Dixie Ecklund

Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine

Background Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established. Methods We conducted a randomized, double‐blind, placebo‐controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28‐day baseline period with the last 28 days of a 24‐week trial. Secondary outcomes were headache‐related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment. Results A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between‐group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between‐group differences in headache‐related disability, headache days, or the percentage of patients who completed the 24‐week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt. Conclusions There were no significant differences in reduction in headache frequency or headache‐related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281).

Cluster-Randomized Trial of a Physician/Pharmacist Collaborative Model to Improve Blood Pressure Control

Background—The purpose of this study was to evaluate if a physician/pharmacist collaborative model would be implemented as determined by improved blood pressure (BP) control in primary care medical offices with diverse geographic and patient characteristics and whether long-term BP control could be sustained. Methods and Results—Prospective, cluster-randomized trial of 32 primary care offices stratified and randomized to control, 9-month intervention (brief), and 24-month intervention (sustained). We enrolled 625 subjects with uncontrolled hypertension; 54% from racial/ethnic minority groups and 50% with diabetes mellitus or chronic kidney disease. The primary outcome of BP control at 9 months was 43% in intervention offices (n=401) compared with 34% in the control group (n=224; adjusted odds ratio, 1.57 [95% confidence interval, 0.99–2.50]; P=0.059). The adjusted difference in mean systolic/diastolic BP between the intervention and control groups for all subjects at 9 months was −6.1/−2.9 mm Hg (P=0.002 and P=0.005, respectively), and it was −6.4/−2.9 mm Hg (P=0.009 and P=0.044, respectively) in subjects from racial or ethnic minorities. BP control and mean BP were significantly improved in subjects from racial minorities in intervention offices at 18 and 24 months (P=0.048 to P<0.001) compared with the control group. Conclusions—Although the results of the primary outcome (BP control) were negative, the key secondary end point (mean BP) was significantly improved in the intervention group. Thus, the findings for secondary end points suggest that team-based care using clinical pharmacists was implemented in diverse primary care offices and BP was reduced in subjects from racial minority groups. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00935077.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUND Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Similar Blood Pressure Values Across Racial and Economic Groups: Baseline Data from a Group Randomized Clinical Trial

This paper examines baseline characteristics from a prospective, cluster‐randomized trial in 32 primary care offices. Offices were first stratified by percentage of minorities and level of clinical pharmacy services and then randomized into 1 of 3 study groups. The only differences between randomized arms were for marital status (P=.03) and type of insurance coverage (P<.001). Blood pressures (BPs) were similar in Caucasians and minority patients, primarily blacks, who were hypertensive at baseline. On multivariate analyses, patients who were 65 years and older had higher systolic BP (152.4±14.3 mm Hg), but lower diastolic BP (77.3±11.8 mm Hg) compared with those younger than 65 years (147.4±15.0/88.6±10.6 mm Hg, P<.001 for both systolic and diastolic BP). Other factors significantly associated with higher systolic BP were a longer duration of hypertension (P=.04) and lower basal metabolic index (P=.011). Patients with diabetes or chronic kidney disease had a lower systolic BP than those without these conditions (P<.0001). BP was similar across racial and socioeconomic groups for patients with uncontrolled hypertension in primary care, suggesting that patients with uncontrolled hypertension and an established primary care relationship likely have different reasons for poor BP control than other patient populations.

The Childhood and Adolescent Migraine Prevention (CHAMP) Study: A Report on Baseline Characteristics of Participants

To describe baseline headache characteristics of children and adolescents participating in a multicenter, randomized, double‐blinded, placebo‐controlled, comparative effectiveness study of amitriptyline, topiramate, and placebo for the prevention of migraine (CHAMP Study).

Designing Clinical Trials for Dystonia

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.

A Cluster-Randomized Trial of a Centralized Clinical Pharmacy Cardiovascular Risk Service to Improve Guideline Adherence

Numerous studies have demonstrated the value of including pharmacists in team‐based care to improve adherence to cardiovascular (CV) guidelines, medication adherence, and risk factor control. However, there is limited information on whether these models can be successfully implemented more widely in diverse settings and populations. The purpose of this study is to evaluate whether a centralized, web‐based cardiovascular risk service (CVRS) managed by clinical pharmacists will improve guideline adherence in multiple primary care medical offices with diverse geographic and patient characteristics.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll‐like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal‐appearing brain tissue, the thickness of the retinal nerve‐fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was ‐0.0010 per year with ibudilast and ‐0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain‐tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT‐MS ClinicalTrials.gov number, NCT01982942.)

Immunohistochemical Method and Histopathology Judging for the Systemic Synuclein Sampling Study (S4)

Immunohistochemical (IHC) α-synuclein (Asyn) pathology in peripheral biopsies may be a biomarker of Parkinson disease (PD). The multi-center Systemic Synuclein Sampling Study (S4) is evaluating IHC Asyn pathology within skin, colon and submandibular gland biopsies from 60 PD and 20 control subjects. Asyn pathology is being evaluated by a blinded panel of specially trained neuropathologists. Preliminary work assessed 2 candidate immunoperoxidase methods using a set of PD and control autopsy-derived sections from formalin-fixed, paraffin-embedded blocks of the 3 tissues. Both methods had 100% specificity; one, utilizing the 5C12 monoclonal antibody, was more sensitive in skin (67% vs 33%), and was chosen for further use in S4. Four trainee neuropathologists were trained to perform S4 histopathology readings; in subsequent testing, their scoring was compared to that of the trainer neuropathologist on both glass slides and digital images. Specificity and sensitivity were both close to 100% with all readers in all tissue types on both glass slides and digital images except for skin, where sensitivity averaged 75% with digital images and 83.5% with glass slides. Semiquantitative (0-3) density score agreement between trainees and trainer averaged 67% for glass slides and 62% for digital images.