Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: The DIAS-3 trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke [phase 3]) did not demonstrate a significant clinical benefit of desmoteplase administered 3 to 9 hours after stroke in patients with major artery occlusion. We present the results of the prematurely terminated DIAS-4 trial together with a post hoc pooled analysis of the concomitant DIAS-3, DIAS-4, and DIAS-J (Japan) trials to better understand the potential risks and benefits of intravenous desmoteplase for the treatment of ischemic stroke in an extended time window. METHODS: Ischemic stroke patients with occlusion/high-grade stenosis in major cerebral arteries were randomly assigned to intravenous treatment with desmoteplase (90 µg/kg) or placebo. The primary outcome was modified Rankin Scale (mRS) score of 0 to 2 at day 90. Safety assessments included mortality, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: In DIAS-4, 52 of 124 (41.9%) desmoteplase-treated and 46 of 128 (35.9%) placebo-treated patients achieved an mRS score of 0 to 2 (odds ratio, 1.45; 95% confidence interval, 0.79; 2.64; P=0.23) with equal mortality, frequency of symptomatic intracranial hemorrhage, and other serious adverse events in both the treatment arms. In the pooled analysis, mRS score of 0 to 2 was achieved by 184 of 376 (48.9%) desmoteplase-treated versus 171 of 381 (44.9%) placebo-treated patients (odds ratio, 1.33; 95% confidence interval, 0.95; 1.85; P=0.096). Treatment with desmoteplase was safe and increased the recanalization rate (107/217 [49.3%] versus 85/222 [38.3%]; odds ratio, 1.59; 95% confidence interval, 1.08-2.35; P=0.019). Recanalization was associated with favorable outcomes (mRS 0-2) at day 90 in both the treatment arms. CONCLUSIONS: Late treatment with intravenous 90 µg/kg desmoteplase is safe, increases arterial recanalization, but does not significantly improve functional outcome at 3 months. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856661.

Safety and efficacy of desmoteplase given 3-9 h after ischaemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries (DIAS-3): a double-blind, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Current treatment of ischaemic stroke with thrombolytic therapy is restricted to 3-4·5 h after symptom onset. We aimed to assess the safety and efficacy of desmoteplase, a fibrin-dependent plasminogen activator, given between 3 h and 9 h after symptom onset in patients with occlusion or high-grade stenosis in major cerebral arteries. METHODS: In a prospective, double-blind, multicentre, parallel-group, randomised trial, we enrolled patients from 77 hospitals in 17 countries who had ischaemic stroke and occlusion or high-grade stenosis in major cerebral arteries. We randomly assigned patients in a 1:1 ratio, using computer-generated randomisation lists with stratification for baseline National Institutes of Health Stroke Scale and age, to treatment with desmoteplase (90 µg/kg) given 3-9 h after symptom onset or to placebo. Patients, investigators, staff, and the funder were masked to treatment assignment. The primary outcome was a favourable modified Rankin Scale score (0-2) at day 90 in all treated patients who had at least one postbaseline measurement of the modified Rankin Scale. Safety was assessed in all randomly assigned patients who received study drugs. This trial is registered with ClinicalTrials.gov, number NCT00790920. FINDINGS: Between Feb 6, 2009, and Nov 27, 2013, we enrolled 492 patients and randomly assigned 247 to desmoteplase and 245 to placebo (236 in the desmoteplase group and 237 in the placebo group were included in the analysis of the primary endpoint). Median time from stroke onset to treatment was 6·9 h (IQR 5·7-8·0) for placebo and 7·0 h (6·0-7·9) for desmoteplase. Modified Rankin Scale score (0-2) at day 90 occurred in 121 (51%) patients given desmoteplase and 118 (50%) patients given placebo (adjusted odds ratio 1·20, 95% CI 0·79-1·81, p=0·40). 24 (10%) of 240 patients given desmoteplase died compared with 23 (10%) of 238 patients given placebo. Serious adverse events occurred in 64 (27%) of 240 patients receiving desmoteplase compared with 69 (29%) of 238 patients receiving placebo; frequency of symptomatic intracranial haemorrhage (six [3%] patients in the desmoteplase group vs five [2%] in the placebo group), symptomatic cerebral oedema (five [2%] vs four [2%]), and major haemorrhage (ten [4%] vs 15 [6%]) was much the same between treatment groups. INTERPRETATION: Treatment with desmoteplase did not cause safety concerns and did not improve functional outcome when given to patients who had ischaemic stroke and major cerebral artery occlusion beyond 3 h of symptom onset. FUNDING: H Lundbeck A/S.

Management of depressive symptoms in schizophrenia.

BACKGROUND: Although depressive symptoms are a frequently occurring phenomenon in schizophrenia, effective treatments remain an area of clinical need. OBJECTIVE: To assess the benefit of short-term treatment with the atypical antipsychotic asenapine versus placebo on depressive symptoms in patients with acute schizophrenia in an exacerbated state. METHODS: Data were pooled from intent-to-treat (ITT) populations of three 6-week, randomized controlled studies with fixed doses of asenapine (ASE; n=427), olanzapine (OLA; n=82), risperidone (RIS; n=54), haloperidol (HAL; n=97), or placebo (PLA; n=254). Change from baseline Calgary Depression Scale for Schizophrenia (CDSS) total score and individual item scores were assessed at Day 21 and Day 42 in the total patient population (n=914), and in patients presenting with a CDSS total score of .6 at baseline (n=248). Mixed model repeated measures (MMRM) analyses were performed on patient data. RESULTS: The observed change from baseline in CDSS total score was significantly larger with ASE.compared to PLA.at both Day 21 (p<0.05) and Day 42 (p<0.01) for the total patient population group, and at Day 21 (p<0.05) in patients with baseline CDSS total score .6. For both populations, there was a significant change from baseline in the CDSS depression item score with ASE.compared to PLA.at Day 21 (p<0.01, all patient population; p<0.05, patients with baseline CDSS .6), and at Day 42 (p<0.01) in the all patient population. Statistically significant changes from baseline, in favor of ASE versus PLA, were also observed in other individual CDSS item scores including hopelessness (p<0.05, Day 21, patients with baseline CDSS .6), self-depreciation (p<0.05, Day 42, all patient population), guilty ideas of reference (p<0.01, Day 42, all patient population), pathological guilt (p<0.01, Day 21, all patient population; p<0.05, Day 21 and Day 42, patients with baseline CDSS score .6), and observed depression (p<0.05, Day 21, all patient population). CONCLUSIONS: ASE significantly improved a range of depressive symptoms in people with an acute exacerbation of schizophrenia, as measured by the CDSS. ASE may represent a beneficial treatment option for the management of depressive symptoms in patients with schizophrenia.

Rapid elimination kinetics of free PSA or human kallikrein-related peptidase 2 after initiation of gonadotropin-releasing hormone-antagonist treatment of prostate cancer: potential for rapid monitoring of treatment responses.

BACKGROUND: The utility of conventional prostate-specific antigen (PSA) measurements in blood for monitoring rapid responses to treatment for prostate cancer is limited because of its slow elimination rate. Prior studies have shown that free PSA (fPSA), intact PSA (iPSA) and human kallikrein-related peptidase 2 (hK2) are eliminated more rapidly after radical prostatectomy. In contrast, all three markers have similarly slow elimination rates after castration induced by gonadotropin-releasing hormone (GnRH) agonists, possibly due to the slow onset of castration. Therefore, we assessed elimination rates of tPSA, fPSA, iPSA and hK2 after rapid induction of castration with degarelix (Firmagon(®)), a novel GnRH antagonist. METHODS: This study included 24 patients treated with degarelix. Blood was taken at 1, 3, 7, 14, 21 and 28 days after injection of degarelix. Free and total PSA were measured with a commercial dual-label assay, and with inhouse research assays of intact PSA and hK2. RESULTS: Median (interquartile range, IQR) tPSA at baseline was 23.4 (15.8, 59.8). Twenty-two patients (92 % ) reached castrate levels of testosterone within 24 h of degarelix initiation, and all patients did so within 72 h. All kallikrein forms declined in an exponential fashion after degarelix administration. The median time to 50 % reduction in biomarker level was 8 ­ 9 days for tPSA or complexed PSA vs. 2-4 days for hK2, iPSA and fPSA. The percentage eliminated at day 3 and day 7 was significantly higher for hK2, iPSA and fPSA than for tPSA (all p < 0.02), while tPSA and complexed PSA were similar. CONCLUSIONS: The rapid decline of fPSA, iPSA and hK2 after fast induction of castration with degarelix is similar to that reported after prostatectomy and offers a novel, informative method to monitor rapid onset of therapeutic action targeting signaling of the androgen receptor.

A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer.

PURPOSE: We investigated the efficacy and safety of degarelix treatment and the effects of switching from leuprolide to degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial. MATERIALS AND METHODS: Patients who completed a 1-year pivotal phase III trial continued on the same monthly degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle-stimulating hormone responses, and prostate specific antigen failure and progression-free survival. RESULTS: During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued on degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time. CONCLUSIONS: Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics.

BACKGROUND: Recent data suggest prostate-specific antigen (PSA) progression may predict overall survival in prostate cancer patients. OBJECTIVE: To compare the activity of degarelix and leuprolide regarding PSA recurrence-free survival. DESIGN, SETTING, AND PARTICIPANTS: Phase 3, 1-yr, multicentre, randomised, open-label trial comparing the efficacy and safety of degarelix at 240 mg for 1 mo, and then 80 mg monthly (240/80 mg); degarelix at 240 mg for 1 mo, and then 160 mg monthly; and leuprolide at 7.5 mg/mo. Overall, 610 patients with histologically confirmed prostate cancer (all stages), for whom androgen deprivation therapy was indicated, were included. The primary end point of this trial has been reported previously; the protocolled and exploratory subgroup analyses reported in this paper focus on degarelix at 240/80 mg (dose approved by the US Food and Drug Administration and the European Medicine Evaluation Association for the treatment of patients with hormone-naive advanced prostate cancer). MEASUREMENTS: PSA progression-free survival (two consecutive increases in PSA of 50% compared with nadir and ≥ 5 ng/ml on two consecutive measurements at least 2 wk apart or death) and change in PSA were reviewed. Effects of baseline disease stage (localised, locally advanced, and metastatic) and PSA level (<10, 10-20, >20-50, and >50 ng/ml) were analysed. RESULTS AND LIMITATIONS: Patients receiving degarelix showed a significantly lower risk of PSA progression or death compared with leuprolide (p=0.05). PSA recurrences occurred mainly in patients with advanced disease and exclusively in those with baseline PSA >20 ng/ml. Patients with PSA >20 ng/ml had a significantly longer time to PSA recurrence with degarelix (p=0.04). The relatively low number of patients in each subgroup is a limitation of this study. CONCLUSIONS: These results generate the hypothesis that degarelix at 240/80 mg offers improved PSA control compared with leuprolide. PSA recurrences occurred almost exclusively in patients with metastatic prostate cancer or high baseline PSA during this 1-yr study. Further studies are warranted to confirm these findings.

Degarelix: a new approach for the treatment of prostate cancer.

Androgen deprivation therapy remains the mainstay of medical treatment for prostate cancer. Generally, this is achieved with medical androgen deprivation rather than orchidectomy, as most patients find the permanency and psychological effects of the latter unacceptable. Gonadotrophin-releasing hormone (GnRH) agonists are the most widely used androgen deprivation therapy, but do have some drawbacks. The most apparent is the induction of a transient surge in serum testosterone that may stimulate tumor growth, causing patients to experience new or worsening cancer symptoms. These may include increased bone pain and urinary retention, and consequently delay the therapeutic benefit of these agents. These shortcomings led to the development of the GnRH antagonists/receptor blockers. Degarelix is a novel GnRH receptor blocker that has an immediate onset of action, producing a rapid decrease in luteinizing hormone and follicle-stimulating hormone leading to fast testosterone suppression without the initial surge associated with the GnRH agonists. Administration of subcutaneous degarelix depot has been investigated in multicenter, open-label, randomized, phase II trials of up to 1 year's duration in patients with prostate cancer. Degarelix induced rapid luteinizing hormone suppression and fast, profound and sustained suppression of serum testosterone (or=2 weeks before clinically relevant changes were induced by the GnRH agonist leuprolide. Degarelix was as effective as leuprolide at reducing testosterone

The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer.

OBJECTIVE: To evaluate the efficacy and safety of degarelix, a new gonadotrophin-releasing hormone (GnRH) antagonist (blocker), vs leuprolide for achieving and maintaining testosterone suppression in a 1-year phase III trial involving patients with prostate cancer. PATIENTS AND METHODS: In all, 610 patients with adenocarcinoma of the prostate (any stage; median age 72 years; median testosterone 3.93 ng/mL, median prostate-specific antigen, PSA, level 19.0 ng/mL) were randomized and received study treatment. Androgen-deprivation therapy was indicated (neoadjuvant hormonal treatment was excluded) according to the investigator's assessment. Three dosing regimens were evaluated: a starting dose of 240 mg of degarelix subcutaneous (s.c.) for 1 month, followed by s.c. maintenance doses of 80 mg or 160 mg monthly, or intramuscular (i.m.) leuprolide doses of 7.5 mg monthly. Therapy was maintained for the 12-month study. Both the intent-to-treat (ITT) and per protocol populations were analysed. RESULTS: The primary endpoint of the trial was suppression of testosterone to

A 1-year, open label, randomized phase II dose finding study of degarelix for the treatment of prostate cancer in North America.

PURPOSE: Degarelix is a gonadotropin-releasing hormone receptor antagonist (blocker) with rapid onset of action suppressing gonadotropins, testosterone and prostate specific antigen in prostate cancer. In the present open label, randomized study in North America we evaluated the efficacy and safety of a starting dose of 200 mg degarelix followed by monthly injections of 60 or 80 mg during 1 year of prostate cancer treatment. MATERIALS AND METHODS: A total of 127 patients (median age 76 years, range 47 to 93) with histologically confirmed prostate cancer were enrolled in the study. Efficacy was assessed by measuring serum testosterone and prostate specific antigen. RESULTS: Median baseline testosterone and prostate specific antigen levels were 4.13 ng/ml (P25-P75 3.03-5.11) and 13.4 ng/ml (P25-P75 6.80-25.7), respectively. The starting dose induced a rapid suppression of testosterone in that 88% of the patients had testosterone levels of 0.5 ng/ml or less 1 month after the injection. For patients who had testosterone levels of 0.5 ng/ml or less after 1 month, 93% and 98% of those receiving maintenance doses of 60 and 80 mg, respectively, had testosterone levels that were consistently 0.5 ng/ml or less at all monthly measurements from 1 month to 1 year. No evidence of testosterone surge was detected. In both groups prostate specific antigen decreased by 96% after 1 year and median time to 90% reduction in prostate specific antigen was 56 days. Six patients (5%) withdrew from the study due to adverse events. CONCLUSIONS: Degarelix treatment for 1 year resulted in a fast, profound and sustained suppression of testosterone and prostate specific antigen with no evidence of testosterone surge. Degarelix was well tolerated.

Degarelix: a novel gonadotropin-releasing hormone (GnRH) receptor blocker--results from a 1-yr, multicentre, randomised, phase 2 dosage-finding study in the treatment of prostate cancer.

BACKGROUND: Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. OBJECTIVE: To determine the efficacy and safety of initial doses of 200 mg or 240 mg of degarelix and thereafter monthly subcutaneous maintenance doses of 80 mg, 120 mg, or 160 mg of degarelix for the treatment of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: The 1-yr study was of open-label, randomised design and involved 187 patients (range: 52-93 yr, median: 72 yr) with histologically confirmed adenocarcinoma of the prostate and a baseline PSA >2 ng/ml. RESULTS AND LIMITATIONS: At baseline, median serum testosterone was 4.13 ng/ml (range: P25-P75, 3.37-5.19 ng/ml) and PSA was 27.6 ng/ml (range: P25-P75, 11.9-55.0 ng/ml). On day 3, 88% and 92% of patients in the groups to whom 200-mg and 240-mg initial doses of degarelix were administered, respectively, had testosterone levels < or =0.5 ng/ml. For patients with testosterone levels < or =0.5 ng/ml at 1 mo, the testosterone levels remained < or =0.5 ng/ml until the end of the study in 100% of the patients treated with a monthly maintenance dosage of 160 mg of degarelix. No evidence of testosterone surge was detected. PSA decreased by 97-98% after 1 yr and the median time to 90% reduction in PSA was 8 wk in all but one patient (from the 80-mg dosage treatment group at the initial 200-mg dose of degarelix). Thirteen patients (6%) withdrew from the study due to adverse events, largely related to androgen deprivation. CONCLUSIONS: Degarelix treatment for 1 yr resulted in a fast, profound, and sustained suppression of testosterone and PSA, with no evidence of testosterone surge. Degarelix was well tolerated.