Valid Endpoint Research Articles

Thrombopoietin Receptor Agonists as Second-Line Treatment in Children With Ongoing Immune Thrombocytopenia

What Is the Issue? Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelets and an increase in bleeding risk; in the pediatric population, the reported incidence rate varies between 2 and 5 per 100,000 children per year. Spontaneous remission may be observed in up to 70% of patients, while 20% of patients may experience severe bleeding symptoms. In children whose ITP does not respond to first-line corticosteroids, IV immunoglobulin (IVIG), or anti-D immunoglobulin, guidelines recommend the use of thrombopoietin receptor agonists (TPO-RAs), i.e., eltrombopag or romiplostim (avatrombopag did not have a marketing authorization and Notice of Compliance at the time that the review was initiated). Rituximab is considered a subsequent-line of therapy. Splenectomy is not usually considered an appropriate treatment option in children. The goal of therapy in pediatric patients with ITP is to reduce bleeding and improve quality of life. Platelet response is considered a valid and appropriate surrogate end point in studies and routine assessment in clinical practice. Children whose ITP does not respond to available first-line drugs may require subsequent treatment with off-label drugs because they do not have access to TPO-RAs. What Did We Do? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence. A systematic review of the literature identified 5 studies (4 randomized controlled trials [RCTs] and 1 observational study), which were synthesized narratively. The review addressed the following policy questions: In children with ongoing, active ITP, what is the overall body of evidence supporting the use of TPO-RAs and rituximab after failure of first-line therapies? Based on the level and quality of clinical evidence, should TPO-RAs be reimbursed for use earlier in the treatment sequencing for children with ongoing, active ITP, instead of being reimbursed only after a course of rituximab? What Did We Find? Evidence from 2 RCTs (n = 159) suggests that eltrombopag likely increases and maintains platelet response over time, in addition to decreasing the use of rescue medication and clinically significant bleeding compared to placebo, which were considered clinically meaningful outcomes for pediatric patients with ITP. There was a low risk of bias in the studies, but uncertainty was introduced due to the small sample sizes. Evidence from 1 RCT (n = 62) suggests that romiplostim may also increase and maintain platelet response, as well as reduce clinically significant bleeding compared to placebo. However, there was some concern due to a high risk of bias in the studies and uncertainty due to the small sample size, which suggests a need for caution in the interpretation of the findings. The effectiveness of rituximab was inconclusive due to the lack of evidence, as no comparative RCTs could be identified, while the observational study included presented only descriptive comparisons. No evidence was identified in support of trying rituximab before accessing TPO-RAs. What Does This Mean? Given that ITP is rare in children, there is a gap in available relevant evidence, and robust evidence from large RCTs in this patient population are unlikely to be conducted. Jurisdictions may consider requesting an implementation advice panel for use of eltrombopag and romiplostim after failure of first-line therapies in children with ongoing, active ITP.

Smartphone-Based Assessment of Mobility and Manual Dexterity in Adult People with Spinal Muscular Atrophy.

More responsive, reliable, and clinically valid endpoints of disability are essential to reduce size, duration, and burden of clinical trials in adult persons with spinal muscular atrophy (aPwSMA). The aim is to investigate the feasibility of smartphone-based assessments in aPwSMA and provide evidence on the reliability and construct validity of sensor-derived measures (SDMs) of mobility and manual dexterity collected remotely in aPwSMA. Data were collected from 59 aPwSMA (23 walkers, 20 sitters and 16 non-sitters) and 30 age-matched healthy controls (HC). SDMs were extracted from five smartphone-based tests capturing mobility and manual dexterity, which were administered in-clinic and remotely in daily life for four weeks. Reliability (Intraclass Correlation Coefficients, ICC) and construct validity (ability to discriminate between HC and aPwSMA and correlations with Revised Upper Limb Module, RULM and Hammersmith Functional Scale - Expanded HFMSE) were quantified for all SDMs. The smartphone-based assessments proved feasible, with 92.1% average adherence in aPwSMA. The SDMs allowed to reliably assess both mobility and dexterity (ICC > 0.75 for 14/22 SDMs). Twenty-one out of 22 SDMs significantly discriminated between HC and aPwSMA. The highest correlations with the RULM were observed for SDMs from the manual dexterity tests in both non-sitters (Typing, ρ= 0.78) and sitters (Pinching, ρ= 0.75). In walkers, the highest correlation was between mobility tests and HFMSE (5 U-Turns, ρ= 0.79). This exploratory study provides preliminary evidence for the usability of smartphone-based assessments of mobility and manual dexterity in aPwSMA when deployed remotely in participants' daily life. Reliability and construct validity of SDMs remotely collected in real-life was demonstrated, which is a pre-requisite for their use in longitudinal trials. Additionally, three novel smartphone-based performance outcome assessments were successfully established for aPwSMA. Upon further validation of responsiveness to interventions, this technology holds potential to increase the efficiency of clinical trials in aPwSMA.

A Pragmatic Approach to Introducing Translational Geroscience Into the Clinic: A Paradigm Based on the Incremental Progression of Aging-Related Clinical Research.

Geroscience posits that molecular drivers underlie the aging process. Gerotherapeutics entail strategies to counter molecular drivers of aging to reduce the chronic diseases and geriatric syndromes they trigger. Although the concept of gerotherapeutics for prevention has generated much excitement, the implications of prescribing potentially harmful medications to older adults who are "healthy" have been associated with many delays. Concerns regarding safety and valid endpoints have contributed to holdups. In contrast, it has been relatively easier to implement trials of medications with gerotherapeutic properties as novel approaches to remedy disease. In these applications, the risks of the medications are easier to justify when therapeutic benefits are perceived as outweighing the harms of the disease. Likewise, metrics of effective disease treatments are often seen as more reliable and quantifiable than metrics of health prolongation. Overall, clarifying geroscience mechanisms in disease therapeutic applications provides key opportunities to advance translational geroscience, especially as preventive geroscience trials are often encumbered. In this review, gerotherapeutic benefits of canakinumab, cholchicine, and zoledronic acid as parts of disease management are considered. Longevity Clinics and other opportunities to advance translational geroscience as parts of contemporary care are also discussed.

Clinical trial design, end-points, and emerging therapies in pulmonary arterial hypertension.

Clinical trials in pulmonary arterial hypertension (PAH) have led to the approval of several effective treatments that improve symptoms, exercise capacity and clinical outcomes. In phase 3 clinical trials, primary end-points must reflect how a patient "feels, functions or survives". In a rare disease like PAH, with an ever-growing number of treatment options and numerous candidate therapies being studied, future clinical trials are now faced with challenges related to sample size requirements, efficiency and demonstration of incremental benefit on traditional end-points in patients receiving background therapy with multiple drugs. Novel clinical trial end-points, innovative trial designs and statistical approaches and new technologies may be potential solutions to tackle the challenges facing future PAH trials, but these must be acceptable to patients and regulatory bodies while preserving methodological rigour. In this World Symposium on Pulmonary Hypertension task force article, we address emerging trial end-points and designs, biomarkers and surrogate end-point validation, the concept of disease modification, challenges and opportunities to address diversity and representativeness, and the use of new technologies such as artificial intelligence in PAH clinical trials.

Reliability of MR Enterography Features for Describing Fibrostenosing Crohn Disease.

Background Clinical decision making and drug development for fibrostenosing Crohn disease is constrained by a lack of imaging definitions, scoring conventions, and validated end points. Purpose To assess the reliability of MR enterography features to describe Crohn disease strictures and determine correlation with stricture severity. Materials and Methods A retrospective study of patients with symptomatic terminal ileal Crohn disease strictures who underwent MR enterography at tertiary care centers (Cleveland Clinic: September 2013 to November 2020; Mayo Clinic: February 2008 to March 2019) was conducted by using convenience sampling. In the development phase, blinded and trained radiologists independently evaluated 26 MR enterography features from baseline and follow-up examinations performed more than 6 months apart, with no bowel resection performed between examinations. Follow-up examinations closest to 12 months after baseline were selected. Reliability was assessed using the intraclass correlation coefficient (ICC). In the validation phase, after five features were redefined, reliability was re-estimated in an independent convenience sample using baseline examinations. Multivariable linear regression analysis identified features with at least moderate interrater reliability (ICC ≥0.41) that were independently associated with stricture severity. Results Ninety-nine (mean age, 40 years ± 14 [SD]; 50 male) patients were included in the development group and 51 (mean age, 45 years ± 16 [SD]; 35 female) patients were included in the validation group. In the development group, nine features had at least moderate interrater reliability. One additional feature demonstrated moderate reliability in the validation group. Stricture length (ICC = 0.85 [95% CI: 0.75, 0.91] and 0.91 [95% CI: 0.75, 0.96] in development and validation phase, respectively) and maximal associated small bowel dilation (ICC = 0.74 [95% CI: 0.63, 0.80] and 0.73 [95% CI: 0.58, 0.87] in development and validation group, respectively) had the highest interrater reliability. Stricture length, maximal stricture wall thickness, and maximal associated small bowel dilation were independently (regression coefficients, 0.09-3.97; P < .001) associated with stricture severity. Conclusion MR enterography definitions and scoring conventions for reliably assessing features of Crohn disease strictures were developed and validated, and feature correlation with stricture severity was determined. © RSNA, 2024 Supplemental material is available for this article. See also the article by Rieder and Ma et al in this issue. See also the editorial by Galgano and Summerlin in this issue.

Advantages of Lissamine Green Vital Staining as an Endpoint in Dry Eye Clinical Trials.

The absence of a standardized diagnostic method for clinical signs of Dry Eye Disease (DED) complicates clinical trials for future treatments. This paper evaluated Lissamine Green (LG) conjunctival staining as a valid, stable and modifiable endpoint for both clinical practice and clinical trials. Screening and pre-randomization data from two identically designed clinical trials for DED resulted in a pooled dataset of 494 subjects. Inclusion was based on reported symptoms, lissamine green (LG) conjunctival staining, Fluorescein (Fl) corneal and conjunctival staining, and Schirmer's Test (ST). Outcome measures were assessed based on the modifiability of LG staining to exposure to a Controlled Adverse Environment (CAE®), correlation of LG to Fl staining, relative variation of LG staining scores and Schirmer test scores, and the correlation of LG staining with symptom scores. The modifiability of LG conjunctival staining to environmental exposure was demonstrated, with nasal LG and FL staining displaying the most similar percent change. Nasal LG conjunctival staining scores for subjects with ST scores of less than 8mm were significantly higher than for subjects with ST greater than 8mm. LG staining scores were more consistent (25% change from baseline threshold) than ST scores. Finally, statistically significant correlations were found between LG staining and a number of symptom scores. This evaluation demonstrates the superiority of the utilization of a clinical endpoint focused on ocular surface damage. The reproducibility and modifiability of LG conjunctival staining to controlled adverse environment, coupled with its significant correlation with symptoms, positions it as an exemplary clinical sign endpoint for clinical management and in clinical trials. Our findings advocate for the adoption of LG conjunctival staining as a primary endpoint in both clinical research and drug development, offering a more effective means of identifying and addressing ocular surface damage in the realm of DED.

Evaluating CR as a surrogate endpoint for PFS in R/R chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A meta-analysis of randomized controlled trials (RCT).

7046 Background: CLL/SLL is the most common leukemia in adults. Achieving a CR by International Workshop on CLL 2018 criteria indicates complete eradication of CLL/SLL in all disease compartments. Patients with R/R CLL/SLL who achieved CR tend to have delayed disease progression/death compared with patients who did not achieve CR. This is the first report to evaluate CR as a surrogate endpoint for PFS in R/R CLL/SLL using aggregate RCT data. Methods: A systematic literature review (SLR) identified published RCTs in R/R CLL/SLL from inception to 10/2023, reporting nonzero CR rates (CRR) and PFS. Association between treatment effects on CR and PFS across RCTs was estimated using a weighted linear model (WLM) in the primary analysis, and Daniels and Hughes (D&amp;H) and Riley bivariate random-effects meta-analysis (BRMA) in sensitivity analyses. Strength of association was assessed based on surrogacy criteria described by D&amp;H. Predictive performance of models was evaluated using leave-one-out cross-validation. Results: The SLR identified 13 RCTs with a total of 4388 patients with R/R CLL/SLL treated with a variety of therapies, including but not limited to BTKi, BCL2i, PI3Ki, CAR T cell therapy, anti-CD20 mAb, and chemotherapy. Across the evidence base, CRR ranged from 0.48% to 38.10% and median PFS was between 1 and 35.9 months (excluding unreached medians). Across RCTs, contrasting treatment and control arms, higher odds of CR resulted in lower hazards of disease progression/death (CRR improvement translated to PFS benefit). D&amp;H surrogacy criteria were met for WLM: 1) a near-zero, statistically nonsignificant intercept, indicating that no treatment effect on CRR implies no effect on PFS; 2) a negative, statistically significant slope, suggesting that improved CRR correlates with longer PFS; and 3) a near-zero conditional variance, meaning that PFS HR variation was primarily explained by CR odds ratio. During cross-validation, treatment effects on CR were predictive of PFS benefits, as the 95% predictive interval of PFS HR contained the observed HR in all RCTs for WLM. Results were largely consistent across all 3 models(Table). Conclusions: Improved CRR corresponds to prolonged PFS across RCTs and treatment comparisons. The results support CRR as an important treatment goal for R/R CLL/SLL and a valid surrogate endpoint. Consistent results and predictive performance across different models indicate the robustness of the results. [Table: see text]

Associations Among Tremor Amplitude, Activities of Daily Living, and Quality of Life in Patients with Essential Tremor.

Essential tremor (ET) is a disabling syndrome consisting of tremor, primarily in the upper limbs. We assessed the correlation of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Item 4 ratings of upper limb tremor with the TETRAS activities of daily living (ADL) subscale and with 2 quality of life (QoL) scales. This noninterventional, cross-sectional, point-in-time survey of neurologists(n = 60), primary care physicians (n = 38), and their patients with ET (n = 1,003) used real-world data collected through the Adelphi ET Disease Specific Programme™. Physician-reported measures (TETRAS Performance Item 4 and TETRAS ADL total) and patient-reported QoL measures (generic EuroQol-5 Dimension 5 Level [EQ-5D-5 L] and ET-specific Quality of Life in Essential Tremor Questionnaire (QUEST)) were assessed with bivariate and multivariable analyses. Sensitivity analyses were also conducted. The bivariate association between TETRAS Performance Item 4 score and TETRAS ADL total score was high (Pearson r = 0.761, P < 0.001). The bivariate associations between TETRAS Performance Item 4 score and EQ-5D-5 L index score (r = -0.410, P < 0.001) and between TETRAS ADL total score and EQ-5D-5 L index score (r = -0.543, P < 0.001) were moderate. The bivariate associations between TETRAS Performance Item 4 score and QUEST total score (r = 0.457, P < 0.001), and between TETRAS ADL total score and QUEST total score (r = 0.630, P < 0.001) were also moderate. These associations were unaltered by the inclusion of covariates. This study showed that greater tremor severity (TETRAS Performance Item 4) was positively correlated with ADL impairment (TETRAS ADL) and negatively associated with QoL (EQ-5D-5 L and QUEST). TETRAS Performance Item 4 score is a robust predictor of TETRAS ADL total score, and TETRAS Performance Item 4 and TETRAS ADL total scores were robust predictors of the 2 QoL scales. The results demonstrate the value of TETRAS scores as valid endpoints for future clinical trials. This real-world study assessed TETRAS scores as predictors of impaired QoL in ET. TETRAS Performance Item 4 and ADL were associated with EQ-5D-5 L and QUEST. TETRAS scores may serve as valid endpoints for future clinical trials.

Comprehensive 3DCRT Hypofractionated Radiotherapy Schedule for Localized Prostate Adenocarcinoma in the Era of IMRT: Dosimetric and Endoscopic Analysis.

Background: Moderate hypofractionated radiotherapy (MHRT) has emerged as the preferred treatment modality for localized prostate cancer based on randomized controlled studies regarding efficacy and toxicity using contemporary radiotherapy techniques. In the setting of MHRT, available data on dosimetric parameters and late rectal toxicity are limited. Aim: To present the effects of MHRT on late rectal toxicity while conducting an extensive dosimetric analysis in conjunction with rectoscopy results. Methods: This is a prospective study including patients with intermediate-risk prostate adenocarcinoma. All patients were treated with MHRT 44 Gy in 16 fractions to the seminal vesicles and to the prostate, followed by a sequential boost to the prostate alone of 16.5 Gy in 6 fractions delivered with three-dimensional conformal radiation therapy (3DCRT). Acute and late toxicity were assessed. Endoscopy was performed at baseline, every 3 months post-therapy for the first year, and every 6 months for the year after. The Vienna Rectoscopy Score (VRS) was used to assess rectal mucosal injury related to radiotherapy. Dosimetric analysis for the rectum, rectal wall, and its subsegments (upper, mid, and low 1/3) was performed. Results: Between September 2015 and December 2019, 20 patients enrolled. Grade 1 late gastrointestinal toxicity occurred in 10% of the patients, whereas 5% had a grade ≥2. Twelve months post radiotherapy: 4 (20%) patients had VRS 1; 2 (10%) patients had VRS 2; 1(5%) patient had VRS 3. 24 months post radiotherapy, VRS 1 was observed in 4 patients (20%) and VRS 2 in 3 (15%) patients. The dosimetric analysis demonstrated noticeable variations between the rectum, rectal wall, and rectal wall subsegments. The dosimetric analysis of the rectum, rectal wall, and its mid and low segments with respect to rectoscopy findings showed that the higher dose endpoints V52.17Gy and V56.52Gy are associated with rectal mucosal injury. Conclusions: A thorough delineation of the rectal wall and its subsegments, together with the dosimetric analysis of these structures, may reduce late rectal toxicity. Dosimetric parameters such as V52.17Gy and V56.52Gy were identified to have a significant impact on rectal mucosal injury; additional dose endpoint validation and its relation to late GI toxicity is needed.

AmpFire HPV and ScreenFire RS HPV validation trial.

The human papillomavirus (HPV) screening assays from Atila Biosystems, including the new AmpFire (14 type) and ScreenFire RS (13 type), were subjected to a series of validation tests. We used a set of samples from the Chinese Multi-Site Screening Trial (previously tested with cobas 4800 and the next-generation SeqHPV) to satisfy Meijer's criteria for clinical end-point validation. We selected 556 self-collected specimens composed of 273 high-risk HPV (hrHPV) positives and 283 hrHPV negatives on the cobas 4800 and SeqHPV. Of the 273 hrHPV-positive cases, 108 had a disease end point of cervical intraepithelial neoplasia grade 2 (CIN2) or higher, including 47 with cervical intraepithelial neoplasia grade 3 (CIN3+) or higher. We simulated the VALGENT framework for inter- and intralaboratory validation and evaluated the new 4-channel risk-stratified ScreenFire assay in a hierarchal fashion. Both AmpFire and ScreenFire detected 106 (98.1%) of 108 cases with CIN2 or higher, with specificities of 56.7% and 58.1%, respectively. Intralaboratory concordance for 2 runs of AmpFire and ScreenFire was 95.13% and 96.03%, respectively, for overall hrHPV types and 99.10% and 99.46%, respectively, for HPV 16. The interlaboratory concordance of AmpFire and ScreenFire was 93.68% and 94.04% for overall hrHPV and 98.92% and 99.28%, respectively, for HPV 16. Other genotype correlation percentages were similarly high, with κs ranging from 0.86 to 0.94. The ScreenFire RS assay demonstrated excellent "genotype-specific concordance" when evaluated for "clinical guidance" in a hierarchal fashion (noting only the highest risk channel) with both the cobas 4800 and SeqHPV for less than CIN2, CIN2, and CIN3 or higher. The excellent intra- and interlaboratory reproducibility and the established clinical performance, together with the platforms' simplicity, make these assays particularly applicable to low-resource settings.

Potential Structural Biomarkers in 3D Images Validated by the First Functional Biomarker for Early Age-Related Macular Degeneration - ALSTAR2 Baseline.

Lack of valid end points impedes developing therapeutic strategies for early age-related macular degeneration (AMD). Delayed rod-mediated dark adaptation (RMDA) is the first functional biomarker for incident early AMD. The relationship between RMDA and the status of outer retinal bands on optical coherence tomography (OCT) have not been well defined. This study aims to characterize these relationships in early and intermediate AMD. Baseline data from 476 participants was assessed including eyes with early AMD (n=138), intermediate AMD (n=101), and normal aging (n=237). Participants underwent volume OCT imaging of the macula and rod intercept time (RIT) was measured. The ellipsoid zone (EZ) and interdigitation zone (IZ) on all OCT B-scans of the volumes were segmented. The area of detectable EZ and IZ, and mean thickness of IZ within the Early Treatment Diabetic Retinopathy Study (ETDRS) grid were computed and associations with RIT were assessed by Spearman's correlation coefficient and age adjusted. Delayed RMDA (longer RIT) was most strongly associated with less preserved IZ area (r=-0.591; P<0.001), followed by decreased IZ thickness (r=-0.434; P<0.001), and EZ area (r=-0.334; P<0.001). This correlation between RIT and IZ integrity was not apparent when considering normal eyes alone within 1.5 mm of the fovea. RMDA is correlated with the status of outer retinal bands in early and intermediate AMD eyes, particularly, the status of the IZ. This correlation is consistent with a previous analysis of only foveal B-scans and is biologically plausible given that retinoid availability, involving transfer at the interface attributed to the IZ, is rate-limiting for RMDA.

Recurrence-free survival as a surrogate for overall survival in esophageal squamous cell carcinoma: Nationwide real-world data from Japan.

269 Background: One of the limitations of the established gold standard, overall survival (OS), is that it requires an extended follow-up period. Addressing this challenge involves investigating appropriate statistically and clinically relevant surrogate endpoints. However, there is a paucity of studies using real-world data (RWD) to explore surrogacy in patients with esophageal squamous cell carcinoma (ESCC). Our study aims to investigate whether recurrence-free survival (RFS) is a valid surrogate endpoint for OS in surgically resectable advanced ESCC patients, utilizing a comprehensive nationwide database in Japan. Methods: The ESCC patients who received neoadjuvant CF (cisplatin and 5-fluorouracil) or DCF (docetaxel, cisplatin and 5-fluorouracil) at 58 Japanese esophageal centers certified by the Japan Esophageal Society were retrospectively reviewed. Kendall's tau between RFS and OS was used at the individual level, and the coefficient of determination was used at the institutional level to assess surrogacy. Additionally, surrogacy between each short-term postoperative endpoint (pathological complete response [pCR] or pathological grade) and OS was investigated using novel statistical methods. Results: Our study encompassed 3154 ESCC patients who underwent subtotal esophagectomy from 2010 to 2015. The cStage I/II/III/IVA/IVB (due to supraclavicular lymph node metastasis) was 224 (7.1%), 1008 (32.0%), 1664 (52.8%), 117 (3.7%), and 140 (4.4%), respectively. The 5-year OS and RFS rate for the entire cohort was 56.6% and 47.7%, respectively. In the primary analysis, a strong correlation between RFS and OS was found (Kendall's tau = 0.797, 95% confidence interval [CI]: 0.782 to 0.812) at the individual level. Subgroup analysis revealed that the better the pathological response, the higher the tau value. An adjusted R2 of 100.0% (95% CI: 40.2 to 100.0) was obtained with the meta-regression model at the institutional level. The surrogate threshold effect was 0.703. Tau between pCR or pathological grade and OS were -0.025 (95% CI: -0.335 to 0.285) and 0.062 (95% CI: -0.086 to 0.209), respectively. Conclusions: The present study was the first nationwide RWD investigation to demonstrate a strong correlation between RFS and OS in surgically resectable ESCC patients who underwent neoadjuvant chemotherapy (NAC). Notably, this correlation was more pronounced in patients who had a more effective response to NAC. These findings hold promise for expediting the development of novel neoadjuvant treatment by shortening the duration of clinical trials.

ЛЕЧЕНИЕ ЛЕГОЧНОЙ ГИПЕРТЕНЗИИ У ПАЦИЕНТОВ С СЕРПОВИДНОКЛЕТОЧНОЙ АНЕМИЕЙ С ИСПОЛЬЗОВАНИЕМ СИЛДЕНАФИЛА

Pulmonary hypertension is a common complication of sickle cell disease associated with hemolysis, impaired bioavailability of nitric oxide, and high mortality. The aim of the study is to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative drugs in this risk group. Materials and methods. After optimizing sickle cell therapy to stabilize fetal hemoglobin levels, we evaluated the safety and efficacy of sildenafil in 9 patients with sickle cell disease and pulmonary hypertension. Results. Sildenafil therapy (mean duration 6 ± 1 month) reduced estimated pulmonary systolic pressure [50 ± 4-41 ± 3 mmHg; 9 mmHg difference, 95% confidence interval (CI): 0.3-17, P = 0.043] and increased the 6-minute walking distance (384 ± 30 to 462 ± 28 m; 78 m difference, 95% CI: 40-117, P = 0.0012). Transient headaches were observed in two patients and transient eyelid edema in four patients. The three men in the study did not have any episodes of priapism. Two of them received chronic exchange transfusions, and one had erectile dysfunction. Conclusions. Patients with sickle cell disease and pulmonary hypertension have significant limitations in physical activity. Walking for 6 minutes may be a valid endpoint in this population. Sildenafil therapy is safe and improves pulmonary hypertension and physical performance. Additional phase I studies in men with sickle cell disease are needed, followed by a placebo-controlled phase II/III to evaluate the safety and efficacy of sildenafil therapy in patients with sickle cell disease and pulmonary hypertension.

Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase.

Aldehyde oxidase (AOX) and other related molybdenum-containing enzymes are known to oxidize the C-H bonds of aromatic rings. This process contributes to the metabolism of pharmaceutical compounds and, therefore, is of vital importance to drug pharmacokinetics. The present work describes an automated computational workflow and its use for the prediction of intrinsic reactivity of small aromatic molecules toward a minimal model of the active site of AOX. The workflow is based on quantum chemical transition state searches for the underlying single-step oxidation reaction, where the automated protocol includes identification of unique aromatic C-H bonds, creation of three-dimensional reactant and product complex geometries via a templating approach, search for a transition state, and validation of reaction end points. Conformational search on the reactants, products, and the transition states is performed. The automated procedure has been validated on previously reported transition state barriers and was used to evaluate the intrinsic reactivity of nearly three hundred heterocycles commonly found in approved drug molecules. The intrinsic reactivity of more than 1000 individual aromatic carbon sites is reported. Stereochemical and conformational aspects of the oxidation reaction, which have not been discussed in previous studies, are shown to play important roles in accurate modeling of the oxidation reaction. Observations on structural trends that determine the reactivity are provided and rationalized.

Establishing Real-World Data-Driven Response Criteria in Pediatric Acute Myeloid Leukemia

Introduction: Disease response criteria in pediatric acute myeloid leukemia (pAML) include complete remission (CR), complete remission without platelet count recovery (CRp), and complete remission with incomplete count recovery (CRi). Although clinicians use CR, CRp, and CRi as valid endpoints, the FDA only accepts CR as a valid response endpoint with the Cheson/European Leukemia Network (ELN) response criteria of absolute neutrophil count (ANC) &amp;gt;1,000 and platelets &amp;gt;100,000. Recent adult data show improved survival in patients achieving CR relative to CRp or CRi. Pediatric data from the Children's Oncology Group (COG) demonstrate similar survival regardless of achieving an ANC &amp;gt;500 or platelets &amp;gt;50,000. However, actual ANC and platelet data were not known, and COG data may not reflect outcomes of patients treated off study. Exclusion of CRp and CRi as valid efficacy endpoints limits clinical trials by potentially excluding patients who achieve remission but proceed to subsequent chemotherapy prior to meeting ELN recovery criteria. To address this data gap, we defined the ANC and platelet count trajectories in a 13-day window at end of course bone marrow (BM) after Induction I/II and Reinduction I/II of relapse therapy. We compared disease-free (DFS) and overall survival (OS) among CR categories and hypothesized that CR, CRp, and CRi after Induction I and Reinduction I would be associated with similar DFS and OS. Methods: Newly diagnosed pAML patients from 2011-2022 with at least one frontline chemotherapy course at one of six pediatric centers (Children's Hospital of Philadelphia, Children's Healthcare of Atlanta, Children's Hospital of Michigan, C.S. Mott Children's Hospital, Lurie Children's Hospital, and Texas Children's Hospital) underwent manual chart abstraction to capture demographic, therapy, toxicity, and BM response data: morphologic and minimal residual disease (MRD). The highest daily ANC and platelet counts were abstracted ±13 days around the last BM aspirate after Induction I/II and reinduction I/II post relapse. ELN and COG recovery criteria for ANC (&amp;gt;1,000 and &amp;gt;500, respectively) and platelet (&amp;gt;100,000 and &amp;gt;50,000, respectively) defined CR, CRp and CRi; CRi was further divided into CRnoANC and CRnoANCnoPlatelet. Standard descriptive statistics and Kaplan-Meier (KM) methods were used for analyses. Course-specific evaluations were restricted to subjects with an end of course BM documenting morphological response and ANC/platelet values on the day of course ending BM or 1 day prior. Results: The source population contained 486 patients with the analysis cohort restricted as described above to include 313 patients in Induction I, 290 patients in Induction II, 70 patients in Reinduction I, and 34 patients in Reinduction II. This represents 707 total courses and 8933 ANC/platelet observation days, restricted from 1166 courses (371 without morphologic response and 88 lacked ANC/platelet at course end BM). Demographic covariates included age, sex, race, ethnicity, risk group, MRD, extramedullary disease, weight category, and insurance. At Induction I, MRD differed significantly by CR category for ELN and COG criteria; risk group approached but did not reach significance; and Hispanic ethnicity differed by CR category only in COG criteria. No covariates differed significantly at Reinduction I in either ELN or COG criteria. At Induction I, CR proportion differed between ELN and COG criteria: 40.9% (95% CI 35.5-46.6%) vs 69.6% (95% CI 64.2%-74.7%). At Reinduction I, CR proportion differed between ELN and COG criteria: 18.6% (95% CI 10.3-29.7%) vs 47.1% (95% CI 35.1-59.4%). Panel 1a shows median ANC at Induction I BM is &amp;lt;1000 (ELN) but &amp;gt;500 (COG) in &amp;gt;75% of individuals. KM analyses showed no significant differences in CR strata in ELN or COG criteria in DFS or OS at Induction I. At Reinduction I, ELN CR strata did not differ, but COG CR strata were significantly different in DFS (p = 0.0007) and OS (p = 0.0019) with CRp and CRnoANC with higher DFS than CR or CRnoANCnoPlatelet (Panel 1b). Conclusion: These real-world data suggest that ELN/COG response criteria may lead to markedly different CR rates that may impact reported response rates in clinical trials. These analyses also support COG CR response criteria in de novo pAML and CR, CRp, and CRnoANC in relapsed pAML, recognizing that the modest relapsed pAML sample size requires additional data to determine optimal response criteria.

Do Hematologic Parameters Predict Thrombosis or Disease Transformation in Essential Thrombocythemia?

Background: Patients with essential thrombocythemia (ET) are burdened with an increased risk of thrombosis and disease transformation, both significant contributors to morbidity and mortality. However, based on the available literature, there are limited tools available to predict the development of these complications. Particularly, the association between hematologic parameters and thrombosis is unclear, making risk stratification and disease management challenging. Utilizing a large retrospective database, we assessed the impact of hematocrit (Hct), red blood cell count (RBC), white blood cell count (WBC), and platelet count (Plt) on the subsequent development of thrombosis and disease transformation to myelofibrosis (MF), polycythemia vera (PV), and acute leukemia. Methods: We included ET patients treated at our institution between 2007 and 2021. The index time was date of diagnosis or date of first contact at Mount Sinai Hospital for patients with a prior history of ET. Hematologic parameters (Hct, RBC, WBC, Plt) were documented at three-month intervals after the index time. Patients were included in the study if they had at least three sets of laboratory values prior to the outcome of interest. For each hematologic parameter, we performed univariate cox analysis of time to thrombosis or progression to either MF, PV, or acute leukemia. Each lab parameter was analyzed as a time dependent covariate, taking into account the length of time the patient was above or below the threshold of interest. Hct and plt were specifically evaluated as dichotomous variables, with a cut off of less than or greater than 45% for Hct based on CYTO-PV results. For plt, two cut-off values were used: less than or greater than 400 (based on ELN response criteria) and less than or greater than 600 (based on Cortelazzo et al HU treatment goal) in plt/microliter. Results: We identified 430 patients who met criteria and were included in the analysis. Our cohort of patients was mostly female (61%), non-Hispanic (66%), white (64%), JAK2 mutated (60%), with an average age at diagnosis of 56 years and a median follow-up time of 33 months. 41 (7%) patients had a history of prior thrombosis. There was a total of 23 major thromboses that occurred after the index time with 12 venous and 11 arterial thrombotic events. 38 patients progressed to post ET-MF, 20 patients developed post ET-PV, and 10 patients transformed to acute leukemia. For the assessment of thrombotic risk, there were no significant associations between any of the hematologic parameters and this outcome. We also evaluated the risk of thrombosis in the JAK2 positive subset of patients (n of 15), and did not find any significant association with any of the lab parameters (in particular, for hct &amp;lt; 45%, p &amp;gt; 0.99). For transformation to MF, plt &amp;lt; 400 x10 9/L was associated with an increased risk of the development of post-ET MF (HR 2.2, p 0.016), and the same was seen with plt &amp;lt; 600 x10 9/L (HR 2.2, p 0.044). The development of PV was less likely with a hct lower than 45% (HR 0.03, p &amp;lt; 0.001), with similar results seen for plt &amp;lt; 400 x10 9/L (HR 0.2, p 0.03) and plt &amp;lt; 600 x10 9/L (HR 0.2, p 0.002). For transformation to acute leukemia, plt &amp;lt; 400 x10 9/L (HR 8.3, p 0.008) was associated with an increased risk of this complication. Conclusions: In this retrospective cohort of 430 patients with ET, we found no associations between four different hematologic parameters over time with thromboses. In particular, this data once again argues against aiming to achieve a particular platelet goal to minimize thrombosis in ET patients. The lack of association between hematologic parameters and thrombotic risk was similarly exemplified in our subset of JAK2 mutated ET patients. Pertaining to disease transformation, plt count appeared to be the most predictive out of all of the parameters, with lower plt values corresponding to increased risk of both post-ET MF and acute leukemia, which both warrant further exploration. A hct level of less than 45% appeared to be protective against the development of post-ET PV. Significant limitations of our study include the retrospective nature as well as the small number of events of interest that our patients experienced. Future studies must continue to focus on surrogate endpoint validation in order to more reliably predict thrombotic events as well as disease progression in patients with ET given the significant morbidity and mortality that such events incur.

Correlation between PFS and OS in FL: Implications for Clinical Trial Endpoint Selection

Introduction: Follicular lymphoma (FL) comprises 15% of all lymphoma cases and 70% of indolent lymphomas. Cytotoxic, targeted, and novel treatments lead to prolonged remission periods, with a median overall survival (OS) of greater than 10 years. For this reason, surrogate endpoints for OS are frequently used in clinical trials of FL to allow for quicker results and shorter time to drug approvals, as well as to offset the likely cost and difficulty in funding long term trials with OS as a primary endpoint. A frequently used surrogate endpoint is progression free survival (PFS); however, PFS has not been previously validated as a surrogate endpoint for OS in the treatment of FL. Previous systematic reviews of multiple trials did not have mature enough data to draw definitive conclusions (Zhu et al, AAPS J 2017). Methods: To evaluate the correlation between PFS and OS in FL trials, we conducted a comprehensive systematic review. We included all completed phase 2 or 3 clinical trials with posted results on ClinicalTrials.gov from the inception of the database until July 2023. Additionally, we manually added trials that were completed before the database inception in February 2000 culled from HemOnc.org. For inclusion, randomized controlled trials reporting a hazard ratio for both PFS and OS were considered. We performed statistical analyses, utilizing unadjusted linear regression weighted by sample size to evaluate the association between hazard ratios for PFS and OS. Results: A total of 169 randomized controlled trials for FL were initially identified. Upon screening, 74 randomized trials reported rates for both PFS and OS. 20 trials with 22 interventional arms that included hazard ratios were eligible for inclusion in final analysis. 21 (96%) phase 3 trials and 1 (4%) randomized phase 2 trial were included, encompassing 10,729 participants. Among the included interventional arms, 12 (55%) were in the first-line setting and 10 (45%) were in the refractory or relapsed setting. 14 (64%) arms demonstrated a PFS benefit, and 4 (18%) demonstrated both a PFS and OS benefit. Disease characteristics and treatment outcomes are included in Table 1. The correlation coefficient between PFS and OS was 0.558 (95% CI 0.545-0.571), indicating a weak association. The coefficient of determination was 0.311 (95% CI: 0.08-0.52) suggesting 31.1% of OS variance could be explained by changes in PFS (Figure 1). Discussion: PFS showed a weak correlation with OS in FL trials, challenging its role as a surrogate endpoint. Factors such as patient heterogeneity, treatment regimens, subsequent therapies, and treatment-related complications may contribute to the discrepancy. While PFS aids regulatory approval and drug development, our study suggests that PFS may not be an appropriate surrogate endpoint for OS in the treatment of FL, and alternative surrogate endpoints should be pursued. Possible alternative endpoints though will need to be validated using similar systematic methods given often contradictory findings between individual studies. For example, progression within 24 months of initial treatment (POD 24) was a valid surrogate endpoint for OS in the PRIMA study, however this was not the case in the GALLIUM study (Bachi et al., Blood Adv 2021). Other surrogate endpoints such as complete response rate at 30 months (CR30) have demonstrated strong correlation with PFS however their association with OS has yet to be established (Shi el, JCO 2016).

Methods for the Clinical Validation of Digital Endpoints: Protocol for a Scoping Review Abstract.

Clinical trials often use digital technologies to collect data continuously outside the clinic and use the derived digital endpoints as trial endpoints. Digital endpoints are also being developed to support diagnosis, monitoring, or therapeutic interventions in clinical care. However, clinical validation stands as a significant challenge, as there are no specific guidelines orienting the validation of digital endpoints. This paper presents the protocol for a scoping review that aims to map the existing methods for the clinical validation of digital endpoints. The scoping review will comprise searches from the electronic literature databases MEDLINE (PubMed), Scopus (including conference proceedings), Embase, IEEE (Institute of Electrical and Electronics Engineers) Xplore, ACM (Association for Computing Machinery) Digital Library, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science Core Collection (including conference proceedings), and Joanna Briggs Institute Database of Systematic Reviews and Implementation Reports. We will also include various sources of gray literature with search terms related to digital endpoints. The methodology will adhere to the Joanna Briggs Institute Scoping Review and the Guidance for Conducting Systematic Scoping Reviews. A search for reviews on the existing evidence related to this topic was conducted and has shown that no such review was previously undertaken. This review will provide a systematic assessment of the literature on methods for the clinical validation of digital endpoints and highlight any potential need for harmonization or reporting of methods. The results will include the methods for the clinical validation of digital endpoints according to device, digital endpoint, and clinical application goal of digital endpoints. The study started in January 2023 and is expected to end by December 2023, with results to be published in a peer-reviewed journal. A scoping review of methodologies that validate digital endpoints is necessary. This review will be unique in its breadth since it will comprise digital endpoints collected from several devices and not focus on a specific disease area. The results of our work should help guide researchers in choosing validation methods, identify potential gaps in the literature, or inform the development of novel methods to optimize the clinical validation of digital endpoints. Resolving these gaps is the key to presenting evidence in a consistent way to regulators and other parties and obtaining regulatory acceptance of digital endpoints for patient benefit. PRR1-10.2196/47119.

Regulatory Framework, Challenges, and Initial Strategic Planning for Advanced Therapy Products (PTAs) Development in Brazil.

Advanced Therapies are a class of innovative complex biological products used for therapeutic purposes, encompassing cell therapy, tissue engineering, and gene therapy products. These are promising therapeutic strategies for several complex diseases with low or non-existent therapeutic alternatives. The proper transposition of basic research in this area into medicinal products must comply with regulatory requirements. Here we review the main regulatory recommendations, emphasizing on the Brazilian regulation. The critical points are the manufacturing process, challenges in characterizing the product, development of non-clinical trials, lack of adequate animal models representative of the clinical situation, and absence of valid and measurable therapeutic endpoints. Based on that, we propose a framework for strategic planning of pre-clinical studies in this field. The detailed example involves producing a nonviral vector-based gene editing product, but the regulations and methods may be extrapolated for developing different types of advanced therapies.

Progression-Free Survival as a Surrogate Endpoint of Overall Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiotherapy: Trial-Level Meta-Analysis and Individual-Level Analysis of NRG/RTOG 0617 and PROCLAIM

Overall Survival (OS) is the gold standard endpoint in randomized clinical trials (RCTs) of Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC). Intermediate endpoints that can be observed at earlier time points and predict OS would improve trial efficiency and expedite the adoption of proven interventions. Atrial-level meta-analysis was conducted using a weighted regression analysis to quantify the correlation between PFS and OS hazard ratios (HRs). Large (n≥ 100) contemporary RCTs in LA-NSCLC that used platinum-based chemoradiation were included. An individual-level surrogacy analysis based on Prentice criteria was performed to evaluate if PFS could reliably predict OS using NRG/RTOG 0617 (NCT00533949), a phase III RCT of dose escalated CRT. The individual-level correlation between PFS and OS was validated using PROCLAIM (NCT00686959) control arm. Nineteen RCTs comprising a total of 5525 patients (pts) were included in the trial-level meta-analysis. A moderately high correlation was observed between PFS HR and OS HR (R2 = 0.68, 95% CI = 0.42-0.94). Individual-level analysis of NRG/RTOG 0617 showed that, as reported, RT dose was associated with OS (HR = 1.28, 95% CI = 1.04-1.58, p = 0.02) and PFS (HR = 1.21, 95% CI = 0.99-1.46, p = 0.06). Progressive disease (PD) was highly associated with OS, where pts having PD within 6mo or 12mo had a significantly higher mortality risk than those not having PD within 6mo or 12 mo, respectively, in landmark analysis (PD within 6mo: HR = 2.56, 95% CI = 1.82-3.59, p<0.0001; PD within 12mo: HR = 3.18, 95% CI = 2.45-4.12, p<0.0001). Accounting for PD moderately reduced RT dose effect on OS (HR = 1.21, 95% CI = 0.98-1.49), suggesting RT dose effect on OS may be mediated partially through PD. The association between OS and PD occurrence within 6mo or 12mo was similar in PROCLAIM control arm (PD within 6mo: HR = 2.06, 95% CI = 1.48-2.86, p<0.0001; PD within 12mo: HR = 2.02, 95% CI = 1.38-2.95, p<0.0001). A moderately high trial-level surrogacy between PFS and OS was identified in trial-level meta-analysis. PD occurrence also reliably predicted OS at the individual patient level in both NRG/RTOG 0617 and PROCLAIM. These results support the use of PFS as a valid endpoint in clinical trials of LA-NSCLC.