Publications by authors named "Annika Lindsten"

12 Publications

  • Page 1 of 1

Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial.

JAMA 2021 06;325(23):2348-2356

Lundbeck La Jolla Research Center, San Diego, California.

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion.

Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack.

Design, Setting, And Participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack.

Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine.

Main Outcomes And Measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours.

Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred.

Conclusions And Relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established.

Trial Registration: ClinicalTrials.gov Identifier: NCT04152083.
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http://dx.doi.org/10.1001/jama.2021.7665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207242PMC
June 2021

Characterization of the changes in supine blood pressure with long-term use of droxidopa in patients with neurogenic orthostatic hypotension.

Health Sci Rep 2021 Mar 20;4(1):e227. Epub 2021 Jan 20.

Lundbeck Deerfield Illinois.

Background And Aims: Patients with neurogenic orthostatic hypotension (nOH) due to autonomic dysfunction may also experience supine hypertension (defined as supine systolic blood pressure [SBP] ≥140 mmHg). Because pressor agents used to improve nOH symptoms by increasing standing blood pressure (BP) may exacerbate or cause supine hypertension, changes in supine BP with nOH treatments are of interest.

Methods: This post hoc study examined changes in SBP in patients receiving droxidopa (100-600 mg, three times daily) during a 12-month long-term extension study based on whether patients had supine hypertension (ie, supine SBP ≥140 mmHg) at baseline. Shifts from baseline in supine hypertension categorization and mean supine and standing SBP after 6 and 12 months of treatment with droxidopa were determined.

Results: At baseline, 64 patients did not have supine hypertension (mean supine SBP, 120 mmHg) and 38 patients had supine hypertension (mean supine SBP, 157 mmHg). A similar percentage of patients shifted from their respective baseline supine hypertension categorization (ie, with or without supine hypertension) to the other category after receiving droxidopa for 6 or 12 months. After 12 months of droxidopa treatment, patients with supine hypertension at baseline had a mean supine SBP decrease of 3 mmHg and a mean standing SBP increase of 9 mmHg. Patients without supine hypertension at baseline had mean supine and standing SBP increases of 12 and 15 mmHg, respectively.

Conclusions: There was no consistent or progressive elevation in supine SBP over time during the 12-month treatment with droxidopa in patients either with or without supine hypertension at baseline. These data suggest that long-term droxidopa treatment for nOH does not adversely affect supine BP.
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http://dx.doi.org/10.1002/hsr2.227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817084PMC
March 2021

Chronobiologic parameter changes in patients with major depressive disorder and sleep disturbance treated with adjunctive brexpiprazole: An open-label, flexible-dose, exploratory substudy.

J Affect Disord 2021 01 11;278:288-295. Epub 2020 Sep 11.

Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, United States.

Background: Circadian rhythm disturbances have been reported in patients with major depressive disorder (MDD). Among these is an increased phase angle between peak cortisol concentration and dim-light melatonin onset (DLMO). The aim of this study was to evaluate changes in chronobiologic parameters of sleep in patients with MDD receiving adjunctive brexpiprazole.

Methods: This was an interventional, multicenter, open-label, flexible-dose, exploratory study in patients with MDD and inadequate response to antidepressant treatment who were experiencing sleep disturbances. Patients received adjunctive brexpiprazole 2-3 mg/day for 8 weeks. Outcome measures included cortisol and melatonin levels, used to calculate phase angle, and the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN).

Results: The mean (standard error) phase angle between peak cortisol and DLMO increased by 108 (61) minutes from baseline to Week 8 (n = 9). BRIAN Total score changed (improved) by -14.6 (4.6) points from baseline to Week 8 (n = 9). Change in phase angle and BRIAN Total score showed a moderate-to-high correlation (Pearson coefficient: 0.68; 95% confidence limits: 0.04, 0.93; p = 0.040).

Limitations: This study is limited by its small sample size, and its single-arm, open-label design.

Conclusions: The findings provide a preliminary indication that the phase angle between peak cortisol and DLMO is of interest as a potential biomarker for depression and therapeutic response. Adjunctive brexpiprazole may represent a strategy for correcting circadian dysfunction in patients with MDD and inadequate response to antidepressant treatment. ClinicalTrials.gov identifier: NCT01942733.
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http://dx.doi.org/10.1016/j.jad.2020.09.026DOI Listing
January 2021

Vortioxetine for attention deficit hyperactivity disorder in adults: A randomized, double-blind, placebo-controlled, proof-of-concept study.

J Psychopharmacol 2019 04 7;33(4):511-521. Epub 2019 Mar 7.

1 Massachusetts General Hospital, Boston, MA, USA.

Background: Stimulants remain the mainstay of treatment for attention-deficit hyperactivity disorder (ADHD) but are often associated with insufficient response or poor tolerability, leading to many patients not wishing to be treated with controlled substances.

Aims: This randomized, placebo-controlled, proof-of-concept study (NCT02327013) evaluated the efficacy of a multimodal antidepressant, vortioxetine, in the treatment of ADHD, using a two-stage sequential parallel comparison design.

Methods: Patients aged 18-55 years with a diagnosis of ADHD (DSM-5) and a total score ⩾24 on the Adult ADHD Investigator Symptom Rating Scale (AISRS) were randomized in study stage I with a 1:1:3 ratio to six weeks of treatment with vortioxetine 10 or 20 mg/day, or placebo ( n = 227). In study stage II, placebo non-responders (AISRS total score reduction <30% from stage I baseline) were re-randomized with a 1:1:1 ratio to six weeks of vortioxetine 10 or 20 mg/day, or placebo ( n = 59).

Results: Across the two study stages combined, ADHD symptoms improved by approximately eight AISRS points in all treatment groups, showing no difference from placebo for either dose of vortioxetine, the study thus failing to meet its primary endpoint. However, both doses of vortioxetine separated from placebo in improving overall patient functioning, as measured by the Sheehan Disability Scale.

Conclusion: Studies are warranted to further investigate this suggested benefit of a multimodal antidepressant for patient functioning in ADHD while addressing issues of non-adherence and placebo response. The study confirmed vortioxetine 10 mg and 20 mg as generally well-tolerated.
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http://dx.doi.org/10.1177/0269881119832538DOI Listing
April 2019

Effect of Brexpiprazole on Prolactin: An Analysis of Short- and Long-Term Studies in Schizophrenia.

J Clin Psychopharmacol 2019 Jan/Feb;39(1):13-19

Otsuka Pharmaceutical Development & Commercialization Inc, Princeton, NJ.

Background: Hyperprolactinemia is an undesirable effect of most antipsychotics because of D2-receptor blockade. We assessed the effect of the D2-receptor partial agonist brexpiprazole on prolactin, based on pooled data from three 6-week, randomized, placebo-controlled studies and two open-label extension studies in patients with schizophrenia.

Methods: In the short-term studies, patients received 0.25, 1, 2, 4 mg brexpiprazole or placebo; or flexible-dose brexpiprazole (2-4 mg/d), placebo, or active reference. The extension studies were 52-week, flexible-dose (1-4 mg/d) studies. We studied changes from baseline and shifts in prolactin status in patients with normal or elevated prolactin levels at baseline, and prolactin-related treatment-emergent adverse events (TEAEs).

Results: Median changes from baseline to week 6 in brexpiprazole-treated patients in short-term studies were as follows: 3.63 ng/mL (females), 0.26 ng/mL (males); placebo: -2.15 ng/mL (females), -1.08 ng/mL (males).Median changes from baseline to week 52 in long-term studies were 0.60 ng/mL (females) and 0.18 ng/mL (males). Prolactin levels in patients with baseline values greater than 1× upper limit of normal tended to decrease over time regardless of previous treatment.The proportions of brexpiprazole-treated patients with greater than 3× upper limit of normal postbaseline prolactin values in short-term studies were as follows: 1.5% (females), 1.6% (males); placebo: 3.6% (females), 3.4% (males). Corresponding figures in long-term studies were 5.3% (females) and 2.0% (males).In short-term studies, the incidence of prolactin-related TEAEs was 1.8% for brexpiprazole and 0.6% for placebo. In long-term studies, the incidence of prolactin-related TEAEs was 1.7%.

Conclusions: Small changes in prolactin levels, low proportions of patients with postbaseline elevated prolactin values, and low incidence of prolactin-related TEAEs were observed after treatment with brexpiprazole.
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http://dx.doi.org/10.1097/JCP.0000000000000979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319696PMC
March 2019

A randomised, placebo-controlled 24-week study evaluating adjunctive brexpiprazole in patients with major depressive disorder.

Acta Neuropsychiatr 2019 Feb 18;31(1):27-35. Epub 2018 Sep 18.

3Otsuka Pharmaceutical Development & Commercialization Inc.,Princeton,NJ,USA.

Objective: To evaluate brexpiprazole adjunctive to antidepressant therapies (ADTs) as maintenance treatment in patients with major depressive disorder with inadequate response to ADT, utilising a novel study design.

Methods: The study comprised an 8-week prospective treatment period with open-label ADT with double-blind placebo treatment and a 24-week randomised treatment period. Investigators and patients were blinded to treatment periods, randomisation criteria, and timing of randomisation. Patients with early response to open-label ADT were withdrawn at Week 6. Patients fulfilling criteria for inadequate response were randomised to ADT+brexpiprazole 1-3 mg/day, or ADT+placebo. The primary endpoint was full remission: Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤10 and ≥50% decrease from randomisation (i.e. baseline) in MADRS total score for at least 8 consecutive weeks.

Results: The primary efficacy analysis failed to show a statistically significant difference between the proportions of patients on ADT+brexpiprazole (21.4%) and ADT+placebo (24.9%) achieving full remission; odds ratio: 0.83; p=0.2641. The secondary endpoint of change from baseline to Week 6 in MADRS total score showed no difference between ADT+brexpiprazole and ADT+placebo (-0.4; p=0.3259). The most frequent treatment-emergent adverse event (TEAE) in patients receiving ADT+brexpiprazole was weight increased (9.5% vs. 5.0% in ADT+placebo). The incidence of TEAEs leading to withdrawal in the randomised treatment period was 6.3% in the ADT+brexpiprazole group and 3.4% in the ADT+placebo group.

Conclusion: Adjunctive brexpiprazole did not differentiate from ADT+placebo on the primary endpoint of full remission. A number of design elements in this previously untried study design may have contributed to the study result. Brexpiprazole was well tolerated.
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http://dx.doi.org/10.1017/neu.2018.23DOI Listing
February 2019

Efficacy of vortioxetine on the physical symptoms of major depressive disorder.

J Psychopharmacol 2018 10 26;32(10):1086-1097. Epub 2018 Jul 26.

2 Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, UK.

Background: Efficacy has been proven for vortioxetine in short-term and long-term treatment of major depressive disorder (MDD), with broad beneficial effects on emotional, physical and cognitive symptoms. Limited specific data on the effects of vortioxetine on depression-related physical symptoms have been published.

Methods: A meta-analysis was carried out of five short-term multinational, double-blind, placebo-controlled studies. These studies were conducted in a total of 2105 adult MDD outpatients (18-75 years) with a major depressive episode of ⩾3 months' duration. Only patients treated with a dose of 5 or 10 mg vortioxetine (therapeutic doses) or placebo were included in this analysis. Efficacy assessment of vortioxetine on the physical symptoms of depression included all items of the Hamilton Depression Scale (HAM-D) assessing physical symptoms, and all somatic items in the Hamilton Anxiety Scale (HAM-A). A subgroup analysis in MDD patients with coexisting anxiety symptoms (i.e. those with a HAM-A ⩾20 at baseline) was also performed.

Results: A significant improvement ( p<0.05) of vortioxetine versus placebo was observed on all HAM-D items measuring physical symptoms, except for the somatic gastrointestinal symptoms and loss of weight items. Significant effects were also observed on the HAM-A somatic items: general somatic symptoms, gastrointestinal symptoms, and autonomic symptoms. In patients with a high baseline level of anxiety, a significant effect of vortioxetine was also observed on the physical symptoms of depression.

Conclusions: These analyses indicate that patients with MDD, including those with a high level of anxiety symptoms, have significant improvements in MDD-associated physical symptoms when treated with vortioxetine.
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http://dx.doi.org/10.1177/0269881118788826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380624PMC
October 2018

Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study.

Pain 2016 10;157(10):2350-2365

aPain Research Group, Department of Surgery and Cancer, Imperial College, London, United Kingdom bEli Lilly and Company, Erl Wood Manor, Windlesham, United Kingdom cDepartment of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden dNeuroscience CNSP iMED, AstraZeneca R&D Södertälje, Södertälje, Sweden eDepartment of Neurobiology, Boston Children's Hospital, MA, USA fDanish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark gCNS Disease Division Research Germany, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach an der Riss, Germany hDepartment of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Heidelberg University, Mannheim, Germany iDepartment of Pharmacology and Biomarker Development, Translational Science and Strategy, Grünenthal GmbH, Aachen, Germany jFaculty of Life Sciences, University of Manchester, Manchester, United Kingdom kEli Lilly and Company, Indianapolis, IN, USA lLaboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan mH. Lundbeck A/S, Valby, Denmark nDeal, Kent, United Kingdom. L. A. Bryden is now with the Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom. W. Huang is now with the Institute of Medical Sciences, University of Aberdeen, United Kingdom. C. Stenfors is now with the R&D CNS Research, Orion Corporation, Orion Pharma, Espoo, Finland.

Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.
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http://dx.doi.org/10.1097/j.pain.0000000000000657DOI Listing
October 2016

Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study.

Pain 2016 Oct;157(10):2350-65

aPain Research Group, Department of Surgery and Cancer, Imperial College, London, United Kingdom bEli Lilly and Company, Erl Wood Manor, Windlesham, United Kingdom cDepartment of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden dNeuroscience CNSP iMED, AstraZeneca R&D Södertälje, Södertälje, Sweden eDepartment of Neurobiology, Boston Children's Hospital, MA, USA fDanish Pain Research Center, Aarhus University Hospital, Aarhus, Denmark gCNS Disease Division Research Germany, Boehringer Ingelheim Pharma GmbH and Co KG, Biberach an der Riss, Germany hDepartment of Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Heidelberg University, Mannheim, Germany iDepartment of Pharmacology and Biomarker Development, Translational Science and Strategy, Grünenthal GmbH, Aachen, Germany jFaculty of Life Sciences, University of Manchester, Manchester, United Kingdom kEli Lilly and Company, Indianapolis, IN, USA lLaboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan mH. Lundbeck A/S, Valby, Denmark nDeal, Kent, United Kingdom. L. A. Bryden is now with the Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom. W. Huang is now with the Institute of Medical Sciences, University of Aberdeen, United Kingdom. C. Stenfors is now with the R&D CNS Research, Orion Corporation, Orion Pharma, Espoo, Finland.

Burrowing, an ethologically relevant rodent behaviour, has been proposed as a novel outcome measure to assess the global impact of pain in rats. In a prospective multicentre study using male rats (Wistar, Sprague-Dawley), replication of suppressed burrowing behaviour in the complete Freund adjuvant (CFA)-induced model of inflammatory pain (unilateral, 1 mg/mL in 100 µL) was evaluated in 11 studies across 8 centres. Following a standard protocol, data from participating centres were collected centrally and analysed with a restricted maximum likelihood-based mixed model for repeated measures. The total population (TP-all animals allocated to treatment; n = 249) and a selected population (SP-TP animals burrowing over 500 g at baseline; n = 200) were analysed separately, assessing the effect of excluding "poor" burrowers. Mean baseline burrowing across studies was 1113 g (95% confidence interval: 1041-1185 g) for TP and 1329 g (1271-1387 g) for SP. Burrowing was significantly suppressed in the majority of studies 24 hours (7 studies/population) and 48 hours (7 TP, 6 SP) after CFA injections. Across all centres, significantly suppressed burrowing peaked 24 hours after CFA injections, with a burrowing deficit of -374 g (-479 to -269 g) for TP and -498 g (-609 to -386 g) for SP. This unique multicentre approach first provided high-quality evidence evaluating suppressed burrowing as robust and reproducible, supporting its use as tool to infer the global effect of pain on rodents. Second, our approach provided important informative value for the use of multicentre studies in the future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028161PMC
http://dx.doi.org/10.1097/j.pain.0000000000000657DOI Listing
October 2016

Safety and Tolerability of Desmoteplase Within 3 to 9 Hours After Symptoms Onset in Japanese Patients With Ischemic Stroke.

Stroke 2015 Sep 6;46(9):2549-54. Epub 2015 Aug 6.

From the Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan (E.M.); Department of Cerebrovascular Medicine (K.M., T.Y.), Department of Integrative Stroke Imaging Center (J.N.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Neurology, St. Marianna University School of Medicine, Kawasaki, Japan (Y.H.); Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan (S.N.); Department of Cerebrovascular Disease, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan (Y.O.); International Clinical Research Neurology (T.T.), Biostatistics (A.L.), H. Lundbeck A/S, Valby, Denmark; and Department of Neurosurgery, Iwate Medical University, Morioka, Japan (A.O.).

Background And Purpose: This study investigated the safety and tolerability of desmoteplase administered within 3 to 9 hours after stroke symptoms onset in Japanese patients with acute ischemic stroke.

Methods: Patients were randomized to treatment with either desmoteplase or placebo in a 2:1 ratio in 2 consecutive cohorts (70 μg/kg and then 90 μg/kg). Included patients had a baseline National Institutes of Health Stroke Scale score of 4 to 24 and occlusion or high-grade stenosis in the middle cerebral artery segment M1 or M2 on magnetic resonance angiography. The incidence of symptomatic intracranial hemorrhage (≤72 hours) was defined as the primary end point. The occurrence of asymptomatic ICH, symptomatic cerebral edemas, and adverse events were other safety outcomes of special interest.

Results: Symptomatic intracranial hemorrhage was observed within 72 hours in 2 patients treated with placebo and in 1 patient treated with 70 μg/kg desmoteplase. Any ICH (symptomatic or asymptomatic ICH) within 72 hours were observed in 7 (43.8%) patients treated with placebo, in 8 (50%) patients treated with 70 μg/kg desmoteplase, and in 9 (56.3%) patients treated with 90 μg/kg desmoteplase. Desmoteplase treatment with 70 or 90 μg/kg was not associated with an increased risk of symptomatic cerebral edema compared with placebo. There were no other serious safety concerns associated with desmoteplase.

Conclusions: Desmoteplase in both 70 and 90 μg/kg doses had a favorable safety profile and was well tolerated in Japanese patients with acute ischemic stroke when administered 3 to 9 hours after stroke symptoms onset.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01104467.
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http://dx.doi.org/10.1161/STROKEAHA.115.009917DOI Listing
September 2015

Refinement of the magnetic resonance diffusion-perfusion mismatch concept for thrombolytic patient selection: insights from the desmoteplase in acute stroke trials.

Stroke 2012 Sep 26;43(9):2313-8. Epub 2012 Jun 26.

Seton/University of Texas Southwestern Clinical Research Institute of Austin, 1400 N. IH 35, Suite 2.240, Austin, TX 78701, USA.

Background And Purpose: The DIAS-2 study was the only large, randomized, intravenous, thrombolytic trial that selected patients based on the presence of ischemic penumbra. However, DIAS-2 did not confirm the positive findings of the smaller DEDAS and DIAS trials, which also used penumbral selection. Therefore, a reevaluation of the penumbra selection strategy is warranted.

Methods: In post hoc analyses we assessed the relationships of magnetic resonance imaging-measured lesion volumes with clinical measures in DIAS-2, and the relationships of the presence and size of the diffusion-perfusion mismatch with the clinical effect of desmoteplase in DIAS-2 and in pooled data from DIAS, DEDAS, and DIAS-2.

Results: In DIAS-2, lesion volumes correlated with National Institutes of Health Stroke Scale (NIHSS) at both baseline and final time points (P<0.0001), and lesion growth was inversely related to good clinical outcome (P=0.004). In the pooled analysis, desmoteplase was associated with 47% clinical response rate (n=143) vs 34% in placebo (n=73; P=0.08). For both the pooled sample and for DIAS-2, increasing the minimum baseline mismatch volume (MMV) for inclusion increased the desmoteplase effect size. The odds ratio for good clinical response between desmoteplase and placebo treatment was 2.83 (95% confidence interval, 1.16-6.94; P=0.023) for MMV >60 mL. Increasing the minimum NIHSS score for inclusion did not affect treatment effect size.

Conclusions: Pooled across all desmoteplase trials, desmoteplase appears beneficial in patients with large MMV and ineffective in patients with small MMV. These results support a modified diffusion-perfusion mismatch hypothesis for patient selection in later time-window thrombolytic trials. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique Identifiers: NCT00638781, NCT00638248, NCT00111852.
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http://dx.doi.org/10.1161/STROKEAHA.111.642348DOI Listing
September 2012

Vascular occlusion enables selecting acute ischemic stroke patients for treatment with desmoteplase.

Stroke 2012 Jun 3;43(6):1561-6. Epub 2012 Apr 3.

Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background And Purpose: Desmoteplase is a novel and highly fibrin-specific thrombolytic agent. Evidence of safety and efficacy was obtained in 2 phase II trials (Desmoteplase In Acute Ischemic Stroke [DIAS] and Desmoteplase for Acute Ischemic Stroke [DEDAS]). The DIAS-2 phase III trial did not replicate the positive phase II efficacy findings. Post hoc analyses were performed with the aim of predicting treatment responders based on CTA and MRA.

Methods: Patients were grouped according to vessel status (Thrombolysis In Myocardial Infarction [TIMI] grade) for logistic regression of clinical response, applying the data from DIAS-2 as well as the pooled data from DIAS, DEDAS, and DIAS-2.

Results: In DIAS-2, a substantial number of mismatch-selected patients (126/179; 70%) presented with a normal flow/low-grade stenosis (TIMI 2-3) at screening, with the majority having a favorable outcome at day 90. In contrast, favorable outcome rates in patients with vessel occlusion/high-grade stenosis (TIMI 0-1) were 18% with placebo versus 36% and 27% with desmoteplase 90 and 125 μg/kg, respectively. The clinical effect based on the pooled data from DIAS, DEDAS, and DIAS-2 was favorable for desmoteplase-treated patients presenting with TIMI 0 to 1 at baseline (OR, 4.144; 95% CI, 1.40-12.23; P=0.010). There was no desmoteplase treatment benefit in patients presenting with TIMI 2 to 3 (OR, 1.109).

Conclusions: In this sample of patients with a mismatch diagnosed, proximal vessel occlusion or severe stenosis was associated with clinically beneficial treatment effects of desmoteplase. Selecting patients using CTA or MRA in clinical trials of thrombolytic therapy is justifiable.
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http://dx.doi.org/10.1161/STROKEAHA.111.642322DOI Listing
June 2012
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