Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial.

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries-the longest, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150-600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, - 0.22 points (95% confidence interval, 0.54-0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population.ClinicalTrials.gov NCT01701362.

Evaluation of composite responder outcomes of pain intensity and physical function in neuropathic pain clinical trials: an ACTTION individual patient data analysis.

Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. All trials assessed pain intensity on a 0 to 10 numeric rating scale and physical function with the 10-item subscale of the Short Form-36, ranging 0 to 100 with higher scores indicating better function. Correlation between change in pain intensity from baseline to posttreatment and change in physical function was small in DPN (ρ = -0.22; P < 0.001) and nonsignificant in PHN (ρ = -0.05; P = 0.08). Assay sensitivities of 10 composite outcomes were examined in a random subsample of patients enrolled in pregabalin trials for DPN and PHN. Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials.

Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

Time to improvement of pain and sleep quality in clinical trials of pregabalin for the treatment of fibromyalgia.

OBJECTIVE: To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia. DESIGN: A post hoc analysis of four 8- to 14-week phase 2-3, placebo-controlled trials of fixed-dose pregabalin (150-600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms. PATIENTS: A total of 2,747 patients with fibromyalgia, aged 18-82 years. METHODS: Pain and sleep quality scores, recorded daily on 11-point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of ≥2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a ≥1-point reduction of the baseline NRS score of patient responders who had a ≥30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at endpoint. RESULTS: Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo. CONCLUSIONS: Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo.

Assessment of sleep in patients with fibromyalgia: qualitative development of the fibromyalgia sleep diary.

OBJECTIVES: Sleep disturbance is a common experience in fibromyalgia (FM). The field lacks a sleep specific patient reported outcome (PRO) measure developed and validated in a FM population. The study objective is to gain an in-depth understanding of sleep in FM and to develop a PRO measure of it. METHODS: Research involved the following stages: 1) A literature review conducted to identify key concepts associated with FM patient experience of sleep and PRO measures that have been used to assess this; 2) Qualitative interviews with therapeutic area experts; 3) Focus groups with FM patients who experienced sleep disturbance; 4) Development of a conceptual framework and the Fibromyalgia Sleep Diary (FMSD); and 5) Cognitive interviews with patients to explore content validity of the FMSD. RESULTS: The literature review and expert interviews supported sleep disturbance being an important aspect of the FM patient experience, and underscored the need for a new FM specific sleep PRO measure. Results from the focus groups demonstrated that FM patients experience sleep disturbances that they attribute to their FM symptoms, such as pain and stiffness, confirming the importance of understanding more about sleep changes. Aspects of sleep raised by FM patients included poor sleep quality and insufficient quantity including difficulty with falling asleep, getting comfortable, and staying asleep; restlessness; light sleep; not feeling rested upon awakening; and difficulty starting the day. Cognitive interview results showed that the 8-item FMSD, developed to reflect the concepts identified above, was relevant to FM patients with content that was interpreted as intended. CONCLUSIONS: The FMSD was developed in line with the recommendations of the FDA PRO guidance and ISPOR PRO Task Force. The qualitative evidence generated thus far strongly supports the content validity of the FMSD as a PRO measure of sleep disturbance in FM populations. Psychometric evaluation of the FMSD to demonstrate reliability, validity and sensitivity to change is recommended as a next step.

A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions.

Pregabalin is approved for the treatment of a variety of clinical conditions and its analgesic, anxiolytic and anticonvulsant properties are well documented. Pregabalin's effects on sleep, however, are less well known. This review summarizes the published data on the effects of pregabalin on sleep disturbance associated with neuropathic pain, fibromyalgia, restless legs syndrome, partial onset seizures and general anxiety disorder. The data demonstrate that pregabalin has a positive benefit on sleep disturbance associated with several different clinical conditions. Polysomnographic data reveal that pregabalin primarily affects sleep maintenance. The evidence indicates that pregabalin has a direct effect on sleep that is distinct from its analgesic, anxiolytic and anticonvulsant effects.

Randomized study of pregabalin in patients with cancer-induced bone pain.

INTRODUCTION: Improvements are needed in the management of cancer-induced bone pain (CIBP). The objective of this study was to assess the efficacy and safety of pregabalin compared with placebo in the adjunctive treatment of patients with moderate to severe CIBP who were receiving opioids. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group, multicenter trial, 152 adults diagnosed with a malignant, solid tumor with metastases to bone were randomized to flexible-dose pregabalin (100, 150, 300, or 600 mg/day) or placebo, as add-on to stable opioid analgesic therapy, which was optimized prior to the start of the study. The primary efficacy endpoint was the duration-adjusted average change (DAAC) from baseline in the daily worst pain at the reference site (measured by 11-point numeric rating scale [NRS]) during the fixed-dosage phase. The study was terminated early following an interim analysis that indicated an increase in sample size would be needed to satisfy statistical assumptions for the primary endpoint. Given the early termination of the study, only descriptive analyses were performed. RESULTS: The mean (standard deviation) DAAC from baseline in NRS score for the primary endpoint favored pregabalin treatment: -1.53 (1.81) in the pregabalin group and -1.23 (1.74) in the placebo group. Mean DAAC for average pain and sleep interference (NRS) also favored pregabalin. More patients treated with pregabalin reported improvement ("very much improved," "much improved," or "minimally improved") based on Patient Global Impression of Change: 81.4% compared with 70.0% in the placebo group. CONCLUSION: Data from this study indicate that pregabalin use may reduce metastatic bone pain. Due to the incomplete analysis, further study of pregabalin in the management of CIBP is required.

Scales as outcome measures for Alzheimer's disease.

The assessment of patient outcomes in clinical trials of new therapeutics for Alzheimer's disease (AD) continues to evolve. In addition to assessing drugs for symptomatic relief, an increasing number of trials are focusing on potential disease-modifying agents. Moreover, participants with AD are being studied earlier in their course of disease. As a result, the limitations of current outcome measures have become more apparent, as has the need for better instruments. In recognition of the need to review and possibly revise current assessment measures, the Alzheimer's Association, in cooperation with industry leaders and academic investigators, convened a Research Roundtable meeting devoted to scales as outcome measures for AD clinical trials. The meeting included a discussion of methodological issues in the use of scales in AD clinical trials, including cross-cultural issues. Specific topics related to the use of cognitive, functional, global, and neuropsychiatric scales were also presented. Speakers also addressed academic and industry initiatives for pooling data from untreated and placebo-treated patients in clinical trials. A number of regulatory topics were also discussed with agency representatives. Panel discussions highlighted areas of controversy, in an effort to gain consensus on various topics.

Open label, multicenter, 28-week extension study of the safety and tolerability of memantine in patients with mild to moderate Alzheimer's disease.

BACKGROUND: Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be safe and to have beneficial effects on cognition, function, behavior, and global patient status in patients with Alzheimer's disease (AD) in studies lasting 3-6 months. It is approved in the U.S. and Europe for the treatment of moderate to severe AD and is currently under investigation for mild to moderate AD. OBJECTIVE: To evaluate the long-term safety of memantine in patients with mild to moderate AD and to investigate the tolerability of once-daily dose administration. METHODS: This 28-week study enrolled 314 patients with mild to moderate AD who had completed a 24-week, double-blind, placebo-controlled lead-in clinical trial of memantine in AD. Following an 8-week double-blind dose titration phase (used to assess the tolerability of different dosing regimens), subjects were assigned to continuous open label memantine (10 mg, bi.d.) treatment for 20 weeks. Safety outcome measures included treatment-emergent adverse events (AEs), deaths, vital signs, electrocardiograms, and laboratory parameters. RESULTS: During the 28-week study (Phase A+Phase B), the most common AEs were falls and other injuries (both 10.8%). AEs resulted in treatment discontinuation in 6.7% of patients. Discontinuations due to AEs were similar in the once-daily dosing groups compared to the twice-daily dosing groups. During dose titration, completion rates were greater than 90% for both groups. Conversion to once-daily dosing in patients already receiving twice-daily doses of memantine was also well tolerated. CONCLUSIONS: Memantine monotherapy in patients with mild to moderate AD is safe and well tolerated for at least one year. Once-daily dosing during titration and short-term maintenance therapy is safe and well tolerated.