Definitions, End Points, and Clinical Trial Designs for Bladder Cancer: Recommendations From the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.

PURPOSE: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel. METHODS: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually). RESULTS: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text. CONCLUSION: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity.

Using a rat model of ischemic paraplegia, we examined the expression of spinal AMPA receptors and their role in mediating spasticity and rigidity. Spinal ischemia was induced by transient occlusion of the descending aorta combined with systemic hypotension. Spasticity/rigidity were identified by simultaneous measurements of peripheral muscle resistance (PMR) and electromyography (EMG) before and during ankle flexion. In addition, Hoffman reflex (H-reflex) and motor evoked potentials (MEPs) were recorded from the gastrocnemius muscle. Animals were implanted with intrathecal catheters for drug delivery and injected with the AMPA receptor antagonist NGX424 (tezampanel), glutamate receptor 1 (GluR1) antisense, or vehicle. Where intrathecal vehicle had no effect, intrathecal NGX424 produced a dose-dependent suppression of PMR [ED50 of 0.44 microg (0.33-0.58)], as well as tonic and ankle flexion-evoked EMG activity. Similar suppression of MEP and H-reflex were also seen. Western blot analyses of lumbar spinal cord tissue from spastic animals showed a significant increase in GluR1 but decreased GluR2 and GluR4 proteins. Confocal and electron microscopic analyses of spinal cord sections from spastic animals revealed increased GluR1 immunoreactivity in reactive astrocytes. Selective GluR1 knockdown by intrathecal antisense treatment resulted in a potent reduction of spasticiy and rigidity and concurrent downregulation of neuronal/astrocytic GluR1 in the lumbar spinal cord. Treatment of rat astrocyte cultures with AMPA led to dose-dependent glutamate release, an effect blocked by NGX424. These data suggest that an AMPA/kainate receptor antagonist can represent a novel therapy in modulating spasticity/rigidity of spinal origin and that astrocytes may be a potential target for such treatment.

Limitations of Levothyroxine Bioequivalence Evaluation: Analysis of An Attempted Study.

The relative bioavailability and therapeutic comparability of four levothyroxine products (two proprietary and two nonbranded) were determined in an open-label, block-randomized, four-way crossover trial with no washout periods in 24 presumed hypothyroid ambulatory care patients who were considered euthyroid while on 100 &mgr;g or 150 &mgr;g of oral levothyroxine daily for at least 3 months. Patients randomly received each of the four levothyroxine products for 6 weeks at the same dosage as their prestudy regimen. Area under the serum concentration versus time curve (AUC), maximum change in serum concentration (C(max)), and time to peak serum concentration (T(max)) were calculated for total thyroxine (TT(4)), total triiodothyronine (TT(3)), free thyroxine index (FT(4)I), and thyrotropin (TSH) for each product, with and without baseline correction and normalization for tablet potency differences. Ninety-percent confidence intervals were determined for each paired treatment comparison. Using the response variable of values uncorrected for baseline (Hour 0), 90% confidence intervals for paired treatment comparisons of nonlogarithmically transformed AUC and C(max) (TT(4), TT(3), and FT(4)I) were within the range of 80% to 120%. However, using the response variable of baseline corrected values, no confidence intervals for TT(4) or TT(3) AUC or TT(3) C(max) were within the range of 80% to 120%. Confidence intervals for TSH AUC and C(max) based on both baseline corrected and uncorrected values were outside the 80--120% range. Results were similar when AUC and C(max) were normalized for tablet potency. Thus, results both within and between response variables were conflicting. Further, results normalized for potency using either response variable also failed to demonstrate bioequivalence, pointing to the serious difficulties inherent in levothyroxine bioequivalence studies. Independent consultant review of study design, execution, and data analysis was used to identify critical issues in the conduct of future levothyroxine bioequivalence studies. Numerous flaws were identified, including many that could significantly impact the interpretation of results. These flaws included evaluation of a heterogeneous population of hypothyroid patients with variable residual thyroid function, failure to achieve steady-state serum thyroid hormone levels, use of levothyroxine preparations with variable and unmatched potency, calculations based on a response variable that requires linear pharmacokinetics, and application of bioequivalence criteria when required assumptions have not been met. By the criteria applied in this study and using a response variable based on uncorrected serum concentrations, the levothyroxine products studied, although appearing to be bioequivalent, were, in fact, therapeutically inequivalent. Yet, using an equally accepted and perhaps more valid response variable of baseline corrected values, this study failed to demonstrate bioequivalence between any two products. Finally, differences in tablet potency must be considered as contributing to the appearance of bioequivalence for the TT(4) comparisons. For these reasons, this study, as well as others based on similar models, cannot support a recommendation to substitute levothyroxine products without careful retesting and retitration. The basis for this position is that interchange of therapeutically inequivalent products may result in over- or under-replacement of thyroid hormone, with the known potential adverse consequences. From an economic perspective, product interchange may lead to additional medical costs that outweigh the initial savings obtained by the product switch.