Decentralized Clinical Trials: Scientific Considerations Through the Lens of the Estimand Framework.

While industry and regulators' interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient's experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site. This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions, and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimands.

Efficacy and safety of levetiracetam as adjunctive therapy in adult patients with uncontrolled partial epilepsy: the Asia SKATE II Study.

This study evaluated the safety and efficacy of levetiracetam as adjunctive therapy for partial seizures in everyday clinical practice in Asian populations. Patients aged > or =16 years (N=251) with inadequately controlled partial epilepsy were recruited from 29 centers across Asia. Levetiracetam was added to existing antiepileptic medication for 16 weeks at a starting dose of 500 or 1000 mg/day and titrated to a maximum of 3000 mg/day according to clinical response. The study completion rate was 86.9%. Adverse events were reported by 73.3% of patients and were generally mild, leading to treatment withdrawal in only 7.2%. The most common adverse events were somnolence (30.3%) and dizziness (14.7%). Compared with pretreatment baseline, 44.0% of patients had a > or =50% reduction in seizure frequency, with a median reduction of 46.4%, and 17.7% became seizure free during the treatment period. Levetiracetam was well tolerated and efficacious as adjunctive therapy for partial epilepsy in clinical practice among Asian populations.

Levetiracetam as add-on therapy for idiopathic generalized epilepsy syndromes with onset during adolescence: analysis of two randomized, double-blind, placebo-controlled studies.

PURPOSE: To assess the efficacy and tolerability of adjunctive levetiracetam in idiopathic generalized epilepsy (IGE) syndromes with onset during adolescence: juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures on awakening (GTCSA). METHODS: Supplementary analysis of two double-blind, placebo-controlled trials. Patients received levetiracetam (target dose: adults 3000 mg/day; children 60 mg/kg/day; n=15 JAE, 78 JME, and 22 GTCSA) or placebo (n=12 JAE, 89 JME, and 27 GTCSA) for 16-24 weeks (including 4-week uptitration) in addition to 1-2 antiepileptic drugs. RESULTS: Responder rates (> or =50%) were significantly higher for levetiracetam versus placebo for JAE (53.3% vs. 25.0%; p=0.004), JME (61.0% vs. 24.7%; p<0.001), and GTCSA (61.9% vs. 29.6%; p=0.024). Seizure freedom rates were significantly higher for levetiracetam versus placebo for JME (20.8% vs. 3.4%; p=0.002); differences between treatment groups for JAE (33.3% vs. 8.3%; p=0.15) and GTCSA (23.8% vs. 11.1%; p=0.45) appeared to be clinically relevant, but did not reach statistical significance. The most frequent adverse events on levetiracetam were headache (levetiracetam 16.8% and placebo 14.8%) and somnolence (levetiracetam 9.7% and placebo 3.9%). CONCLUSIONS: Adjunctive levetiracetam was well tolerated and provided effective seizure control over 16-24 weeks in patients with insufficiently controlled IGE syndromes with onset during adolescence (JAE, JME, and GTCSA), supporting levetiracetam's broad spectrum of efficacy.

Measurement of seizure freedom in adjunctive therapy studies in refractory partial epilepsy: the levetiracetam experience.

PURPOSE: To assess the advantages and disadvantages of six methodologies used in calculating seizure freedom rates in placebo-controlled, adjunctive therapy trials of new antiepileptic drugs (AEDs) in partial epilepsy, and two methodologies for long-term follow-up studies. METHODS: Data from levetiracetam trials were used to illustrate the impact of different methodologies on seizure freedom rates. Seizure-freedom data for several new AEDs were identified from the published medical literature using MEDLINE and from a recent comprehensive textbook. RESULTS: Most randomized, placebo-controlled add-on clinical trials of new AEDs contain little or no information about seizure freedom. Importantly, the methodology used can profoundly affect results when calculating seizure-free rates. Seizure freedom data should be reported as well as the methodology used. The minimum duration for assessing seizure freedom should be the entire stable dose period in short-term trials and at least six months for long-term follow-up studies. It is proposed that the seizure freedom rates be calculated and reported with at least two different methodologies, one that considers patients withdrawing from treatment without having had a seizure as successes, and one that considers the same patients as failures. For an effective and well-tolerated AED, seizure freedom rates will be consistent across the two methodologies. CONCLUSIONS: Seizure freedom is the ultimate goal of AED therapy and should be reported for all clinical trials. Methodological differences among the few clinical studies reporting seizure freedom rates make it difficult to compare results across trials. Improved reporting of methodologies and seizure-free rates is warranted.

Identifying baseline characteristics of placebo responders versus nonresponders in randomized double-blind trials of refractory partial-onset seizures.

In add-on studies of partial-onset seizures, the placebo response, defined as a 50% decrease from baseline in seizure frequency, ranges from 0-19%. Reasons for this significant difference between placebo groups in different trials are not given in the literature. This exploratory analysis was undertaken to compare the baseline characteristics of placebo responders and nonresponders, in an attempt to identify common features. The pooled statistical analysis was performed on the database for three pivotal studies of levetiracetam (n = 904). Using the 50% response definition, we found that 45.6% of placebo nonresponders were on one antiepileptic drug at baseline, compared with 69% of placebo responders. The difference in number of baseline antiepileptic drugs was almost statistically significant (p = 0.056). Placebo nonresponders also tended to have epilepsy for longer than responders. The mean age at onset of epilepsy was consistently different between placebo nonresponders and responders (15.2 versus 20.8 years, respectively; p = 0.019). These findings suggest that the placebo response is higher in patients with partial-onset seizures who are taking only one antiepileptic drug at baseline and have later onset and shorter duration of epilepsy than in patients on more than one antiepileptic drug at baseline with earlier onset and longer duration of epilepsy.

Efficacy and safety of levetiracetam (up to 2000 mg/day) in Taiwanese patients with refractory partial seizures: a multicenter, randomized, double-blind, placebo-controlled study.

PURPOSE: To assess the efficacy and safety of adjunctive levetiracetam (LEV) therapy in controlling partial-onset seizures refractory to other antiepileptic drugs (AEDs) in a multicenter study in Taiwanese adults. METHODS: Ninety-four patients aged 16-60 years with refractory partial seizures were randomized to receive LEV (n = 47) or placebo (47) for 14 weeks and composed the intention-to-treat (ITT) population. After the first 2 weeks, LEV patients had their dosage increased from 500 mg twice daily to 1,000 mg twice daily. A 12-week maintenance phase followed, after which patients switched to long-term, open-label LEV therapy or entered a 4-week phase of medication discontinuation. RESULTS: All patients from the ITT population, except one LEV-treated patient with missing seizure-count data, were included in the primary efficacy analysis. The least square mean of logarithmically transformed weekly partial-seizure frequency was significantly lower in the LEV than in the placebo group (0.813 vs. 1.085; p = 0.001). LEV reduced log-transformed weekly partial-seizure frequency by 23.8% (95% confidence interval, 10.4-35.2%) relative to placebo. Significantly more LEV than placebo patients (43.5% vs. 10.6%) experienced a response of a >or=50% decrease from baseline in weekly frequency of partial seizures [odds ratio, 6.5 (95% CI, 2.2-19.3); p < 0.001]. Adverse events were reported in 34 (72.3%) of 47 LEV-treated patients and 32 (68.1%) of 47 placebo patients. The three most common adverse events in the LEV and placebo groups were somnolence (40.4% and 14.9%), dizziness (14.9% and 8.5%), and headache (10.6% and 8.5%), respectively. Only four patients (three LEV-treated patients and one placebo patient) were withdrawn from the study because of adverse events. CONCLUSIONS: Adjunctive LEV therapy,

Tolerability of levetiracetam in elderly patients with CNS disorders.

The purpose of this analysis was to compare treatment-emergent adverse events (TEAE) related to use of levetiracetam (LEV) reported by young and elderly patients with anxiety and cognitive disorders, and young epilepsy patients. The LEV database includes reports of TEAE from trials of patients with diagnoses of a cognitive disorder (N=719), an anxiety disorder (N=1510), or localization-related epilepsy (N=1023) who participated in clinical trials lasting up to 16 weeks. Patients were grouped as young (<65 years) or elderly (> or = 65 years). The most common TEAE occurring most frequently in the LEV-treated groups were abdominal pain, asthenia, headache, anorexia, weight loss, dizziness, insomnia, somnolence, and tremor. The only significant differences in TEAE were seen between young and elderly groups with anxiety disorders (>3% higher for LEV than for placebo-treated patients) in headache (5.2% elderly, -0.9% young, P=0.041), and tremor (5.2 and -0.5%, respectively, P=0.022) and between young anxiety patients and young epilepsy patients for somnolence (-0.7 and 5.4%, respectively, P=0.036). For the other TEAEs there was no evidence for consistent differences between young and elderly patients and between patients with different CNS disorders. Overall, LEV was well tolerated by all patient groups. The favorable adverse event profile suggests that LEV might be suitable for use by elderly patients.

A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials.

This report reviews behavioral adverse events occurring among adults receiving levetiracetam (LEV) or placebo who participated in short-term, placebo-controlled studies in epilepsy (1023), cognitive disorders (719), or anxiety disorders (1510) and epilepsy patients (1393) observed in long-term trials. Behavioral events (affective, psychotic, and suicidal symptoms) were significantly more common among epilepsy patients than cognition or anxiety patients treated with LEV for similar durations (P=0.022). Affective symptoms occurring at 1% or more often in epilepsy placebo-controlled trials included depression (3.8% LEV-2.1% placebo), nervousness (3.8%-1.8%), hostility (2.3%-0.9%), anxiety (1.8%-1.1%), and emotional lability (1.7%-0.2%). Patients with cognitive and anxiety disorders had lower incidences of these symptoms. The incidence of behavioral events in LEV-treated epilepsy patients was lower than rates reported for some other antiepileptic drugs. These data support the hypothesis that some feature related to epilepsy is the cause of many behavioral events rather than the addition of a specific antiepileptic drug.

Evidence for sustained efficacy of levetiracetam as add-on epilepsy therapy.

PURPOSE: To evaluate the long-term clinical usefulness of levetiracetam (LEV, Keppra((R))(1)) as add-on therapy in patients with refractory epilepsy. METHODS: Data for all 1422 patients with refractory epilepsy treated with LEV during the development program were analyzed for changes in seizure frequency per week, seizure freedom, and adverse events. RESULTS: Median percent reduction from baseline in seizure frequency per week over the whole treatment period was 39.6%, and no decrease over time was observed within each cohort exposed to LEV for durations ranging from 6 to 54 months. The median treatment period was 399 days (range 1-8 years). The proportion of responders during the first 3 months of LEV treatment was 39.2%. This proportion remained stable at 6 months (36.1%). Overall, 38.6 and 20.1% of patients had reductions in seizure frequency of at least 50 and 75%. Sixty-five (4.6%) patients were seizure-free over their entire treatment period, compared with 167 (11.7%) and 126 (8.9%) during their last 6 and 12 months of follow-up. Ninety-seven (19.8%) of 491 patients who received only one other antiepileptic drug (AED) in addition to LEV were seizure-free during their last 6 months. The proportion of patients who reduced their number of concomitant AEDs was 14.4% (205 patients), while 5.5% (79 patients) were treated with LEV only at the end of follow-up. Accidental injury (28.0%), infection (26.6%), headache (25.8%), somnolence (23%), asthenia (22.6%), and dizziness (18.9%) were among the most common adverse events. CONCLUSION: LEV offers sustained efficacy in patients with refractory partial seizures, and its long-term tolerability is similar to that seen in the short-term placebo-controlled trials.