Michael P. McDermott

Core outcome domains for chronic pain clinical trials: IMMPACT recommendations

AbstractObjective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of d

Variable expression of Parkinson's disease: A base‐line analysis of the DAT ATOP cohort

The DATATOP database, which includes clinical information on 800 patients with early untreated Parkinsons disease (PD), is well suited to explore clinical heterogeneity in PD. Patients with early-onset PD (≤40 years, N = 33) reached the same level of disability as the late-onset PD (≥70 years, N = 85) group at a significantly slower rate (2.9 vs. 1.7 years). Early-onset PD patients functioned cognitively better than late-onset PD patients. Bradykinesia, and postural instability and gait difficulty (PIGD), were more common at onset in patients with a rapid rate of disease progression (“malignant PD”; duration of symptoms <1 year and Hoehnflahr stage of 2.5, N = 11) as compared with those with a relatively slow rate of progression (“benign PD”; duration of symptoms >4 years, N = 65). Comparisons of tremor-dominant PD (mean tremor score/ mean PIGD score ≤1.5, N = 441) with the PIGD-dominant type (mean tremor score/mean PIGD score ≥1.0, N = 233) provided support for the existence of clinical subtypes. The PIGD group reported significantly greater subjective intellectual, motor, and occupational impairment than the tremor group. Stage II patients had higher depression scores than stage I patients. Among the patients participating in the DATATOP, older age at onset with bradykinesia, or with the PIGD form of PD, is associated with more functional disability than when the symptoms are dominated by tremor or begin at a younger age.

Core outcome domains for chronic pain clinical trials

&NA; Objective. To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. Methods. Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. Conclusions. There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.

HIV-associated cognitive impairment before and after the advent of combination therapy

The objective of this study was to describe the occurrence of HIV dementia and neuropsychological testing abnormalities in a new cohort of HIV-seropositive individuals at high risk for HIV dementia and to compare these results to a cohort before the advent of highly active antiretroviral therapy (HAART). HAART has been associated with improvements in cognitive performance in some HIV-infected patients. However, it is uncertain whether HAART has changed the frequency of specific neurocognitive abnormalities. Baseline data from 272 HIV-seropositive subjects in the Dana cohort recruited from January, 1994, to December, 1995, and 251 HIV-seropositive subjects in the Northeastern AIDS Dementia Consortium (NEAD) cohort recruited from April, 1998, to August, 1999, were compared. Participants in both cohorts received nearly identical assessments. After adjusting for differences in age, education, gender, race, and CD4 count between the two cohorts, there were no differences in the occurrence of HIV dementia or abnormalities either 1 SD or 2 SDs below established norms for any of the neuropsychological tests. Even though HAART has reduced the incidence of HIV dementia, HIV-associated cognitive impairment continues to be a major clinical problem among individuals with advanced infection.

Treatment of ADHD in children with tics: A randomized controlled trial

BACKGROUND The treatment of children with attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS) has been problematic because methylphenidate (MPH)--the most commonly used drug to treat ADHD--has been reported to worsen tics and because clonidine (CLON)--the most commonly prescribed alternative--has unproven efficacy. METHODS The authors conducted a multicenter, randomized, double-blind clinical trial in which 136 children with ADHD and a chronic tic disorder were randomly administered CLON alone, MPH alone, combined CLON + MPH, or placebo (2 x 2 factorial design). Each subject participated for 16 weeks (weeks 1-4 CLON/placebo dose titration, weeks 5-8 added MPH/placebo dose titration, weeks 9-16 maintenance therapy). RESULTS Thirty-seven children were administered MPH alone, 34 were administered CLON alone, 33 were administered CLON + MPH, and 32 were administered placebo. For our primary outcome measure of ADHD (Conners Abbreviated Symptom Questionnaire--Teacher), significant improvement occurred for subjects assigned to CLON (p < 0.002) and those assigned to MPH (p < 0.003). Compared with placebo, the greatest benefit occurred with combined CLON + MPH (p < 0.0001). CLON appeared to be most helpful for impulsivity and hyperactivity; MPH appeared to be most helpful for inattention. The proportion of individual subjects reporting a worsening of tics as an adverse effect was no higher in those treated with MPH (20%) than those being administered CLON alone (26%) or placebo (22%). Compared with placebo, measured tic severity lessened in all active treatment groups in the following order: CLON + MPH, CLON alone, MPH alone. Sedation was common with CLON treatment (28% reported moderate or severe sedation), but otherwise the drugs were tolerated well, including absence of any evident cardiac toxicity. CONCLUSIONS Methylphenidate and clonidine (particularly in combination) are effective for ADHD in children with comorbid tics. Prior recommendations to avoid methylphenidate in these children because of concerns of worsening tics are unsupported by this trial.

Freezing of gait in PD Prospective assessment in the DATATOP cohort

Objective: To study the development of freezing of gait in PD. Background: Freezing of gait is a common, disabling, and poorly understood symptom in PD. Methods: The authors analyzed data from 800 patients with early PD from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) clinical trial who were assigned either placebo, deprenyl, tocopherol, or the combination of deprenyl and tocopherol. The primary outcome measure was the time from randomization until the freezing of gait score on the Unified Parkinson’s Disease Rating Scale (UPDRS) became positive. Results: Fifty-seven patients (7.1%) had freezing of gait at study entry and 193 (26%) of the remaining patients experienced the symptom by the end of the follow-up period. Those with freezing of gait at baseline had significantly more advanced disease than those without the symptom, as measured by total UPDRS and Hoehn and Yahr stage. High baseline risk factors for developing freezing of gait during the follow-up period were the onset of PD with a gait disorder; higher scores of rigidity, postural instability, bradykinesia and speech; and longer disease duration. In contrast, tremor was strongly associated with a decreased risk for freezing of gait. At the end of follow-up, the signs most strongly associated with the freezing phenomenon were gait, balance, and speech disorders, not rigidity or bradykinesia. Deprenyl treatment was strongly associated with a decreased risk for developing freezing of gait; tocopherol had no effect. Conclusions: Freezing of gait is directly related to duration of PD. Risk factors at onset of disease are the absence of tremor and PD beginning as a gait disorder. The development of freezing of gait in the course of the illness is strongly associated with the development of balance and speech problems, less so with the worsening of bradykinesia, and is not associated with the progression of rigidity. These results support the concept that the freezing phenomenon is distinct from bradykinesia. Deprenyl, in the absence of l-dopa, was found to be an effective prophylactic treatment and should be considered for patients with PD who have an onset of gait difficulty.

Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations.

ABSTRACT An essential component of the interpretation of results of randomized clinical trials of treatments for chronic pain involves the determination of their clinical importance or meaningfulness. This involves two distinct processes—interpreting the clinical importance of individual patient improvements and the clinical importance of group differences—which are frequently misunderstood. In this article, we first describe the essential differences between the interpretation of the clinical importance of patient improvements and of group differences. We then discuss the factors to consider when evaluating the clinical importance of group differences, which include the results of responder analyses of the primary outcome measure, the treatment effect size compared to available therapies, analyses of secondary efficacy endpoints, the safety and tolerability of treatment, the rapidity of onset and durability of the treatment benefit, convenience, cost, limitations of existing treatments, and other factors. The clinical importance of individual patient improvements can be determined by assessing what patients themselves consider meaningful improvement using well‐described methods. In contrast, the clinical meaningfulness of group differences must be determined by a multi‐factorial evaluation of the benefits and risks of the treatment and of other available treatments for the condition in light of the primary goals of therapy. Such determinations must be conducted on a case‐by‐case basis, and are ideally informed by patients and their significant others, clinicians, researchers, statisticians, and representatives of society at large.

Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial☆

OBJECTIVE To evaluate whether treatment with the anticonvulsant gabapentin may be effective in reducing hot flash frequency and severity. METHODS A randomized, double-blind, placebo-controlled trial was conducted in 59 postmenopausal women with seven or more hot flashes per day examining the effects of gabapentin 900 mg per day on hot flash frequency after 12 weeks of treatment. Subsequently, study patients were enrolled in a 5-week, open-label treatment phase, during which patients could increase the dose of gabapentin to 2700 mg per day, if needed. RESULTS After 12 weeks of double-blind treatment, intention-to-treat analysis showed that gabapentin 900 mg per day was associated with a 45% reduction in hot flash frequency and a 54% reduction in hot flash composite score (frequency and severity combined into one score) from baseline, compared with 29% (P = .02) and 31% (P = .01) reductions, respectively, for placebo. Four patients (13%) in the gabapentin group and one (3%) in the placebo group withdrew from the double-blind study because of adverse events. Fifteen patients (50.0%) in the gabapentin group reported at least one adverse event, compared with eight patients (27.6%) in the placebo group. Higher, open-label gabapentin dosing was associated with 54% and 67% reductions in hot flash frequency and composite score from baseline, respectively. CONCLUSION Gabapentin is effective in reducing hot flash frequency and severity in postmenopausal women.

Research design considerations for confirmatory chronic pain clinical trials: IMMPACT recommendations.

&NA; There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.

Developing patient-reported outcome measures for pain clinical trials : IMMPACT recommendations

a University of Washington, Seattle, WA 98195, USA b University of Rochester School of Medicine and Dentistry, Rochester, NY, USA c United States Food and Drug Administration, Rockville, MD, USA d Northwestern University, Chicago, IL, USA e Johnson and Johnson, Raritan, NY, USA f AstraZeneca, Wilmington, DE, USA g University of California San Diego, La Jolla, CA, USA h Merck and Company, Blue Bell, PA, USA i University of Texas, M.D. Anderson Cancer Center, USA j American Chronic Pain Association, Rocklin, CA, USA k Allergan, Inc, Irvine, CA, USA l National Institute of Dental and Craniofacial Research, Bethesda, MD, USA m University of Pennsylvania, Philadelphia, PA, USA n Johns Hopkins University, Baltimore, MD, USA o University Health Network and University of Toronto, Toronto, Canada p Novartis Pharmaceuticals, East Hanover, NJ, USA q VA Connecticut Healthcare System, West Haven, CT, USA r Yale University, New Haven, CT, USA s Celgene Corporation, Warren, NJ, USA t Pfizer Global Research and Development, Ann Arbor, MI, USA u Dalhousie University, Halifax, Nova Scotia, Canada v London Regional Cancer Centre, London, Ont., Canada