Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials

OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period

Add-On Cannabidiol Treatment for Drug-Resistant Seizures in Tuberous Sclerosis Complex A Placebo-Controlled Randomized Clinical Trial

IMPORTANCE Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC). OBJECTIVE To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medicationresistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication. INTERVENTIONS Patients received oral cannabidiol at 25mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES The prespecified primary outcomewas the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period. RESULTS Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6%(95%CI, 40.4%-55.8%) for the CBD25 group, 47.5%(95%CI, 39.0%-54.8%) for the CBD50 group, and 26.5%(95%CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95%CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5%(95%CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo. CONCLUSIONS AND RELEVANCE Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0254476

Comparative utility of disability progression measures in PPMS: Analysis of the PROMiSe data set.

OBJECTIVE: To assess the comparative utility of disability progression measures in primary progressive MS (PPMS) using the PROMiSe trial data set. METHODS: Data for patients randomized to placebo (n = 316) in the PROMiSe trial were included in this analysis. Disability was assessed using change in single (Expanded Disability Status Scale [EDSS], timed 25-foot walk [T25FW], and 9-hole peg test [9HPT]) and composite disability measures (EDSS/T25FW, EDSS/9HPT, and EDSS/T25FW/9HPT). Cumulative and cross-sectional unconfirmed disability progression (UDP) and confirmed disability progression (CDP; sustained for 3 months) rates were assessed at 12 and 24 months. RESULTS: CDP rates defined by a ≥20% increase in T25FW were higher than those defined by EDSS score at 12 and 24 months. CDP rates defined by T25FW or EDSS score were higher than those defined by 9HPT score. The 3-part composite measure was associated with more CDP events (41.4% and 63.9% of patients at 12 and 24 months, respectively) than the 2-part measure (EDSS/T25FW [38.5% and 59.5%, respectively]) and any single measure. Cumulative UDP and CDP rates were higher than cross-sectional rates. CONCLUSIONS: The T25FW or composite measures of disability may be more sensitive to disability progression in patients with PPMS and should be considered as the primary endpoint for future studies of new therapies. CDP may be the preferred measure in classic randomized controlled trials in which cumulative disability progression rates are evaluated; UDP may be feasible for cross-sectional studies.This study was funded by Teva Pharmaceutical Industries

A randomized, placebo-controlled phase 2 trial of laquinimod in primary progressive multiple sclerosis

OBJECTIVE: To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS). METHODS: In the randomized, double-blind, placebo-controlled, phase 2 study ARPEGGIO (A Randomized Placebo-controlled trial Evaluating laquinimod in PPMS, Gauging Gradations In MRI and clinical Outcomes), eligible PPMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016 due to findings of cardiovascular events. RESULTS: 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg versus placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio = 0.4; 95% confidence interval, 0.26-0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) versus laquinimod 1.5 mg (66%) and placebo (78%). CONCLUSIONS: Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48

Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome A Randomized Clinical Trial

Question Is adjunctive cannabidiol at doses of 10 and 20 mg/kg/d superior to placebo in reducing convulsive seizure frequency in patients with Dravet syndrome? Findings This double-blind clinical trial randomized 199 children with Dravet syndrome to cannabidiol (10 or 20 mg/kg/d) or matched placebo for 14 weeks. Convulsive seizure frequency compared with baseline was reduced by 48.7% in the 10-mg/kg/d cannabidiol group and 45.7% in the 20-mg/kg/d cannabidiol group vs 26.9% in the placebo group. Meaning Both doses of adjunctive cannabidiol were similarly efficacious in reducing convulsive seizures associated with Dravet syndrome

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNB-1b trial

OBJECTIVE: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis

Carotid artery plaque composition : Relationship to clinical presentation and ultrasound B-mode imaging

Objective: To correlate B-mode ultrasound findings to carotid plaque histology. Design: European multicentre study (nine centres). Material and Methods: Clinical presentation and risk factors were recorded and preoperative ultrasound Duplex scanning with special emphasis on B-mode imaging studies was performed in 270 patients undergoing carotid endarterectomy. Perioperatively macroscopic plaque features were evaluated and the removed specimens were analysed histologically for fibrous tissue, calcification and 'soft tissue' (primarily haemorrhage and lipid). Results: Males had more soft tissue than females (p = 0.0006), hypertensive patients less soft tissue than normotensive (p = 0.01) and patients with recent symptoms more soft tissue than patients with earlier symptoms (p = 0.004). There was no correlation between surface description on ultrasound images compared to the surface judged intraoperatively by the surgeon. Echogenicity on B-mode images was inversely related to soft tissue (p=0.005) and calcification ions directly related to echogenicity (p < 0.0001). Heterogeneous plaques contained more calcification than homogeneous (p = 0.003), however there was no difference in content of soft tissue. Conclusion: Ultrasound B-mode characteristics are related to the histological composition of carotid artery plaques and to patient's history. These results may imply that patients with distant symptoms may be regarded and treated as asymptomatic patients whereas asymptomatic patients with echolucent plaques should be considered for carotid endarterectomy

Relationship between early clinical characteristics and long term disability outcomes: 16 year cohort study (follow-up) of the pivotal interferon β-1b trial in multiple sclerosis

Background: Evaluating the long term benefit of therapy in multiple sclerosis (MS) is challenging. Although randomised controlled trials (RCTs) demonstrate therapeutic benefits on short term outcomes, the relationship between these outcomes and late disability is not established. Methods: In a patient cohort from the pivotal interferon β-1b trial, the value of clinical and MRI measures were analysed, both at baseline and during the RCT, for predicting long term physical and cognitive outcome. Results: Baseline disability correlated with both physical (R 2=0.22; p&lt;0.0001) and cognitive (R 2=0.12; p&lt;0.0001) outcome after 16 years. Accrual of disability during the RCT (R 2=0.12; p&lt;0.0001) and annualised relapse rates during the trial correlated with physical outcome (R 2=0.12; p&lt;0.0001) but not with cognition. In contrast, baseline MRI measures of atrophy and lesion burden correlated with cognitive (R 2=0.21; p&lt;0.0001), but not with physical, outcome. Accumulation of plaque burden measured by MRI did not correlate with late physical disability or with cognitive outcome. Multivariate regression analysis using stepwise elimination demonstrated that baseline variables contributed independently to predicting long term outcomes while trial outcome variables contributed little. Overall, and considerably dependent on baseline measures, the models developed by this method accounted for approximately half of the variance in long term cognitive and disability outcome. Conclusions: Although on-trial change in some short term clinical measures correlated with long term physical and disability outcomes, the proportion of the variance explained by single commonly employed on-study variables was often small or undetectable. Better correlations were observed for several baseline measures, suggesting that long term outcome in MS may be largely determined early in the disease course. Trial registration number: http://Clinical Trials.gov, study registration NCT00206635

Mortality in patients with multiple sclerosis.

Mortality in patients with multiple sclerosis (MS) is significantly increased compared with the general population. Many questions concerning survival in MS are still unanswered due to the difficulty of comparing information collected at different times and in different geographic areas. The increasing incidence of MS, the improvement in care of the chronically disabled, and different methodologies may explain the lack of coherence among studies' results. Reported times to death from birth and from disease onset/diagnosis are highly variable. Patients older at onset or with primary progressive course have shorter survival; however, data on sex and mortality are contradictory. Changes in sex ratio in MS over time represent one possible explanation. MS is the main cause of death in ≥50% of patients and the incidence of deaths not due to MS varies among countries. Particularly, suicide is substantially increased in patients with MS, and, despite its varying incidence, mainly due to "cultural bias," it should be considered an MS-related cause of death. Recent results of the long-term follow-up study of interferon-β-1b demonstrated a significant reduction of mortality among treated patients. Notwithstanding its long latency, mortality is therefore an unambiguously valid long-term outcome in randomized controlled trials. It usefully combines the net impact of treatment efficacy on longevity and adverse events, which may reduce it