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After 6 months in the extension, dose adjustments were made based on LIC measurement [ 9].
The first open-label extension dose was administered more than 14 days after the first double-blind dose and more than 24 hours after the last double-blind dose.
We analyzed the AV accumulation data on mean counts of AVs per cell using mixed models including subject id as a random effect and cohort (dose-finding vs. melanoma extension), dose, and time (baseline vs. after HCQ vs. after HCQ + TMZ) as fixed factors.
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Extension dosing therefore differed from the core; patients could start the extension receiving 20 mg/kg/day whereas in the core starting doses were randomly assigned as 5 or 10 mg/kg/day.
39 In the extension, doses were first up-titrated to a maximum of 80 mg three times daily at week 6 in a masked fashion while the 80 mg group had sham titration.
The extension of dosing intervals (or dose reductions) is recommended by the Acromegaly Consensus Group for patients achieving good biochemical control with long-acting somatostatin analogues (3).
Time to discontinuation due to treatment failure and time to any discontinuation were compiled starting from the first extension study dose.
For the open label extension phase, dose titration was more flexible and the rate of withdrawal was decreased to 19% (Farlow et al 2000).
During the extension study, dose adjustments in increments of 5 or 10 mg/kg per d were allowed every 3 months based on trends in serum ferritin levels and safety parameters.
For comparison, intraperitoneal injection of phenytoin and sodium valproate 30 min before the electroshock fully prevented hind limb extension at doses of 20 mg/kg and 500 mg/kg, respectively (not shown).
In this open label extension, high-dose rivastigmine therapy was safe and well tolerated over a 5-year period.
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