Browsing by Author "Chase, Marianne"

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    Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis
    (Wiley, 2023-09) Quintana, Melanie; Saville, Benjamin R.; Vestrucci, Matteo; Detry, Michelle A.; Chibnik, Lori; Shefner, Jeremy; Berry, James D.; Chase, Marianne; Andrews, Jinsy; Sherman, Alexander V.; Yu, Hong; Drake, Kristin; Cudkowicz, Merit; Paganoni, Sabrina; Macklin, Eric A.; HEALEY ALS Platform Trial Study Group; Physical Medicine and Rehabilitation, School of Medicine
    Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design.
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    Prospective biomarker study in newly diagnosed glioblastoma: Cyto-C clinical trial
    (Oxford University Press, 2021-12-24) Griguer, Corinne E.; Oliva, Claudia R.; Coffey, Christopher S.; Cudkowicz, Merit E.; Conwit, Robin A.; Gudjonsdottir, Anna L.; Ecklund, Dixie J.; Fedler, Janel K.; Neill-Hudson, Tina M.; Nabors, Louis B.; Benge, Melanie; Hackney, James R.; Chase, Marianne; Leonard, Timothy P.; Patel, Toral; Colman, Howard; de la Fuente, Macarena; Chaudhary, Rekha; Marder, Karen; Kreisl, Teri; Mohile, Nimish; Chheda, Milan G.; McNeill, Katharine; Kumthekar, Priya; Dogan, Aclan; Drappatz, Jan; Puduvalli, Vinay; Kowalska, Agnes; Graber, Jerome; Gerstner, Elizabeth; Clark, Stephen; Salacz, Michael; Markert, James; Neurology, School of Medicine
    Background: Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods: This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results: OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions: Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.