Maintenance Of Blinding Research Articles

324 Tralokinumab provides progressive and sustained efficacy in adolescents with moderate-to-severe atopic dermatitis: a post-hoc analysis of the ECZTRA 6 trial

Abstract Limited treatment options are available for adolescents with moderate-to-severe atopic dermatitis (AD). Tralokinumab is a high-affinity, fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of inflammation in AD. In the phase III ECZTRA 6 trial (NCT03526861), tralokinumab 150 or 300 mg monotherapy every 2 weeks (Q2W) was effective and well tolerated in paediatric patients aged 12–17 years, and tralokinumab 300 mg was recently approved in Europe for the treatment of adolescents with moderate-to-severe AD. To report the efficacy and safety of tralokinumab 300 mg in adolescents with AD over the entire 52-week ECZTRA 6 study period. Patients were randomized to tralokinumab 300 mg Q2W (n = 97) or placebo (n = 94) for 16 weeks. At week 16, patients were initiated on tralokinumab and achieved the primary endpoints (Investigator’s Global Assessment [IGA] 0/1 and/or Eczema Area and Severity Index [EASI]-75), without the use of rescue treatment (topical/systemic AD therapy), were re-randomized to tralokinumab 300 mg Q2W/Q4W monotherapy for 36 additional weeks. During this blinded maintenance period, patients exhibiting a pre-defined relapse relative to their week 16 response were transferred to the open-label arm and treatment with tralokinumab 300 mg Q2W plus optional topical calcineurin inhibitors (TCIs) or topical corticosteroids (TCSs). Patients not achieving the primary endpoints were transferred to the open-label arm at week 16. A pre-specified treatment policy approach for the analyses was adopted using observed data, regardless of rescue medication and treatment discontinuation, to better reflect real-world treatment scenarios. Missing data were imputed using multiple imputations. Treatment differences for the binary endpoints were analysed using the Cochran-Mantel-Haenszel method stratified by region, and baseline IGA. Continuous endpoints were analysed using analysis of covariance accounting for the treatment, region, baseline IGA and baseline outcome value. Post-hoc analyses were conducted by pooling week 16–52 data for all patients initially randomized to tralokinumab 300 mg Q2W, irrespective of the response achieved at week 16, the dosing regimen received beyond week 16, or whether discontinuing treatment before week 16. At week 16, greater proportions of tralokinumab-treated patients (300 mg Q2W vs. placebo) achieved EASI-75 (38.4% vs. 23.5%; difference 15.4% [standard error, SE 6.53%]; P = 0.0186) and EASI-90 (23.9% vs. 10.4%, difference 13.6% [SE 5.55%]; P = 0.0142). Pooling all patients initially randomized to tralokinumab 300 mg Q2W and subsequently continuing on Q2W/Q4W monotherapy or Q2W plus optional TCI/TCS, response rates increased to 68.8% (EASI-75) and 42.8% (EASI-90) at week 52. Similarly, mean [SE] EASI and SCORing AD (SCORAD) improved with tralokinumab vs. placebo (EASI: 59.62% [4.36%] vs. 37.90% [5.16%]; P = 0.0006 and SCORAD: 43.72% [3.13%] vs. 24.91% [3.31%]; P < 0.0001) at week 16, with further improvement to 77.95% [2.96%] and 60.77% [2.81%] at week 52, respectively. Cumulative proportions of patients using concomitant TCI/TCS as rescue therapy during the first 16 weeks were lower with tralokinumab (29.9%) vs. placebo (54.3%). Over 52 weeks, the cumulative proportion of tralokinumab-treated patients using TCI/TCS increased to 47.4%, as TCI/TCS was permitted as optional concomitant medication in the open-label arm. Through week 16, proportions of patients with ≥1 adverse event (AE) were (tralokinumab 300 mg vs. placebo) 64.9 vs. 61.7%; ≥1 serious AE, 1.0 vs. 5.3%; AEs leading to discontinuation, 0% vs. 0%. The number of patients with conjunctivitis (incl. bacterial and allergic) was low (3.1% vs. 2.1%). The safety profile of tralokinumab 300 mg through week 52 was consistent with that at week 16. At week 16, tralokinumab 300 mg improved the extent and severity of AD compared with a placebo in adolescent patients with moderate-to-severe AD. Response rates progressively improved with continued tralokinumab plus optional TCS/TCI. Tralokinumab was well tolerated with a reassuring long-term safety profile over 52 weeks.

Fatigue crack-propagation law of diaphragm-to-rib welded joint in steel bridge deck

The crack-growth characteristics at different lengths are diverse, while blind maintenance for cracks cannot achieve satisfactory arresting effect. By carrying out numerical simulation and fatigue tests of diaphragm-to-rib welded joint (DU) specimens, the crack-growth rates, morphology and stress state at the crack tip were explored. The crack-growth process was segmented and reasonable maintenance occasions for DU cracks were proposed. The result shows that the oblique DU crack is affected by in-plane shear under out-of-plane deformation of diaphragm, driving the crack to grow to the horizontal. The DU crack presents the three-stage characteristics of fast-slow-rapid growth with the approximate demarcations of 8 mm and 40 mm. It is recommended to carry out maintenance in the first two stages to avoid entering the third rapid-growth stage. Combined with the applicability of maintenance technologies, classified maintenance methods of ICR, drilling and bolt reinforcement were proposed for cracks in three stages, respectively.

MIRIKIZUMAB REDUCES ABDOMINAL PAIN IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE

Abstract BACKGROUND Mirikizumab (miri), an anti-IL-23p19 inhibitor, has demonstrated efficacy in patients with ulcerative colitis and moderately to severely active Crohn’s disease (CD) in a Phase 2, randomised, double-blind, placebo-controlled study (NCT02891226). This analysis evaluated the effect of miri versus placebo (PBO) on worst abdominal pain (AP) utilising an 11-point AP Numeric Reporting Scale (AP NRS). METHODS During induction, patients were randomised 2:1:1:2 to receive PBO, 200mg, 600mg, or 1000mg miri administered intravenously (IV) every four weeks (Q4W). At week (W)12, patients entered a blinded maintenance treatment. Patients who received miri during induction and achieved ≥1 point improvement in Simple Endoscopic Score for Crohn’s Disease (SES-CD) at W12 were randomised 1:1 to either continue induction treatment (IV 200mg, 600mg, 1000mg miri Q4W) or receive 300mg miri Q4W administered subcutaneously (SC) for 40W (maintenance). Because of small patient numbers, the randomised maintenance groups results were combined for those who continued the same IV induction treatment (All IV-C) and those who were randomised to SC treatment (All SC). SES-CD non-improvers (NI/1000mg IV Miri) and patients who received PBO (PBO/1000mg IV Miri) during induction received 1000mg miri IV Q4W during maintenance. Patients recorded “worst AP in the past 24 hours” each day using an 11-point AP NRS (0=no pain to 10=worst possible pain) on an electronic diary. The Pain NRS is a valid, reliable, and responsive patient reported outcome that can be used to assess pain among patients with CD. Weekly average score was calculated and compared to placebo using a mixed model for repeated measures (MMRM) for visits in the induction period. Observed change in Pain NRS is presented for maintenance. RESULTS Significant reduction in AP NRS was reported by patients treated with 600mg miri compared to patients treated with placebo at W8 (least square mean difference ± standard error [95% confidence interval]: -1.01 ± 0.4 [-1.87, -0.14], p=0.02) (Table 1) and in all miri treatment groups: 200mg (-0.92 ± 0.4 [-1.80, -0.03], p=0.04), 600mg (-1.23 ± 0.4 [-2.11, -0.36], p=0.006) and 1000mg (-0.86 ± 0.4 [-1.57, -0.15], p=0.02) miri versus PBO at W12 (Table 1). Patients who received miri during induction continued to show improvements at W52 (Table 1). Patients treated with PBO/1000mg IV during maintenance reported similar improvements to patients who received miri from W0-52 (Table 1). CONCLUSION Using an 11-point Abdominal Pain Numeric Reporting Scale, mirikizumab treatment was associated with statistically significant improvements in abdominal pain when compared to placebo after 12 weeks in patients with moderately to severely active Crohn’s disease. Additional numeric reductions in abdominal pain were observed through 52 weeks in all mirikizumab treated patient groups.

DOP16 An evaluation of the exposure–efficacy relationship for subcutaneous vedolizumab maintenance treatment of Crohn’s disease: Pharmacokinetic findings from VISIBLE 2

Abstract Background The exposure–efficacy relationship and immunogenicity rates of the new vedolizumab subcutaneous (SC) formulation have been established for maintenance treatment of ulcerative colitis (UC).1 Here, we report vedolizumab SC exposure–efficacy and immunogenicity in Crohn’s disease (CD). Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a pivotal, phase 3, randomised, double-blind, placebo-controlled trial evaluating the efficacy and safety of vedolizumab SC (108 mg every 2 weeks) as maintenance treatment in patients with moderately to severely active CD. Following intravenous (IV) vedolizumab (300 mg Week 0 and 2) induction, patients with a clinical response at Week 6 (≥70-point decrease in CD activity index [CDAI] from Week 0) were randomised to blinded maintenance treatment and included in the analyses. Vedolizumab serum concentrations were measured prior to dosing using an enzyme-linked immunosorbent assay. Immunogenicity was assessed with a drug-tolerant electrochemiluminescence assay. Predicted vedolizumab trough concentrations at Week 52 were grouped by quartiles (Q), and Week 52 efficacy outcome rates calculated for each Q. Missing efficacy outcome data were imputed as failures. Efficacy outcomes were clinical remission (CDAI ≤150) and enhanced clinical response (≥100-point decrease in CDAI from Week 0 at Week 52). Results Following vedolizumab IV induction (N = 644), patients with a clinical response were randomised and received vedolizumab SC (N = 275) or placebo (N = 134) as maintenance treatment. At Week 52, patients on vedolizumab SC maintenance had a positive exposure–efficacy relationship for clinical remission (Q1: 37.7%; Q4: 50.7%) and enhanced clinical response (Q1: 37.7%; Q4: 53.6%; Figures 1 and 2). Overall, 7/275 (2.5%) patients on vedolizumab SC (following vedolizumab IV induction) developed anti-vedolizumab antibodies (AVAs): 3/7 patients were persistently AVA positive and 4/7 had neutralising antibodies. Five of 7 AVA-positive patients on vedolizumab SC did not achieve clinical remission and enhanced clinical response at Week 52; 2 of those patients were persistently AVA-positive. Immunogenicity was not associated with injection-site reactions or hypersensitivity reactions. Conclusion These preliminary results suggest a trend for higher vedolizumab SC serum concentrations with greater efficacy in CD, but the association was less pronounced than was reported in UC. (1) The AVA rate was similar to what was observed in prior vedolizumab IV studies. (2) In this study, vedolizumab immunogenicity appeared to be associated with clinical outcome. References

Sustained response with ixekizumab treatment of moderate-to-severe psoriasis with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, UNCOVER-3)

Background: Scalp is a frequently affected and difficult-to-treat area in psoriasis patients.Objective: We assessed the efficacy of ixekizumab in the treatment of patients with scalp psoriasis over 60 weeks using the Psoriasis Scalp Severity Index (PSSI).Methods: In three Phase 3, multicenter, double-blind, placebo-controlled trials, patients with moderate-to-severe psoriasis in UNCOVER-1 (N = 1296), UNCOVER-2 (N = 1224) and UNCOVER-3 (N = 1346) were randomized to subcutaneous 80 mg ixekizumab every two weeks (Q2W) or every four weeks (Q4W) after a 160 mg starting dose, or placebo through Week 12. Additional UNCOVER-2 and UNCOVER-3 cohorts were randomized to 50 mg bi-weekly etanercept through Week 12. Patients entering the open-label long-term extension (LTE) (UNCOVER-3) received ixekizumab Q4W; UNCOVER-1 and UNCOVER-2 included a blinded maintenance period in which static physician global assessment (sPGA) 0/1 responders were re-randomized to placebo, ixekizumab Q4W, or 80 mg ixekizumab every 12 weeks (Q12W) through Week 60.Results: In patients with moderate-to-severe psoriasis with baseline scalp involvement, PSSI 90 and 100 were achieved at Week 12 in higher percentages of patients treated with ixekizumab Q2W (81.7% and 74.6%) or ixekizumab Q4W (75.6% and 68.9%) compared with patients treated with placebo (7.6% and 6.7%; p < .001 each ixekizumab arm versus placebo) or etanercept (55.5% and 48.1%; p < .001 each ixekizumab arm versus etanercept). These outcomes were maintained through Week 60 of the maintenance (UNCOVER-1 and UNCOVER-2) and LTE (UNCOVER-3) period in patients who continued on ixekizumab Q4W.Conclusion: Ixekizumab was efficacious in treating scalp psoriasis in patients with moderate-to-severe psoriasis, with most patients achieving complete or near-complete resolution of scalp psoriasis and maintaining this response over 60 weeks.

Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study)

ObjectiveThe phase III IUNO trial assessed the benefit of maintenance erlotinib versus erlotinib at progression in advanced/metastatic non-small-cell lung cancer (NSCLC) that had not progressed following four cycles of platinum-based chemotherapy. Materials and MethodsPatients had stage IIIB/IV NSCLC, no known epidermal growth factor receptor (EGFR)-activating mutation, and objective response or disease stabilization after platinum-based induction chemotherapy. Central EGFR-mutation testing was undertaken on tumors from patients with unknown or wild-type EGFR status following local testing. Patients were randomized to receive blinded maintenance erlotinib 150mg/day (‘early erlotinib’) or placebo. Those who progressed on placebo received open-label erlotinib (‘late erlotinib’); patients who progressed on erlotinib received approved second-line chemotherapy or best supportive care. Primary endpoint: overall survival (OS). Results643 patients were randomized to receive maintenance erlotinib (n=322) or placebo (n=321). As of March 23, 2015, 242 (75.2%) OS events had occurred with ‘early erlotinib’ versus 235 (73.2%) with ‘late erlotinib’. Median OS was 9.7 and 9.5 months with ‘early erlotinib’ and ‘late erlotinib’, respectively (HR, 1.02, 95% CI: 0.85–1.22; log-rank p=0.82). No progression-free survival, objective response rate, or disease control rate benefit was observed with maintenance erlotinib. 410 patients entered the second-line phase of the study: 160 patients (50%) from the maintenance erlotinib arm and 250 patients (78%) from the maintenance placebo arm. The pattern of adverse events (AEs) was consistent with previous trials; 11 patients who received blinded erlotinib and 3 who received placebo died during the blinded maintenance phase due to nontreatment-related AEs. ConclusionsOS with maintenance erlotinib was not superior to second-line treatment in patients whose tumor did not harbor an EGFR-activating mutation. Safety results were consistent with the established safety profile of erlotinib. Thus, maintenance treatment with erlotinib in patients with advanced/metastatic NSCLC without EGFR-activating mutations is considered unfavorable.

Maintenance of Blinding in Clinical Trials and the Implications for Studying Analgesia Using Cannabinoids.

The design of analgesic clinical trials invariably involves a comparison between placebo and active study medication. An assumption is made that treatment effects can be approximated by subtracting the response to placebo from that attained with the use of active study medication. However, the psychoactivity of cannabinoids may unmask their presence and lead to an expectation and/or conditioning of pain relief. For example, study participants biased toward the belief that cannabis is beneficial for their condition might be more inclined to report positive effects if they were to accurately identify the active treatment because of its psychoactivity. This may lead to incorrect assumptions regarding the efficacy of a cannabinoid. Methodologies designed to counteract unmasking need to be implemented in the design phase of a study. During the clinical trial, it is also important to query participants as to which treatment they believe they have received. Blinding can be considered to be preserved when the accuracy of treatment guesses is not considerably different than random guessing, which is estimated to be correct 50% of the time. After a study has been completed, the use of statistical methodologies such as regression and mediation analysis are worthy of consideration to see whether psychoactive effects biased the results.

Effect of Disease Duration on “Deep Remission”: Results from the EXTEND Trial

Purpose: Adalimumab (ADA) therapy in patients with shorter Crohn's disease (CD) duration appears to be associated with improved clinical outcomes and less side effects in the CHARM trial.1 We investigated the relationship between CD duration and response to ADA in the EXTEND trial. Methods: EXTEND was a placebo (PBO)-controlled study of moderate to severe CD patients with baseline mucosal ulceration. Patients received openlabel ADA 160/80 mg induction therapy at Weeks 0/2 and were randomized at Week 4 to blinded maintenance therapy with ADA 40 mg every other week or PBO through Week 52. Effects of CD duration (≤2, >2-≤5, >5 years) on deep remission (defined as complete mucosal healing and clinical remission [CDAI <150]) was compared at Week 52 for ADA and PBO-treated patients from the intention-to-treat population. Results: Of 129 patients randomized at Week 4 (64, ADA; 65, PBO), CD duration was ≤2 years for 18 patients (14%), >2-≤5 years for 26 patients (20%), and >5 years for 85 patients (66%). An overall significant effect of ADA therapy vs. PBO was shown on deep remission after stratifying by CD duration (Table, CMH test). Because of small sample size for patients with shorter CD duration, patients from the <2 and >2-≤5 groups were pooled. The rate of deep remission with ADA was significantly higher than PBO in patients within each CD duration ≤5 and >5 years (p=0.009 and 0.008, respectively, Chi-square test). There was a numerical trend for a relationship between rates of deep remission and CD duration with ADA therapy (Table), but no statistical significance. Conclusion: ADA maintenance therapy led to higher rates of deep remission compared to PBO in patients regardless of CD duration. There was a trend for higher rates of deep remission with shorter CD duration with ADA therapy, which was not statistically significant, likely because of small sample size. Reference: 1. Schreiber S et al. Early Crohn's Disease Shows High Levels of Remission to Therapy With Adalimumab: Sub-analysis of CHARM. Abstract: Presented at Digestive Diseases Week, 2007. Disclosure: Dr Colombel - Advisory Committees or Review Panels: Abbott, AstraZeneca Pharmaceuticals LP, Centocor, Inc, Danone Research, Elan Pharmaceuticals, Inc, Millennium Research Group, Schering-Plough Corp, UCB, Inc; Consulting: Abbott, ActoGeniX, Albireo Pharma: Consulting, AstraZeneca Pharmaceuticals LP, Bayer AG, Biogen Idec, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Cellerix SL, Centocor, Inc., Chemocentryx, Cosmo Technologies Ltd, Danone Research, Elan Pharmaceuticals, Inc., Genentech Inc., Giuliani SpA, Given Imaging, GlaxoSmithKline, Hutchison MediPharma Limited, Milan, Millennium Research Group, Ocera Therapeutics, Inc., Pfizer Inc,, Schering-Plough Corp., UCB, Inc.; Speaking and Teaching: Abbott, Centocor, Inc, Elan Pharmaceuticals, Inc, Given Imaging Dr Schreiber - Financial support for research: UCB; Lecture fee(s): Abbott, Essex; Consultancy: Abbott, Schering-Plough Dr Rutgeerts - Consulting: Abbott, Actogenics, Bristol-Myers Squibb Co., Centocor, Inc., Genentech Inc., Italfarmako, Millennium Research Group, NovImmune, Schering-Plough Corp., UCB Pharma; Grant/Research Support: Abbott, Centocor, Inc, Schering-Plough, UCB Pharma Dr Sandborn - Financial Support for Research: Abbott Laboratories, Bristol Meyers Squibb, CentocorOrthoBiotech, Genentech, Millennium Pharmaceuticals, Novartis, Pfizer, Shire Pharmaceuticals, UCB Pharma, Warner Chilcott (previously Procter & Gamble); Consultancy: ActoGenix, Abbott Laboratories (fees paid to Mayo), AGI Therapeutics, Albireo, Alfa Wassermann, AM-Pharma, Amgen, Anaphore, Astellas Pharma, Athersys, Atlantic Healthcare Limited, Axcan Pharma, BioBalance Corporation, Celegene, Bristol Meyers Squibb (fees paid to Mayo), Celek Pharmaceuticals, Cellerix, CentocorOrthoBiotech (fees paid to Mayo), Chemocentryix, CoMentis, Cosmo Technologies, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research, Elan Pharmceuticls (fees paid to Mayo), Eli Lilly, Enteromedics, Ferring Pharmaceuticals, Flexion Therapeutics, Funxional Therapeutics Limited, Genentech (fees paid to Mayo), Given Imaging, GlaxoSmithKline, KaloBios Pharmaceuticals, Merck Research Laboratories, Merck Serono, Novo Nordisk, Pfizer (fees paid to Mayo), Procter & Gamble (fees paid to Mayo), Purgenesis Technologies, Regeneron Pharmaceuticals, Salient Pharmaceuticals, Salix Pharmaceuticals, Santarus, Schering Plough Corporation, Shire Pharmaceuticals (fees paid to Mayo), Sigmoid Pharma, Sitrtis Pharmaceuticals, SLA Pharma, Takeda (fees paid to Mayo), Tillotts Pharma, UCB Pharma (fees paid to Mayo), Vascular Biogenics, Viamet Pharmaceuticals, Wyeth Drs Yang, Lomax, Pollack, Thakkar, Camez, Huang, Zhou, Mulani, Chao - Employment: Abbott; Shareholder: Abbott. This research was supported by an industry grant from Abbott.Table

The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design.

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9-17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for 2 years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of 200. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity (ClinicalTrials.gov number, NCT00006400).

Relationship of open acute mania treatment to blinded maintenance outcome in bipolar I disorder

BackgroundMost bipolar treatment guidelines recommend that acutely effective therapy be continued as maintenance treatment, unless contraindicated. No published studies have statistically evaluated the relationship between the outcomes in maintenance treatment and the principal acute agent. MethodsPost-hoc analysis of prophylactic results obtained during a 12-month maintenance study in recently manic patients assessed the relationship between open treatment and randomized maintenance treatment. Patients were grouped according to mood stabilizer (if any) received on the last day of the open-label, stabilization phase (divalproex, lithium, or no mood stabilizer), and the mood stabilizer to which they were randomly assigned in the double-blind, maintenance phase (divalproex, lithium, or placebo). ResultsPatients treated with open-phase divalproex and randomized to divalproex maintenance therapy had a significantly longer period before development of a mood episode compared to those randomized to either placebo (Log-rank, p=0.05) or lithium (Log-rank, p=0.04), and better tolerability than those randomized to lithium. Patients treated with open-phase lithium showed no treatment-related differences in time to a mood episode after being randomized to lithium, divalproex, or placebo and tolerability was comparable in all groups. LimitationsOpen treatment was selected by treating physicians, contributing to possible selection bias. More patients were randomized to divalproex than to lithium or placebo. The study was therefore better powered to detect divalproex effects. ConclusionsAcute response to divalproex predicted both superior prophylactic response and tolerability to divalproex, than to placebo (efficacy) and to lithium (efficacy and tolerability). Results could have implications for both clinical practice and clinical trial design.

Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience

Limited placebo-controlled data are available to assess the long-term fracture efficacy of bisphosphonates. In order to determine the effects of 5 years of risedronate treatment, we extended a 3-year, placebo-controlled vertebral fracture study in osteoporotic women for an additional 2 years; women who entered the extension study continued to receive 5 mg risedronate or placebo according to the original randomization, with maintenance of blinding. End points included vertebral and nonvertebral fracture assessments, bone mineral density measurements, and changes in biochemical markers of bone turnover. A total of 265 women (placebo, 130; 5 mg risedronate, 135) entered the study extension and 220 (83%) completed the additional 2 years. Fracture results observed in the study extension were consistent with those observed in the first 3 years. The risk of new vertebral fractures was significantly reduced with risedronate treatment in years 4 and 5 by 59% (95% confidence interval, 19 to 79%, P = 0.01) compared with a 49% reduction in the first 3 years. Rapid and significant decreases in markers of bone turnover observed in the first 3 years were similarly maintained in the next 2 years of treatment. Increases in spine and hip bone mineral density that occurred in the risedronate group during the first 3 years were maintained or increased with a further 2 years of treatment. The mean increase from baseline in lumbar spine BMD over 5 years was 9.3% ( P < 0.001). This study demonstrates that the effects of risedronate over 3 years on vertebral fracture and BMD are maintained with a further 2 years of treatment.

Evidence-based medicine and randomized double-blind clinical trials: a study of flawed implementation.

The randomized double-blind clinical trial (RDBCT) is a key source of information for evidence-based medicine. However, anomalous and unexplainable results have prompted suggestions that 'unknown and unidentifiable biases' may exist. This paper identifies that a possible flaw in the implementation of RDBCTs may account for these biases. The flaw relates to the breaking of the double blind through the generation of beliefs and expectations in experimenters. These, in turn, may lead to unconscious biases in assessment and cues to patients. It is then uncertain how much of an observed effect is due to such expectations or the treatment itself. Therefore, any RDBCT in which the maintenance of blinding is not monitored throughout its course is at risk of its conclusions being compromised. It is not sufficient to assert that blinding must have been maintained through arguments based on design features. The burden of proof is on the researchers to demonstrate, through data, that blinding has been maintained. The need to address social psychological issues in implementing RDBCTs is discussed and it is recommended that to avoid this confound, methods of monitoring and accounting for experimenter beliefs and expectations should be routinely included in future RDBCTs.

Olanzapine: Preclinical and Clinical Profiles of a Novel Antipsychotic Agent

ABSTRACTThe novel antipsychotic agent olanzapine (Zyprexa, Eli Lilly and Company) is a thienobenzodiazepine analog marketed for the treatment of schizophrenia. Olanzapine's diverse receptor binding profile and greater affinity for serotonin receptors over dopamine receptors is thought to impart antipsychotic efficacy with a low incidence of serious extrapyramidal symptoms (EPS). With once daily dosing steady‐state plasma concentrations reached within approximately 1 week. Olanzapine is extensively metabolized by the liver, is mostly excreted in the urine, and has few drug intractions. In clinical trials, the efficacy of olanzapine for treating schizophrenia is better than placebo and haloperidol and comparable to risperidone. Olanzapine may also ameliorate some comorbid symptoms including negative symptoms, depression, anxiety, substance abuse, and cognitive dysfunction, and it is effective in the long‐term maintenance of response, treatment‐resistance, and improving quality of life. The overall direct costs are lower with olanzapine treatment compared with haloperidol or risperidone treatment. In clinical trials, olanzapine demonstrates a favorable safety profile. The most frequently reported treatment‐emergent adverse events are somnolence, schizophrenic reaction, insomnia, headache, agitation, rhinitis, and weight gain. Significantly fewer EPS (based on formal rating scales) and incidences of tardive dyskinesia have been reported for olanzapine compared with haloperidol. Olanzapine has not been associated with persistent elevations of prolactin above the upper limit of normal nor has it been associated with clinically significant changes in cardiac QTc interval. Fewer incidences of suicide attempts have been reported with olanzapine compared with placebo, haloperidol, or risperidone treatments. There is evidence that olanzapine may be effective in the treatment of mood disorders, psychosis associated with Alzheimer's disease, obsessive‐compulsive disorder, pervasive developmental disorders, and delirium. Patients with schizophrenia have been successfully switched from other antipsychotics to olanzapine. In conclusion, olanzapine offers a significantly improved risk‐to‐benefit profile compared with haloperidol and possibly risperidone, and thus should be considered an important treatment option for schizophrenia and related disorders.SUMMARYOlanzapine is an innovative pharmaceutical product that has been prescribed to more than four million individuals worldwide. Olanzapine has a diverse neurotransmitter receptor binding profile that is similar to clozapine, with selective affinity for the serotonin receptors over the dopamine receptors. In vitro and in vivo preclinical experimentation has provided evidence for the antipsychotic efficacy of olanzapine with a low incidence of serious EPS. In addition, olanzapine has a pharmacokinetic profile that allows for single daily dosing and has minimal metabolic interactions with commonly coadministered medications. Through its distinct pharmacology, olanzapine offers patients a significantly improved risk‐benefit profile.Across the diverse series of clinical studies discussed in this review, olanzapine has helped to redefine the expectations for the pharmacotherapy of schizophrenia. Olanzapine (5 to 20 mg/day) has demonstrated an improvement in total psychopathology, which was significantly greater than that seen with placebo or the active comparator, haloperidol. This effect was comprised of at least comparable benefits to haloperidol on positive psychotic symptoms and superior results for the more chronic and disabling features of negative, concurrent anxious and depressive, and cognitive symptoms. This broadened range of treatment‐responsive symptoms is complemented by a greater depth of clinical response as well. Given the historical challenge of compliance with the older antipsychotic drugs, it is also noteworthy that these outcomes were achieved with an adverse event discontinuation rate similar to placebo. Compared with conventional antipsychotic agents, the incidence of troublesome EPS or hyperprolactinemia was low. Studies in special populations (i.e., the geriatric patient) appear to confirm this safety profile.Because schizophrenia is a chronic disease, controlled and blinded maintenance studies showing the superiority of olanzapine to placebo or active comparators (haloperidol, risperidone) are also reassuring, especially in the context of the long‐term safety experience with olanzapine. In particular, data suggesting a lower incidence of potentially irreversible movement disorders, such as tardive dyskinesia, are striking and of importance to treatment decision makers. Moreover, these advantages appear to translate into improved quality of patient life, increased functional well‐being (i.e., return to work), and an overall reduction in the total direct cost of managing schizophrenia.While further studies are ongoing, the data on olanzapine in mood disorders and psychosis associated with Alzheimer's disease are encouraging. Additional studies evaluating olanzapine in nonschizophrenic disorders are awaited. As more “atypical” agents enter the marketplace, head‐to‐head comparisons are encouraged to properly evaluate the relative merits of each compound. Experience to date tells us that the newer agents to treat psychosis are not all alike. Based on the clinical review in this paper, olanzapine does seem to represent a novel and compelling first‐line option for the management of psychotic disorders.

Population pharmacokinetics. A regulatory perspective.

The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants. Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives. The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of 'good pharmacometric practice'. Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data. Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims. The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as 'Guidance for Industry: Population Pharmacokinetics' (see the FDA home page http:/(/)www.fda.gov for further information).