Endpoints In Clinical Trials Research Articles

What is the weight of expectation bias in oncology trials?

What is the weight of expectation bias in oncology trials?

When a joint model should be preferred over a linear mixed model for analysis of longitudinal health-related quality of life data in cancer clinical trials

BackgroundPatient-reported outcomes such as health-related quality of life (HRQoL) are increasingly used as endpoints in randomized cancer clinical trials. However, the patients often drop out so that observation of the HRQoL longitudinal outcome ends prematurely, leading to monotone missing data. The patients may drop out for various reasons including occurrence of toxicities, disease progression, or may die. In case of informative dropout, the usual linear mixed model analysis will produce biased estimates. Unbiased estimates cannot be obtained unless the dropout is jointly modeled with the longitudinal outcome, for instance by using a joint model composed of a linear mixed (sub)model linked to a survival (sub)model. Our objective was to investigate in a clinical trial context the consequences of using the most frequently used linear mixed model, the random intercept and slope model, rather than its corresponding joint model.MethodsWe first illustrate and compare the models on data of patients with metastatic pancreatic cancer. We then perform a more formal comparison through a simulation study.ResultsFrom the application, we derived hypotheses on the situations in which biases arise and on their nature. Through the simulation study, we confirmed and complemented these hypotheses and provided general explanations of the bias mechanisms.ConclusionsIn particular, this article reveals how the linear mixed model fails in the typical situation where poor HRQoL is associated with an increased risk of dropout and the experimental treatment improves survival. Unlike the joint model, in this situation the linear mixed model will overestimate the HRQoL in both arms, but not equally, misestimating the difference between the HRQoL trajectories of the two arms to the disadvantage of the experimental arm.

An Apple a Day to Keep the Parkinson's Disease Doctor Away?

It is challenging to reliably assess the motor features of Parkinson's disease in real-time. This has motivated the search for new digital outcomes that can objectively and remotely measure the severity of parkinsonian motor impairments over an extended period of time. The United States Food and Drug Administration (FDA) has recently granted a 510(k) clearance to the Rune Labs Kinematics System, an ambulatory, smartwatch-based monitoring system to remotely track tremor and dyskinesias in persons with Parkinson's disease. The FDA clearance means that this new digital approach can be regarded as being safe for use in daily practice, with acceptable correlations to clinically based measures. However, the immediate implications for clinicians are limited, because it remains to be demonstrated whether the digital signals correlate well to clinically meaningful outcomes at patient level. The impact on research is also restricted for now, as more validation studies are needed before this new digital approach can be used as primary or secondary endpoint in clinical trials. ANN NEUROL 2023;93:681-685.

Progression of Stargardt Disease as Determined by Fundus Autofluorescence Over a 24-Month Period (ProgStar Report No. 17)

To estimate the progression rate of atrophic lesions in Stargardt disease derived from fundus autofluorescence (FAF). International, multicenter, prospective cohort study. A total of 259 participants aged ≥6 years with disease-causing variants in the ABCA4 gene were enrolled from 9 centers and followed over a 24-month period. FAF images were obtained every 6 months, and areas of definitely decreased autofluorescence (DDAF) and decreased autofluorescence (DAF) were quantified. Progression rates were estimated from linear mixed models with time as the independent variable. A total of 488 study eyes of 259 participants (88.8% with both eyes) were enrolled and images from 432 eyes were followed for 24 months. The overall estimated progression of DDAF was 0.74 mm2/y (95% CI 0.64-0.85, P < .0001) and that of DAF was 0.64 mm2/y (95% CI 0.57-0.71) over a 24-month period in univariate analysis. Growth rates were strongly dependent on baseline lesion area. After square root transformation, the DDAF growth rate was not dependent on baseline lesion radius (P=.11), whereas the DAF growth rate was dependent (P < .0001). Genotype was not found to significantly impact the growth rate of DDAF or DAF lesions. FAF may serve as a convenient monitoring tool and suitable end point for interventional clinical trials that aim to slow disease progression. DDAF and DAF lesion sizes at baseline are strong predicting factors for lesion area growth and can be partially accounted for by square root transformation.

Quantitative cone contrast threshold testing in patients with differing pathophysiological mechanisms causing retinal diseases

BackgroundCone contrast threshold testing (CCT) provides quantitative measurements of color and contrast function to reveal changes in vision quality that are not standard endpoints in clinical trials. We utilize CCT to measure visual function in patients with multiple sclerosis (MS), age-related macular degeneration (AMD), epiretinal membrane (ERM), and retinal vein occlusion (RVO).MethodsRetrospective data was gathered from 237 patients of the Gavin Herbert Eye Institute. Subjects included 17 patients with MS, 45 patients with AMD, 41 patients with ERM, 11 patients with RVO, and 123 healthy controls. Patients underwent the primary measurement outcome, CCT testing, as well as Sloan visual acuity test and spectral domain optical coherence tomography during normal care.ResultsColor and contrast deficits were present in MS patients regardless of history of optic neuritis. AMD with intermediate or worse disease demonstrated reduced CCT scores. All 3 stages of ERM demonstrated cone contrast deficits. Despite restoration of visual acuity, RVO-affected eyes demonstrated poorer CCT performance than unaffected fellow eyes.ConclusionsCCT demonstrates color and contrast deficits for multiple retinal diseases with differing pathophysiology. Further prospective studies of CCT in other disease states and with larger samples sizes is warranted.

Histopathological evaluation of Onchocerca volvulus nodules by microscopy and by digital image analysis for the study of macrofilaricidal drug efficacy.

Novel drugs or drug combinations that kill or permanently sterilize adult Onchocerca volvulus worms would be very helpful for treatment and elimination of onchocerciasis. In absence of a reliable biomarker for viable adult worms, histopathological assessment of worms within onchocercal nodules is a standard method to determine macrofilaricidal activity. The goal of the present study was to determine the agreement between two independent experts in the analysis of nodule sections and to assess the value of digital imaging as a means of standardizing the analysis. Two expert microscopists independently assessed 605 nodules by direct microscopy. At least two sections with two different stains hematoxylin & eosin (H&E, APR immunostain) of paraffin-embedded, ethanol-fixed whole-nodule cross-sections were analyzed. After variables were identified prone to observer discrepancies, we performed a second study to compare consolidated results for 100 nodules obtained by the two readers by microscopy and by analysis of scanned, high resolution digital images (20x magnification). The last data set analyzed was a quality panel of 100 nodules that has been previously examined by microscopy, and included additional immunostains for Wolbachia endobacteria. These slides were digitalized, read by the two assessors and results were compared with original microscopy results. The degree of agreement between assessors varied for different parameters. Agreement for female worm counts in nodules was approximately 80%, while agreement regarding female worm viability was 98%. There were no major differences observed between results obtained by microscopy or digital images. Good agreement for important parameters was also observed for the nodules of the quality panel. Nodule analysis by experienced microscopists was reproducible with regard to important parameters such as identification of living female worms or detection of normal embryogenesis. Assessments varied more for other parameters, and we recommend continued use of two independent readers for detailed analyzes. Analysis of scanned images provided similar results to direct microscopy. This facilitates training and comparison of nodule findings by readers in different locations. Analysis of high quality digital images that can be viewed remotely should improve the quality and availability of nodule assessments that are primary endpoints for onchocerciasis clinical trials.

P814 Clinical trial design in Crohn’s disease: interpreting future endpoints based on post hoc analyses of the vedolizumab phase 3 trials GEMINI 2 and VISIBLE 2

Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy. Methods Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and ClinicalTrials.gov. Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1). Results Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI &amp;lt; 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1). Conclusion Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.

P578 Exploring duration of corticosteroid withdrawal in definitions of corticosteroid-free remission endpoints in ustekinumab clinical trials: results from the IM-UNITI, UNIFI, and SEAVUE trials

Abstract Background Remission off steroids is a major treatment goal in inflammatory bowel disease. In the recent CORE-IBD consensus,1 the preferred definition of “corticosteroid-free” remission in clinical trials was withdrawal ≥12 weeks before the assessment timepoint. We evaluated the rates of corticosteroid-free remission according to three different definitions (ie, cross-sectional, ≥30, and ≥90 days) in the analysis of the corticosteroid-free remission endpoint using data from the IM-UNITI and SEAVUE trials of patients with Crohn’s disease (CD) and the UNIFI trial of patients with ulcerative colitis (UC). Methods In IM-UNITI and UNIFI, patients with moderate-to-severe CD and UC, respectively, who had previously responded to ustekinumab (UST) induction were randomized to placebo (PBO), UST 90mg SC q12w, or UST 90mg SC q8w. In SEAVUE, biologic naïve patients with moderate-to-severe CD were randomized to adalimumab 160mg SC at week 0, 80mg SC at week 2, and 40mg SC q2w or UST ~6mg/kg IV at week 0 and 90mg SC q8w. Each trial included protocols for mandatory corticosteroid tapering after the induction phase unless medically inappropriate (required in IM-UNITI and UNIFI starting at week 8 and recommended in SEAVUE starting at week 8 but required starting at week 16). Corticosteroid-free remission was defined as clinical remission (CDAI&amp;lt;150 in IM-UNITI and SEAVUE and a Mayo score ≤2 with no individual subscore &amp;gt;1 in UNIFI) and not receiving steroids at the assessment timepoint or ≥30 or ≥90 days before the assessment timepoint. Corticosteroid-free remission at week 44 was a major secondary endpoint in IM-UNITI and UNIFI (both cross-sectional). Corticosteroid-free remission (≥30 days before week 52) was a major secondary endpoint in SEAVUE. Results The proportions of patients who achieved corticosteroid-free remission were consistent, regardless of the corticosteroid-free duration used in the assessment (Tables 1 and 2). The results were consistent for both ustekinumab treatment groups (q12w and q8w) and placebo in the pivotal IM-UNITI and UNIFI studies (Table 1) and for both ustekinumab and adalimumab groups in the SEAVUE study (Table 2). Conclusion In CD and UC clinical trials of ustekinumab maintenance, which included protocol-mandated corticosteroid tapering regimens, corticosteroid-free remission results at 1 year were similar regardless of the corticosteroid-free duration used in the outcome definition.

P227 Patient experiences in ulcerative colitis: conceptual model and review of patient-reported outcome measures

Abstract Background Symptoms of ulcerative colitis (UC) negatively affect patients’ health-related quality of life (HRQoL). The aim of this study was to identify symptoms and impacts experienced by patients with UC, develop a conceptual model (CM) and evaluate available patient-reported outcome (PRO) measures for appropriateness for inclusion in UC clinical studies. Methods We conducted a landscape assessment that included: targeted literature reviews (TLRs) to identify concepts of interest and frequently used PRO measures among patients with UC; label claims searches for US and European regulatory and health technology assessment (HTA) submissions; and US and European clinical trial database searches to identify PRO measures used as primary and secondary endpoints in ongoing clinical trials. Results from the TLR informed a CM of UC. Concepts from the CM were mapped to selected PRO measures. Appropriateness of selected PRO measures for UC populations was evaluated via a gap analysis. Results Fifty-two symptoms and 72 impacts of UC were identified from the TLR. The most frequently reported symptoms were diarrhoea, incontinence/leaking/lack of bowel control, urgency, rectal bleeding, frequent bowel movements and fatigue. The most frequently reported impacts were anxiety, depression, inability to conduct daily activities, embarrassment and affected relationships with others. The CM grouped the 52 symptom concepts into eight dimensions, the 29 impacts proximal to UC into two dimensions and the 43 impacts distal to UC into five dimensions (Figure 1). Of the 69 PRO measures identified, eight were selected for conceptual analysis based on being disease-specific and having evidence of use in regulatory label claims, HTA submissions, as UC clinical trial endpoints and/or having US Food and Drug Administration (FDA) qualification status. The five PRO measures that covered the most concepts when mapped against the CM and included in the gap analysis were: the Inflammatory Bowel Disease Questionnaire (IBDQ); Symptoms and Impacts Questionnaire for UC (SIQ-UC); UC-PRO symptoms modules (UC-PRO-Signs and Symptoms [UC-PRO/SS] and UC-PRO-Systemic Symptoms); UC-PRO impact modules (UC-PRO-Daily Coping [UC-PRO-DC], UC-PRO-Daily Life Impact [UC-PRO-DLI] and UC-PRO-Emotional Impact [UC-PRO-EI]); and Crohn’s and Ulcerative Colitis Questionnaire (CUCQ) (Table 1). All five PRO measures had good or excellent support for content validity; the UC-PRO/SS fully met FDA PRO guidance for content validity and most psychometric properties. Conclusion Based on the CM and PRO measures review, the IBDQ plus UC-PRO/SS are recommended to capture UC symptoms and IBDQ plus UC-PRO impact modules to capture proximal impacts. All PRO measures reviewed require further psychometric evaluation.

Comparison of 3D quantitative osteoarthritis imaging biomarkers from paired CT and MR images: data from the IMI-APPROACH study

IntroductionMRI bone surface area and femoral bone shape (B-score) measures have been employed as quantitative endpoints in DMOAD clinical trials. Computerized Tomography (CT) imaging is more commonly used for 3D visualization of bony anatomy due to its high bone-soft tissue contrast. We aimed to compare CT and MRI assessments of 3D imaging biomarkers.MethodsWe used baseline and 24-month image data from the IMI-APPROACH 2-year prospective cohort study. Femur and tibia were automatically segmented using active appearance models, a machine-learning method, to measure 3D bone shape, area and 3D joint space width (3DJSW). Linear regression was used to test for correlation between measures. Limits of agreement and bias were tested using Bland-Altman analysis.ResultsCT-MR pairs of the same knee were available from 434 participants (78% female). B-scores from CT and MR were strongly correlated (CCC = 0.967) with minimal bias of 0.1 (SDD = 0.227). Area measures were also correlated but showed a consistent bias (MR smaller). 3DJSW showed different biases (MR larger) in both lateral and medial compartments.DiscussionThe strong correlation and small B-score bias suggests that B-score may be measured reliably using either modality. It is likely that the bone surface identified using MR and CT will be at slightly different positions within the bone/cartilage boundary. The negative bone area bias suggests the MR bone boundary is inside the CT boundary producing smaller areas for MR, consistent with the positive 3DJSW bias. The lateral-medial 3DJSW difference is possibly due to a difference in knee pose during acquisition (extended for CT, flexed for MR).Trial registrationNCT03883568

METHODS TO DERIVE A MODIFIED MAYO SCORE FROM ELECTRONIC HEALTH RECORDS DATA

Abstract BACKGROUND The modified Mayo Score (MMS), which consists of stool frequency, rectal bleeding, and endoscopic subscores, is the most commonly used method for measuring disease activity in Ulcerative Colitis (UC) patients. It is a standard outcome measure in clinical trials, and is recommended as a clinical trial endpoint by the US Food and Drug Administration. Each component has a score from 0-3; the total MMS ranges from 0 to 9. MMS is infrequently recorded in routine care, in part because it requires an endoscopic assessment. Real world data, including electronic health record (EHR) databases, are useful for studying longitudinal disease and treatment outcomes, but most EHR databases do not include Mayo scores. Building off the methods described by Rudrapatna et al., 2021, we calculated a derived MMS using data elements available in EHRs. METHODS Data were derived from the OM1 PremiOM UC Dataset (OM1, Boston, MA), a multisource real-world database with linked healthcare claims and EHR data on US patients with UC (2013-present). Each of the three subscores was extracted from clinical notes and endoscopy reports, either by automated natural language processing methods or by abstraction by a trained medical abstractor. Rectal bleeding and stool frequency scores occurring within 4 months before or up to 1 month after the endoscopic score were combined to calculate a MMS. Multiple MMSs could be calculated for each patient, but each component score could contribute to only one MMS. RESULTS Among 12,849 UC patients, only 38 had a full Mayo score recorded in their notes, and 1 had a modified Mayo recorded. After applying the above algorithm, we were able to calculate a derived MMS for 739 patients. 220 patients had &amp;gt; 1 score available. Figure 1 shows the distribution of derived MMSs. Patients with a MMS were younger and more likely to be Asian, more likely to be treated with biologic therapies and less likely to be treated with mesalamine compared with those who could not have a MMS calculated (Table 1). CONCLUSIONS A derived MMS can be calculated from data that may be recorded in the medical record. Further work to validate these measures against a gold standard should be considered, but was not feasible in the OM1 dataset due to the paucity of observed Mayo scores in EHR data. Increased emphasis on standardized collection of relevant information in EHR systems would further improve the availability of derived MMSs. The population for which a MMS can be derived may have more severe disease and more frequent interactions with the healthcare system as evidenced by higher proportion of patients prescribed biologic therapies. MMSs can be derived and used to describe UC patients and could potentially be used to study longitudinal changes in patient disease status and treatment effectiveness in settings where observed scores are not available.

Erhalt von Leistungsfähigkeit und Lebensqualität bei chronischer Herzinsuffizienz (Teil 3)

Endpoints of large clinical intervention trials in heart failure are usually designed to assess the number of hospital admissions and cardiovascular mortality; however, patients with heart failure also suffer from reduced physical exercise capacity and poor quality of life. The aim of this 3‑part review article is to show therapeutic possibilities to maintain mobility and quality of life in patients with heart failure, covering the aspects of guideline-conform drug treatment, treatment of comorbidities, and physical training options. This third part shows that exercise training is safe and effective to improve performance and quality of life. Exercise training is recommended for all patients who think they are capable of doing this, which is independent of whether heart failure with preserved or reduced ejection fraction is present.

Considerations for Drug Development in Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.

Patient-reported outcome measures for physical function in cancer patients: content comparison of the EORTC CAT Core, EORTC QLQ-C30, SF-36, FACT-G, and PROMIS measures using the International Classification of Functioning, Disability and Health

BackgroundPatient-reported physical function (PF) is a key endpoint in cancer clinical trials. Using complex statistical methods, common metrics have been developed to compare scores from different patient-reported outcome (PRO) measures, but such methods do not account for possible differences in questionnaire content. Therefore, the aim of our study was a content comparison of frequently used PRO measures for PF in cancer patients.MethodsRelying on the framework of the International Classification of Functioning, Disability and Health (ICF) we categorized the item content of the physical domains of the following measures: EORTC CAT Core, EORTC QLQ-C30, SF-36, PROMIS Cancer Item Bank for Physical Function, PROMIS Short Form for Physical Function 20a, and the FACT-G. Item content was linked to ICF categories by two independent reviewers.ResultsThe 118 items investigated were assigned to 3 components (‘d – Activities and Participation’, ‘b – Body Functions’, and ‘e – Environmental Factors’) and 11 first-level ICF categories. All PF items of the EORTC measures but one were assigned to the first-level ICF categories ‘d4 – Mobility’ and ‘d5 – Self-care’, all within the component ‘d – Activities and Participation’. The SF-36 additionally included item content related to ‘d9 – Community, social and civic life’ and the PROMIS Short Form for Physical Function 20a also included content related to ‘d6 – domestic life’. The PROMIS Cancer Item Bank (v1.1) covered, in addition, two first-level categories within the component ‘b – Body Functions’. The FACT-G Physical Well-being scale was found to be the most diverse scale with item content partly not covered by the ICF framework.DiscussionOur results provide information about conceptual differences between common PRO measures for the assessment of PF in cancer patients. Our results complement quantitative information on psychometric characteristics of these measures and provide a better understanding of the possibilities of establishing common metrics.

Using qualitative interviews to identify patient-reported clinical trial endpoints and analyses that are the most meaningful to patients with advanced breast cancer.

Designing clinical trials with the emphasis on the patient-centered approach and focusing on clinical outcomes that are meaningful to patients is viewed as a priority by drug developers, regulatory agencies, payers, clinicians, and patients. This study aimed to capture information on clinical trial endpoints that would be most important and relevant for patients with advanced breast cancer, based on patient-reported outcomes. Patients with either advanced triple-negative breast cancer [TNBC] and a maximum of two lines of systemic therapy or hormone receptor-positive/human epidermal growth factor receptor 2-negative [HR+/HER2-] breast cancer and a maximum of three lines of systemic therapy, participated in semi-structured concept elicitation interviews. Concept saturation was assessed. A sign, symptom, or impact was defined as "salient" if mentioned by ≥ 60% of participants, with an average bother rating of ≥ 5 (0-10 Scale). Participants were also asked about treatment priorities and to evaluate hypothetical scenarios showing different health-related functioning and quality-of-life treatment outcomes, using graphical representations. Thirty-two participants (97% women; aged 29+ years) with TNBC (n = 17) or HR+/HER2- breast cancer (n = 15) provided generally similar reports on symptom experience, with fatigue and pain being most salient, though importance of certain treatment-related symptoms varied between the two groups. Patients reported consistent perspectives on the importance of treatment outcomes: when considering a new treatment, they prioritized efficacy of the therapy, acceptable tolerability, stability, predictability of symptoms over time, and the duration of preserved health-related quality of life and physical functioning. The meaningful difference in preserved physical functioning was 2-3 months for 46% of participants with TNBC, whereas for most participants with HR+/HER2- breast cancer it started from 6-7 months. Both groups of participants found it easier to accept some toxicity at the beginning of therapy if it was followed by improvement, as opposed to improvement followed by deterioration. The results may help to inform the design of patient-centered clinical trials, to interpret health-related quality of life and/or patient-reported outcomes, and to optimize care for patients with advanced breast cancer.

Comparing ability and norm-referenced scores as clinical trial outcomes for neurodevelopmental disabilities: a simulation study

BackgroundFor genetic conditions associated with neurodevelopmental disorder (GCAND), developmental domains such as motor ability, thinking and learning, social abilities, and communication are potential intervention targets. Performance on measures of developmental concepts can be expressed using several types of scores. Norm-referenced scores are intended for the diagnostic context, allowing for the identification of impairment relative to age-based expectations, and can exhibit dramatic floor effects when used in individuals with more significant limitations. Person ability scores, which are derived via Rasch analysis or item response theory, are available on many standardized tests and are intended to measure within-person change. However, they have not been used or evaluated as primary endpoints in GCAND clinical trials. In this study, we simulated a series of parallel-arm clinical trials under several chronological age and impairment conditions, to compare empirically the power and type I error rate of operationalizing test performance using ability scores rather than norm-referenced scores.ResultsUsing the Vineland Adaptive Behavior Scales as the example, we demonstrated an advantage in statistical power of ability scores over norm-referenced scores at extreme levels of impairment. This advantage was at least partially driven by floor effects in norm-referenced scores. For simulated conditions where impairment was less severe, ability scores outperformed norm-referenced scores, but they were more similar. The type I error rate closely approximated the nominal type I error rate of 5% for both scores.ConclusionThe results of this simulation demonstrate a substantial power and interpretative advantage of ability scores over norm-referenced scores for studies of GCAND that will enroll participants with high levels of impairment. These results are expected to generalize to studies of developmental concepts, regardless of the etiology or specific test. However, the relative advantage of ability scores is expected to be even greater for tests with a higher floor than the Vineland.

Latent variable indirect response modeling of clinical efficacy endpoints with combination therapy: application to guselkumab and golimumab in patients with ulcerative colitis.

Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently. This study aims to demonstrate that the latent variable IDR approach provides a convenient longitudinal exposure-response modeling framework to assess potential interaction effects of combination therapies. This is illustrated by an application to the exposure-response modeling of guselkumab, a monoclonal antibody in clinical development that blocks the interleukin-23p19 subunit, and golimumab, a monoclonal antibody that binds with high affinity to tumor necrosis factor-alpha. A Phase 2a study was conducted in 214 patients with moderate-to severe active ulcerative colitis for which longitudinal assessments of disease severity based on patient-reported measures of rectal bleeding, stool frequency, and symptomatic remission were evaluated as categorical endpoints, and fecal calprotectin as a continuous endpoint. The modeling results suggested independent pharmacodynamic guselkumab and golimumab effects on fecal calprotectin as a continuous endpoint, as well as interaction effects on the categorical endpoints that may be explained by an additional pathway of competitive interaction.

Discordant Clinical and Microbiological Outcomes Are Associated With Late Clinical Relapse in Clinical Trials for Complicated Urinary Tract Infections.

Current US Food and Drug Administration guidance recommends that the primary endpoint for complicated urinary tract infection clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed point after therapy. Although some participants meet the criteria for clinical success, they do not meet the criteria for microbiological eradication and are classified as treatment failures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. We analyzed participant data from 13 phase 3 clinical trials submitted to the US Food and Drug Administration (N = 4842). Outcomes were determined at the test of cure (TOC) visit, recommended to occur at least 5 days after therapy and at the late follow-up visit, recommended to occur 21 to 28 days after randomization. Clinical and microbiological success were defined as the resolution of complicated urinary tract infection symptoms present at study entry, with no new symptoms (clinical cure), and a reduction in density of the original pathogen to <103 CFU/mL on urine culture (microbiological eradication). Among included participants, 70.7% were concordant successes at the TOC visit, 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). Discordant participants were at an increased risk for clinical failure at the late follow-up visit, and the risk of late clinical failure increased with time. Discordant clinical and microbiological outcomes at the TOC visit were associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component of the endpoint.

The other immuno-PET: Metabolic tracers in evaluation of immune responses to immune checkpoint inhibitor therapy for solid tumors.

Unique patterns of response to immune checkpoint inhibitor therapy, discernable in the earliest clinical trials, demanded a reconsideration of the standard methods of radiological treatment assessment. Immunomonitoring, that characterizes immune responses, offers several significant advantages over the tumor-centric approach currently used in the clinical practice: 1) better understanding of the drugs' mechanism of action and treatment resistance, 2) earlier assessment of response to therapy, 3) patient/therapy selection, 4) evaluation of toxicity and 5) more accurate end-point in clinical trials. PET imaging in combination with the right agent offers non-invasive tracking of immune processes on a whole-body level and thus represents a method uniquely well-suited for immunomonitoring. Small molecule metabolic tracers, largely neglected in the immuno-PET discourse, offer a way to monitor immune responses by assessing cellular metabolism known to be intricately linked with immune cell function. In this review, we highlight the use of small molecule metabolic tracers in imaging immune responses, provide a view of their value in the clinic and discuss the importance of image analysis in the context of tracking a moving target.

Neuropsychological endpoints for clinical trials in methylmalonic acidemia and propionic acidemia: A pilot study

IntroductionThis pilot study assessed instruments measuring relatively discrete neuropsychological domains to inform the selection of clinical outcome assessments that may be considered for interventional trials in methylmalonic acidemia (MMA) and propionic acidemia (PA). MethodsTests and questionnaires were selected for their possible relevance to MMA and PA and potential sensitivity to modest changes in functioning and behavior. ResultsTwenty-one patients (<18 years, n = 10;>18 years, n = 11) and/or their caregivers responded to video interviews and paper tests. Language deficits and significant motor deficits in some participants impacted scoring, especially in the verbal and processing speed sections of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). However, all participants ≥12 years of age were able to complete the Cookie Theft Picture Task. Thus, verbal discourse remains a potentially useful endpoint for participants in this age group. The Vineland Adaptive Behavior Scales (VABS-3) Adaptive Behavior Composite and Communication Scores confirmed delayed or immature functioning in day-to-day activities in these participants. Significant motor deficits prevented completion of some tests. Computerized processing speed tasks, which require pressing a button or tapping a computer screen, may be easier than writing or checking off boxes on paper in this cohort. Sleep characteristics among MMA participants were within normative ranges of the Child and Adolescent Sleep Checklist (CASC), indicating that this measurement would not provide valuable data in a clinical trial. Despite their challenges, responses to the Metabolic Quality of Life Questionnaire indicated these patients and their caregivers perceive an overall high quality of life. ConclusionOverall, test and questionnaire results were notably different between participants with MMA and participants with PA. The study demonstrates that pilot studies can detect instruments that may not be appropriate for individuals with language or motor deficits and that may not provide a broad range of scores reflecting disease severity. It also provides a rationale for focusing on discrete neuropsychological domains since some aspects of functioning were less affected than others and some were more closely related to disease severity. When global measures are used, overall scores may mask specific deficits. A pilot study like this one cannot ensure that scores will change over time in response to a specific treatment in a clinical trial. However, it can avert the selection of instruments that do not show associations with severity or biomedical parameters likely to be the target of a clinical trial. A pilot study can also identify when differences in diagnoses and baseline functioning need to be addressed prior to developing the analytical plan for the trial.