Implementing Digital Technologies in Clinical Trials: Lessons Learned.

Multiple digital health technologies have been evaluated across clinical development programs, including external, wearable, implantable, and ingestible devices and sensors, along with digital mobile health applications (apps) that are accessible via users' personal electronic devices (e.g., smartphones, tablets, and computers). Several of these technologies have been incorporated into our ongoing neurology and respiratory clinical development programs. Based on our experience, one of the greatest potential benefits of digital health technologies is the ability to collect objective and/or biological data continuously or at regular intervals outside of office visits during a patient's normal daily activities to provide additional efficacy and safety information, versus data capture from traditional episodic, time point-based office visits. Many challenges encountered with digital health technologies can be successfully addressed by providing the appropriate training to staff and patients, ensuring availability of appropriate infrastructure support, and conducting pilot studies before scaling up to larger trials. Overall, our experience with digital health technologies demonstrated their potential to increase the amount of objective data collected in clinical trials, expand patient access to trials, and facilitate further improvement of clinical outcomes.

The impact of background antiepileptic drugs on the efficacy and safety of pregabalin in treating partial-onset seizures: a post hoc analysis of combined clinical trials.

Pregabalin is used as adjunctive treatment for partial-onset seizures and is often combined with multiple antiepileptic drugs (AEDs) from different classes. The objectives of this post hoc analysis were to evaluate the efficacy and safety of pregabalin when added to different AED regimens and to identify specific AED combinations that in conjunction with pregabalin yield high responder rates. Data from six double-blind, randomized studies of pregabalin in patients with partial-onset seizures were pooled for analysis (N=1775). When the treatment groups (placebo, 150mg, 300mg, 600mg, and flexible dose) were stratified by the number of concomitant AEDs (one, two or three or more), modeling results suggested that the magnitude of improvement on either ≥50% responder rate or mean response ratio remained consistent regardless of the number of concomitant AEDs. Adverse events were typical of pregabalin and, in general, did not vary as the number of concomitant AEDs increased. A cluster analysis was performed to identify possible combinations of AEDs that yielded high ≥50% responder rates. The majority of patients (>90%) fell within two clusters that yielded high responder rates, while <10% of the patients fell within two clusters that yielded low responder rates. Numerous AED combinations, ranging from 6 to 11, occurred within each cluster. In summary, pregabalin provided a consistent improvement in seizure reduction and comparable tolerability in patients with partial-onset epilepsy regardless of the number of concomitant AEDs.

Pregabalin or placebo used adjunctively with levetiracetam in refractory partial-onset epilepsy: a post hoc efficacy and safety analysis in combined clinical trials.

OBJECTIVE: Some patients with epilepsy require treatment with >1 adjunctive antiepileptic drug (AED) to achieve adequate seizure remission. The purpose of this analysis was to evaluate the efficacy and safety of adding adjunctive pregabalin to an AED regimen that included levetiracetam in patients with refractory partial-onset epilepsy. RESEARCH DESIGN AND METHODS: Data from the pregabalin and placebo arms of two placebo-controlled, double-blind, randomized studies of pregabalin in patients who received adjunctive treatment with levetiracetam in addition to ≥1 other AEDs were pooled for this post hoc analysis. Patients (aged ≥18 years) had ≥4 partial-onset seizures and no 28-day period free of seizures during baseline. Efficacy outcomes included Response Ratio (RRatio), change from baseline in seizure frequency, proportion of patients with ≥50% reduction in seizure frequency, and 28-day seizure-freedom rate. Safety was evaluated using adverse events (AEs). RESULTS: In total, 138 patients were included in the analysis (placebo, n = 47; pregabalin, n = 91). Pregabalin was significantly better than placebo for difference in least squares mean of the RRatio (-16.4; 95% confidence interval [CI]: -28.5, -4.5; p = 0.0085), median of the difference in percentage change from baseline in seizure frequency (-22.3; 95% CI: -40.1, -7.2; p = 0.0095), and proportion of 50% responders (36.3 vs. 17.0; odds ratio, 3.2; 95% CI: 1.3, 8.3; p = 0.018), but not 28-day seizure-freedom rate (7 [7.7%] vs. 2 [4.3%]; p = 0.353). The most common AEs when adding pregabalin were dizziness/vertigo, fatigue, somnolence, blurred vision, and increased weight that were not proportional to the number of concomitant AEDs. CONCLUSIONS: In this population of patients with refractory partial-onset seizures, adding pregabalin to an AED regimen with levetiracetam produced further seizure reductions. The safety profile of pregabalin in patients receiving levetiracetam and ≥1 other AEDs did not appear to be compromised by the number of concomitant AEDs.

Effect of divalproex on metabolic parameters is dose related in migraine prophylaxis.

OBJECTIVE: To examine the metabolic effects of three divalproex dosing regimens in patients with migraine. BACKGROUND: Epidemiological and clinical studies have demonstrated a strong association between serum lipid levels and the development of coronary artery disease. Thus, it is important to understand the impact of chronically administered medications on serum lipids. Metabolic properties of divalproex, an approved and commonly used treatment for migraine prophylaxis, have not been systematically studied in patients with migraine. METHODS: Adult patients with migraine were randomized to receive one of three daily doses of divalproex (500 mg [n = 45], 1000 mg [n = 43], or 1500 mg [n = 44]) or placebo (n = 44) for 12 weeks. Post hoc analyses were performed to determine the effects of divalproex on total cholesterol, glucose, weight, and body mass index (BMI). RESULTS: The treatment groups were similar at baseline based on demographic and clinical characteristics and the use of concomitant medications. Divalproex resulted in a dose-related mean decrease from baseline in total cholesterol: -5.7 mg/dL or 3% reduction with 500 mg/day; -8.4 mg/dL or 4% reduction with 1000 mg/day; and -12.8 mg/dL or 7% reduction with 1500 mg/day (P < .05 for 1500 mg/day vs. placebo). There were no differences between any divalproex dose group and placebo for mean change from baseline in glucose, weight, or BMI. CONCLUSIONS: Divalproex results in a dose-dependent reduction in serum cholesterol within the first 3 months of therapy, with no significant change in serum glucose or BMI.