Last Observation Carried Forward Research Articles

Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: the randomized controlled trial of balloon kyphoplasty versus non-surgical care for vertebral compression fracture (FREE)

BackgroundClinical trial participants may be temporarily absent or withdraw from trials, leading to missing data. In intention-to-treat (ITT) analyses, several approaches are used for handling the missing information - complete case (CC) analysis, mixed-effects model (MM) analysis, last observation carried forward (LOCF) and multiple imputation (MI). This report discusses the consequences of applying the CC, LOCF and MI for the ITT analysis of published data (analysed using the MM method) from the Fracture Reduction Evaluation (FREE) trial.MethodsThe FREE trial was a randomised, non-blinded study comparing balloon kyphoplasty with non-surgical care for the treatment of patients with acute painful vertebral fractures. Patients were randomised to treatment (1:1 ratio), and stratified for gender, fracture aetiology, use of bisphosphonates and use of systemic steroids at the time of enrolment. Six outcome measures - Short-form 36 physical component summary (SF-36 PCS) scale, EuroQol 5-Dimension Questionnaire (EQ-5D), Roland-Morris Disability (RMD) score, back pain, number of days with restricted activity in last 2 weeks, and number of days in bed in last 2 weeks - were analysed using four methods for dealing with missing data: CC, LOCF, MM and MI analyses.ResultsThere were no missing data in baseline covariates values, and only a few missing baseline values in outcome variables. The overall missing-response level increased during follow-up (1 month: 14.5%; 24 months: 28%), corresponding to a mean of 19% missing data during the entire period. Overall patterns of missing response across time were similar for each treatment group. Almost half of all randomised patients were not available for a CC analysis, a maximum of 4% were not included in the LOCF analysis, and all randomised patients were included in the MM and MI analyses. Improved estimates of treatment effect were observed with LOCF, MM and MI compared with CC; only MM provided improved estimates across all six outcomes considered.ConclusionsThe FREE trial results are robust as the alternative methods used for substituting missing data produced similar results. The MM method showed the highest statistical precision suggesting it is the most appropriate method to use for analysing the FREE trial data.Trial RegistrationThis trial is registered with ClinicalTrials.gov (number NCT00211211).

Comparison of the effects of aliskiren/valsartan in combination versus valsartan alone in patients with Stage 2 hypertension

The extent to which the combination of a renin inhibitor with an angiotensin receptor blocker (ARB) lowers clinic and ambulatory blood pressure (BP) versus an ARB alone in stage 2 hypertension is not well known. Hence, we performed an 8-week, randomized, double-blind study in 451 patients with stage 2 hypertension to compare the efficacy of the combination of aliskiren/valsartan 300/320 mg versus valsartan 320 mg. The primary endpoint was change in seated systolic BP from baseline to week 8 analyzed on the intent-to-treat (ITT) population using the last-observation-carried-forward (LOCF) approach; patients completing the entire treatment period (per-protocol completers) were similarly analyzed. For the predefined primary analysis, systolic BP reductions for aliskiren/valsartan (n = 230) and valsartan (n = 217) were −22.1 and −20.5 mm Hg, respectively (P = .295). In per-protocol completers, aliskiren/valsartan (n = 201) lowered BP significantly greater than valsartan (n = 196); −23.7 mm Hg versus −20.3 mm Hg, respectively (P = .028). Although limited by a small sample size (n = 76) using ambulatory BP monitoring, aliskiren/valsartan lowered the 24-hour BP significantly more than valsartan alone (−14.6/−9.0 mm Hg versus −5.9/−4.2 mm Hg; P < .01). Safety and tolerability were similar for the two treatment groups. These data demonstrate the importance of multiple modalities to assess BP changes in clinical trials of antihypertensive therapies, particularly in stage 2 hypertension.

Cardiometabolic Complications after Androgen Deprivation Therapy in a Man with Prostate Cancer: Effects of 3 Years Intermittent Testosterone Supplementation

Androgen deprivation therapy (ADT) for prostate carcinoma (PCa) may cause cardiometabolic complications unless intermittent androgen blockade (IAB) is instituted. An 80-year-old caucasian man was diagnosed intermediate grade (Gleason 4 + 3) PCa and was treated with continuous ADT with triptorelin plus bicalutamide. After 6 months of treatment, he experienced an acute myocardial infarction and 1 month after hospitalization he came to our outpatient clinic for fatigue, weight gain, and hyperglycemia. Due to iatrogenic hypogonadism, we decided to proceed with IAB, but after 3 months ADT withdrawal his serum testosterone (T) was still 0.5 ng/mL. Due to very low concomitant PSA levels (0.1 ng/mL) he was then proposed intermittent T-gel supplementation (Tostrex®) which was initiated according to the following scheme: 6 months on and 3 months off. T-gel dose was titrated tri-weekly in order to achieve T plasma levels below 3.49 ng/mL. After 6 months on, his serum T raised to a mean value of about 2.0 ng/mL without increments in PSA. After overall 12 months on, his serum T peaked to a mean value of 3.0 ng/mL while a delay in PSA rise was seen after 24 months (0.6 ng/mL) but remained stable until the last observation carried forward (LOCF), at 45 months. No clinical and biochemical PCa progression were observed at LOCF. Reversion of iatrogenic metabolic syndrome started after 6 months of T supplementation without using any add-on treatment. This case provides support that once regression of PCa growth is attained, T supplementation may be administered in well differentiated PCa, especially if IAB is not successful in reverting iatrogenic hypogonadism and its associated cardiac and metabolic complications.

Atomoxetine treatment for nicotine withdrawal: a pilot double-blind, placebo-controlled, fixed-dose study in adult smokers

BackgroundMany effective treatments for nicotine addiction inhibit noradrenaline reuptake. Three recent studies have suggested that another noradrenaline reuptake inhibitor, atomoxetine, may reduce smoking behaviors.MethodsThe present double-blind, placebo-controlled, fixed-dose study was carried out over 21 days during which administration of 40 mg atomoxetine was compared to placebo in 17 individuals. Of these, nine were randomized to atomoxetine and eight to placebo. Baseline and weekly measurements were made using the Cigarette Dependence Scale (CDS), Cigarette Withdrawal Scale (CWS), Questionnaire of Smoking Urges (QSU), reported number of cigarettes smoked, and salivary cotinine levels.ResultsThe study results showed that all those on placebo completed the study. In marked contrast, of the nine individuals who started on atomoxetine, five dropped out due to side effects. In a completer analysis there were statistically significant differences at 14 and 21 days in several measures between the atomoxetine and placebo groups, including CDS, CWS, QSU, number of cigarettes smoked (decreasing to less than two per day in the treatment group who completed the study), and a trend towards lower mean salivary cotinine levels. However, these differences were not seen in a last observation carried forward (LOCF) analysis.ConclusionsIn summary, this is the first study to examine the use of atomoxetine in non-psychiatric adult smokers for a period of more than 7 days, and the findings suggest that atomoxetine might be a useful treatment for nicotine addiction. However, the dose used in the current study was too high to be tolerated by many adults, and a dose-finding study is required to determine the most appropriate dose for future studies of this potential treatment for smoking cessation.

P-1074 - Efficacy of venlafaxine compared with selective serotonin reuptake inhibitors (SSRI) in severe major depressive disorder (MDD): a retrospective pooled analysis

Introduction/objective There are no data on the comparative efficacy of venlafaxine to other SSRI's in severe MDD. Methods In a post hoc analysis, data were pooled from 8 double-blind active controlled studies in outpatients with a diagnosis of MDD. Patients randomly assigned to venlafaxine (dose range 75-225 mg) or SSRI (fluoxetine (20–80 mg/day), fluvoxamine (100 mg/day), or paroxetine (20 mg/day)) were included in the analysis. Severe MDD was defined as baseline HAM-D 17 >24 and alternatively as baseline MADRS≥ 31. Treatment groups were compared by mean improvement in the 17-item Hamilton Rating Scale for Depression (HAM-D 17 ) (and alternatively MADRS) scores from baseline to last observation carried forward (LOCF). Secondary outcomes included HAM-D 17 response (≥50% reduction in HAM-D 17 ) and remission (HAM-D 17 ≤7) rates, MADRS response (≥50% reduction in MADRS) and remission (MADRS≤10). Changes from baseline for the primary end point were evaluated using analysis of covariance with treatment, study, and baseline in the model. Results A total of 1503 patients were included in the analysis (venlafaxine n = 805; SSRI, n = 698); 649/1503 (43%) patients had severe depression (HAM-D 17 >24) at baseline. Venlafaxine improved HAM-D 17 scores vs. SSRI in patients with severe MDD (venlafaxine, −15.26 [0.73]; SSRI, −12.91 [0.81]; P = 0.003). Response and remission were significantly higher in venlafaxine compared with SSRI (Response: Venlafaxine = 63% vs SSRI= 53% (p = 0.004); Remission: 41% vs. 31% (p = 0.005)). The results of the analyses were similar when baseline severity was defined by MADRS scores. Conclusions In this retrospective pooled analysis, venlafaxine was superior to SSRI's in treating severe MDD.

A randomised, double-blind, placebo controlled, duloxetine-referenced, fixed-dose study of three dosages of Lu AA21004 in acute treatment of major depressive disorder (MDD)

The efficacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with DSM-IV-TR diagnosed major depressive disorder (MDD) were evaluated in this 8-week, multi-site study. Patients (n=766) had a baseline Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26 and were randomly assigned (1:1:1:1:1) to 2.5, 5 or 10mg Lu AA21004, placebo, or 60mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specified order. In the pre-defined primary efficacy analysis [mean change from baseline in MADRS total score at Week 8, full analysis set, ANCOVA, last observation carried forward (LOCF)], the differences to placebo (n=145) of −1.7 (Lu AA21004 5mg, n=155) and −1.5 points (Lu AA21004 10mg, n=151) were not statistically significant; nor were those for Lu AA21004 2.5mg (−1.4 points, n=155) or duloxetine (−2.0 points, n=149). Using mixed model, repeated measures (MMRM) analyses of the primary endpoint and most secondary endpoints were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Treatment-emergent adverse events led to the withdrawal of 72 patients: 8% (placebo), 12% (duloxetine), and 6%, 11% and 9% in the Lu AA21004 groups (2.5mg, 5mg and 10mg, respectively). The most common adverse events were nausea, headache, dizziness, and dry mouth. No clinically relevant changes were seen in vital signs, weight, ECG, or laboratory results. In summary, none of the active treatment groups, including duloxetine, separated from placebo in the primary analysis in this 'failed' study. Findings on secondary outcome measures, using MMRM instead of LOCF, were supportive of likely efficacy for Lu AA21004 5mg and 10mg and duloxetine. Lu AA21004 (2.5, 5 and 10mg) was well tolerated.

Move over LOCF: Principled methods for handling missing data in sleep disorder trials

Missing data, e.g. patient attrition, are endemic in sleep disorder clinical trials. Common approaches for dealing with this situation include complete-case analysis (CCA) and last observation carried forward (LOCF). Although these methods are simple to implement, they are deeply flawed in that they may introduce bias and underestimate uncertainty, leading to erroneous conclusions. There are alternative principled approaches, however, that are available in statistical software namely mixed-effects models and multiple imputation. In this paper we introduce terminology used to describe different assumptions about missing data. We emphasize that understanding reasons for missingness is a critical step in the analysis process. We describe and implement both linear mixed-effects models and an inclusive multiple imputation strategy for handling missing data in a randomized trial examining sleep outcomes. These principled strategies are compared with "complete-case analysis" and LOCF. These analyses illustrate that methodologies for accommodating missing data can produce different results in both direction and strength of treatment effects. Our goal is for this paper to serve as a guide to sleep disorder clinical trial researchers on how to utilize principled methods for incomplete data in their trial analyses.

Effects of escitalopram on sleep problems in patients with major depression or generalized anxiety disorder

Disturbed sleep is a key symptom in major depressive disorder (MDD) and generalized anxiety disorder (GAD). First-line antidepressants, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs), may have different effects on sleep. Data from 22 randomized, controlled trials comparing escitalopram with SSRIs, SNRIs, or placebo in the treatment of adult MDD or GAD were included. Both last observation carried forward (LOCF) and repeated measurements (MMRM) were used to analyze the sleep item of the Montgomery Åsberg Depression Rating Scale (MADRS) or Hamilton Anxiety Rating Scale (HAM-A) after 8 weeks of treatment. Sleep-related treatment-emergent adverse events were also compared across groups. For patients with MDD (n = 5133), the treatment difference on MADRS item 4 ("reduced sleep") was significantly in favor of escitalopram versus placebo (LOCF [P = 0.0017] and MMRM [P = 0.0002]), versus SSRIs (LOCF [P = 0.0020] and MMRM [P < 0.0031]), and versus SNRIs (LOCF [P = 0.0002] and MMRM [P = 0.0352]). For the 53% of patients with MDD who suffered from sleep problems at baseline (baseline MADRS item 4 score ≥ 4), the improvement in sleep symptoms was significantly in favor of escitalopram versus placebo (LOCF [P = 0.0022] and MMRM [P < 0.0005]), versus SSRIs (LOCF [P = 0.0001] and MMRM [P = 0.0002]), and versus SNRIs (LOCF [P < 0.0067] but not MMRM [P > 0.0787]). For patients with GAD (n = 2052) the treatment difference in sleep symptoms measured by HAM-A item 4 ("insomnia") was significantly in favor of escitalopram versus placebo (LOCF [P = 0.0005] and MMRM [P < 0.0001]), but not different to paroxetine or venlafaxine. The same pattern was seen for the large proportion (67%-82%) of GAD patients reporting sleep problems at baseline (baseline HAM-A item 4 score ≥ 2). In MDD, the rate of insomnia as an adverse event after escitalopram was higher than placebo, similar to SSRIs, and lower than SNRIs. Additional research assessing the comparative effects of antidepressants with polysomnography is needed. In the interim, from a clinical perspective, escitalopram appears to be beneficial for the treatment of sleep problems in MDD and GAD.

Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: Reply to Costa et al.

Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: Reply to Costa et al.

Combining escitalopram with gaboxadol provides no additional benefit in the treatment of patients with severe major depressive disorder

The aim of this proof-of-concept study was to compare the efficacy of escitalopram (20 mg/d) in combination with fixed doses of gaboxadol to escitalopram (20 mg) in the treatment of patients with severe major depressive disorder (MDD). Adult patients were randomized to 8 wk of double-blind treatment with fixed doses of placebo (n=71), escitalopram (20 mg, n=140), escitalopram (20 mg)+gaboxadol (5 mg) (n=139), or escitalopram (20 mg)+gaboxadol (10 mg) (n=140). The pre-defined primary analysis of efficacy was an analysis of covariance (ANCOVA) of change from baseline to endpoint (week 8) in Montgomery-Åsberg Depression Rating Scale (MADRS) total score using last observation carried forward (LOCF). There was no statistically significant difference in the mean change from baseline in MADRS total score between the 20 mg escitalopram+10 mg gaboxadol group and the 20 mg escitalopram group [difference=-0.45 MADRS points (95% CI -2.5 to 1.6, p=0.6619, full analysis set (FAS), LOCF, ANCOVA)] at week 8. The mean treatment differences to placebo at week 8 were -5.6 (95% CI -8.0 to -3.1, p<0.0001) (20 mg escitalopram), -5.1 (95% CI -7.5 to -2.7, p<0.0001) (20 mg escitalopram+5 mg gaboxadol), and -6.0 (95% CI -8.4 to -3.6, p<0.0001) (20 mg escitalopram+10 mg gaboxadol). The most common adverse events reported in the active treatment groups for which the incidence was higher than that in the placebo group, comprised nausea, anxiety and insomnia. There were no clinically relevant efficacy differences between a combination of escitalopram and gaboxadol compared to escitalopram alone in the treatment of severe MDD. All active treatment groups were superior in efficacy to placebo and were well tolerated.

Pharmacological Treatment of Bipolar Depression: Qualitative Systematic Review of Double-Blind Randomized Clinical Trials

Randomized clinical trial (RCT) is the best study design for treatment-related issues, yet these studies may present a number of biases and limitations. The objective of this study is to carry out a qualitative analysis of RCT methodology in the treatment of bipolar depression (BD). A systematic review covering the last 20 years was performed on PubMed selecting double-blind RCTs for BD. The identification items of the articles, their design, methodology, outcome and grant-related issues were all analyzed. Thirty articles were included, all of which had been published in journals with an impact factor >3. While almost half studies (46.7%) used less than 50 patients as a sample, 70% did not describe or did not perform sample size calculation. The Last Observation Carried Forward (LOCF) method was used in 2/3 of the articles and 53.4% of the studies had high sample losses (>20%). Almost half the items were sponsored by the pharmaceutical industry and 33.3% were sponsored by institutions or research foundations. Articles on the pharmacological treatment of BD have several limitations which hinder the extrapolation of the data to clinical practice. Methodological errors and biases are common and statistical simplifications compromise the consistency of the findings.

Bayesian Optimal Adaptive Designs for Delayed-Response Dose-Finding Studies

Bayesian adaptive design has been broadly recognized as a method of improving the efficiency of determining dose-response relationships in clinical trials, thus leading to reliable dose selection for phase III clinical trials. However, in some disease areas such as diabetes and obesity, patients may need to be studied for several weeks or months for a drug effect to emerge. These delayed-response studies provide challenges for using traditional adaptive design methods. Many current methods for analyzing the data at the time of the interim analysis only use the last observation from patients who have completed the study. Data for those patients who have not completed the study are often ignored or imputed via last observation carried forward (LOCF) or other imputation method. Therefore, data collected at intermediate timepoints are not fully used for decision making. These approaches are useful for studies where the final responses can be quickly observed. However, in delayed-response studies, where longitudinal data are normally collected for each patient, using all available information instead of just endpoint values is critical to improving efficiency. Fu and Manner (2010) proposed an integrated two-component prediction (ITP) model for delayed-response adaptive design. In this paper, we extend their ITP model to incorporate a dose-response model in it and propose an ITP Emax model. Furthermore, we derive a method to find the minimum effective dose (MED) for our newly proposed model by using an optimal design theorem. By using the proposed method, a better understanding of the dose-response relationship and the MED was achieved more efficiently. Potential sample size reduction is also discussed in this paper.

P.2.e.023 Long -term metabolic effects of aripiprazole adjunctive to lithium, valproate or lamotrigine

Introduction: Bipolar disorder patients are often overweight or obese, and likely to meet criteria for metabolic syndrome, placing them at increased risk of developing cardiovascular disease, stroke and type 2 diabetes. Moreover, several medications used to treat bipolar disorder pose hazards for increasing body weight and worsening metabolic parameters. Methods: This was a post-hoc analysis of metabolic data from two separate randomised, double-blind, placebo-controlled trials that tested efficacy of aripiprazole (ARI) in combination with mood stabilisers lithium or valproate (LI/VAL) (CN138-189), or lamotrigine (LTG) (CN138-392), in the long-term treatment (52 weeks) of patients with bipolar disorder. Changes in body weight (kg) were compared between treatment groups using analysis of covariance on the last observation carried forward (LOCF) and observed case (OC) datasets. Median change in fasting metabolic parameters (glucose, high-density lipoprotein-cholesterol [HDL-C], low-density lipoprotein-cholesterol [LDL-C], total cholesterol and triglycerides) were compared using the Wilcoxon Rank Sum Test stratified by mood stabiliser. Results: In both studies most patients were overweight/obese at baseline (body mass index ≥25 kg/m): CN138-189: placebo (PLB)+LI/ VAL 62.7% vs. ARI+LI/VAL 70.8%; CN138-392: PLB+LTG 71.6% vs. ARI+LTG 71.9%. Mean weights at baseline were: CN138-189: PLB+LI/ VAL 81.3 kg vs. ARI+LI/VAL 80.2 kg; CN138-392: PLB+LTG 88.2 kg vs. ARI+LTG 84.5 kg. Changes in weight and metabolic parameters over the 52-week treatment period are shown below.

P4‐230: Substituting placebo in long‐term trials with pre‐symptomatic Alzheimer's disease patients: The placebo group simulation approach (PGSA)

Background: Top-line results of a 24-week, multinational, randomized, placebo-controlled trial in patients with moderate to severe Alzheimer’s disease (AD) receiving stable concurrent cholinesterase inhibitor treatment (MEM-MD-50, NCT00322153) demonstrated the efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) on primary outcome measures (SIB and CIBIC-plus), as well as on the NPI and a verbal fluency test. In this post-hoc analysis, we examined the effects of memantine ER on individual SIB domains, as well as on aggregated domains defined previously (Schmitt et al., 2006). Methods: Treatment groups were compared in terms of mean change from Baseline at Endpoint for nine SIB domains (Social Interaction, Memory, Orientation, Language, Attention, Praxis, Visuospatial Ability, Construction, and Orienting to Name) and combinations of domains aggregated using a face-valid approach into three higher-order subscales: MEMORY (memory, attention, orientation, orienting to naming), LANGUAGE (language, social interaction), and PRAXIS (praxis, visuospatial ability, construction). Between-group comparisons were based on the intent-to-treat population (placebo: n 1⁄4 328; memantine ER: n 1⁄4 333) and performed by means of an ANCOVAmodel with treatment group and study center as factors and baseline value as covariate, using observed cases (OC) and the last observation carried forward (LOCF) approach to missing data. In addition, a mixed-effects model with repeated measures (MMRM) that included terms for treatment group, visit, treatment-by-visit interaction, baseline score, baseline-by-treatment interaction, and center was used to compare the groups across the entire trial. No adjustments for multiple comparisons were made. Results: Significant advantage of memantine ER over placebo was observed for the domains of Memory (OC, P 1⁄4 0.021; LOCF, P 1⁄4 0.016; MMRM, P 1⁄4 0.008), Language (OC, P 1⁄4 0.003; LOCF, P 1⁄4 0.004; MMRM, P 1⁄4 0.001), Attention (OC, P 1⁄4 0.014; LOCF, P 1⁄4 0.003; MMRM, P 1⁄4 0.004), Praxis (OC, P 1⁄4 0.015; LOCF, P 1⁄4 0.002; MMRM, P 1⁄4 0.002), Orientation (LOCF, P 1⁄4 0.043; MMRM, P 1⁄4 0.028), and Construction (OC, P 1⁄4 0.042), and for all three higher-order subscales (MEMORY: OC, P 1⁄4 0.002; LOCF, P 1⁄4 0.003; MMRM P < 0. 001; LANGUAGE: OC, LOCF, P 1⁄4 0.003; MMRM, P 1⁄4 0.001; PRAXIS: OC, P 1⁄4 0.012; LOCF, P 1⁄4 0.004; MMRM, P 1⁄4 0.004). Conclusions: In this post-hoc analysis, memantine ER was associated with significant improvement relative to placebo on several cognitive domains, including memory, language, praxis, and attention.

PMS70 A COMPARISON OF NON-RESPONDER IMPUTATION AND LAST-OBSERVATION-CARRIED-FORWARD ANALYSIS METHODS IN RHEUMATOID ARTHRITIS CLINICAL TRIALS

To highlight the importance and impact of imputation approach used in reporting rheumatoid arthritis (RA) clinical trial results when data are analyzed using non-responder imputation (NRI) versus last observation carried forward (LOCF). Non-responder imputation is a conservative analysis method in which participant dropouts are assumed to be non-responders regardless of actual response status at the time of dropout. Last observation carried forward is an analysis method in which the last measured value of a variable, such as treatment response, is carried forward and assumed to be valid for a future point of analysis. Results at 52 weeks from the PREMIER trial, a double-blind, randomized trial in adult patients with early RA (<3 years) that compared among adalimumab plus methotrexate (ADA+MTX) and monotherapies with either drug were compared using NRI and LOCF analyses. Outcome measures presented here are American College of Rheumatology (ACR) 50%, and 70% responses, and remission based on 28-joint Disease Activity Score (DAS28<2.6). In the ADA+MTX treatment group, outcome measures calculated using NRI and LOCF, respectively, were 62% and 68% for ACR50, 46% and 48% for ACR70, and 43% and 47% for remission. In the MTX-monotherapy group, NRI and LOCF values, respectively, were 46% and 49% for ACR50, 28% and 29% for ACR70, and 21% and 22% for DAS28 <2.6. For all outcome measures, the estimate of drug effect was lesser when using NRI analysis compared with LOCF analysis. Non-responder imputation analyses tend to result in more conservative estimates of drug effect on outcome measures than LOCF analyses. In trials in which there are high numbers of participant dropouts, the difference in results using NRI versus LOCF could be substantial. Thus, caution is warranted in comparisons of results across clinical trials using these different imputation methods.

Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naïve HIV-1-infected patients (the ARTEN study)

Dyslipidaemic effects of antiretrovirals (ARVs) may contribute to increased cardiovascular risk (CR) in HIV-1-infected patients. The ARTEN (atazanavir/ritonavir on a background of tenofovir and emtricitabine vs. nevirapine on the same background, in naïve HIV-1-infected patients) study compared prospectively ritonavir-boosted atazanavir (ATZ/r) 300 mg/100 mg once daily (qd) with immediate release nevirapine (NVP) 200 mg twice daily or 400 mg qd, each combined with fixed-dose tenofovir 300 mg/emtricitabine 200 mg qd in 569 ARV-naïve HIV-1-infected patients. Lipid profiles and CR from baseline to week 48 are reported. Changes from baseline to week 48 in fasting plasma levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), TC:HDL-c ratio, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and total triglycerides (TG) were determined. The Framingham algorithm was used to estimate CR. Analysis was by intention-to-treat (ITT) with last observation carried forward (LOCF) for missing data. At week 48, NVP treatment resulted in significantly greater mean increases from baseline in TC (24.4 vs. 19.6 mg/dL; P=0.038), HDL-c (9.7 vs. 3.9 mg/dL; P<0.0001), LDL-c (15.0 vs. 10.4 mg/dL; P=0.011) and ApoA1 (0.18 vs. 0.08 g/L; P<0.0001) but not ApoB (0.02 vs. 0.02 g/L) compared with ATZ/r treatment. ATZ/r use was associated with higher mean TG increases (27.80 vs. 0.02 mg/dL; P=0.0001). Significantly greater mean decreases in TC:HDL-c and ApoB/ApoA ratios were observed with NVP vs. ATZ/r (P=0.0001 and P=0.008, respectively). Framingham CR scores were low and comparable between the arms, with only a slight mean increase from baseline to week 48 of 0.70 for NVP and 0.80 for ATZ/r [difference -0.069; 95% confidence interval (CI) -0.61 to 0.46; P=0.80]. In ARV-naïve patients with low CR at the outset, NVP showed a potentially less atherogenic lipid profile compared with ATZ/r.

Adalimumab 160-/80-mg Induction Regimen is Associated With Better Outcomes Compared With the 80-/40-mg Regimen During Maintenance Therapy in Patients With Crohn's Disease

Aim: To investigate the effects of adalimumab maintenance therapy on health-related quality of life (HRQOL) through 52 weeks in patients with ulcerative colitis (UC). Methods: 494 patients with moderate to severe UC (Mayo score, 6-12 points; endoscopic subscore, 2-3 points; anti-tumor necrosis factor [anti-TNF]-naive and anti-TNF-experienced [40.3%]) who had failed conventional therapy were enrolled in a 52-week, randomized, double-blind, placebo-controlled maintenance trial. Adalimumab-treated patients received induction therapy (160/80 mg at Weeks 0/2) and 40-mg every-other-week (eow) maintenance therapy. Patients with inadequate response could switch to open-label eow therapy after Week 12 and subsequently to weekly therapy. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ). The intent-to-treat population was analyzed. IBDQ response rates were compared between the treatment groups using the Cochran-Mantel-Haenszel test stratified for prior anti-TNF use whereas the chi-square test was used in anti-TNF-naive patients. Non-responder imputation was used for response variables. For change of IBDQ scores, the ANCOVA model with treatment and prior anti-TNF status as factors and baseline value as covariate was used. Missing values were imputed through last observation carried forward (LOCF). Results: Significantly more adalimumab-treated patients were IBDQ responders (increase in IBDQ score ≥16 points from baseline) throughout Weeks 8, 32, and 52 compared with placebo. Mean changes from baseline IBDQ scores were consistently greater for adalimumabvs. placebo-treated patients (table). In anti-TNF-naive patients, the improvements from baseline for IBDQ were 34±38 and 22±37 at Week 8 (p=0.002), 33±43 and 24±43 at Week 32 (p=0.03), and 33±44 and 23±42 at Week 52 (p=0.02) for ADA and placebo, respectively. The IBDQ responder rates were 68% and 52% at Week 8 (p=0.004), 42% and 27% at Week 32 (p=0.006), 32% and 21% at Week 52 (p=0.040) for ADA and placebo, respectively, among anti-TNF-naive patients. Conclusion: For patients with moderate to severe UC who failed conventional therapy, adalimumab was more effective than placebo for inducing and maintaining improvements in HRQOL, as measured by IBDQ through 52 weeks. Improvement in IBDQ Over Time

Adalimumab Improves Health-Related Quality of Life for 52 Weeks in Patients With Ulcerative Colitis

Introduction We investigated effects of adalimumab (ADA) maintenance therapy on health-related quality of life (HRQOL) through 52 weeks (wks) in patients (pts) with ulcerative colitis (UC). Methods 494 pts with moderate to severe UC (Mayo score, 6–12 points; endoscopic subscore, 2–3 points; anti–tumour necrosis factor [anti-TNF]–naive and anti-TNF–experienced [40.3%]) who had failed conventional therapy were enrolled in a 52-wk, randomised, double-blind, placebo (PBO)-controlled maintenance trial. ADA-treated pts received induction therapy (160/80 mg @ Wks 0/2) and 40-mg every-other-week (eow) maintenance therapy. Pts with inadequate response could switch to open-label eow therapy after Wk 12 and subsequently to weekly therapy. HRQOL was measured by Inflammatory Bowel Disease Questionnaire (IBDQ). Intent-to-treat population was analysed. IBDQ response rates were compared between treatment groups using Cochran-Mantel-Haenszel test stratified for prior anti-TNF use whereas χ 2 test was used in anti-TNF-naive pts. Non-responder imputation was used for response variables. For change of IBDQ scores, ANCOVA model with treatment and prior anti-TNF status as factors and baseline value as covariate was used. Missing values were imputed through last observation carried forward (LOCF). Results Significantly more ADA-treated pts were IBDQ responders (increase in IBDQ score ≥16 points from baseline) throughout Wks 8, 32, and 52 compared with PBO. Mean changes from baseline IBDQ scores were consistently greater for ADA- vs PBO-treated pts (Abstract PWE-253 table 1). In anti-TNF–naive pts, improvements from baseline for IBDQ were 34±38 and 22±37 at Wk 8 (p=0.002), 33±43 and 24±43 at Wk 32 (p=0.03), and 33±44 and 23±42 at Wk 52 (p=0.02) for ADA and PBO, respectively. IBDQ responder rates were 68% and 52% at Wk 8 (p=0.004), 42% and 27% at Wk 32 (p=0.006), 32% and 21% at Wk 52 (p=0.040) for ADA and PBO, respectively, among anti-TNF–naive pts. Conclusion For pts with moderate to severe UC who failed conventional therapy, ADA was more effective than PBO for inducing and maintaining improvements in HRQOL, as measured by IBDQ through 52 wks. Competing interests W Sandborn Grant/Research Support from: Abbott, Consultant for: Abbott, G Van Assche Grant/Research Support from: Abbott, R Thakkar Shareholder with: Abbott, Employee of: Abbott, A Lazar Shareholder with: Abbott, Employee of: Abbott, M Kron Shareholder with: Abbott, Employee of: Abbott, M Yang Shareholder with: Abbott, Employee of: Abbott, S Patel Shareholder with: Abbott, Employee of: Abbott, J Chao Shareholder with: Abbott, Employee of: Abbott, P Mulani Shareholder with: Abbott, Employee of: Abbott.

Crohn's Disease Patients With Persistently Elevated CRP Plasma Concentration Have Higher Rates of Remission With Certolizumab Pegol 400 mg Every 2 Weeks vs. Every 4 Weeks

Aim: To investigate the effects of adalimumab maintenance therapy on health-related quality of life (HRQOL) through 52 weeks in patients with ulcerative colitis (UC). Methods: 494 patients with moderate to severe UC (Mayo score, 6-12 points; endoscopic subscore, 2-3 points; anti-tumor necrosis factor [anti-TNF]-naive and anti-TNF-experienced [40.3%]) who had failed conventional therapy were enrolled in a 52-week, randomized, double-blind, placebo-controlled maintenance trial. Adalimumab-treated patients received induction therapy (160/80 mg at Weeks 0/2) and 40-mg every-other-week (eow) maintenance therapy. Patients with inadequate response could switch to open-label eow therapy after Week 12 and subsequently to weekly therapy. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ). The intent-to-treat population was analyzed. IBDQ response rates were compared between the treatment groups using the Cochran-Mantel-Haenszel test stratified for prior anti-TNF use whereas the chi-square test was used in anti-TNF-naive patients. Non-responder imputation was used for response variables. For change of IBDQ scores, the ANCOVA model with treatment and prior anti-TNF status as factors and baseline value as covariate was used. Missing values were imputed through last observation carried forward (LOCF). Results: Significantly more adalimumab-treated patients were IBDQ responders (increase in IBDQ score ≥16 points from baseline) throughout Weeks 8, 32, and 52 compared with placebo. Mean changes from baseline IBDQ scores were consistently greater for adalimumabvs. placebo-treated patients (table). In anti-TNF-naive patients, the improvements from baseline for IBDQ were 34±38 and 22±37 at Week 8 (p=0.002), 33±43 and 24±43 at Week 32 (p=0.03), and 33±44 and 23±42 at Week 52 (p=0.02) for ADA and placebo, respectively. The IBDQ responder rates were 68% and 52% at Week 8 (p=0.004), 42% and 27% at Week 32 (p=0.006), 32% and 21% at Week 52 (p=0.040) for ADA and placebo, respectively, among anti-TNF-naive patients. Conclusion: For patients with moderate to severe UC who failed conventional therapy, adalimumab was more effective than placebo for inducing and maintaining improvements in HRQOL, as measured by IBDQ through 52 weeks. Improvement in IBDQ Over Time

PREPARED: Comparison of prolonged and immediate release ropinirole in advanced Parkinson's disease

PREPARED was a randomized, parallel-group, double-blind, multicenter study to evaluate the efficacy of adjunctive ropinirole prolonged release (PR) versus immediate release (IR) in patients with advanced Parkinson's disease (PD). Patients received once-daily PR (2-24 mg/d; n = 177) or three-times-daily IR (0.75-24 mg/d; n = 173) for 24 weeks. The primary endpoint was the proportion of patients maintaining ≥ 20% reduction from baseline in "off" time over two consecutive visits at Week 24 last observation carried forward (LOCF). At Week 24 LOCF, PR significantly increased the proportion of patients maintaining ≥ 20% reduction in "off" time versus IR (adjusted odds ratio: 1.82; 95% CI: 1.16, 2.86; P = 0.009). Mean (SD) doses at Week 24 LOCF were: PR, 18.6 (6.5) mg/d; IR, 10.4 (6.4) mg/d; mean (SD) reductions from baseline in levodopa (L-dopa) dose were -162 (226) mg and -113 (138) mg, respectively. Adverse events (AEs) were reported by 72% of patients in the PR group and 61% in the IR group; 12% and 9% of patients, respectively, withdrew from the study due to an AE, and 6% and 5%, respectively, reported serious AEs. Adjunctive PR provided a significantly greater improvement in symptom control in terms of the odds of achieving ≥ 20% maintained reduction in time spent "off" compared with IR. Interpretation may be confounded by the higher doses of PR versus IR that were achieved, in combination with lower doses of L-dopa by the study end. Despite dosing differences, the PR titration regimen was generally well tolerated, with an AE profile similar to that of IR.