Baseline Observation Carried Forward Research Articles

Effects of a minimal‐guided on‐line intervention for alcohol misuse in Estonia: a randomized controlled trial

Background and AimsEstonia has one of the highest alcohol‐attributable mortality rates within the European Union. The aim of this study was to estimate the efficacy of an on‐line self‐help intervention to reduce problem drinking at the population level.DesignOn‐line open randomized controlled trial with an 8‐week intervention and an active control group (intervention n = 303, control n = 286). Assessments took place at baseline and at 6 months follow‐up.SettingOn‐ and offline channels were used for population‐based recruitment within a nation‐wide prevention campaign in Estonia.ParticipantsInclusion criteria were age ≥ 18 years, heavy drinking [Alcohol Use Disorders Identification (AUDIT) test score ≥ 8], literacy in Estonian and at least weekly access to the internet; n = 589 participants were randomized (50% male, 1% other; mean age 37.86 years; 45% with higher level of education).Intervention and comparatorThe intervention consisted of 10 modules based on principles of cognitive–behavioral therapy and motivational interviewing. The active control group received access to a website with a self‐test including personalized normative feedback and information for standard alcohol treatment.MeasurementsThe primary outcome was AUDIT scores at 6 months follow‐up adjusted for baseline scores.FindingsIntention‐to‐treat analyses were applied. Missing data were addressed by using baseline observation carried forward (BOCF) and multiple imputation by chained equations (MI); 175 completed follow‐up in the intervention group and 209 in the control group. AUDIT score at follow‐up was significantly smaller in the intervention [BOCF mean = 13.91, standard deviation (SD) = 7.61, MI mean = 11.03, SD = 6.55] than control group (BOCF mean = 15.30, SD = 7.31; MI mean = 14.30, SD = 7.21), with a group difference of −1.38 [95% confidence interval (CI) = –2.58, –0.18], P = 0.02 for BOCF and −3.26 (95% CI = –2.01, –4.51), P < 0.001 for MI.ConclusionsA randomized controlled trial has found that an on‐line self‐help intervention with minimal guidance was effective at reducing problem drinking in Estonia.

Transcranial Photobiomodulation for the Treatment of Major Depressive Disorder. The ELATED-2 Pilot Trial.

Objective: Our objective was to test the antidepressant effect of transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light in subjects suffering from major depressive disorder (MDD). Background: t-PBM with NIR light is a new treatment for MDD. NIR light is absorbed by mitochondria; it boosts cerebral metabolism, promotes neuroplasticity, and modulates endogenous opioids, while decreasing inflammation and oxidative stress. Materials and methods: We conducted a double-blind, sham-controlled study on the safety and efficacy [change in Hamilton Depression Rating Scale (HAM-D17) total score at end-point] of adjunct t-PBM NIR [823 nm; continuous wave (CW); 28.7 × 2 cm2; 36.2 mW/cm2; up to 65.2 J/cm2; 20-30 min/session], delivered to dorsolateral prefrontal cortex, bilaterally and simultaneously, twice a week, for 8 weeks, in subjects with MDD. Baseline observation carried forward (BOCF), last observation carried forward (LOCF), and completers analyses were performed. Results: The effect size for the antidepressant effect of t-PBM, based on change in HAM-D17 total score at end-point, was 0.90, 0.75, and 1.5 (Cohen's d), respectively for BOCF (n = 21), LOCF (n = 19), and completers (n = 13). Further, t-PBM was fairly well tolerated, with no serious adverse events. Conclusions: t-PBM with NIR light demonstrated antidepressant properties with a medium to large effect size in patients with MDD. Replication is warranted, especially in consideration of the small sample size.

Neurofeedback of Slow Cortical Potentials in Children with Attention-Deficit/Hyperactivity Disorder: A Multicenter Randomized Trial Controlling for Unspecific Effects.

Background: Neurofeedback (NF) in children with attention-deficit/hyperactivity disorder (ADHD) has been investigated in a series of studies over the last years. Previous studies did not unanimously support NF as a treatment in ADHD. Most studies did not control for unspecific treatment effects and did not demonstrate that self-regulation took place. The present study examined the efficacy of NF in comparison to electromyographic (EMG) feedback to control for unspecific effects of the treatment, and assessed self-regulation of slow cortical potentials (SCPs).Methods: A total of 150 children aged 7–9 years diagnosed with ADHD (82% male; 43% medicated) were randomized to 25 sessions of feedback of SCPs (NF) or feedback of coordination of the supraspinatus muscles (EMG). The primary endpoint was the change in parents’ ratings of ADHD core symptoms 4 weeks after the end of treatment compared to pre-tests.Results: Children in both groups showed reduced ADHD-core symptoms (NF 0.3, 95% CI -0.42 to -0.18; EMG 0.13, 95% CI -0.26 to -0.01). NF showed a significant superiority over EMG (treatment difference 0.17, 95% CI 0.02–0.3, p = 0.02). This yielded an effect size (ES) of d = 0.57 without and 0.40 with baseline observation carried forward (BOCF). The sensitivity analysis confirmed the primary result. Successful self-regulation of brain activity was observed only in NF. As a secondary result teachers reported no superior improvement from NF compared to EMG, but within-group analysis revealed effects of NF on the global ADHD score, inattention, and impulsivity. In contrast, EMG feedback did not result in changes despite more pronounced self-regulation learning.Conclusions: Based on the primary parent-rated outcome NF proved to be superior to a semi-active EMG feedback treatment. The study supports the feasibility and efficacy of NF in a large sample of children with ADHD, based on both specific and unspecific effects.Trial Register: Current controlled trials ISRCTN76187185, registered 5 February 2009.

A Simple Correction to Completer Analyses and Improvement on Baseline Observation Carried Forward

Replacing missing data using the baseline observation carried forward (BOCF) technique is known to be fraught with problems. Despite recommendations to the contrary, BOCF and the related last observation carried forward (LOCF) continue to be used in some fields of research. We first show the use of BOCF in testing for a change in a single sample is essentially equivalent to what results from a completer analysis. Next, we derive a simple method based only on summary statistics for adjusting inference from a completer analysis in situations where the estimand of the completer analysis is expected to be close to that of the full analysis set. For those with missing follow-up data, the method assumes a mean change of zero from baseline, with variance equivalent to that estimated from the patients who complete; in other words, it is essentially BOCF analysis with plausible variance inflation. The extension to two samples is considered and a similar adjustment of the completer analysis is presented. The method presented here can be used to reanalyze results from publications that treat missing data inadequately, to adjust for missing data in power calculations and as a quick way of checking the plausibility of an appropriate treatment of missing data. These practical tools are meant to complement, rather than compete with, established methods for dealing with missing data. Numerical simulations are used to elucidate some properties of the proposed method and, finally, we apply the method to data from a recent trial which evaluated weight loss programs.

Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials.

BackgroundNalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO 2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication.Methods and FindingsThree reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane’s Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI [0.08; 2.01]) and 1 y (RR = 0.98, 95% CI [0.04; 23.95]) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI [−0.32; 2.01]; SF-36 mental component summary score: MD = 1.01, 95% CI [−1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = −1.65, 95% CI [−2.41; −0.89]) and at 1 y (MD = −1.60, 95% CI [−2.85; −0.35]) and total alcohol consumption at 6 mo (SMD = −0.20, 95% CI [−0.30; −0.10]). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI [2.02; 6.63]) and 1 y (RR = 7.01, 95% CI [1.72; 28.63]). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used.ConclusionsThe value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption.

PTU-188 Statistical approaches to missing data in trials of irritable bowel syndrome with constipation: experience with linaclotide (constella®): Abstract PTU-188 Table 1

Introduction Missing data may affect validity and interpretation of clinical trials, as different statistical approaches for handling missing data may lead to different conclusions. As patterns of missing data are often unknown until unblinding, study design should be guided by similar trials. Information on handling missing data in trials in irritable bowel syndrome with constipation (IBS-C) is limited. Method This post-hoc analysis compared imputation methods for missing data in 2 pivotal randomised, double-blind, placebo (PBO)-controlled, multicentre Phase 3 clinical trials (Trials 31 and 302) of linaclotide 290 μg once-daily (Constella ® ; LIN) in IBS-C. In both trials, pre-specified European Medicines Agency (EMA)-recommended co-primary endpoints were: 1) 12-week abdominal pain/discomfort responder rate and 2) 12-week IBS degree-of-relief responder rate. These endpoints were analysed using observed cases (OC), last observation carried forward (LOCF), baseline observation carried forward (BOCF), drop-out as non-responder and multiple imputation approaches. Results In Trial 302, the different imputation methods for missing data yielded results consistent with the initial OC approach for both co-primary endpoints (Table 1). Results were similar for Trial 31, with statistically significant treatment differences for all imputation methods for both endpoints ( P 0.0001 for all except for 12-week abdominal pain/discomfort responder: OC, P = 0.0002 and drop-out as non-responder, P = 0.0056). Conclusion All five imputation methods yielded non-biassed results in both LIN Phase 3 IBS-C trials, supporting the robustness of LIN treatment effects on EMA endpoints. The ‘drop-out as non-responder’ approach could be considered to be the most conservative, as using this method the treatment-effect estimates for both co-primary endpoints were lower than those obtained using other methods. Disclosure of interest M. Falques Employee of: Almirall S. A., C. Diaz Employee of: Almirall S. A., D. Vilardell Employee of: Almirall S. A., J. Fortea Employee of: Almirall S. A., J. Johnston Employee of: Ironwood Pharmaceuticals.

Tapentadol for chronic musculoskeletal pain in adults.

Chronic musculoskeletal pain is a prevalent condition and a major cause of disability and absence from the workplace worldwide. Opioids are frequently used to treat chronic pain, although adverse effects often restrict their long-term benefits. Tapentadol is an opioid and norepinephrine re-uptake inhibitor, which may cause a lower incidence (and severity) of adverse effects compared to other strong opioids. To determine the efficacy, safety and tolerability of tapentadol extended release for moderate-to-severe pain for at least three months for any musculoskeletal cause. We searched electronic databases (CENTRAL, MEDLINE, EMBASE, Web of Science) to March 2014, unrestricted by language, as well as trials registers and reference lists from retrieved studies. We contacted drug manufacturers for further information. Randomised controlled trials (RCTs) of tapentadol in people with chronic musculoskeletal pain, compared to placebo or active control. Two review authors independently selected trials for inclusion, assessed risk of bias of included studies and extracted data. We performed two meta-analyses for the comparisons tapentadol extended release vs. placebo, and tapentadol extended release vs. active-control (oxycodone). We used random-effects and fixed-effect models according to the presence or not of heterogeneity, respectively. Also, we performed subgroup analyses. The primary efficacy outcome was pain control assessed by change in pain intensity scores and responder's rate (at least 50% pain relief). Primary safety outcome was withdrawal rate due to adverse effects. Four parallel-design RCTs of moderate quality including 4094 patients with osteoarthritis or back pain, or both, met the inclusion criteria. Three trials were phase III studies with 12-weeks follow-up and the fourth trial was an open-label safety study of 52-weeks follow-up. All trials were oxycodone-controlled and three were also placebo-controlled. Two trials included patients with knee osteoarthritis, one evaluated patients with low back pain and one enrolled both. All studies reported last-observation-carried-forward (LOCF) as imputation method. We requested baseline-observation-carried-forward (BOCF) imputed analyses and any unpublished data from the manufacturer but the manufacturers denied the request. Two out of the four oxycodone-controlled studies and one out of the three placebo-controlled studies did not provided data on responder's rate. Two studies were considered to be of high risk of bias.In comparison to placebo, tapentadol was associated with a mean reduction of 0.56 points (95% confidence interval (CI) 0.92 to 0.20) in the 11-point numerical rating scale (NRS) at 12 weeks and with a 1.36 increase (95% CI 1.13 to 1.64) in the risk of responding to treatment (number needed to treat for an additional beneficial outcome (NNTB) 16; 95% CI 9 to 57, for 12-weeks). Moderate-to-high heterogeneity was found for the efficacy outcome estimates. Tapentadol was associated with a 2.7 fold increase (95% CI 2.05 to 3.52) in the risk of discontinuing treatment due to adverse effects number needed to treat for an additional harmful outcome (NNTH) 10; 95%CI 7 to 12, for 12 weeks).In comparison to oxycodone, pooled data showed a 0.24 points (95%CI 0.43 to 0.05) reduction in pain intensity from baseline in the 11-point NRS. The two studies that evaluated responder's rate showed a non-significant 1.46 increase (95% CI 0.92 to 2.32) in the risk of responding to treatment among tapentadol treated patients. Tapentadol was associated with a 50% risk reduction (95% CI 42% to 60%) of discontinuing treatment due to adverse effects (NNTB 6; 95% CI 5 to 7, for 12 weeks). Tapentadol was also associated with a 9% reduction (95% CI 4 to 15) in the overall risk of adverse effects (NNTH 18; 95% CI 12 to 35, for 12 weeks) and with a non-significant 43% reduction (95% CI 33 to 76) in the risk of serious adverse effects. Moderate to high heterogeneity was found for most efficacy (except for the primary outcome) and safety outcome estimates. Subgroup analysis showed a higher improvement with tapentadol among patients with knee osteoarthritis and among pooled results from studies of higher quality and shorter follow-up period, although there were no statistical significant differences in the effect size between these subgroups. Tapentadol extended release is associated with a reduction in pain intensity in comparison to placebo and oxycodone. However, the clinical significance of the results is uncertain due to the following reasons: modest difference between interventions in efficacy outcomes, high heterogeneity in some comparisons and outcomes, high withdrawals rates, lack of data for the primary outcome in some studies and impossibility to use BOCF as imputation method. Tapentadol is associated with a more favourable safety profile and tolerability than oxycodone.

Clinical effectiveness of very low calorie diets. Systematic review and meta-analysis of randomised controlled trials

Very low calorie diets (VLCDs) are an option for the management of obesity, but are not used in primary care. This abstract presents an ongoing review to examine whether VLCDs could be an effective option for GPs to manage obesity. Literature databases were searched from database inception to February 2013. Studies were included if they were randomised controlled trials that recruited overweight or obese adults, with or without comorbidities. The intervention needed to incorporate a VLCD and comparator could be a no intervention control or an intervention that could be given in primary care. The primary outcome was weight change at 12 months from baseline. Secondary outcomes were HbA1c, lipids, and blood pressure and we recorded adverse events. We included 11 studies in the analysis which randomised 425 participants to VLCD and 349 participants to a comparator. Compared with a behavioural weight loss programme, VLCDs achieved an additional −4.1 kg (−7.3 to −0.8) greater weight loss at 12 months. Using baseline observation carried forward (BOCF), the differencewas −3.4 kg (−6.7 to −0.05). The difference in weight loss using BOCF at 18–24 months was −1.6 kg (−3.3 to −0.01) and at 42–60 months was −1.5 kg (−4.0 to 1.0). Data on secondary outcomes, adverse events and subgroup analyses will be available for an updated abstract and be presented at the conference. We will conclude on whether VLCDs appear safe and effective and hence a useful option for achieving weight loss in primary care.

Pregabalin in Patients With Inadequately Treated Painful Diabetic Peripheral Neuropathy

This study used a randomized withdrawal design to evaluate the efficacy of pregabalin versus placebo for pain relief in patients with painful diabetic peripheral neuropathy inadequately treated by other therapies. A total of 665 patients received pregabalin in a 6-week single-blind phase. Two hundred ninety-four patients who achieved a ≥ 30% pain response were randomized to receive pregabalin or placebo in a double-blind phase for a further 13 weeks. The primary endpoint was the change in mean pain score from single-blind baseline to double-blind endpoint for pregabalin versus placebo (last observation carried forward [LOCF]). Secondary endpoints included a baseline observation carried forward (BOCF) analysis of mean pain score; time to loss of pain response; and other assessments of pain, sleep, function, and quality of life (QOL). Pregabalin numerically improved all measures assessed during the single-blind phase. At the end of the double-blind withdrawal phase, there was no significant difference in the primary endpoint of mean pain score (LOCF) between pregabalin and placebo (least squares mean difference, -0.32), although there was a significant difference in the BOCF analysis (least squares mean difference, -0.51). Pregabalin was associated with a significantly longer time to loss of pain response versus placebo during double-blind treatment, and some aspects of sleep and QOL also showed significant improvements with pregabalin. This is the first reported placebo-controlled trial of pregabalin in patients with inadequately treated painful diabetic peripheral neuropathy. Although the primary endpoint was not met, pregabalin was associated with clinically relevant improvements versus placebo in this difficult-to-treat population.

How to use published complete case results from weight loss studies in a missing data sensitivity analysis

In randomized controlled trials of weight loss interventions, high dropout rates are a problem resulting in a large amount of missing outcome data. It is common for participants with missing data to be excluded from analysis (complete-case analysis). The aim of this article is to demonstrate how published complete-case results can be used to explore how study results would change depending on assumptions about dropout weight loss. The methods are based on three extensions to a method for obtaining baseline observation carried forward (BOCF) results from complete-case results. The first extension is a generalization to any dropout weight loss. Second, to show that it is not necessary to assume that dropout weight loss is the same in each treatment arm. Third, to show that variation in dropout weight loss can be incorporated. Using these extensions, sensitivity analyses to the missing data can be conducted via the use of plots. The methods are demonstrated using two examples of published results from studies of weight loss interventions. It is also shown how the BOCF method could be useful to meta-analysts. By using simple plots, readers can explore how different assumptions about dropout weight loss affect the results of published weight loss trials.

The challenge of a 2-year follow-up after intervention for weight loss in primary care.

Background:Many weight loss programmes show short-term success, but long-term data in larger studies are scarce, especially in community settings. Attrition is common and complicates the interpretation of long-term outcomes.Objective:To investigate 2-year outcomes and explore issues of attrition and missing data.Subjects:A total of 772 overweight and obese adults recruited by primary care practices in Australia, Germany and the UK and randomised to a 12-month weight loss intervention delivered in a commercial programme (CP) or in standard care (SC).Measurement:Weight change from 0–24 and 12–24 months including measured weights only and measured and self-reported weights, using last observation carried forward (LOCF), baseline observation carried forward (BOCF), completers-only and missing-at-random (MAR) analyses.Results:A total of 203 participants completed the 24-month visit. Using measured weights only, there was a trend for greater 24-month weight loss in CP than in SC, but the difference was only statistically significant in the LOCF and BOCF analyses: LOCF: −4.14 vs −1.99 kg, difference adjusted for centre −2.08 kg, P<0.001; BOCF: −1.33 vs −0.74 kg, adjusted difference −0.60 kg, P=0.032; completers: −4.76 vs −2.99 kg, adjusted difference −1.53 kg, P=0.113; missing at random: −3.00 vs −1.94 kg, adjusted difference −1.04 kg, P=0.150. Both groups gained weight from 12–24 months and weight regain was significantly (P<0.001) greater for CP than for SC in all analysis approaches. Inclusion of self-reported weights from a further 138 participants did not change the interpretation of the findings.Conclusion:Initial weight loss was poorly maintained during the no-intervention follow-up, but both groups did have lower weight over the 24 months. Attrition was high in both groups, and assumptions about missing data had considerable impact on the magnitude and statistical significance of treatment effects. It is vital that trials on weight loss interventions consider the plausibility of these differences in an analytical approach when interpreting research findings and comparing data between studies.

Nitroglycerin 0.4% ointment vs placebo in the treatment of pain resulting from chronic anal fissure: a randomized, double-blind, placebo-controlled study.

BackgroundComplications of chronic anal fissure (CAF) treatments are prompting interest in lower-risk therapies. This study was conducted to compare nitroglycerin (NTG) 0.4% ointment with placebo for pain associated with CAF.MethodsIn this randomized, double-blind, placebo-controlled trial, patients with one CAF and moderate-to-severe pain (≥50 mm on a 100 mm visual analog scale [VAS]) received 375 mg NTG 0.4% (1.5 mg active ingredient) or 375 mg placebo ointment applied anally every 12 hours for 21 days. The primary end point was change from baseline VAS score in 24-hour pain averaged over days 14–18. Review of data from patients who withdrew early was blinded to treatment. To control for the confounding effects of analgesics, all patients received 650 mg acetaminophen for headache prophylaxis before each application.ResultsA total of 247 patients were enrolled (NTG, n = 123; placebo, n = 124). The prespecified baseline observation carried forward (BOCF) analysis found no significant difference between groups; however, a last observation carried forward (LOCF) analysis showed a significant advantage for NTG. A post hoc analysis (LOCF/BOCF hybrid) demonstrated a significant adjusted mean difference of −7.0 mm in favor of NTG 0.4% (95% CI −13.6, –0.4; P = .038). Headache was the most common adverse event in the NTG (69.9%) and placebo (47.6%) groups.ConclusionsThis was the first placebo-controlled study that also controlled for the confounding effects of analgesics used to treat NTG-induced headache. In patients with moderate-to-severe CAF pain, NTG 0.4% ointment effectively reduced CAF pain compared with placebo.Trial registrationClinicalTrials.gov, NCT00522041

OP0155 Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality of life results of the randomised, controlled swefot trial

BackgroundIn RA, direct comparisons of the quality of life effects associated with different therapies remain sparse.ObjectivesTo compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) over 21 months in patients...

Gastroretentive Gabapentin (G-GR) Formulation Reduces Intensity of Pain Associated With Postherpetic Neuralgia (PHN)

To evaluate the safety and efficacy of a once-daily gastroretentive formulation of gabapentin (G-GR; 1800 mg). This was an 11-week, double-blind, randomized, placebo-controlled Phase 3 clinical trial in patients with postherpetic neuralgia. Patients underwent a 2-week dose titration, 8 weeks of stable dosing, and 1 week of dose tapering. The primary endpoint was the change in average daily pain intensity score from Baseline to Week 10 using Baseline Observation Carried Forward (BOCF) imputation. Four-hundred and fifty-two patients (mean age 65.6 y, BMI 29 Kg/m) were randomized. Baseline average daily pain intensity score during the week prior to randomization was 6.6 and 6.5 for the G-GR and placebo treatment groups, respectively. Three hundred and seventy-seven patients completed the study (84% G-GR, 83% placebo). G-GR significantly reduced BOCF change in average daily pain intensity compared with placebo (-2.1 vs. -1.6; G-GR vs. placebo, P=0.013). Compared with placebo, more G-GR-treated patients reported "much" or "very much" improvement (patient global impression of change, 43% vs. 34%; P<0.0434), and G-GR reduced sleep interference (-2.3 vs. -1.59; P<0.0001), although neither endpoint was considered statistically significant based on a stringent hierarchical statistical paradigm. Other secondary endpoints showed similar trends. The most common adverse events were dizziness (G-GR, 11.3% vs. placebo, 1.7 %) and somnolence (G-GR, 5.4% vs. placebo, 3.0%). Once-daily G-GR 1800 mg was effective and well tolerated for the relief of pain in patients with postherpetic neuralgia.

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial

ObjectiveTo compare EuroQol 5-Dimensions (EQ-5D) utility and quality-adjusted life-years (QALYs) in patients with early, methotrexate (MTX) refractory rheumatoid arthritis (RA), randomised to addition of infliximab (IFX) or sulfasalazine and hydroxychloroquine...

Results of a Double‐blind, Placebo‐controlled, Fixed‐dose Assessment of Once‐daily OROS® Hydromorphone ER in Patients with Moderate to Severe Pain Associated with Chronic Osteoarthritis

Opioids are recommended for patients with moderate to severe pain due to osteoarthritis (OA), who do not receive adequate analgesia from nonopioid treatment. The objective of this study was to evaluate the efficacy and safety of OROS hydromorphone extended-release (ER) compared with placebo in patients with moderate to severe pain associated with OA. This was a randomized, placebo-controlled, double-blind, fixed-dose study. Patients received placebo or fixed-dose OROS hydromorphone ER (8 or 16 mg). The primary efficacy measure was pain intensity score (11-point Numeric Rating Scale) at Maintenance Week 12, analyzed with baseline observation carried forward (BOCF) imputation for missing data. This study did not meet the primary efficacy measure using the BOCF imputation. Study discontinuation was high (52%). When analyzed using last observation carried forward (LOCF) imputation, the prespecified alternate method, OROS hydromorphone ER 16 mg provided significantly better analgesia than placebo (P = 0.0009). Treatment was associated with significant improvements in patient global assessment (P = 0.01), the overall Western Ontario and McMaster Osteoarthritis Index (WOMAC) (P = 0.0003), and its subscales: pain (P = 0.0001), stiffness (P = 0.0023), and physical function (P = 0.0006). Gastrointestinal adverse events, such as constipation and nausea, were common among patients receiving OROS hydromorphone ER. OROS hydromorphone ER failed to achieve statistical significance for the primary endpoint using the prespecified imputation method (BOCF), likely due to the high discontinuation rate associated with the fixed-dose design. When data were analyzed according to an alternate method of imputation (LOCF), OROS hydromorphone ER demonstrated statistically significant improvements in pain, stiffness, and physical function.

Effect of study country on efficacy and adverse event profile of once-daily gabapentin extended-release (G-ER) for the treatment of postherpetic neuralgia (PHN)

G-ER has been demonstrated to be efficacious and well tolerated for treatment of PHN in a placebo-controlled, Phase 3 study conducted in the USA, Russia and Argentina. We examined the efficacy and tolerability of once-daily G-ER (1800 mg) as a function of study country. Patients with PHN ≥6 months and average daily pain (ADP) score ≥4 were randomized to G-ER or placebo for 10 weeks. The primary endpoint was baseline observation carried forward (BOCF) change in ADP, and rates of adverse events were compared.

Getting carried away: a note showing baseline observation carried forward (BOCF) results can be calculated from published complete-cases results

Randomized controlled trials (RCTs) in obesity are plagued by missing data due to participant dropouts. Most methodologists and regulatory bodies agree that the primary analysis of such RCTs should be based on the intent-to-treat (ITT) principle, such that all randomized subjects are included in the analysis, even those who dropped out. Unfortunately, some authors do not include an ITT analysis in their published reports. Here we show that one form of ITT analysis, baseline observation carried forward (BOCF), can be performed utilizing only information available in a published complete-case (CC) analysis, permitting readers, editors, meta-analysts and regulators to easily conduct their own ITT analyses when the original authors do not report one. We mathematically derive a simple method for estimating and testing treatment effects using the BOCF to allow a more conservative comparison of treatment effects when there are dropouts in a clinical trial. We provide two examples of this method using available CC analysis data from reported obesity trials to illustrate the application for readers who wish to determine a range of treatment effects based on published summary statistics. Commonly used CC analyses may lead to inflated type I error rates and/or treatment effect estimates. The method described herein can be useful for researchers who wish to estimate a conservative range of plausible treatment effects based on limited reported data. Limitations of this method are discussed.

Defining, Evaluating, and Removing Bias Induced by Linear Imputation in Longitudinal Clinical Trials with MNAR Missing Data

Missing not at random (MNAR) post-dropout missing data from a longitudinal clinical trial result in the collection of “biased data,” which leads to biased estimators and tests of corrupted hypotheses. In a full rank linear model analysis the model equation, E[ Y ] = X β, leads to the definition of the primary parameter β = (X′X)−1 X′E[ Y ], and the definition of linear secondary parameters of the form θ = L β = L(X′X)−1 X′E[ Y ], including, for example, a parameter representing a “treatment effect.” These parameters depend explicitly on E[ Y ], which raises the questions: What is E[ Y ] when some elements of the incomplete random vector Y are not observed and MNAR, or when such a Y is “completed” via imputation? We develop a rigorous, readily interpretable definition of E[ Y ] in this context that leads directly to definitions of β, , , and the extent of hypothesis corruption. These definitions provide a basis for evaluating, comparing, and removing biases induced by various linear imputation methods for MNAR incomplete data from longitudinal clinical trials. Linear imputation methods use earlier data from a subject to impute values for post-dropout missing values and include “Last Observation Carried Forward” (LOCF) and “Baseline Observation Carried Forward” (BOCF), among others. We illustrate the methods of evaluating, comparing, and removing biases and the effects of testing corresponding corrupted hypotheses via a hypothetical but very realistic longitudinal analgesic clinical trial.

Missing Data Handling in Chronic Pain Trials

In chronic pain trials, proper handling of missing data due to dropout is an important issue because the dropout rate is high and the study conclusion may depend on the method chosen. The intent-to-treat (ITT) principle usually requires imputations for missing data to include the dropouts as well as completers in the statistical analysis. However, a statistical analysis with imputation might lead to a misinterpretation of clinical data. In chronic pain trials, treatment-related dropouts are clinical outcomes themselves. For example, an early dropout due to toxicity usually indicates a treatment failure, as does a dropout due to lack of efficacy. Problems with traditional methods such as last observation carried forward (LOCF) or baseline observation carried forward (BOCF) are identified especially in the chronic pain setting. Alternative methods, such as continuous responder analysis and two-part model analysis, treating dropouts as clinical events, are introduced with an example of osteoarthritis clinical trial data.