Dose Justification Clause Samples

Dose Justification. To date, the current capsule utilized in clinical studies is not associated with a maximum tolerated dose (MTD). Initial MTD assessments were performed using SAGE-217 in an oral solution (OS) at steady-state in healthy participants, which provided an MTD with a Cmax of 125 ng/mL at 30 mg OS. While reidentification of the MTD using the capsule formulations was not conducted, steady-state 30-mg capsules provide a model-derived Cmax approximately 50% lower (64 ng/mL) than the concentration associated with the MTD of 30 mg OS (125 ng/mL). Studies 217-MDD-201 and 217-PPD-201, employing 30-mg capsules administered each evening for 14 days, demonstrated significant reduction in symptoms of depression, anxiety and insomnia. The safety profile in these studies is consistent with the GABAA neurosteroid mechanism, including adverse drug reactions (ADRs) of somnolence, sedation, and dizziness at rates of 4% to 15%; the majority with mild intensity. Phase 3 studies in a broader patient population demonstrate activity of SAGE-217 associated with improvement in depressive symptoms, however, both the efficacy and safety findings support investigation of a higher dose, with predictable ADRs expected to be within an acceptable range. Study 217-MDD-301A, a randomized, multicenter, 3-arm study examining SAGE-217 20-and 30-mg capsules compared to placebo, found significant antidepressant effects compared to placebo at Days 3, 8, and 12 but not Day 15 (primary endpoint) for the 30-mg dose. The 20-mg dose did not separate from placebo at any time point. The rates of expected ADRs of somnolence, sedation and dizziness in the 30-mg arm were each less than 10%; rates of discontinuation for adverse events were lower with SAGE-217 30 mg (2.1%) than with placebo (3.2%). No clinically relevant changes in ▇▇▇▇▇ ▇▇▇▇▇, laboratory results, electrocardiogram measures, or suicidal thinking were observed in either 217-MDD-301A or across the full SAGE-217 program, now with over 2000 participants exposed to treatment. Relevant results from 217-MDD-301A are available in the Investigator’s Brochure. Direct and modeled data from completed studies to date (including efficacy studies 217-MDD-201 and 217-PPD-201) in addition to 217-MDD-301A (through Day 42 of the double-blind period), have been used to assess and predict the efficacy and safety outcomes at SAGE-217 concentrations expected with higher doses of SAGE-217 capsules (eg, 40 and 50 mg). Direct safety data come from more than 140 participan...
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Dose Justification. 5.4.1. Safety Measures
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