Dose response with onabotulinumtoxinA for post-stroke spasticity: a pooled data analysis.

Clinical trials demonstrate that onabotulinumtoxinA reduces upper limb post-stroke spasticity, with therapeutic response influenced by injected dose. Individual studies provide limited insight regarding muscle group-specific dose-response relationships. Our objective was to characterize dose-response relationships between onabotulinumtoxinA and muscle tone in specific upper limb muscles. Individual patient data from seven multicenter, randomized, double-blind, placebo-controlled trials were pooled. Of 544 post-stroke patients enrolled, 362 received onabotulinumtoxinA and 182 received placebo, injected into the flexor carpi radialis (FCR), flexor carpi ulnaris (FCU), flexor digitorum superficialis (FDS), flexor digitorum profundus (FDP), and/or biceps brachii (BB). Ashworth Scale score change at week 6 (AshworthCBL) was the primary outcome measure for muscle tone. For a broader analysis of response, AshworthCBL/onabotulinumtoxinA dosage relationships were characterized using three techniques: (1) AshworthCBL plotted as a function of onabotulinumtoxinA dose in Units (U) [dose-response curve]; (2) mean AshworthCBL per onabotulinumtoxinA dose depicting the responses seen with specific dose injection clusters/groups for each specific muscle group; and (3) onabotulinumtoxinA dose estimated to produce a mean 1-point decrease in AshworthCBL as an indicator of clinically meaningful benefit of treatment. Increasing onabotulinumtoxinA doses produced greater AshworthCBLs (muscle tone improvements). The maximal week 6 response (E(max)) model indicated a saturating dose-response relationship, with mean E(max) AshworthCBL values of -1.48, -1.48, -0.63, -0.77, and -0.61 in the FCR, FCU, FDS, FDP, and BB, respectively. OnabotulinumtoxinA doses estimated to produce a mean 1-point decrease in AshworthCBL were: 22.5U, 18.4U, 66.3U, 42.5U in the FCR, FCU, FDS, and FDP, respectively, and not determinable in the BB. These analyses demonstrate a saturating effect of greater muscle tone improvements with increasing onabotulinumtoxinA doses in post-stroke spasticity patients. These findings suggest potentially effective onabotulinumtoxinA doses in selected muscle groups in this study population.

Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications.

This meta-analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open-label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1-15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20-500 units in cervical dystonia. The numbers of subjects who converted from an antibody-negative status at baseline to antibody-positive status at any post-treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post-stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post-treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy. © 2010 Movement Disorder Society.

Health economics and the value of therapy in Alzheimer's disease.

In increasingly aging societies throughout the developed and developing world, Alzheimer's disease and related dementias are fast becoming a critical public health issue, exacting an enormous toll on individuals and healthcare systems. Over the past 10 years, five drugs have been developed and approved for the symptomatic treatment of Alzheimer's dementia, and several disease-modifying drugs are in various stages of clinical development. While symptomatic medications were consistently shown to have clinical benefit in numerous efficacy studies, the cost effectiveness of antidementia therapies and their value to healthcare systems remain unclear. The pharmacoeconomics of antidementia therapies is an evolving field, with several unanswered questions. This poses many challenges for biopharmaceutical companies developing these therapies, regulatory agencies responsible for their approval, and payers responsible for ensuring their availability to patients. The challenge partly relates to the unique nature of dementia as a disease of impaired cognition, behavior, and function. Thus, the selection of appropriate outcome measures that directly relate to healthcare utilization, quality of life, caregiver burden, and pharmacoeconomic analysis has been difficult. The development of meaningful and widely acceptable outcome measures, as well as novel clinical-study designs, is needed to better evaluate cost effectiveness and to demonstrate the value of therapeutics for Alzheimer's disease. Providing the decision-makers in healthcare systems with a body of evidence that demonstrates a positive relationship between clinical outcomes and the economic and humanistic benefits of antidementia therapeutics will improve patient access to novel drugs as they become available.

Pain-free rates with zolmitriptan 2.5 mg ODT in the acute treatment of migraine: results of a large double-blind placebo- controlled trial.

CONTEXT: Zolmitriptan 2.5 mg orally disintegrating tablets (ODT) allow patients to take the medication without fluids, which is convenient and avoids the risk of fluid-induced exacerbation of nausea/vomiting. OBJECTIVE: To evaluate the efficacy and tolerability of zolmitriptan 2.5 mg ODT taken as soon as possible after onset of a migraine. DESIGN: Multicenter, double-blind, parallel-group, placebo-controlled two-attack trial. SETTING: Outpatient headache clinics in the US. PATIENTS: 608 patients were randomized; 566 patients treated at least 1 migraine and were included in the tolerability assessment (565 patients were included in the intent-to-treat population). INTERVENTION: Patients were randomized to either zolmitriptan 2.5 mg ODT or placebo. Patients treated up to 2 migraine attacks as soon as possible after the start of their migraine pain. MAIN OUTCOME MEASURE: Pain-free rates at 2 h. RESULTS: Zolmitriptan 2.5 mg ODT (n = 281) demonstrated a significant pain-free rate vs. placebo (n = 284) at 2 h (40% vs. 20%, p < 0.001), 1.5 h (25% vs. 15%, p < 0.001), and 1 h (13% vs. 8%, p = 0.004). Sustained pain-free rate was significantly higher than placebo (31% vs. 15%; p < 0.001). Return to normal activities favored zolmitriptan 2.5 mg ODT at 1 h (p = 0.004), 1.5 h (p < 0.001), and 2 h (p < 0.001). Adverse events associated with zolmitriptan 2.5 mg ODT were those commonly reported with the use of triptans. CONCLUSIONS: Zolmitriptan 2.5 mg ODT, taken as early as possible after onset of a migraine attack, is effective in the treatment of migraine, producing a significantly higher pain-free rate than placebo 2 h post-dose, and also at the earlier time points of 1 h and 1.5 h post-dose.

Zolmitriptan nasal spray: advances in migraine treatment.

Zolmitriptan nasal spray was developed specifically to achieve fast, high effectiveness and to overcome many of the limitations associated with oral and sc migraine therapies. Pharmacokinetic studies have demonstrated a very rapid appearance of zolmitriptan in plasma as early as 5 minutes after intranasal dosing, with about 40% of peak plasma concentration (C(max)) being achieved within 10 to 15 minutes of dosing. Comparison of plasma concentration-time profiles of zolmitriptan and its active metabolite after oral and intranasal administration, together with PET scanning, clearly indicate direct absorption of zolmitriptan across the nasal mucosa after intranasal administration. The remainder of the dose is then swallowed and is absorbed through the gastrointestinal tract. In one blinded, randomized, placebo-controlled, multiple-attack study of zolmitriptan nasal spray, headache response was superior to placebo as early as 15 minutes after dosing (p < 0.05). In the zolmitriptan 5 mg treatment group, the primary end point of 2-hour headache response was achieved in 70% (300/427) of attacks versus 31% of attacks (119/389 attacks) in the placebo group (p < 0.001). Patients achieved a 2-hour headache response, had no recurrence, and used no additional or escape medications for up to 24 hours in 49% of attacks versus 14% of attacks in the placebo group (p < 0.001). Zolmitriptan 5 mg nasal spray was well tolerated. These data and those from other similar studies demonstrate that zolmitriptan nasal spray combines early, sustained efficacy and good tolerability, making it an optimal acute treatment for migraine.

Efficacy and tolerability of oral zolmitriptan in menstrually associated migraine: a randomized, prospective, parallel-group, double-blind, placebo-controlled study.

BACKGROUND: Approximately 60% of female migraineurs report experiencing migraine in association with menstruation, while 7% to 25% experience attacks almost exclusively with menstruation. OBJECTIVE: To examine the efficacy and tolerability of oral zolmitriptan in the acute treatment of menstrually associated migraine. In this study, menstrually associated migraine was defined as migraine that consistently occurred from 72 hours before to 5 days after onset of menses. Methods.-Participants were women with regular menstrual cycles, aged 18 to 55 years, who had experienced migraine with at least two thirds of prior menstrual cycles. Subjects were randomized to treat one attack per menstrual cycle for 3 months with either zolmitriptan or placebo. Treatment was intensity based: mild migraines were treated with half of a 2.5-mg zolmitriptan tablet, moderate migraines were treated with zolmitriptan 2.5 mg, and severe migraines were treated with 5 mg (two 2.5-mg tablets) of zolmitriptan, or placebo. RESULTS: Of the 579 women enrolled in the study, 260 were treated with zolmitriptan and 251 were assigned placebo. Twelve hundred thirty-two attacks were treated, and a 2-hour headache response was achieved in 48% of zolmitriptan-treated attacks as compared with 27% of placebo-assigned attacks (P <.0001). Zolmitriptan was superior to placebo in achieving a headache response as early as 30 minutes (18% versus 14%, P=.03) and at 1 hour (33% versus 23%, P <.001). Drug-related adverse events were reported in 16% of subjects receiving zolmitriptan and 9% of subjects receiving placebo. CONCLUSION: Oral zolmitriptan exhibits efficacy and good tolerability in the treatment of menstrually associated migraine. Improvement over placebo was observed as early as 30 minutes following treatment.