symptoms).” (opens the source at this quote in a new tab)

Exploratory cognition endpoint: Cogstate battery

“The Cogstate Computerized Schizophrenia Battery of Tests is a measure of cognitive ability in subject with Schizophrenia in both the acute and chronic stages and will take approximately 22 to 35 minutes to complete.” (opens the source at this quote in a new tab)

“Changes from baseline in the individual tests were prespecified exploratory endpoints, with composite scores generated post hoc in the total population:” (opens the source at this quote in a new tab)
“Based on previously published literature, the threshold for clinical importance of the treatment effect size was pre-determined as 0.2.” (opens the source at this quote in a new tab)

Safety and tolerability assessments

“Safety was evaluated through AEs, assessment of body weight/waist circumference, vital signs, clinical laboratory parameters, and 12-lead electrocardiograms. Suicidal ideation was evaluated using the Columbia-Suicide Severity Rating Scale (C-SSRS).” (opens the source at this quote in a new tab)
“The evaluation of neuromotor AEs was assessed using the Simpson-Angus Scale (SAS; range, 0-40).” (opens the source at this quote in a new tab)
“Akathisia was evaluated using the Barnes Akathisia Rating Scale (BARS; range, 0-14).” (opens the source at this quote in a new tab)
“The Abnormal Involuntary Movement Scale (AIMS; total dyskinesia score range, 0-28) assessed the presence and severity of tardive dyskinesia and other involuntary motor AEs.” (opens the source at this quote in a new tab)
“defined as any AE that began on or after the first dose of trial medication or any preexisting condition that reappeared during the treatment period and 14 days or less after the last dose” (opens the source at this quote in a new tab)

Planned sample size and power

“A sample size of 350 participants was estimated to provide greater than or equal to 85% power at a 2-sided 5% significance level to detect an assumed between-group treatment difference of 8 points in change from baseline in PANSS total score between either LB-102 50 mg or 75 mg and placebo, assuming an SD of 18, overall dropout rate of 25%, and a multiplicity adjustment using the Hochberg procedure.” (opens the source at this quote in a new tab)

Planned allocation by arm

“~105 patients will get placebo, ~105 will get 50 mg LB-102 QD, ~105 will get 75 mg LB-102 QD, ~35 will get 100 mg LB-102 QD” (opens the source at this quote in a new tab)

Participants screened and randomized

“Of 622 individuals screened, 263 (42.3%) were excluded. The primary reasons for screen failure included not meeting randomization criteria (229 [87.1%]) and study withdrawal (27 [10.3%]).” (opens the source at this quote in a new tab)
“There were 359 participants randomized (mean [SD] age, 39.1 [9.3] years; 69 female [19.2%]; 290 male [80.8%]; placebo, 108 [30.1%]; LB-102 50 mg, 107 [29.8%]; 75 mg, 108 [30.1%]; 100 mg, 36 [10.0%]), with all receiving 1 or more treatment doses and no protocol exceptions” (opens the source at this quote in a new tab)

Participants with observed week 4 data in the efficacy table

Measure	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
PANSS total score, No.	“93”	“91”	“84”	“23”
CGI-S score, No.	“94”	“91”	“83”	“23”

Participants analyzed in the registry results

Measure	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Started	“108”	“107”	“108”	“36”
Primary outcome, overall number of participants analyzed	“108”	“107”	“108”	“36”
CGI-S outcome, overall number of participants analyzed	“94”	“91”	“83”	“23”

“N for analyzed participants reflects all participants (i.e., including those with missing data imputed). Missing PANNS total scores were imputed using a mixture of MAR and MNAR approaches depending on the reason for missingness.” (opens the source at this quote in a new tab)
“N for Analyzed participants reflects observed CGI-S data at Week 4.” (opens the source at this quote in a new tab)

Safety and modified intention-to-treat populations

“The safety population comprised all randomized participants who received 1 or more doses of LB-102 or placebo, with participants grouped according to actual treatment received.” (opens the source at this quote in a new tab)
“Efficacy analyses were conducted in the modified intention-to-treat population (mITT), comprising all randomized participants who received 1 or more doses of LB-102 or placebo, according to randomized treatment.” (opens the source at this quote in a new tab)

Analysis sets defined in the statistical analysis plan

“The ITT Analysis Set will include all randomized patients, irrespective of whether they received the drug or not. This will be the main analysis population for efficacy analysis purposes and patients will be analyzed based on the treatment they were randomized to.” (opens the source at this quote in a new tab)
“The mITT Analysis Set will include all randomized patients with at least 1 dose of study drug.” (opens the source at this quote in a new tab)
“This will be a secondary analysis set for the analysis of the primary endpoint, however should the ITT and the mITT substantially overlap (i.e. at least 95% of ITT patients are also in the mITT), the latter will be used as primary efficacy analysis set for all efficacy endpoints.” (opens the source at this quote in a new tab)
“The Safety Analysis Set will include all patients who received any study drug. Analyses based on this population will use the actual treatment received rather than the randomized one.” (opens the source at this quote in a new tab)

Per-protocol analysis set in the protocol

“Per-Protocol (PP) Analysis Set: all patients included in the mITT Analysis Set that do not have a major protocol violation. The PP Analysis Set will be used for supportive analyses of the primary and key secondary efficacy endpoints.” (opens the source at this quote in a new tab)

Primary analysis model and handling of missing data

“The primary efficacy end point was analyzed using a mixed model for repeated measures (MMRM), including treatment group, study site, visit, and treatment × visit interaction as fixed effects, baseline PANSS total score as a covariate, and an unstructured covariance matrix to account for within-patient correlation.” (opens the source at this quote in a new tab)
“Missing data due to a discontinuation related to either lack of efficacy or a drug-related AE were imputed assuming a missing-not-at-random mechanism.” (opens the source at this quote in a new tab)
“Missing data due to discontinuation for any other reason or nonmonotone missing data were imputed under a missing-at-random mechanism.” (opens the source at this quote in a new tab)

Estimand and intercurrent events in the protocol

“Taking a prohibited medication prior to Week 4” (opens the source at this quote in a new tab)
“Starting an emergency treatment prior to Week 4” (opens the source at this quote in a new tab)
“The primary estimand for all the above events will follow the treatment-policy strategy” (opens the source at this quote in a new tab)

Multiplicity control and status of the 100 mg arm

“Formal statistical testing of LB-102 50 mg and 75 mg compared with placebo was performed for the primary end point only and included a multiplicity strategy (Hochberg correction) to control the familywise error rate at the 5% significance level” (opens the source at this quote in a new tab)
“No formal hypothesis was tested for LB-102 100 mg; however, data were analyzed using identical methods as prespecified for 50 mg and 75 mg across all end points for descriptive purposes.” (opens the source at this quote in a new tab)
“Hereafter, P values were not multiplicity controlled.” (opens the source at this quote in a new tab)

“No formal hypothesis will be tested for the LB-102 100 mg arm, but data will be included in any analysis model for all the primary and secondary efficacy endpoints and CIs and p-values provided for descriptive purposes.” (opens the source at this quote in a new tab)

“Results from the analysis of the primary endpoint will be adjusted for multiplicity using a standard Hochberg procedure.” (opens the source at this quote in a new tab)

Analysis of secondary endpoints

“All continuous secondary efficacy variables will be analyzed using similar approaches to what was described for the primary endpoint, using the appropriate Baseline measurement instead of the Baseline PANSS score, without any data imputation.” (opens the source at this quote in a new tab)
“which will only be displayed for informative/descriptive purposes (i.e., no multiplicity correction will be implemented)” (opens the source at this quote in a new tab)
“This endpoint will be analyzed using a logistic regression model including treatment and Baseline PANSS score as covariates to estimate the odds ratio of response of any active dose vs placebo.” (opens the source at this quote in a new tab)

Sensitivity analyses of the primary endpoint

“Three sensitivity analyses evaluated the robustness of the primary outcome across all 3 doses” (opens the source at this quote in a new tab)

“The primary analysis will be repeated but including PANNS values obtained during early termination assessments in the analysis” (opens the source at this quote in a new tab)
“For this sensitivity analysis, all missing data due to drop-out will be imputed using a pattern-mixture model, whereby data will be imputed only using data from patients with no missing data from the Placebo (reference) arm” (opens the source at this quote in a new tab)

“As a sensitivity analysis, missing data that was imputed under a MAR mechanism in the primary analysis will be imputed under a MNAR mechanism using a tipping-point approach to check robustness of the main analysis results.” (opens the source at this quote in a new tab)

Post hoc effect size calculations

“A post hoc calculation of Hedges g effect size (bias-corrected standardized mean differences) was conducted on participants who competed the trial, using the absolute value of the difference in the observed mean change in PANSS total score from baseline to week 4 between each individual LB-102 treatment arm and placebo, divided by the pooled SD.” (opens the source at this quote in a new tab)

Prespecified subgroups

“BMI at Baseline: ≤ 25 kg/m2, 25 to 30 kg/m2, ≥ 30 kg/m2” (opens the source at this quote in a new tab)
“Baseline PANSS (disease severity): ≤95, > 95” (opens the source at this quote in a new tab)

Population used for the post hoc cognition analysis

“290 participants completed week 4, and provided both valid PANSS and Cogstate testing scores, with data included in the assessment of the Global Cognition composite score.” (opens the source at this quote in a new tab)

Screening and randomization

“Of 622 individuals screened, 263 (42.3%) were excluded.” (opens the source at this quote in a new tab)
“Initially, 270 participants did not pass screening; however, after rescreening 13 participants, 7 were found to be eligible and were randomized.” (opens the source at this quote in a new tab)

Overall completion and reasons for early termination

“The completion rate after 4 weeks of treatment was 81.6% across all arms, with 72.7% completing the end-of-study visit.” (opens the source at this quote in a new tab)
“The most common reasons for early termination were participant withdrawal (56 [57.1%]), lost to follow-up (26 [26.5%]), and AEs (10 [10.2%]).” (opens the source at this quote in a new tab)

Completion of week 4 and of the study by arm

Milestone	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Randomized	“108 randomized to placebo”	“107 randomized to LB-102 50 mg”	“108 randomized to LB-102 75 mg”	“36 randomized to LB-102 100 mg”
Completed week 4	“94 (87%)”	“91 (85%)”	“85 (79%)”	“23 (64%)”
Completed study	“83 (77%)”	“76 (71%)”	“80 (74%)”	“22 (61%)”

Registry participant flow and reasons for not completing

Milestone or reason	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Started	“108”	“107”	“108”	“36”
Completed	“83”	“76”	“80”	“22”
Not completed	“25”	“31”	“28”	“14”
Withdrawal by subject	“11”	“16”	“19”	“10”
Lost to follow-up	“9”	“12”	“4”	“1”
Adverse event	“2”	“2”	“3”	“3”
Protocol violation	“1”	“0”	“1”	“0”
Physician decision	“0”	“1”	“1”	“0”
Lack of efficacy	“1”	“0”	“0”	“0”
Death	“1”	“0”	“0”	“0”

Discontinuation rate described by the sponsor

“The discontinuation rate reached approximately 18% during the treatment period (four weeks) and approximately 27% when taking into account up to 14 days following the last dose.” (opens the source at this quote in a new tab)

Demographics and ongoing medical history, safety analysis set

Characteristic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)	Overall (N = 359)
Age at informed consent, mean (SD), y	“39.1 (9.11)”	“39.0 (9.64)”	“39.2 (9.17)”	“39.1 (9.19)”	“39.1 (9.26)”
Female, No. (%)	“23 (21.3)”	“20 (18.7)”	“18 (16.7)”	“8 (22.2)”	“69 (19.2)”
Male, No. (%)	“85 (78.7)”	“87 (81.3)”	“90 (83.3)”	“28 (77.8)”	“290 (80.8)”
Hispanic or Latino, No. (%)	“17 (15.7)”	“12 (11.2)”	“8 (7.4)”	“6 (16.7)”	“43 (12.0)”
Black or African American, No. (%)	“80 (74.1)”	“87 (81.3)”	“83 (76.9)”	“25 (69.4)”	“275 (76.6)”
White, No. (%)	“24 (22.2)”	“17 (15.9)”	“18 (16.7)”	“9 (25.0)”	“68 (18.9)”
Weight at screening, mean (SD), kg	“85.6 (17.2)”	“84.0 (19.5)”	“88.4 (18.5)”	“85.9 (18.0)”	“86.0 (18.4)”
BMI at screening, mean (SD)	“28.2 (5.2)”	“27.4 (6.0)”	“28.8 (5.6)”	“28.0 (6.0)”	“28.1 (5.7)”
Insomnia, No. (%)	“79 (73.1)”	“83 (77.6)”	“75 (69.4)”	“29 (80.6)”	“266 (74.1)”
Anxiety, No. (%)	“59 (54.6)”	“68 (63.6)”	“63 (58.3)”	“21 (58.3)”	“211 (58.8)”
Depressive symptoms, No. (%)	“36 (33.3)”	“43 (40.2)”	“34 (31.5)”	“5 (13.9)”	“118 (32.9)”
Agitation, No. (%)	“32 (29.6)”	“41 (38.3)”	“26 (24.1)”	“9 (25.0)”	“108 (30.1)”
Headache, No. (%)	“41 (38.0)”	“49 (45.8)”	“37 (34.3)”	“17 (47.2)”	“144 (40.1)”

Baseline symptom severity

Baseline measure, mean (SD)	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
PANSS total score	“93.8 (8.17)”	“93.9 (7.53)”	“93.6 (7.79)”	“93.9 (9.01)”
PANSS total score, median (range)	“93 (80 to 118)”	“92 (82 to 115)”	“92 (81 to 116)”	“92 (82 to 114)”
CGI-S score	“4.8 (0.57)”	“4.8 (0.57)”	“4.9 (0.53)”	“4.8 (0.61)”
PANSS Positive Symptoms subscale	“25.1 (3.61)”	“25.2 (2.92)”	“25.5 (2.88)”	“25.0 (3.46)”
PANSS Negative Symptoms subscale	“23.3 (3.50)”	“23.4 (3.35)”	“22.8 (3.20)”	“23.4 (3.60)”

Race and ethnicity of the randomized population

“Participants self-reported the following races: 2 American Indian or Alaska Native (0.6%), 3 Asian (0.8%), 275 Black or African American (76.6%), 4 multiracial (1.1%), 68 White (18.9%), and 7 other (1.9%).” (opens the source at this quote in a new tab)
“Participants self-reported the following ethnicities: 43 Hispanic or Latino (12.0%) and 316 not Hispanic or Latino (88.0%).” (opens the source at this quote in a new tab)

Years since diagnosis

Characteristic	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)	Overall (N=359)
Years since diagnosis, mean (range)	“16.4 (2–41)”	“15.2 (2–38)”	“16.2 (2–39)”	“13.5 (2–36)”	“15.8 (2–41)”

Baseline CGI-S categories

“All participants were categorized at least as moderately ill, or a 4 on the CGI-S scale, with the majority of participants (range of 61.1% to 70.4% across the four cohorts) categorized as being markedly ill, or a 5 on the CGI-S scale, at baseline.” (opens the source at this quote in a new tab)

Participants with a baseline PANSS Negative Symptoms subscale score of 24 or more

“171 participants (47.6% of the total population) had a PANSS Negative Symptoms subscale score ≥24 at baseline.” (opens the source at this quote in a new tab)

Baseline cognitive impairment

“No cognitive impairment assessment was used to determine clinical trial eligibility.” (opens the source at this quote in a new tab)

Prior antipsychotic treatment, number of prior hospitalizations, and smoking status at baseline

No evidence found.

Primary endpoint: change from baseline to week 4 in PANSS total score, modified intention-to-treat analysis set

Statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Baseline, mean (SD)	“93.8 (8.17)”	“93.9 (7.53)”	“93.6 (7.79)”	“93.9 (9.01)”
Day 28, mean (SD)	“83.4 (12.24)”	“77.6 (12.25)”	“79.5 (13.49)”	“77.2 (8.91)”
LS mean change (SE)	“−9.3 (1.08)”	“−14.3 (1.10)”	“−14.0 (1.11)”	“−16.1 (1.91)”
LS mean difference from placebo (SE) and 95% CI	“NA”	“−5.0 (1.51) [−8.0 to −2.1]”	“−4.7 (1.53) [−7.7 to −1.7]”	“−6.8 (2.17) [−11.1 to −2.6]”
P value	“NA”	“<.001”	“.002”	“.002”

“Results from the analysis of the primary endpoint for 50 mg and 75 mg were adjusted for multiplicity using a standard Hochberg procedure.” (opens the source at this quote in a new tab)
“LB-102 100 mg treatment resulted in a significant LS mean (SE) change from baseline to week 4 in PANSS total score of −16.1 (1.91; P = .002 vs placebo; post hoc Hedges g = 0.83 [Δ = 0.64]).” (opens the source at this quote in a new tab)

Primary endpoint: P values to four decimal places

“The 50 mg dose arm (n=107) achieved an effect size of 0.61 and participants experienced a 5.0-point reduction in PANSS total score compared to placebo (p=0.0009). Treatment with the 75 mg dose arm (n=108) achieved an effect size of 0.41 and led to a 4.7-point reduction in PANSS total score compared to placebo (p=0.0022). The study also included an exploratory dose of 100 mg (n=36), which demonstrated an effect size of 0.83 with a 6.8-point reduction in PANSS total score compared to placebo (p=0.0017).” (opens the source at this quote in a new tab)

Primary endpoint in the registry results

Statistic	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Overall number of participants analyzed	“108”	“107”	“108”	“36”
Least squares mean (standard error), score on a scale	“-9.27(1.078)”	“-14.28(1.097)”	“-13.95(1.108)”	“-16.08(1.906)”

Effect sizes for the primary endpoint

“The primary end point of the change from baseline to week 4 in PANSS total score showed statistical superiority with LB-102 50 mg and 75 mg compared with placebo using the Hochberg correction (least-squares [LS] mean change [SE]: placebo, −9.3 [1.08]; 50 mg, −14.3 [1.10], P < .001; post hoc Hedges g = 0.61 [Δ = 0.50]; 75 mg, −14.0 [1.11], P = .002; post hoc Hedges g = 0.41 [Δ = 0.45])” (opens the source at this quote in a new tab)
“Post hoc analysis of MMRM-based effect sizes yielded directionally consistent results as Hedges g (LB-102 50 mg, Δ = 0.50; 75 mg, Δ = 0.45; 100 mg, Δ = 0.64)” (opens the source at this quote in a new tab)

“Effect size is calculated by taking the difference in average observed PANSS change among completers between two groups (an active treatment arm and placebo) and dividing it by a single measure of variability that combines both groups’ spreads” (opens the source at this quote in a new tab)
“We also calculated effect size versus placebo based on all patients with at least one post-baseline PANSS assessment combining both observed and imputed data and yielding effect sizes of 0.50 at 50 mg, 0.45 at 75 mg, and 0.64 at 100 mg.” (opens the source at this quote in a new tab)

Sensitivity analyses of the primary endpoint

“Sensitivity analyses supported the primary findings” (opens the source at this quote in a new tab)

Time course of the PANSS total score

“The effect of LB-102 on PANSS total score was observed as early as week 1 and maintained throughout the 4-week treatment period” (opens the source at this quote in a new tab)

“(p-values) for 50, 75 and 100 mg at Day 8 (<.0001, 0.0032, 0.0181); Day 15 (0.0006, 0.0344, 0.0276); Day 21 (0.0006, 0.0025, 0.0050)” (opens the source at this quote in a new tab)

Least squares mean change in PANSS total score at weeks 1, 2, and 3 by arm

No evidence found.

Placebo response

“Although LB-102 demonstrated a statistically significant improvement in PANSS total score vs placebo, the 9-point reduction observed with placebo may reflect inpatient stabilization or design-related factors (eg, number of treatment arms and site participation).” (opens the source at this quote in a new tab)

CGI-S score change and CGI-S responder rate at week 4

Statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Baseline, mean (SD)	“4.8 (0.57)”	“4.8 (0.57)”	“4.9 (0.53)”	“4.8 (0.61)”
Day 28, mean (SD)	“4.3 (0.74)”	“3.9 (0.77)”	“4.1 (0.85)”	“4.0 (0.60)”
LS mean change (SE)	“−0.39 (0.07)”	“−0.72 (0.08)”	“−0.67 (0.08)”	“−0.84 (0.14)”
LS mean difference from placebo (SE) and 95% CI	“NA”	“−0.33 (0.10) [−0.52 to −0.14]”	“−0.28 (0.10) [−0.47 to −0.09]”	“−0.45 (0.15) [−0.74 to −0.16]”
P value for score change	“NA”	“<.001”	“.005”	“.003”
CGI-S responders, No. (%) and 95% CI	“8 (7.4) [2.0 to 12.8]”	“25 (23.4) [14.9 to 31.9]”	“19 (17.6) [10.0 to 25.2]”	“4 (11.1) [0.0 to 22.8]”
Responder difference vs placebo (95% CI)	“NA”	“16.0 (6.5 to 25.4)”	“10.2 (1.5 to 18.9)”	“3.7 (−7.7 to 15.1)”
P value for responder rate	“NA”	“.001”	“.02”	“.35”

“A CGI-S responder was defined as a participant with a CGI-S rating of 3 (mildly ill), 2 (borderline mentally ill), or 1 (normal, not at all ill). Most CGI-S responders at week 4 were rated mildly ill; there were 4 participants rated borderline mentally ill (LB-102 50 mg, n = 2 of 91 [2.2%]; LB-102 75 mg, n = 1 of 83 [1.2%]; LB-102 100 mg, n = 0 of 23; and placebo, n = 1 of 94 [1.1%]) and none rated normal, not at all ill.” (opens the source at this quote in a new tab)

Shift in CGI-S category from baseline to week 4

“With these changes, the majority of participants shifted from markedly ill (CGI-S of 5) at baseline to moderately ill (CGI-S of 4, range of 45.8% to 65.2% of participants across all three dose cohorts) or mildly ill (CGI-S of 3, range of 17.4% to 25.3% of participants across all three dose cohorts).” (opens the source at this quote in a new tab)

PANSS Positive and Negative Symptoms subscale scores at week 4

Statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Positive Symptoms subscale, LS mean change (SE)	“−3.1 (0.41)”	“−4.8 (0.43)”	“−4.9 (0.43)”	“−5.3 (0.76)”
Positive Symptoms subscale, LS mean difference (SE) and 95% CI	“NA”	“−1.7 (0.59) [−2.8 to −0.5]”	“−1.7 (0.59) [−2.9 to −0.6]”	“−2.2 (0.86) [−3.8 to −0.5]”
Positive Symptoms subscale, P value	“NA”	“.005”	“.004”	“.01”
Negative Symptoms subscale, LS mean change (SE)	“−1.1 (0.31)”	“−2.2 (0.31)”	“−1.7 (0.32)”	“−1.8 (0.55)”
Negative Symptoms subscale, LS mean difference (SE) and 95% CI	“NA”	“−1.1 (0.43) [−1.9 to −0.2]”	“−0.6 (0.44) [−1.5 to 0.3]”	“−0.7 (0.63) [−1.9 to 0.5]”
Negative Symptoms subscale, P value	“NA”	“.01”	“.16”	“.26”

“Analysis of the PANSS Negative Symptoms subscale score showed a numerical improvement from baseline to week 4 for all LB-102 doses, with significant improvement for 50 mg compared with placebo” (opens the source at this quote in a new tab)

PANSS Marder factor scores at week 4

Marder factor and statistic	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Positive Symptoms, LS mean change (SE)	“−2.5 (0.42)”	“−4.4 (0.43)”	“−4.4 (0.44)”	“−5.4 (0.82)”
Positive Symptoms, LS mean difference (SE) and 95% CI	“NA”	“−1.9 (0.60) [−3.0 to −0.7]”	“−1.9 (0.60) [−3.1 to −0.7]”	“−2.8 (0.91) [−4.6 to −1.1]”
Positive Symptoms, P value	“NA”	“.002”	“.002”	“.002”
Negative Symptoms, LS mean change (SE)	“−1.6 (0.36)”	“−2.5 (0.37)”	“−1.9 (0.37)”	“−3.0 (0.70)”
Negative Symptoms, LS mean difference (SE) and 95% CI	“NA”	“−0.9 (0.50) [−1.9 to 0.1]”	“−0.4 (0.51) [−1.4 to 0.7]”	“−1.4 (0.78) [−3.0 to 0.1]”
Negative Symptoms, P value	“NA”	“.08”	“.50”	“.07”
Disorganized Thought, LS mean change (SE)	“−2.0 (0.30)”	“−3.6 (0.31)”	“−2.9 (0.31)”	“−3.3 (0.58)”
Disorganized Thought, LS mean difference (SE) and 95% CI	“NA”	“−1.6 (0.42) [−2.5 to −0.8]”	“−0.9 (0.43) [−1.8 to −0.1]”	“−1.3 (0.65) [−2.6 to 0.0]”
Disorganized Thought, P value	“NA”	“<.001”	“.03”	“.04”
Uncontrolled Hostility/Excitement, LS mean change (SE)	“−0.7 (0.26)”	“−1.5 (0.26)”	“−1.5 (0.27)”	“−1.9 (0.50)”
Uncontrolled Hostility/Excitement, LS mean difference (SE) and 95% CI	“NA”	“−0.8 (0.36) [−1.6 to −0.1]”	“−0.8 (0.37) [−1.5 to −0.1]”	“−1.2 (0.56) [−2.3 to −0.1]”
Uncontrolled Hostility/Excitement, P value	“NA”	“.02”	“.02”	“.03”
Anxiety/Depression, LS mean change (SE)	“−2.4 (0.31)”	“−2.7 (0.32)”	“−3.2 (0.32)”	“−3.5 (0.60)”
Anxiety/Depression, LS mean difference (SE) and 95% CI	“NA”	“−0.3 (0.43) [−1.1 to 0.6]”	“−0.7 (0.44) [−1.6 to 0.1]”	“−1.0 (0.67) [−2.3 to 0.3]”
Anxiety/Depression, P value	“NA”	“.54”	“.09”	“.13”

“For PANSS Marder factor scores for Negative Symptoms and Anxiety/Depression, each LB-102 dose demonstrated numerically greater improvements vs placebo that did not reach statistical significance” (opens the source at this quote in a new tab)

PANSS total score responder rates at week 4

Analysis and statistic	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
Prespecified 20% or greater response, No. (%) and 95% CI	“17 (18.3) [10.4 to 26.1]”	“29 (31.9) [22.3 to 41.4]”	“27 (32.1) [22.2 to 42.1]”	“10 (43.5) [23.2 to 63.7]”
Prespecified, OR (95% CI)	“NA”	“1.91 (0.98 to 3.74)”	“2.27 (1.16 to 4.41)”	“2.87 (1.17 to 7.05)”
Prespecified, P value	“NA”	“.06”	“.02”	“.02”
Post hoc floor-adjusted 20% or greater response, No. (%) and 95% CI	“36 (38.7) [28.8 to 48.6]”	“52 (57.1) [47.0 to 67.3]”	“45 (53.6) [42.9 to 64.2]”	“18 (78.3) [61.4 to 95.1]”
Post hoc floor-adjusted, OR (95% CI)	“NA”	“1.92 (1.08 to 3.40)”	“1.95 (1.10 to 3.46)”	“4.75 (1.83 to 12.34)”
Post hoc floor-adjusted, P value	“NA”	“.03”	“.02”	“.001”

Responder rates at 30% or 50% PANSS reduction

No evidence found.

Post hoc analysis in participants with a baseline PANSS Negative Symptoms subscale score of 24 or more

“LB-102 50 mg, −3.4 (Δ −1.70, p=0.0045 vs placebo; effect size=0.67)” (opens the source at this quote in a new tab)
“LB-102 75 mg, −2.6 (Δ −1.00, p=0.1501 vs placebo, effect size=0.34)” (opens the source at this quote in a new tab)
“LB-102 100 mg, −3.3 (Δ −1.70, p=0.0658 vs placebo, effect size=0.60)” (opens the source at this quote in a new tab)

“We also conducted an exploratory post-hoc analysis of our Phase 2 data on the treatment effect in patients with negative symptoms at baseline (i.e., those patients with a PANSS Negative Subscore greater than or equal to 24). In patients with negative symptoms at baseline, the LS Mean change in negative symptom scores at Week 4 was -1.6 (placebo), -3.4 (50 mg, Δ -1.7, p=0.0045 versus placebo; effect size=0.67), -2.6 (75 mg, Δ -1.00, p=0.1501, effect size=0.34), and -3.3 (100 mg, Δ -1.70, p=0.0658, effect size=0.60).” (opens the source at this quote in a new tab)

Exploratory cognition results: post hoc Cogstate composite scores after 4 weeks

Composite score	LB-102 50 mg vs placebo, effect size	P value	LB-102 75 mg vs placebo, effect size	P value	LB-102 100 mg vs placebo, effect size	P value
Global Cognition (N=290)	“0.26”	“0.0476”	“0.41”	“0.0027”	“0.66”	“0.0018”
Attention (Psychomotor Function) (n=290)	“0.13”	“0.3331”	“0.29”	“0.0277”	“0.24”	“0.2062”
Memory (Executive Function) (n=265)	“0.15”	“0.3128”	“0.19”	“0.1957”	“0.53”	“0.0273”

“Post hoc analysis. Analysis of Effect Size was calculated via ANCOVA with visit, treatment, and visit by treatment as fixed effects, and with baseline Global Cognition composite score as a covariate.” (opens the source at this quote in a new tab)
“Mediation analysis highlighted a significant and direct effect of LB-102 on cognitive performance in all NOVA1 participants with acute schizophrenia, with no impact mediated by the improvement in schizophrenia symptoms (r=0.05, p=0.44).” (opens the source at this quote in a new tab)

Dose response described by the authors

“LB-102 produced significant reductions at all doses, with broadly similar effects at 50 to 75 mg, with a numerically larger (but less certain) signal with 100 mg with no clear dose-related increase from 50 to 100 mg in extrapyramidal symptoms.” (opens the source at this quote in a new tab)

Indirect comparison with established antipsychotics described by the authors

“The magnitude of effect falls within the range reported for established oral antipsychotics in multiepisode acute schizophrenia in a large network meta-analysis (eg, standardized mean difference [95% credible interval]: amisulpride, −0.73 [−0.89 to −0.58]; olanzapine, −0.56 [−0.62 to −0.50]; risperidone, −0.55 [−0.62 to −0.48])” (opens the source at this quote in a new tab)

Results of prespecified subgroup analyses by baseline body mass index and baseline PANSS total score

No evidence found.

Pharmacokinetic results from the first 60 randomized participants

No evidence found.

Patient-reported outcome and health-related quality of life results

No evidence found.

Overview of adverse events by arm

Outcome, No. (%)	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Any AE	“67 (62.0)”	“77 (72.0)”	“68 (63.0)”	“28 (77.8)”
Any TEAE	“60 (55.6)”	“74 (69.2)”	“62 (57.4)”	“27 (75.0)”
Any treatment-related TEAE	“23 (21.3)”	“49 (45.8)”	“34 (31.5)”	“17 (47.2)”
Any serious TEAE	“2 (1.9)”	“1 (0.9)”	“1 (0.9)”	“1 (2.8)”
Serious treatment-related TEAE	“0”	“1 (0.9)”	“1 (0.9)”	“0”
TEAE leading to early withdrawal	“2 (1.9)”	“2 (1.9)”	“3 (2.8)”	“3 (8.3)”
TEAE leading to death	“1 (0.9)”	“0”	“0”	“0”

“TEAEs were reported in 223 participants (62.1%; 560 events), with a higher incidence in the groups receiving LB-102 100 mg (27 [75.0%]; 60 events) and 50 mg (74 [69.2%]; 204 events) than the groups receiving 75 mg (62 [57.4%]; 139 events) and placebo (60 [55.6%]; 157 events).” (opens the source at this quote in a new tab)
“Treatment-related TEAEs occurred in 123 participants (34.3%; 212 events), with the most common being insomnia, weight increase, headache, and blood prolactin increased” (opens the source at this quote in a new tab)

Treatment-emergent adverse events occurring in 5% or more of participants

TEAE, No. (%)	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Insomnia	“24 (22.2)”	“27 (25.2)”	“23 (21.3)”	“14 (38.9)”
Headache	“10 (9.3)”	“12 (11.2)”	“9 (8.3)”	“2 (5.6)”
Anxiety	“9 (8.3)”	“10 (9.3)”	“9 (8.3)”	“4 (11.1)”
Agitation	“10 (9.3)”	“11 (10.3)”	“6 (5.6)”	“4 (11.1)”
Weight (increase)	“4 (3.7)”	“13 (12.1)”	“8 (7.4)”	“3 (8.3)”
Blood prolactin (increase)	“0”	“7 (6.5)”	“6 (5.6)”	“3 (8.3)”
Hyperprolactinemia	“0”	“4 (3.7)”	“2 (1.9)”	“3 (8.3)”
Blood creatine phosphokinase (increase)	“3 (2.8)”	“4 (3.7)”	“1 (0.9)”	“2 (5.6)”
Alanine aminotransferase (increase)	“1 (0.9)”	“3 (2.8)”	“1 (0.9)”	“2 (5.6)”
Somnolence	“0”	“1 (0.9)”	“4 (3.7)”	“2 (5.6)”
Constipation	“0”	“4 (3.7)”	“1 (0.9)”	“2 (5.6)”

Treatment-related adverse events occurring in 5% or more of participants

Treatment-related TEAE, No. (%)	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Insomnia	“5 (4.6)”	“11 (10.3)”	“6 (5.6)”	“3 (8.3)”
Weight (increase)	“2 (1.9)”	“11 (10.3)”	“6 (5.6)”	“3 (8.3)”
Headache	“5 (4.6)”	“9 (8.4)”	“6 (5.6)”	“1 (2.8)”
Blood prolactin (increase)	“0”	“7 (6.5)”	“6 (5.6)”	“3 (8.3)”
Somnolence	“0”	“1 (0.9)”	“4 (3.7)”	“2 (5.6)”
Alanine aminotransferase (increase)	“0”	“3 (2.8)”	“1 (0.9)”	“2 (5.6)”
Agitation	“2 (1.9)”	“2 (1.9)”	“0”	“2 (5.6)”

Severe and serious adverse events and deaths

“Most TEAEs were mild or moderate. Severe TEAEs were reported in 5 participants (1.4%), including dystonia (75 mg, n = 1), psychotic disorder (100 mg, n = 1), schizophrenia (placebo, n = 2), and death (placebo, n = 1).” (opens the source at this quote in a new tab)
“One death was reported in the placebo group.” (opens the source at this quote in a new tab)

“There were five reported serious adverse events, or SAEs, overall with two SAEs in the placebo cohort (psychotic disorder and death), one SAE in the 50 mg cohort (suicidal ideation – deemed possibly related to treatment), one SAE in the 75 mg cohort (dystonia – deemed possibly related to treatment) and one SAE in the 100 mg cohort (psychotic disorder – deemed not related to treatment).” (opens the source at this quote in a new tab)

Serious adverse events and all-cause mortality in the registry results

Event, affected / at risk (%)	Placebo	LB-102 50 mg	LB-102 75 mg	LB-102 100 mg
All-cause mortality	“1/108 (0.93%)”	“0/107 (0.00%)”	“0/108 (0.00%)”	“0/36 (0.00%)”
Serious adverse events, total	“2/108 (1.85%)”	“1/107 (0.93%)”	“1/108 (0.93%)”	“1/36 (2.78%)”
Death	“1/108 (0.93%)”	“0/107 (0.00%)”	“0/108 (0.00%)”	“0/36 (0.00%)”
Dystonia	“0/108 (0.00%)”	“0/107 (0.00%)”	“1/108 (0.93%)”	“0/36 (0.00%)”
Psychosis	“1/108 (0.93%)”	“0/107 (0.00%)”	“0/108 (0.00%)”	“1/36 (2.78%)”
Suicidal ideation	“0/108 (0.00%)”	“1/107 (0.93%)”	“0/108 (0.00%)”	“0/36 (0.00%)”

Adverse events leading to discontinuation

“TEAEs leading to trial drug discontinuation occurred in 10 participants (placebo, n = 2; 50 mg, n = 2; 75 mg, n = 3; 100 mg, n = 3) with 5 serious TEAEs (placebo, n = 2 [including 1 death]; each LB-102 arm, n = 1)” (opens the source at this quote in a new tab)
“The only TEAE leading to trial discontinuation occurring in more than 1 participant was worsening schizophrenia (placebo, n = 2; LB-102 50 mg, n = 1). Other discontinuation-related TEAEs included psychotic disorder, suicidal ideation, alanine aminotransferase increase, lipase increase, toothache, COVID-19, and dystonia.” (opens the source at this quote in a new tab)

Extrapyramidal symptoms, dystonia, and akathisia

“Extrapyramidal symptom incidence was low across all groups (placebo, 2 [1.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 1 [0.9%]; 100 mg, 1 [2.8%]), as was dystonia (placebo, 1 [0.9%]; LB-102 50 mg, 0 [0%]; 75 mg, 3 [2.8%]; 100 mg, 1 [2.8%]).” (opens the source at this quote in a new tab)
“Evaluation of the SAS, BARS, and AIMS demonstrated values that remained stable over time, with little to no emergence of any antipsychotic-induced parkinsonism, akathisia, tardive dyskinesia, or other involuntary motor AEs.” (opens the source at this quote in a new tab)

TEAE related to extrapyramidal symptoms, n (%)	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Dystonia	“1 (0.9%)”	“0”	“3 (2.8%)”	“1 (2.8%)”
Akathisia	“1 (0.9%)”	“1 (0.9%)”	“2 (1.9%)”	“0”
Extrapyramidal disorder	“2 (1.9%)”	“0”	“1 (0.9%)”	“1 (2.8%)”
Total related to EPS	“4 (3.7%)”	“1 (0.9%)”	“6 (5.6%)”	“2 (5.6%)”

Prolactin concentrations

“Elevated prolactin levels at day 28 were reported across all arms (placebo, 5.2%, mean [SD] increase, 1.3 [6.0] ng/mL; 50 mg, 91.0%, mean [SD] increase, 59.9 [55.1] ng/mL; 75 mg, 94.0%, mean [SD] increase, 51.4 [52.0] ng/mL; 100 mg, 87.5%, mean [SD] increase, 51.2 [48.1] ng/mL; to convert to micrograms per liter, multiply by 1)” (opens the source at this quote in a new tab)

Clinical adverse events related to prolactin increase

“Clinical AEs related to prolactin increase were reported in 5 participants, including galactorrhea (50 mg, n = 2; 75 mg, n = 1), breast enlargement (100 mg, n = 1), and erectile dysfunction (100 mg, n = 1).” (opens the source at this quote in a new tab)

TEAE related to prolactin increase, n (%)	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Galactorrhea	“0”	“2 (1.9%)”	“1 (0.9%)”	“0”
Breast enlargement	“0”	“0”	“0”	“1 (2.8%)”
Erectile dysfunction	“0”	“0”	“0”	“1 (2.8%)”
Total related to prolactin	“0”	“2 (1.9%)”	“1 (0.9%)”	“2 (5.6%)”

“Prolactin-related AEs Low rate (~1-5.6%); AEs were mild to moderate and did not result in discontinuation” (opens the source at this quote in a new tab)

Prolactin change by sex and course of prolactin after treatment discontinuation

No evidence found.

Change from baseline to day 28 in weight, prolactin, glucose, cholesterol, and QTc

Parameter	Placebo (n = 108)	LB-102 50 mg (n = 107)	LB-102 75 mg (n = 108)	LB-102 100 mg (n = 36)
Weight, mean (SD), kg	“2.0 (2.9)”	“4.3 (3.2)”	“3.3 (2.8)”	“2.9 (2.5)”
Weight increase ≥7%, No. participants (%)	“11 (10%)”	“27 (26%)”	“20 (19%)”	“3 (9%)”
Prolactin, mean (SD), ng/mL	“1.3 (6.03)”	“59.9 (55.11)”	“51.4 (52.02)”	“51.2 (48.07)”
Fasting glucose, mean (SD), mg/dL	“0.2 (12.07)”	“2.3 (24.52)”	“2.0 (13.62)”	“7.0 (19.39)”
Total cholesterol, mean (SD), mg/dL	“0.8 (25.06)”	“7.7 (24.75)”	“5.4 (23.98)”	“5.8 (25.52)”
QTc, mean (SD), millisecond	“1.2 (12.56)”	“4.9 (13.39)”	“4.3 (12.55)”	“5.4 (9.44)”
QTc mean change ≥30 millisecond, No. participants (%)	“1 (0.9)”	“5 (4.7)”	“1 (0.9)”	“1 (2.8)”

“Analyzed using a last-observation-carried-forward approach in participants with postbaseline weight data (placebo, n=106; 50 mg, n=105; 75 mg, n=107; 100 mg, n=34).” (opens the source at this quote in a new tab)

Weight gain

“Weight increase was the only TEAE to occur in 5% or more of the total population at a rate at least twice that observed with placebo but was not dose-dependent (placebo, 4 [3.7%], mean increase, 2.1 kg; 50 mg, 13 [12.1%], mean increase, 4.3 kg; 75 mg, 8 [7.4%], mean increase, 3.3 kg; 100 mg, 3 [8.3%], mean increase, 2.9 kg).” (opens the source at this quote in a new tab)
“A 7% or greater weight increase, using a last-observation-carried-forward approach, was reported by 61 participants (placebo, 11 [10.4%], mean increase, 6.9 kg; 50 mg, 27 [25.7%], mean increase, 8.2 kg; 75 mg, 20 [18.7%], mean increase, 7.2 kg; 100 mg, 3 [8.8%], mean increase, 7.2 kg)” (opens the source at this quote in a new tab)

“There was an increase in weight across all treatment arms by the end of Week 4 (placebo, 2.1 kg; 50 mg, 4.6 kg; 75 mg, 3.5 kg; 100 mg, 3.7 kg).” (opens the source at this quote in a new tab)

“Over the course of the trial, we observed approximately 1.6 kg placebo-adjusted weight gain on a last observation carried forward basis.” (opens the source at this quote in a new tab)

“Average placebo-adjusted weight gain for treated subjects was 2 kg.” (opens the source at this quote in a new tab)

Metabolic laboratory parameters

“Despite the weight gain observed in the four-week trial, no clinically meaningful signal in metabolic parameters such as cholesterol, LDL, HDL, triglycerides or fasting glucose were observed.” (opens the source at this quote in a new tab)

Change in triglycerides, LDL cholesterol, HDL cholesterol, and HbA1c by arm

No evidence found.

QTc interval and vital signs

“There were no clinically meaningful changes in blood pressure, pulse rate, or body temperature from baseline to day 28, and no notable shifts observed in QTcF (Fridericia-corrected QT interval) values” (opens the source at this quote in a new tab)

QTcF, ms	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Baseline QTcF	“393.5”	“393.3”	“394.8”	“390.0”
Change at day 28	“1.2”	“4.9”	“4.3”	“5.4”

“QTc Prolongation Minimal QT prolongation (4.3-5.4 ms); no patients met pre-specified stopping criteria” (opens the source at this quote in a new tab)

“there were no reports of orthostasis among patients treated with LB-102 in the trial” (opens the source at this quote in a new tab)

Sedation and somnolence

TEAE, n (%)	Placebo (n=108)	LB-102 50 mg (n=107)	LB-102 75 mg (n=108)	LB-102 100 mg (n=36)
Sedation	“0”	“0”	“1 (0.9%)”	“0”
Somnolence	“0”	“1 (0.9%)”	“4 (3.7%)”	“2 (5.6%)”

“Across 251 dosed subjects, only one case of sedation was reported.” (opens the source at this quote in a new tab)

Insomnia and other events that were common baseline conditions

“TEAEs were generally balanced across treatment arms, except insomnia (more frequent with 75 mg) and weight increase.” (opens the source at this quote in a new tab)
“Common baseline comorbidities (ie, insomnia, anxiety, headache, and agitation) were among the most common TEAEs, suggesting that some TEAEs may represent the re-emergence, exacerbation, or fluctuation of preexisting symptoms rather than new, drug-related effects.” (opens the source at this quote in a new tab)

Suicidal ideation and behavior

“There was no change in suicidal ideation or behavior at the end of Week 4, as measured by the Columbia–Suicide Severity Rating Scale (C-SSRS).” (opens the source at this quote in a new tab)

Authors' comparison of tolerability with other antipsychotics

“Elevated prolactin was reported from 6.5% of those receiving LB-102 50 mg to 8.3% of those receiving LB-102 100 mg; by comparison, data for amisulpride indicate significantly higher rates of hyperprolactinemia (25%-100%).” (opens the source at this quote in a new tab)
“Extrapyramidal symptoms, QTc prolongation, and hepatic enzyme changes with LB-102 remained similar to placebo.” (opens the source at this quote in a new tab)

Summary

NOVA-1 was a 4-week inpatient trial conducted at 25 sites in the United States. The authors state that it was not designed to evaluate long-term durability of treatment and that further studies are needed to assess generalizability to outpatients. The trial had no active comparator, so the comparisons with amisulpride, olanzapine, risperidone, and xanomeline and trospium chloride in the publication are indirect. European Medicines Agency guidance names 6 weeks as the preferred duration for short-term efficacy trials and states that a 4-week trial could also be considered.

Formal hypothesis testing with multiplicity control covered the primary endpoint for the 50 mg and 75 mg doses only. The 100 mg arm was exploratory, with 36 participants randomized and 23 with an observed week 4 PANSS total score, and P values for the 100 mg dose and for all secondary endpoints were not controlled for multiplicity. The placebo group improved by 9.3 points on the PANSS total score. The differences from placebo were 5.0 points for 50 mg and 4.7 points for 75 mg, compared with the 8-point difference assumed in the sample size calculation. The Hedges g values of 0.61, 0.41, and 0.83 were calculated post hoc in participants who completed the trial, and the model-based values in the modified intention-to-treat population were 0.50, 0.45, and 0.64. The prespecified 20% PANSS responder comparison for 50 mg had a P value of .06, and the floor-adjusted responder analysis was post hoc. On negative symptoms, the difference from placebo had a P value below .05 for the 50 mg dose on the PANSS Negative Symptoms subscale and for no dose on the Marder Negative Symptoms factor; the authors state that negative symptom improvement in a 4-week acute trial may be secondary to resolution of positive symptoms. Cognition results are post hoc composite scores in the 290 participants who completed week 4 with valid PANSS and Cogstate scores. No patient-reported or quality of life endpoint appears among the protocol endpoints.

Completion of week 4 was 81.6% overall and 64% (23 of 36 participants) in the 100 mg arm. Of 359 participants, 290 (80.8%) were male and 275 (76.6%) were Black or African American, and eligibility was limited to ages 18 to 55 years and excluded first-episode and treatment-resistant illness. Elevated prolactin levels at day 28 were reported in 87.5% to 94.0% of participants in the LB-102 arms and 5.2% in the placebo arm, with mean increases of 51.2 to 59.9 ng/mL and 1.3 ng/mL. Weight increase of 7% or more occurred in 25.7% (50 mg), 18.7% (75 mg), 8.8% (100 mg), and 10.4% (placebo) of participants, and the authors state that smoking restrictions, limited physical activity, and minimal dietary restrictions at the sites may have contributed. Four weeks of treatment do not characterize long-term endocrine or metabolic outcomes; an investigator quoted in a news report stated that clinical value will depend on phase 3 data, longer-term metabolic and endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons.

Sources differ on some figures. Table 3 of the publication reports mean weight change of 2.0 kg with placebo and 2.9 to 4.3 kg with LB-102, while the discussion of the publication and a 2025 poster report 2.1 kg with placebo and 3.5 to 4.6 kg with LB-102; the sponsor reported placebo-adjusted weight gain of 2 kg in January 2025 and approximately 1.6 kg in its Form 10-K. The registry lists primary completion on December 4, 2024, and the publication states that the trial was conducted between December 2023 and August 2024. The sponsor funded the trial and the medical writing and participated in the design, conduct, analysis, and interpretation.

Limitations stated by the authors: duration, setting, and comparator

“was conducted over 4 weeks and was not designed to evaluate the long-term durability of treatment.” (opens the source at this quote in a new tab)
“The inpatient setting minimized risks related to nonadherence, illicit substance use, and unauthorized concomitant medications; further studies are needed to assess whether these findings are generalizable to an outpatient population.” (opens the source at this quote in a new tab)
“The trial did not include an active comparator group, and thus, no direct comparison can be made with other medications.” (opens the source at this quote in a new tab)

Limitations stated by the authors: weight gain, negative symptoms, and study population

“Site-level smoking restrictions and limited opportunity for physical activity, combined with minimal dietary or food restrictions, may have contributed to weight gain, limiting the ability to fully assess the metabolic profile of LB-102 under real-world outpatient conditions.” (opens the source at this quote in a new tab)
“Additionally, although LB-102 demonstrated broad symptomatic efficacy, it is possible that, in an acute 4-week trial, improvements in negative symptoms may be secondary to the resolution of positive symptoms (pseudospecificity); further studies are required to disentangle these effects.” (opens the source at this quote in a new tab)
“Many sites had a trial population that was predominantly Black, reflecting the urban US clinical settings in which recruitment for many sites occurred.” (opens the source at this quote in a new tab)

Caution on cross-trial comparisons

“although methodological differences warrant cautious interpretation” (opens the source at this quote in a new tab)

Sponsor role and medical writing support

“In collaboration with the academic authors, the funder participated in the design and conduct of the trial and in the collection, management, analysis, and interpretation of the data.” (opens the source at this quote in a new tab)
“The preparation, review, and approval of the manuscript were undertaken by all authors and the sponsor, with support from professional medical writers funded by the sponsor.” (opens the source at this quote in a new tab)

Investigator comment on what remains to be shown

“He noted, however, that NOVA-1 was a short, 4-week phase 2 inpatient study without an active comparator.” (opens the source at this quote in a new tab)
“The real and full clinical value will depend on phase 3 data, longer-term metabolic/endocrine outcomes, relapse prevention, functioning, adherence, and head-to-head comparisons” (opens the source at this quote in a new tab)

Comment from a psychiatrist not involved in the study

“It’s a promising new asset that seems to have replicated efficacy across psychotic, negative, and depressive symptoms” (opens the source at this quote in a new tab)

Regulatory guidance on short-term trial duration and comparators

“The preferred design for demonstrating short term efficacy is a 6 week clinical trial.” (opens the source at this quote in a new tab)
“Shorter study duration (e.g. 4 weeks) could also be considered, especially for drugs with a similar profile to existing antipsychotic drugs. This carries the risk of negative results if maximal therapeutic effect is not obtained at 4 weeks and the shorter duration is disadvantageous in terms of the ability to demonstrate stability of effect.” (opens the source at this quote in a new tab)
“If the aim of the study is to demonstrate non-inferiority to an active comparator, then a three-arm study of placebo, test product and active comparator is recommended” (opens the source at this quote in a new tab)