Pivotal Clinical Study Research Articles

Justification of Widened Dissolution Specifications of an Extended Release Product Using Physiologically Based Biopharmaceutics Modeling

Drug product meeting the dissolution specifications is crucial in order to ensure consistent clinical performance. However, in certain cases wider dissolution specifications may be required based on product behavior. While justification of such wider specifications may be challenging from a regulatory context, approaches such as physiological based biopharmaceutics modeling (PBBM) can be utilized for this purpose. Product DRL is a fixed dose combination product consisting of an immediate (IR) and extended release (ER) portions. For the ER portion, the dissolution specifications consisted of four time points and a proposal was made to relax the specification at the 2h time point (from 50-70% to 45-67%) to reduce the batch failures at commercial scale. To support wider specification, a PBBM was developed and extensively validated with literature & in-house studies. Virtual bioequivalence was performed using the pivotal clinical study data. Virtual dissolution profiles for proposed wider specifications were generated using three different approaches. Incorporation of lower and upper dissolution profiles into the model indicated absence of impact on in vivo performance thereby justifying the specifications. Regulatory acceptance of proposed specifications with PBBM indicated the significance of using modeling approaches to reduce repeated testing thereby facilitating faster approvals.

Budget Impact Analysis of Olaparib in Combination with Bevacizumab for Maintenance Therapy for Ovarian Cancer in Argentina.

To perform a budget impact analysis (BIA) of introducing olaparib as maintenance therapy in women who have BRCA mutations (BRCAm) with platinum-sensitive recurrent ovarian cancer (PSROC) in combination with bevacizumab in Argentina. A BIA model was used to analyse over a 5-year time horizon the change in the health system's budget following the adoption of olaparib as maintenance therapy in BRCAm patients with PSROC. The BIA for each year was estimated by comparing the cost difference between the current scenario (treatment with bevacizumab) and the new scenario (the addition of olaparib) for a third-party payer. The BIA is estimated at the national health system level, and by healthcare sectors in Argentina (public sector, social security and private sector). International and national epidemiological data were used to determine the target patient population. Clinical efficacy, safety outcomes and duration of treatments were obtained from the pivotal clinical study report. Relevant direct medical costs were obtained from public data in Argentina and expert consultation. All the costs are reported in US dollars as of October 2022 ($1 = 152.59 Argentine pesos). A scenario analysis assessed the full coverage of the homologous recombination deficiency (HRD) test in Argentina. In addition, one-way sensitivity analysis was conducted to evaluate the model robustness. For a third-party payer with a cohort of 1,000,000 women covered, the estimated target population was 2 individuals in year 1 and 6 individuals in year 5. The incorporation of olaparib, with a wholesale price per pack of $3176.32, was associated with a weighted average of the budget impact per member per month (PMPM) of $0.062 for the national health system, being above the estimated health system budget impact threshold ($0.0153). By healthcare sector, the results of budget impact PMPM for year 5 ranged between $0.08 (public sector) and $0.114 (private sector). For all perspectives, the variables that most influenced the budget impact was the incidence of ovarian cancer, the drug acquisition cost and the treatment duration. The introduction of olaparib for the treatment of BRCAm women with PSROC has a high budget impact for all three health systems in Argentina.

A Review of Protein-Based COVID-19 Vaccines: From Monovalent to Multivalent Formulations.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in the COVID-19 pandemic, has profoundly impacted global healthcare systems and the trajectory of economic advancement. As nations grapple with the far-reaching consequences of this unprecedented health crisis, the administration of COVID-19 vaccines has proven to be a pivotal strategy in managing this crisis. Protein-based vaccines have garnered significant attention owing to their commendable safety profile and precise immune targeting advantages. Nonetheless, the unpredictable mutations and widespread transmission of SARS-CoV-2 have posed challenges for vaccine developers and governments worldwide. Monovalent and multivalent vaccines represent two strategies in COVID-19 vaccine development, with ongoing controversy surrounding their efficacy. This review concentrates on the development of protein-based COVID-19 vaccines, specifically addressing the transition from monovalent to multivalent formulations, and synthesizes data on vaccine manufacturers, antigen composition, pivotal clinical study findings, and other features that shape their distinct profiles and overall effectiveness. Our hypothesis is that multivalent vaccine strategies for COVID-19 could offer enhanced capability with broad-spectrum protection.

PANOVA-4 (EF-39): Pilot study of tumor treating fields (TTFields) therapy with atezolizumab, gemcitabine (GEM), and nab-paclitaxel (NabP) as first-line (1L) treatment for metastatic pancreatic ductal adenocarcinoma (mPDAC).

TPS718 Background: TTFields are electric fields that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields therapy is noninvasive, locoregional, and is delivered via a portable electric field generator and skin-placed arrays. TTFields therapy has low risk of systemic toxicity and is approved for glioblastoma (and grade 4 glioma in Europe), and pleural mesothelioma. In vitro, TTFields (150 kHz) application decreased pancreatic cancer cell proliferation and clonogenicity; in vivo, TTFields concomitant with chemotherapy (chemo) had greater antitumor effect than chemo alone in orthotopic pancreatic tumors. Co-application of TTFields with immune checkpoint inhibitors (ICIs) significantly decreased tumor volume, increased tumor infiltration and IFN-γ production, and did not impede ICI-induced effector memory T-cell production versus in vivo controls. The pilot (phase 2) PANOVA clinical study (NCT01971281) showed safety and feasibility with TTFields therapy plus NabP and GEM in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). The randomized, pivotal (phase 3) PANOVA-3 clinical study (NCT03377491), evaluating TTFields therapy with GEM and NabP in LAPC, is ongoing. Methods: PANOVA-4 (pilot, single-arm clinical study) assesses the safety and efficacy of TTFields therapy (NovoTTF-200T device) concomitant with atezolizumab, GEM, and NabP as 1L treatment for mPDAC. Eligible patients (pts) are ≥18 years of age and have a new mPDAC diagnosis, measurable abdominal disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1, and no prior systemic PDAC therapy. Atezolizumab (1680 mg, IV infusion) is given before chemo on day 1 of each 28-d cycle, with NabP (125 mg/m2 IV) and GEM (1000 mg/m2 IV) given on days 1, 8, and 15. TTFields therapy (150 kHz) is delivered for ≥18 h/d until disease progression per RECIST v1.1 or loss of clinical benefit. Clinical follow-up occurs every 4 weeks (q4w) with CT scans q8w. Survival is assessed every 3 mo post last on-site visit. The primary endpoint is disease control rate (DCR). Secondary endpoints include overall survival (OS), progression-free survival (PFS), 1-year OS rate, objective response rate, PFS at 6 mo, duration of response, and safety. 76 pts are required to achieve 80% power (1-sided α level 0.05) to detect a 63% DCR vs historical 48% DCR in pts with mPDAC receiving 1L GEM and NabP. Clinical trial information: EUCTR2022-003157-55 .

328MO The pivotal clinical study of IM19 CAR-T cells in the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphomas

328MO The pivotal clinical study of IM19 CAR-T cells in the treatment of relapsed or refractory aggressive B cell non-Hodgkin lymphomas

Pivotal Clinical Study to Evaluate the Efficacy and Safety of Assistive Artificial Intelligence-Based Software for Cervical Cancer Diagnosis.

Colposcopy is the gold standard diagnostic tool for identifying cervical lesions. However, the accuracy of colposcopies depends on the proficiency of the colposcopist. Machine learning algorithms using an artificial intelligence (AI) system can quickly process large amounts of data and have been successfully applied in several clinical situations. This study evaluated the feasibility of an AI system as an assistive tool for diagnosing high-grade cervical intraepithelial neoplasia lesions compared to the human interpretation of cervical images. This two-centered, crossover, double-blind, randomized controlled trial included 886 randomly selected images. Four colposcopists (two proficient and two inexperienced) independently evaluated cervical images, once with and the other time without the aid of the Cerviray AI® system (AIDOT, Seoul, Republic of Korea). The AI aid demonstrated improved areas under the curve on the localization receiver-operating characteristic curve compared with the colposcopy impressions of colposcopists (difference 0.12, 95% confidence interval, 0.10-0.14, p < 0.001). Sensitivity and specificity also improved when using the AI system (89.18% vs. 71.33%; p < 0.001, 96.68% vs. 92.16%; p < 0.001, respectively). Additionally, the classification accuracy rate improved with the aid of AI (86.40% vs. 75.45%; p < 0.001). Overall, the AI system could be used as an assistive diagnostic tool for both proficient and inexperienced colposcopists in cervical cancer screenings to estimate the impression and location of pathologic lesions. Further utilization of this system could help inexperienced colposcopists confirm where to perform a biopsy to diagnose high-grade lesions.

Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.

9110 Background: SY-3505 is a potent, brain-penetrant, 3rd-generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1st and 2nd-gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2nd-gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2nd-gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .

Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease: ADAPT-PD clinical trial methodology and early data (P1-11.002)

Adaptive DBS Algorithm for Personalized Therapy in Parkinson’s Disease: ADAPT-PD clinical trial methodology and early data (P1-11.002)

Abstract 4347: A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine

Abstract Precision cancer therapy has the potential to revolutionize treatment outcome. While genomic analysis has become central to cancer personalized medicine, recent studies have not shown that it drastically improves the patient’s survival as compared to standard drug selection. Additionally, genomic mutations may suggest several treatment protocols without elucidating which approach will yield the best clinical response. To advance cancer precision guidance, we have developed cResponse, a combined genomic-functional drug sensitivity platform to determine individualized patient treatment regimens. Fresh patient cancer samples are taken by biopsy or resection and sectioned into 250uM slices which when cultured in cResponse platform demonstrate similar architecture and tissue proliferation to those found in vivo. An initial clinical study showed that cResponse can preserve human cancer tissue in 3D culture together with its microenvironment, including endothelial and immune cells, at a high viability (&amp;gt;90%) with continued cell division for more than 7 days. On a cohort of 34 patients treated with neoadjuvant therapy or systemic therapy for metastatic disease, the assay was able to predict patient response to drug treatment with a sensitivity of 96% and a specificity of 77.7%. To further validate the capacity of the cResponse platform to predict patient response to cancer therapy, a follow up pivotal clinical study was established at 7 major cancer centers located in the UK with the goal of recruiting a total of 170 patients to provide a large statistical validation of the previous results. Here we report on the outcome of the first 50 patients recruited to the pivotal trial and describe the predictive results correlated to patient response. Citation Format: Seth Salpeter, Vered Bar, Guy Neev, Adi Zundelevich, Gil Rosen, Sandra Hanks, Naoise Costelloe, Jonathan Krell, Ravid Straussman. A pivotal clinical trial of cResponse, a functional assay for cancer precision medicine. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4347.

Rationale and design of the Lead Evaluation for Defibrillation and Reliability study: Safety and efficacy of a novel ICD lead design.

Implantable cardioverter defibrillators (ICD) are indicated for primary and secondary prevention of sudden cardiac arrest. Despite enhancements in design and technologies, the ICD lead is the most vulnerable component of the ICD system and failure of ICD leads remains a significant clinical problem. A novel, small-diameter, lumenless, catheter-delivered, defibrillator lead was developed with the aim to improve long-term reliability. The Lead Evaluation for Defibrillation and Reliability (LEADR) study is a multi-center, single-arm, Bayesian, adaptive design, pre-market interventional pivotal clinical study. Up to 60 study sites from around the world will participate in the study. Patients indicated for a de novo ICD will undergo defibrillation testing at implantation and clinical assessments at baseline, implant, pre-hospital discharge, 3 months, 6 months, and every 6 months thereafter until official study closure. Patients may be participating for a minimum of 18 months to approximately 3 years. Fracture-free survival will be evaluated using a Bayesian statistical method that incorporates both virtual patient data (combination of bench testing to failure with in-vivo use condition data) with clinical patients. The clinical subject sample size will be determined using decision rules for number of subject enrollments and follow-up time based upon the observed number of fractures at certain time points in the study. The adaptive study design will therefore result in a minimum of 500 and a maximum of 900 patients enrolled. The LEADR Clinical Study was designed to efficiently provide evidence for short- and long-term safety and efficacy of a novel lead design using Bayesian methods including a novel virtual patient approach.

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States

Background aimsRegulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions. MethodsA retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions. ResultsIn the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU. ConclusionsThe current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.

Combined Methylome and Transcriptome Analyses Reveals Potential Therapeutic Targets for EGFR Wild Type Lung Cancers with Low PD-L1 Expression.

Simple SummaryLow expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLCs) are refractory, and only few therapeutic options exist. This study aims to clarify the molecular basis of this special subtype of NSCLC and identify potential therapeutic targets. We performed integrating data from multiple sources including transcriptome, methylome, and clinical outcome to uncover the effect of epigenetic changes acting this special subtype lung cancer. We elucidated both aberrant methylation and associated aberrant gene expression and the emerging methylation-transcription patterns were classified as HypoUp, HypoDown, HyperUp, or HyperDown. We found that the aberrant methylation-transcription patterns significantly affect the overall survival time of the patients. We used protein–drug interaction data and molecular docking analysis to identify potential therapeutic candidates. This study uncovered the distinct methylation-transcription characteristics of this special subtype lung cancer, and provided an adaptable way to identify potential therapeutic targets.Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated remarkable treatment efficacy in advanced non-small cell lung cancer (NSCLC). However, low expression of programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) wild-type NSCLCs are refractory, and only few therapeutic options exist. Currently, combination therapy with ICIs is frequently used in order to enhance the treatment response rates. Yet, this regimen is still associated with poor treatment outcome. Therefore, identification of potential therapeutic targets for this subgroup of NSCLC is strongly desired. Here, we report the distinct methylation signatures of this special subgroup. Moreover, several druggable targets and relevant drugs for targeted therapy were incidentally identified. We found hypermethylated differentially methylated regions (DMRs) in three regions (TSS200, TSS1500, and gene body) are significantly higher than hypomethylated ones. Downregulated methylated genes were found to be involved in negative regulation of immune response and T cell-mediated immunity. Moreover, expression of four methylated genes (PLCXD3 (Phosphatidylinositol-Specific Phospholipase C, X Domain Containing 3), BAIAP2L2 (BAR/IMD Domain Containing Adaptor Protein 2 Like 2), NPR3 (Natriuretic Peptide Receptor 3), SNX10 (Sorting Nexin 10)) can influence patients’ prognosis. Subsequently, based on DrugBank data, NetworkAnalyst 3.0 was used for protein–drug interaction analysis of up-regulated differentially methylated genes. Protein products of nine genes were identified as potential druggable targets, of which the tumorigenic potential of XDH (Xanthine Dehydrogenase), ATIC (5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase), CA9 (Carbonic Anhydrase 9), SLC7A11 (Solute Carrier Family 7 Member 11), and GAPDH (Glyceraldehyde-3-Phosphate Dehydrogenase) have been demonstrated in previous studies. Next, molecular docking and molecular dynamics simulation were performed to verify the structural basis of the therapeutic targets. It is noteworthy that the identified pemetrexed targeting ATIC has been recently approved for first-line use in combination with anti-PD1 inhibitors against lung cancer, irrespective of PD-L1 expression. In future work, a pivotal clinical study will be initiated to further validate our findings.

Abstract PR12: Detection of EV-based signatures in prostate cancer using microflow cytometry and machine learning

Abstract Microflow cytometry (µFCM) has recently emerged as a viable technology to enumerate and quantify individual EVs from complex biologic fluids. This method is a promising alternative to biopsy collection because it is highly sensitive and allows for longitudinal assessment of patients. EVs are highly abundant and analysis by µFCM allows for sophisticated multiparametric analysis of organ-specific, disease-specific, and outcome-specific proteins, genes, or metabolites. Detection of EVs with µFCM requires very little sample yet provides exceptional specificity and sensitivity for low abundance events. By combining µFCM analysis of EVs with advanced machine learning approaches, we have developed a platform technology called ClarityDX to generate EV fingerprints that significantly improve the diagnosis of diseases such as prostate cancer using a few drops of blood. Here I will discuss the development and clinical validation of new blood tests for prostate cancer that utilize the ClarityDX platform. Prostate cancer is the most commonly diagnosed cancer and the third leading cause of cancer deaths in men. Screening has enabled the early detection of many latent prostate cancers, and it is estimated that up to 50% of new prostate cancer diagnoses detect a tumor that was unlikely to surface clinically in the absence of PSA screening. In the majority of cases, the treatment of indolent cancer causes a patient more harm than good. Consequently, there is an urgent need for a noninvasive test to detect clinically significant prostate cancer, or perhaps even more importantly, to detect metastatic disease. ClarityDX Prostate is a µFCM-based test to predict clinically significant prostate cancer prior to a prostate biopsy. A prospective clinical validation of ClarityDX Prostate was performed in a cohort of 377 Albertan men. The overall average AUC for ClarityDX Prostate in this population was 0.83, which was significantly higher than PSA alone. While PSA alone provided only 17% specificity for aggressive prostate cancer at a 95% sensitivity, ClarityDX Prostate was 56% specific for aggressive prostate cancer. We are now conducting a pivotal clinical validation study, in which up to 2,800 men will be enrolled to assess the performance of ClarityDX Prostate in a “real-world” clinical environment. Overall, we have established a robust µFCM EV platform for the development of novel and clinically viable diagnostic tests. Incorporating ClarityDX Prostate into routine prostate cancer screening could reduce the number of unnecessary biopsies by up to 40%. This abstract is also being presented as Poster B57. Citation Format: John D. Lewis, Robert J. Paproski, Desmond B. Pink, Catalina Vasquez, Eric Hyndman, Adrian Fairey, APCaRI. Detection of EV-based signatures in prostate cancer using microflow cytometry and machine learning [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR12.

Pivotal Clinical Study to Evaluate the Safety and Effectiveness of the MANTA Vascular Closure Device During Percutaneous EVAR and TEVAR Procedures

Purpose: To evaluate the safety and effectiveness of the MANTA percutaneous vascular closure device in patients undergoing percutaneous endovascular aneurysm repair (PEVAR) or thoracic endovascular aortic repair (TEVAR). Materials and Methods: The SAFE MANTA Study (ClinicalTrials.gov identifier NCT02908880) was a prospective, single-arm, multicenter trial in patients undergoing endovascular interventions using large-bore sheaths (transcatheter aortic valve replacement, PEVAR, or TEVAR) at 20 sites in North America. Patient selection intended to test the MANTA device in populations without morbid obesity, severe calcification, or a severely scarred femoral access area. Of the 263 patients enrolled in the primary analysis cohort, 53 (20.2%) patients (mean age 74.9±8.9 years; 41 men) underwent PEVAR (n=51) or TEVAR (n=2) procedures and form the cohort for this subgroup analysis. Per protocol a single MANTA device was deployed in all PEVAR/TEVAR cases. Results: The mean time to hemostasis in the PEVAR/TEVAR cohort was 35±91 seconds, with a median time of 19 seconds vs 24 seconds in the overall SAFE MANTA population. The MANTA device met the definition for technical success in 52 (98%) of 53 PEVAR/TEVAR cases compared with 97.7% in the overall SAFE MANTA population. One (1.9%) major complication (access-site stenosis) occurred in this subgroup compared to 14 (5.3%) events in the SAFE population. In the PEVAR/TEVAR group, 1 pseudoaneurysm was noted prior to discharge, another at 30-day follow-up, and one at 60 days. One (1.9%) of the 3 minor pseudoaneurysms was treated with ultrasound-guided compression and the other 2 required no treatment. Conclusion: The MANTA device demonstrated a short time to hemostasis and low complication rates compared with published literature results of other percutaneous closure devices. Time to hemostasis and complication rates were comparable between the PEVAR/TEVAR patients and the full SAFE MANTA study cohort. The MANTA device provides reliable closure with a single percutaneous device for PEVAR/TEVAR procedures.

Population pharmacokinetics, efficacy, and safety of moxetumomab pasudotox in patients with relapsed or refractory hairy cell leukaemia.

To characterize the pharmacokinetics (PK) of moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, in adults with relapsed or refractory hairy cell leukaemia, we examined data from a phase 1 study (Study 1001; n = 49) and from the pivotal clinical study (Study 1053; n = 74). Data from both studies were pooled (n = 123) to develop a population PK model. Covariates included demographics, disease state, liver and kidney function, prior treatment, and antidrug antibodies (ADAs). Exposure-response and exposure-safety were analysed separately by study. A 1-compartment model with linear elimination from the central compartment and 2 clearance (CL) rates was developed. Moxetumomab pasudotox was cleared more rapidly after cycle 1, day 1 (CL1 = 24.7 L/h) than subsequently (CL2 = 3.76 L/h), with high interindividual variability (116 and 109%, respectively). In Study 1053, patients with ADA titres >10 240 showed ~4-fold increase in CL. Higher exposures (≥median) were related to higher response rates, capillary leak syndrome and increased creatinine (Study 1053 only), or grade ≥3 adverse events (Study 1001 only). Clinical benefits were still observed in patients with lower exposure or high ADA titres. Despite a high incidence of immunogenicity with increased clearance, moxetumomab pasudotox demonstrated efficacy in hairy cell leukaemia.

Abstract WMP102: Pilot Study of a Non-invasive Radiofrequency Method to Monitor Intracranial Hemorrhage: A First-in-Human Study

Introduction: Intracerebral hemorrhage (ICH) is a devastating form of stroke. Hemorrhage expansion after ICH occurs in ~40% of patients and leads to worse outcomes. Currently, ICH patients are monitored for hemorrhage expansion by neurologic exam and head CT. CT studies are a source of radiation exposure and can require transporting the patient out of the ICU. There is a clinical need for a non-invasive bedside monitor of ICH. Methods: A radiofrequency based monitor (RFM) was developed as a non-invasive method to monitor ICH at the bedside. The RFM consists of a 9-antenna array mounted around the head, cables, and driving electronics. A 913 MHz signal is transmitted from a given antenna, crosses the brain, and is received by the remaining 8 antennae. A complete measurement consists of one cycle with all antenna serving as the transmitting antenna. As the signal traverses the brain, it is partially scattered and absorbed by the ICH, thus changing the signal at the receiving antennae. The altered signal can be compared to signals at earlier times to detect changes induced by ICH expansion. Based upon pre-clinical work it was hypothesized that ICH expansion of ≥3 ml would be detected by the RFM. The RFM device was approved for human study under an IDE from the FDA. The device was tested on 10 ICH subjects admitted within 24 hours of stroke onset. All subjects received a baseline head CT and a repeat head CT at 12 (+/- 6) hours. ICH volumes were determined by a blinded neuroradiologist. Subjects were scanned with the device every 10 minutes. Results: Data from one subject was lost due to user error. Among the remaining nine, two experienced hemorrhage expansion of ≥ 3ml (3 and 8.2 ml respectively). The RFM readings were 100% concordant with CT scans in identifying presence and absence of hemorrhage expansion. The figure shows monitor readings from a subject with expansion. Conclusion: The RFM may be useful in detection of real-time hemorrhage expansion in ICH patients. A pivotal clinical study is planned.

Statistical Considerations for Bias and Protocol Deviation in Medical Device Pivotal Clinical Study.

The gold standard in conducting clinical trials/studies is to follow what is prespecified in the study protocol. However, deviations from the study protocol may occur. This article discusses the issues of protocol deviation in pivotal clinical trials or studies for medical device and provides statistical approaches to mitigating bias such as selection bias specifically for diagnostic test clinical trials or studies. Bias correction methods are developed for 2 specific types of selection biases, prescreening bias and verification bias. Statistical approaches are discussed on how to estimate device performance adjusted for enrollment enrichment and discrepant testing results. We use an FDA-approved Roche Cobas Human Papillomavirus (HPV) test for detecting high-grade cervical disease (>CIN2) as an example to illustrate how to correct for verification bias. A recently FDA-cleared Microarray Assay in detecting copy number variation is used to illustrate how to properly estimate sensitivity and specificity for the discrepancy analysis. The unadjusted sensitivity and specificity based on verified samples were 83.2% and 60.4% for the Roche's HPV test. However, using the correction method with the missing-at-random assumption, the verification bias-adjusted sensitivity and specificity were 34.5% and 93.6%, respectively. Protocol deviations can lead to biased estimates of device clinical performance if not handled appropriately. Statistical methods correcting for bias and protocol deviations are recommended in estimating device performance.

Clinical Outcome After Anterior Lumbar Interbody Fusion With a New Osteoinductive Bone Substitute Material: A Randomized Clinical Pilot Study.

Pilot, single-center, single-blinded, parallel-group, randomized clinical study. The aim of this study was to pilot a randomized clinical study to evaluate whether instrumented anterior lumbar interbody fusion (ALIF) with a new nanocrystalline hydroxyapatite embedded in a silica gel matrix (NH-SiO2) leads to superior radiologic and clinical outcomes at 12-month follow-up compared with instrumented ALIF with homologous bone. ALIF completed with interbody cages is an established technique for performing arthrodesis of the lumbar spine. There is ongoing discussion about which cage-filling material is most appropriate. This is the first study to assess the efficacy of NH-SiO2 in ALIF surgery. This randomized, clinical, pilot trial included 2 groups of 20 patients with monosegmental or multisegmental degenerative disease of the lumbar spine who were suitable to undergo monosegmental or bisegmental ALIF fusion at the level L4/L5 and L5/S1 with a carbon fiber reinforced polymer ALIF cage filled with either NH-SiO2 or homogenous bone. Primary outcome was postoperative disability as measured by the Oswestry Disability Index (ODI). Secondary outcomes were postoperative radiographic outcomes, pain, and quality of life. Patients were followed 12 months postoperatively. Mean (±SD) 12-month ODI was 24±17 in the NH-SiO2 group and 27±19 in the homologous bone group (P=0.582). Postoperative radiography, functional outcomes, and quality-of-life indices did not differ significantly between groups at any of the regularly scheduled follow-up visits. This clinical study showed similar functional, radiologic, and clinical outcomes 12 months postoperatively for instrumented ALIF procedures with the use of NH-SiO2 or homologous bone as cage filling. In the absence of any relevant differences in outcome, we postulate that the pivotal clinical study should be designed as an equivalence trial.

Pivotal Clinical Study to Assess the Anti-adhesive Effect and Safety of ABT13107 Applied to Postoperative Intrauterine

Pivotal Clinical Study to Assess the Anti-adhesive Effect and Safety of ABT13107 Applied to Postoperative Intrauterine

Proposal of an endpoint for a phase III clinical study of essential thrombocythemia: Balancing between short term effects and long term benefits.

7055 Background: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN), covering broad spectrum of clinical scenarios, from asymptomatic patients with only isolated high platelets to highly morbid patients in late stage disease. Due to heterogenous patient population, designing clinical studies in ET is difficult, and after anagrelide there was no new drug approval to treat ET during the past 15 years, thus, high unmet medical to treat patients with ET remains. Interferons alpha (IFNa) are known to have beneficial effects in MPN (Kiladjian et al, 2016). P1101 is a next generation monopegylated IFNa, developed specifically to treat MPNs, including ET. Methods: External published clinical data in ET were analyzed to design optimal clinical study. Proposed endpoints are meant to cover all relevant clinical aspects of ET, and suffice for a regulatory relevant pivotal clinical study. Results: Composite primary endpoint scale is based on modified ELN criteria. Short term study endpoints should have clinical meaningfulness at time of measurement but also predict the later outcomes. The scale consists of: normalization of platelets (&lt;400 G/L) and leukocytes (&lt;9.5 G/L); normalization in size or non-progression of palpable spleen; lack of major cardiovascular event during the observation period; and improvement of Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (MPN-SAF TSS). MPN-SAF TSS is a 10 items questionnaire, allowing concise, valid, and accurate assessment of MPN symptom burden over time (Emanuel et al, 2012). For TSS-10 score, to qualify for response, following rules were elaborated: 10 points or higher reduction for patients with baseline score of ≥20, for patients with baseline score 15-19 – 5 points reduction, baseline scores 10-14 – reduction below 10 points, and for TSS baseline score &lt;10 – stay &lt;10. Bone marrow analysis is not to be a mandatory test for assessment of overall benefit of therapy. Extensive genetic workup is planned to document any change in observed genetic and chromosomal abnormalities, including level of circulating mutant CALR. This would allow for objective evaluation of IFNa’s ability to modify the disease. Long term observation, going beyond the 12 month of initial observation, is planned. Conclusions: Authors conclude that proposed endpoint scale covers well all clinically relevant aspects of ET, in order to make clinically relevant conclusions on durable benefits and risks of P1101 therapy.