Extension Study Baseline Research Articles

Safety, Tolerability, and Efficacy of Desvenlafaxine in Children and Adolescents with Major Depressive Disorder: Results from Two Open-Label Extension Trials.

Two similarly designed extension studies evaluated the long-term safety and tolerability of desvenlafaxine for the treatment of children and adolescents with major depressive disorder (MDD). Efficacy was evaluated as a secondary objective. Both 6-month, open-label, flexible-dose extension studies enrolled children and adolescents who had completed one of two double-blind, placebo-controlled, lead-in studies. One lead-in study included a 1-week transition period prior to the extension study. Patients received 26-week treatment with flexible-dose desvenlafaxine (20-50 mg/d). Safety assessments included comprehensive psychiatric evaluations, vital sign assessments, laboratory evaluations, 12-lead electrocardiogram, physical examination with Tanner assessment, and Columbia-Suicide Severity Rating Scale. Adverse events (AEs) were collected throughout the studies. Efficacy was assessed using the Children's Depression Rating Scale-Revised (CDRS-R). A total of 552 patients enrolled (completion rates: 66.4 and 69.1%). AEs were reported by 79.4 and 79.1% of patients in the two studies; 8.9 and 5.2% discontinued due to AEs. Treatment-emergent suicidal ideation or behavior was reported for 16.6 and 14.1% of patients in the two studies. Mean (SD) CDRS-R total score decreased from 33.83 (11.93) and 30.92 (10.20) at the extension study baseline to 24.31 (7.48) and 24.92 (8.45), respectively, at week 26. Desvenlafaxine 20 to 50 mg/d was generally safe and well tolerated with no new safety signals identified in children and adolescents with MDD who received up to 6 months of treatment in these studies. Patients maintained the reduction in severity of depressive symptoms observed in all treatment groups at the end of the lead-in study.

Long-term safety, tolerability, and efficacy of OROS® hydromorphone in patients with chronic pain

To assess the safety and efficacy of long-term repeated dosing of OROS hydromorphone in chronic pain patients. This multicenter, open-label extension trial enrolled patients from three short-term OROS hydromorphone trials. Fifty-six centers in the United States and Canada. Adults with chronic cancer pain or chronic nonmalignant pain who were receiving stable doses of OROS hydromorphone (> or = 8 mg/day). Three hundred and eighty-eight patients were enrolled, 106 patients completed at least 12 months of therapy. OROS hydromorphone (individualized doses) was administered once daily. Safety and efficacy (Brief Pain Inventory and patient and investigator global evaluations) were assessed at monthly visits. The median duration of extended OROS hydromorphone therapy was 274 days. The median daily dose of study medication was 32.0 mg at extension-study baseline, 40.0 mg at month 3, and 48.0 mg at months 6, 9, and 12, respectively. The most frequently reported adverse events were nausea (n = 93, 24.0 percent) and constipation (n = 75, 19.3 percent). The analgesic effects of OROS hydromorphone, assessed using the Brief Pain Inventory, were maintained throughout the extension. At 12 months, 72.4 percent of patients and 75.9 percent of investigators rated overall treatment as good, very good, or excellent. Once-daily OROS hydromorphone is an osmotically driven, controlled-release preparation that may be particularly well suited to long-term use, because it provides consistent plasma concentrations and sustained around-the-clock analgesia. In this study, the benefits of OROS hydromorphone attained in short-term studies were maintained in the long-term when daily administration was continued.

Safety and Efficacy of Long-Term Open-Label Dosing of Romiplostim in Thrombocytopenic Pediatric Patients (Pts) with Immune Thrombocytopenia (ITP)

Safety and Efficacy of Long-Term Open-Label Dosing of Romiplostim in Thrombocytopenic Pediatric Patients (Pts) with Immune Thrombocytopenia (ITP)

Long-term (1 year) safety and efficacy of methylphenidate modified-release long-acting formulation (MPH-LA) in adults with attention-deficit hyperactivity disorder: a 26-week, flexible-dose, open-label extension to a 40-week, double-blind, randomised, placebo-controlled core study.

IntroductionPreviously, in a 40-week, randomised, double-blind, placebo-controlled core study comprising three phases (9-week dose confirmation, 5-week open-label dose optimisation and 6-month maintenance of effect) in adults with attention-deficit/hyperactivity disorder (ADHD), methylphenidate modified-release long-acting formulation (MPH-LA) at 40–80 mg/day controlled ADHD symptoms as well as decreased functional impairment with a good tolerability profile (NCT01259492). Here, we report the long-term efficacy and safety from a 26-week, open-label extension phase of the same study (NCT01338818).MethodsPatients in the extension study (n = 298) initiated treatment with MPH-LA (20 mg/day), up-titrated in increments of 20 mg/week to reach individual patient’s daily optimal dose of 40–80 mg. Adverse events (AEs) and serious adverse events (SAEs) were reported at the end of extension study for events monitored from (1) maintenance of effect phase baseline (core study; 12 months) and (2) extension study baseline (6 months). Mean changes in DSM-IV ADHD Rating Scale (DSM-IV ADHD RS) and Sheehan Disability Scale (SDS) total scores are reported for both the timelines. Efficacy was also evaluated using clinician-rated instruments, namely Clinical Global Impression-Improvement Scale (CGI-I) and Clinical Global Impression-Severity Scale (CGI-S).ResultsNo unexpected AEs were reported in the extension study. Incidence of SAEs reported during 6 months and 12 months were similar (0.7 %), and no deaths were reported. No SAEs were considered attributable to the drug at the end of 12 months. There were no reports of patients with QT, QTcB or QTcF >500 ms. The mean improvement in DSM-IV ADHD RS and SDS total scores at the end of 12 months were 0.9 and 1.4 points, respectively; and at the end of 6 months were 7.2 and 4.8, respectively. The proportion of patients with improvement in CGI-S scale was 31.4 % and 52.1 % at the end of 12 and 6 months, respectively. Overall, 69.4 % of patients showed clinical improvement in CGI-I scale at the end of 6 months.ConclusionsIn adult patients with ADHD, use of MPH-LA up to 1 year continued to be well tolerated while maintaining the clinical efficacy.

Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial

SummaryIn a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study.IntroductionThe purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.MethodsIn the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.ResultsOf the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.ConclusionContinued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.

Safety and efficacy of olanzapine monotherapy and olanzapine with a mood stabilizer in 18-week treatment of manic/mixed episodes for Japanese patients with bipolar I disorder

Objective:To assess the safety and efficacy of 18-week olanzapine monotherapy in Japanese patients with bipolar mania, following a 6-week, placebo- and haloperidol-controlled double-blind study (acute study). For those who discontinued the acute study due to lack of efficacy, safety and efficacy was assessed with a combination therapy of olanzapine and a mood stabilizer.Research design and methods:In this open-label, multicenter extension study, patients who completed the acute study received olanzapine (5–20 mg/day) as monotherapy, and patients who discontinued the acute study due to lack of efficacy with greater Young Mania Rating Scale (YMRS) total score than the acute study baseline, received olanzapine in combination with one of three mood stabilizers: lithium, carbamazepine, or valproate. Safety was assessed by treatment-emergent adverse events (TEAEs), vital signs, weight, and extrapyramidal symptoms (EPSs). Efficacy measures included YMRS total score, and response and remission rates of manic symptoms.Main outcome and measures:There were no deaths or serious adverse events considered potentially related to olanzapine in the monotherapy group (N = 100) or the combination-therapy group (N = 39). TEAEs occurred in 59.0% and 79.5% of patients in the monotherapy and combination-therapy groups, respectively, and their severities were mostly mild or moderate. Regarding the efficacy measures, in the monotherapy group, mean YMRS change from extension study baseline to endpoint was −3.0, and the response and remission rates at endpoint were 97.0% and 93.0%, respectively. In the combination-therapy group, mean YMRS change from extension-study baseline was −19.8; response and remission rates increased from the extension-study baseline (both 0.0%) to 64.1% and 61.5% respectively by endpoint.Conclusion:Olanzapine was generally well tolerated during the 18-week extension period in Japanese patients with bipolar mania. Results of both groups were also generally consistent with US and European studies. Monitoring of metabolic parameters is recommended.

Longterm Therapeutic Response to Milnacipran Treatment for Fibromyalgia. A European 1-Year Extension Study Following a 3-Month Study

This double-blind, 1-year extension study investigated the longterm efficacy and safety of milnacipran 100, 150, and 200 mg/day in the treatment of fibromyalgia (FM) in completers of a 3-month European double-blind lead-in study of milnacipran 200 mg/day versus placebo. A total of 468 patients with FM successfully completing the lead-in study were either blindly maintained on milnacipran 200 mg/day (MLN200:MLN200, n = 198) or (if previously receiving placebo) rerandomized to milnacipran 100 mg/day (PBO:MLN100, n = 91), 150 mg/day (PBO:MLN150, n = 92), or 200 mg/day (PBO:MLN200, n = 87) for an additional 12 months (including a 4-week dose escalation). The main efficacy endpoint was a 2-measure composite responder rate (relative to lead-in study baseline) incorporating the weekly-recall pain score recorded on a visual analog scale and the Patient Global Impression of Change score. A panel of other assessments including the Fibromyalgia Impact Questionnaire explored the multidimensional aspects of FM. Descriptive analyses using the last observation carried forward approach were performed. At the 1-year endpoint, the proportion of composite responders (relative to the lead-in study baseline) ranged from 27.5% (PBO:MLN100) to 35.9% (MLN200:MLN200), and had increased from the extension study baseline by 15.2% (PBO:MLN150) to 20.7% (PBO:MLN200 and MLN200:MLN200). At endpoint, an improvement from both baselines was shown in all groups on pain, fatigue, sleep, and quality of life measures. Up to 1 year, all doses of milnacipran were safe and well tolerated. The most common drug-related adverse events were hyperhidrosis and nausea. Over 1 year, milnacipran 100, 150, and 200 mg/day exhibited sustained and safe therapeutic effects on predominant symptoms of FM. Registered as trial no. NCT00757731.

Long-Term Safety and Efficacy of Donepezil in Patients with Severe Alzheimer’s Disease: Results from a 52-Week, Open-Label, Multicenter, Extension Study in Japan

Background/Aims: A 6-month, randomized, double-blind, placebo-controlled study was extended to evaluate long-term safety and efficacy of donepezil in community-dwelling Japanese patients with severe Alzheimer’s disease (AD). Methods: 189 patients were enrolled from the double-blind study into a 52-week, open-label extension study. After a 2- to 8-week washout, donepezil was escalated within 6 weeks to 10 mg/day. Main outcomes were Severe Impairment Battery (SIB), Alzheimer’s Disease Cooperative Study-Activities of Daily Living scale for severe AD (ADCS-ADL-sev) and Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD). Safety parameters were monitored throughout. Results: Overall, mean change from extension study baseline in SIB scores improved until week 24; however, scores were influenced by prior treatment during the double-blind study and by length of washout. Patients treated with donepezil retained some treatment benefits after a washout of 2–4 weeks but lost all treatment benefits after a washout of 4–8 weeks. There was no change in ADCS-ADL-sev or BEHAVE-AD scores. Adverse events were consistent with the known donepezil safety profile. Conclusion: Donepezil is effective and safe for symptomatic treatment of severe AD for at least 1 year. Patients who receive donepezil 10 mg daily with little or no interruption achieve the best long-term outcome.

Comparison of clinical and pharmacokinetic profiles of etanercept 25 mg twice weekly and 50 mg once weekly in patients with psoriasis

Etanercept is a tumour necrosis factor antagonist that is approved in the U.S.A., Canada and Europe for treating adult patients with chronic moderate to severe plaque psoriasis. To assess whether clinical efficacy, safety and pharmacokinetic (PK) profiles of etanercept 50 mg once weekly are comparable to etanercept 25 mg twice weekly. Patients from a U.S. phase 3 study and a global phase 3 study were subsequently enrolled in an open-label extension study (extension study) where they all received etanercept at a dose of 50 mg once weekly for an initial 12 weeks. Patients who had received at least 24 weeks of etanercept 25 mg twice weekly in the global phase 3 study and were enrolled in the extension study (n = 265) were assessed for efficacy and safety at extension study baseline and after 12 weeks of etanercept 50 mg once weekly. Efficacy endpoints included the Psoriasis Area and Severity Index (PASI), the Dermatology Life Quality Index and the Physician's Global Assessment of psoriasis. In addition, PK profiles from patients in the U.S. phase 3 study were compared with PK profiles from another set of patients in the extension study. Comparison was made between a subset of patients receiving etanercept 25 mg twice weekly dosing in the U.S. phase 3 study (n = 13) and those receiving etanercept 50 mg once weekly in the extension study (n = 84). The mean PASI score was 5.77 at extension study baseline after treatment with etanercept 25 mg twice weekly, which was sustained at 5.82 after 12 weeks of etanercept 50 mg once weekly. Similar results were observed in other efficacy endpoints. Etanercept 50 mg once weekly was generally well tolerated. No new safety findings were reported. PK profiles overlapped extensively between the two dosing regimens. In this report, we demonstrate that efficacy, safety and PK profiles were comparable between etanercept 25 mg twice weekly and 50 mg once weekly in patients who had received at least 24 weeks of etanercept 25 mg twice weekly prior to receiving etanercept 50 mg once weekly in the extension study.

Long-Term Sertraline Treatment of Children and Adolescents With Obsessive-Compulsive Disorder

To evaluate the safety and effectiveness of sertraline in the long-term treatment of pediatric obsessive-compulsive disorder (OCD). Children (6-12 years; n= 72) and adolescents (13-18 years; n = 65) with DSM-III-R-defined OCD who had completed a 12-week, double-blind, placebo-controlled sertraline study were given open-label sertraline 50 to 200 mg/day in this 52-week extension study. Concomitant psychotherapy was allowed during the extension study Outcome was evaluated by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS), National Institute of Mental Health Global Obsessive-Compulsive Scale, and Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) scores. Significant improvement (p < .0001) was demonstrated on all four outcome parameters on an intent-to-treat analysis for the overall study population (n = 132), as well as the child and the adolescent samples. At endpoint, 72% of children and 61% of adolescents met response criteria (>25% decrease in CY-BOCS and a CGI-I score of 1 or 2). Significant (p < .05) improvements were also demonstrated from the extension study baseline to endpoint on all outcome parameters in those patients who received sertraline during the 12-week, double-blind acute study. Long-term sertraline treatment was well tolerated, and there were no discontinuations due to changes in vital signs, laboratory values, or electrocardiograms. Sertraline (50-200 mg/day) was effective and generally well tolerated in the treatment of childhood and adolescent OCD for up to 52 weeks. Improvement was seen with continued treatment.