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Indication: As adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older
CADTH recommends that Epidiolex be reimbursed by public drug plans as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, if certain conditions are met.
Epidiolex should only be covered to treat patients aged 2 years or older who have a clinical diagnosis of seizures associated with LGS and experience at least 2 drop seizures per week over the course of 28 days, and whose seizures are not adequately controlled with 2 or more other antiseizure medications.
Epidiolex should be reimbursed if prescribed by a physician with expertise in the diagnosis and management of patients with LGS and if the price of Epidiolex is reduced.
LGS is a rare and severe form of epilepsy that starts in childhood. Patients experience multiple types of seizures that cannot be completely controlled by medications and are associated with life-threatening injuries and cognitive and behavioural impairments. The prevalence of LGS in Canada is estimated to be 12 in 100,000 people.
There is a need for new treatments to help patients attain and maintain seizure control with few side effects and better quality of life.
Treatment with Epidiolex is expected to cost approximately $5,200 to $83,193 per patient per year, depending on patient weight and dosage.
The Canadian Drug Expert Committee (CDEC) recommends that cannabidiol be reimbursed for the adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age and older only if the conditions listed in Table 1 are met.
Evidence from 2 randomized, placebo-controlled, phase III studies (the CARE 3 trial [N = 225] and CARE 4 trial [N = 171]) demonstrated that treatment with cannabidiol (at 10 mg/kg/day and 20 mg/kg/day doses), when added on to 1 or more (median = 3) background antiseizure medications (ASMs), may result in added clinical benefit for patients with LGS aged 2 to 55 years. In the CARE 3 trial, a statistically significant reduction was observed in median percentage change in drop seizure frequency after 14 weeks of treatment with cannabidiol 20 mg/kg/day (median difference −21.6%; 95% confidence interval [CI], −34.8 to −6.7; P = 0.0047) and cannabidiol 10 mg/kg/day (median difference −19.2%; 95% CI, −31.2 to −7.7; P = 0.0016), when compared to placebo. In the CARE 4 trial, a statistically significant reduction was observed in the median percentage change in drop seizure frequency after 14 weeks of treatment with cannabidiol 20 mg/kg/day (median difference −17.2%; 95% CI, −30.3 to −4.1; P = 0.0135), when compared to placebo. In addition, the results from the CARE 3 and CARE 4 trials showed that adjunctive cannabidiol (at both 10 mg/kg/day and 20 mg/kg/day doses) may be associated with a greater proportion of patients with at least a 50% reduction in drop seizures from baseline.
Patients identified a need for disease-modifying treatments that provide seizure control with sustained effectiveness, minimal adverse effects, and improved quality of life. Although there was insufficient evidence to evaluate the effects of cannabidiol on health-related quality of life (HRQoL) and drop seizure–free days, CDEC concluded that cannabidiol meets some patient needs by reducing seizure frequency and the associated burden for patients with LGS and their caregivers.
Using the sponsor-submitted price for cannabidiol and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for cannabidiol in combination with usual care was $186,373 per quality-adjusted life-year (QALY) compared with usual care alone. At this ICER, cannabidiol plus usual care is not cost-effective at a $50,000 per QALY willingness-to-pay threshold for patients aged 2 years or older with LGS whose symptoms are inadequately controlled by usual care. A price reduction is required for cannabidiol to be considered cost-effective at a $50,000 per QALY threshold.
Reimbursement Conditions and Reasons.
LGS is a lifelong, complex epilepsy syndrome associated with multiple seizure types that vary across patients. LGS presents in the first 4 years of life (peak age of onset: 3 to 5 years) in typically developing children, and is associated with refractory and multiple treatment-resistant seizure types, cognitive and behavioural impairments, and poor outcomes into adulthood. LGS has various etiologies, and patients exhibit multiple seizure types with distinctive electroencephalogram (EEG) features, including tonic seizures (stiffening of the body, upward eye gaze, dilated pupils, and altered breathing patterns) and atypical absence seizures (staring spells), followed by myoclonic jerks (sudden muscle jerks), tonic or atonic “drops” (brief loss of muscle tone), generalized tonic-clonic seizures (muscle stiffness and rhythmic jerking), and focal seizures. Atonic and tonic seizures can be accompanied by dangerous falls or “drop seizures” that often lead to injury. Indeed, LGS is considered a life-threatening condition associated with high rates of sudden unexpected death in epilepsy (SUDEP), and a risk of death among children with LGS that is 14 times higher than the risk in the US general population. Currently, LGS is diagnosed using clinical criteria; there are no specific diagnostic tests or biologic markers for the diagnosis of LGS. LGS affects between 3% and 10% of children with epilepsy, more commonly in males. The peak age for onset is between 3 and 5 years, with extreme incidence occurring in the first and 10th years of life. The prevalence of LGS in Canada, as estimated by the sponsor, is 12 in 100,000 people.
The goal of treatment is to achieve seizure freedom. In Canada, the only drugs currently indicated specifically for LGS are rufinamide and lamotrigine, both as add-ons to other ASMs. While lamotrigine is available through the Ontario Drug Benefit program, access to rufinamide must be obtained through the Exceptional Access Program. In addition to ASMs, most patients are also managed using enteral medications; dietary therapies such as ketogenic, modified Atkins, or low glycemic index diets; neuromodulation with vagus nerve stimulation or deep brain stimulation; and nonresective surgeries, such as corpus callosotomy. Surgical resection has limited use when the source of seizure activity can be identified. The clinical expert consulted by CADTH noted that purified cannabidiol from a licensed producer (so-called “artisanal cannabidiol” or medical cannabis) is available in Canada and has been used extensively for the treatment of drug-resistant LGS in children and adults, albeit at lower doses than what was used in clinical trials of cannabidiol.
Cannabidiol has been approved by Health Canada for the adjunctive treatment of seizures associated with LGS, Dravet syndrome, and tuberous sclerosis complex in patients aged 2 years and older. Cannabidiol is a cannabinoid. It is available as an oral solution, and the dosage recommended in the product monograph is up to a maximum dose of 10 mg/kg twice daily (20 mg/kg/day).
To make its recommendation, the committee considered the following information:
Patient group input was provided by the CEA. The CEA is a network of organizations supporting and advocating for people living with epilepsy and their families. Patient input was sourced from knowledge and experiences of patients, caregivers, clinicians, volunteers, donors, and funders, collected from 24 member associations. Based on input from the CEA, current treatments may fail in 30% of patients with epilepsy. According to the input, patients living with uncontrolled epilepsy are often socially isolated due to stigma and fear of rejection in social, work, and educational settings. Patients often experience depression and anxiety upon initial diagnosis, and continue to experience these conditions when ASMs stop working. Caregivers and family members are also impacted by epilepsy, as their lives may revolve around the seizures. Anxiety among caregivers is common, as they worry about when the next seizure will occur, the consequences of the epilepsy, and how to navigate social gatherings (e.g., when a young patient gets invited to a birthday party). In addition, caregivers often experience compassion fatigue because they cannot leave the patient alone, and are often sleep deprived due to sleep interruptions or anxiety, while living with many unpleasant side effects (e.g., mood swings, sexual dysfunction, suicidal thoughts, memory loss, fatigue, exhaustion, and so on) of the medications their loved ones are taking. Both patients and caregivers emphasized the importance of treatment that results in seizure freedom. However, patients and caregivers noted that they would accept a treatment that resulted in a reduction in the absolute number of seizures, as even a reduction in seizures could improve overall quality of life. Of note, because patients with intractable epilepsy are very often unemployed or underemployed, not covered under employer-funded insurance plans, and have restricted incomes, most drugs to treat their epilepsy are inaccessible. Accordingly, the CEA stressed the importance of having new medications placed on the provincial formulary so that patients with intractable epilepsy have access to novel treatments. Input provided by the CEA did not include input regarding experience with cannabidiol (Epidiolex).
The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of LGS.
The clinical experts consulted by CADTH for the purpose of the review noted that despite the multiple treatment options available, there are currently no treatments available to reverse the course of LGS. Using the available treatment options, the overall prognosis of LGS remains unfavourable, and not all patients respond to the available treatment. The clinical experts added that there is a need for treatment that can meaningfully improve quality life for both patients and their caregivers. The clinical experts noted that despite its novel mechanism of action compared to available therapies, cannabidiol does not address the underlying disease process any more than other available treatments. Accordingly, the clinical experts suggest that cannabidiol would complement other available treatments as a symptom management treatment. The clinical experts opined that cannabidiol could be combined with 1 or 2 first-line antiseizure drugs. The clinical experts also felt that it would be reasonable to require adequate trials of 1 or 2 other ASMs before the use of cannabidiol. The clinical experts expected that the approval of cannabidiol would lead to a shift away from the use of medical cannabidiol in jurisdictions where cannabidiol is reimbursed by either public or private drug insurance plans. Based on input from the clinical experts, it is difficult to predict which patients with LGS would be most likely to benefit from cannabidiol. Patients whose symptoms have not responded to multiple ASMs are generally less likely to respond to the next ASM; however, these are the patients who are most in need of novel therapies. The clinical experts suggested that patients should be screened for treatment according to the clinician’s judgment based on seizure characterization and frequency, etiology investigation, and previous ASM trialled, along with EEG interpretation. Based on the clinical experts’ input, a clinically meaningful response to treatment in epilepsy is assessed as the median reduction in seizure frequency over a 28-day period, a 50% or greater seizure reduction, and seizure freedom rates (i.e., reduction of total seizures per day and seizure-free days per month). The clinical experts added that seizure frequency should be assessed every 4 weeks. The clinical experts also noted that quality of life for both patients and caregivers is an important secondary outcome. Based on the clinical experts’ input, treatment with cannabidiol should be discontinued if patients develop persistent and progressive elevation of transaminases, and recurrent vomiting and diarrhea, which would compromise the absorption of antiseizure agents. In addition, treatment with cannabidiol should be reassessed if patients develop status epilepticus with no other reasonable explanation. Based on input received from the clinical experts, the prescribing and monitoring of cannabidiol for LGS should be limited to pediatric or adult neurologists who have special expertise in the management of epilepsy.
No clinician group input was received with this submission.
Responses to Questions From the Drug Programs.
Two studies were included in the sponsor-conducted systematic review: the CARE 3 and CARE 4 trials.
Both the CARE 3 and CARE 4 trials were multicentre, randomized, double-blind, phase III randomized controlled trials (RCTs) evaluating the efficacy of cannabidiol as adjunctive treatment in reducing drop seizures in patients aged 2 to 55 years with a clinical diagnosis of LGS.
In the CARE 3 trial, a total of 225 patients across 29 sites in 4 countries (US, Spain, France, and the UK) were randomized 1:1:1 to receive treatment with cannabidiol 20 mg/kg/day (n = 76), cannabidiol 10 mg/kg/day (n = 73), or volume-matched placebo (n = 76). Patients in the placebo group were split into 2 equivalent cohorts: half receiving 10 mg/kg/day (n = 38) dosing volumes, and half receiving 20 mg/kg/day (n = 38) dosing volumes. In the CARE 4 trial, a total of 171 patients across 24 sites in 3 countries (US, Netherlands, and Poland) were randomized to receive treatment with either cannabidiol 20 mg/kg/day (n = 86) or volume-matched placebo (n = 86). The randomization in both the CARE 3 trial and the CARE 4 trial was stratified by age group (2 to 5 years, 6 to 11 years, 12 to 17 years, and 18 to 55 years). Patients were titrated from a starting dose of 2.5 mg/kg up to 10 mg/kg/day over 7 days or 20 mg/kg/day over 11 days and remained at this dose level for the duration of the treatment period. Assigned treatments were add-ons to 1 or more background ASMs.
The primary efficacy end point for both trials was the reduction in the number of drop seizures (per 28 days) when compared with placebo in patients with LGS. Drop seizure was defined as a seizure event (atonic, tonic, or tonic-clonic) involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or hitting the one’s head on a surface. The key secondary outcome of interest was the number of patients considered treatment responders, defined as having a 50% reduction in drop seizures at the end of the treatment period. Other outcomes that were assessed in the CARE 3 and CARE 4 trials included in the CADTH report included: proportions of patients who experienced a 25%, 75%, or 100% reduction in drop seizures at the end of the treatment period; number of inpatient hospitalizations due to epilepsy; and HRQoL as assessed by the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire (for patients aged 2 to 18 years) or the Quality of Life in Epilepsy, Version 2 (QOLIE-31-P) questionnaire (for patients aged 19 years and older), and number of drop seizure–free days.
In the CARE 3 trial, the mean age of patients enrolled in the trial was 16.01 years (standard deviation [SD] = 10.77 years) in the cannabidiol 20 mg/kg/day group, 15.43 years (SD = 9.48 years) in the cannabidiol 10 mg/kg/day group, and 15.29 years (SD = 9.26 years) in the pooled placebo group. In the CARE 3 trial, the median number of drop seizures at baseline was higher in the cannabidiol 10 mg/kg/day group (median = 86.90; interquartile range [IQR], 14.0 to 7,494.0) than in the cannabidiol 20 mg/kg/day group (median = 85.53; IQR, 13.0 to 1,092.0) and the pooled placebo group (median = 80.25; IQR, 8.7 to 1,278.3). The proportion of patients reporting convulsive seizures lasting longer than 30 minutes was higher in the cannabidiol 20 mg/kg/day group (10.5%) than in the cannabidiol 10 mg/kg/day group (2.7%) and the pooled placebo group (3.9%). The mean number of prior ASMs was approximately 7, and the mean number of current ASMs being used at baseline was approximately 3 across treatment groups.
In the CARE 4 trial, the mean age of patients enrolled in the trial was 15.3 years (SD = 9.8 years) and 15.6 years (SD = 8.7 years) in the cannabidiol 20 mg/kg/day group and volume-matched placebo group, respectively. The median number of drop seizures at baseline was higher in the volume-matched placebo group (median = 74.67; IQR, 11.2 to 3,174.6) compared to the cannabidiol 20 mg/kg/day group (median = 71.43; IQR, 10.3 to 855.9). The mean number of ASMs was approximately 7, and the mean number of current ASMs being used at baseline was approximately 3 across treatment groups.
At the end of the 14-week treatment period in the CARE 3 trial, a reduction in median percentage change in drop seizure frequency was associated with treatment with cannabidiol 20 mg/kg/day (median difference = −21.6%; 95% CI, −34.8% to −6.7%; P = 0.0047) and cannabidiol 10 mg/kg/day (median difference = −19.2%; 95% CI, −31.2% to −7.7%; P = 0.0016), compared to the pooled placebo group.
At the end of the treatment period in the CARE 4 trial, a reduction in the median percentage change in drop seizure frequency was associated with treatment with cannabidiol 20 mg/kg/day compared to volume-matched placebo (median difference = −17.2%; 95% CI, −30.3% to −4.1%; P = 0.0135)
In the CARE 3 trial, during the treatment period, the difference in proportion of patients with at least a 50% reduction in drop seizure frequency from baseline between the cannabidiol 20 mg/kg/day group and the pooled placebo group was 25.0% (95% CI, 11.0% to 38.5%), and was 21.1% (95% CI, 7.6% to 34.7%) between the cannabidiol 10 mg/kg/day group and the pooled placebo group.
In the CARE 4 trial, the difference in proportion between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group was 20.7% (95% CI, 6.8% to 34.5%).
In the CARE 3 trial, during the treatment period, the difference in the proportion of patients with at least a 25% reduction in drop seizure frequency from baseline between the cannabidiol 20 mg/kg/day group and the pooled placebo group was 18.4% (95% CI, 2.8% to 34.0%), and was 19.6% (95% CI, 3.9% to 35.3%) between the cannabidiol 10 mg/kg/day group and the pooled placebo group.
In the CARE 4 trial, the difference in proportion between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group was 20.4% (95% CI, 5.8% to 35.1%).
In the CARE 3 trial, during the treatment period, the difference in the proportion of patients with at least a 75% reduction in drop seizure frequency from baseline between the cannabidiol 20 mg/kg/day group and the pooled placebo group was 22.4% (95% CI, 12.0% to 55.13%), and was 8.3% (95% CI, 0.3% to 16.3%) between the cannabidiol 10 mg/kg/day group and the pooled placebo group.
In the CARE 4 trial, the difference in proportion of patients with at least a 75% reduction in drop seizure frequency from baseline during the treatment period between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group was 11.5% (95% CI, 1.3% to 21.8%).
No patients experienced a 100% reduction in drop seizure frequency during the treatment period in either the CARE 3 trial or the CARE 4 trial.
In the CARE 3 trial, the number of patients with 1 or more inpatient hospitalizations due to epilepsy was 7 (9.2%) in the cannabidiol 20 mg/kg/day group, 6 (8.2%) in the cannabidiol 10 mg/kg/day group, and 6 (7.9%) in the pooled placebo group.
In the CARE 4 trial, the number of patients with 1 or more inpatient hospitalizations due to epilepsy was 10 (11.6%) in the cannabidiol 20 mg/kg/day group and 5 (5.9%) in the volumed-matched placebo group.
In the CARE 3 trial, overall QOLCE scores were available for 33 patients (43.4%) in the cannabidiol 20 mg/kg/day group, 36 patients (49.3%) in the cannabidiol 10 mg/kg/day group, and 38 patients (50%) in the pooled placebo group. At baseline, the overall mean QOLCE scores were comparable across the cannabidiol 20 mg/kg/day group, cannabidiol 10 mg/kg/day group, and the pooled placebo group, at 41.6 (SD = 15.6), 40.6 (SD = 15.4), and 41.4 (SD = 16.1), respectively. The adjusted mean treatment difference in change from baseline in overall QOLCE scores between the cannabidiol 20 mg/kg/day group and the pooled placebo group was −5.1 (−11.4 to 1.2), and was 1.6 (95% CI, −4.5 to 7.8) between the cannabidiol 10 mg/kg/day group and the pooled placebo group.
In the CARE 4 trial, overall QOLCE scores were available for 26 patients (30.2%) and 38 patients (44.7%) in the cannabidiol 20 mg/kg/day group and the volumed-matched placebo group, respectively. At baseline, the overall mean QOLCE scores were comparable between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group at 39.5 (SD = 12.6) and 39.1 (SD = 15.2), respectively. The adjusted mean treatment difference in change from baseline in overall QOLCE scores between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group was 3.7 (95% CI, −3.3 to 10.7).
In the CARE 3 trial, total QOLIE-31-P scores were available for 13 patients in the cannabidiol 20 mg/kg/day group, 14 patients in the cannabidiol 10 mg/kg/day group, and 10 patients in the pooled placebo group. At baseline, the total mean QOLIE-31-P scores were 50.2 (SD = 16.6) in the cannabidiol 20 mg/kg/day group, 56.0 (SD = 19.2) in the cannabidiol 10 mg/kg/day group, and 62.5 (SD = 13.6) in the pooled placebo group. The adjusted mean treatment difference in change from baseline in total QOLIE-31-P scores between cannabidiol 20 mg/kg/day group and the pooled placebo group was 2.9 (95% CI, −0.3 to 13.1), and was 3.6 (95% CI, −7.0 to 14.3) between the cannabidiol 10 mg/kg/day group and the pooled placebo group.
In the CARE 4 trial, total QOLIE-31-P scores were available for 14 patients (16.3%) in the cannabidiol 20 mg/kg/day group and 14 patients (16.5%) in the volume-matched placebo group. At baseline, the total QOLIE-31-P scores were comparable between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group, at 55.8 (SD = 13.5) and 57.3 (SD = 19.5), respectively. The adjusted mean treatment differences in total QOLIE-31-P were not calculated due to the low number of completed assessments.
In the CARE 3 trial, the mean number of drop seizure–free days increased in all treatment groups at the end of the treatment period. Compared to the pooled placebo group, treatment with cannabidiol 20 mg/kg/day was associated with an increase in the mean number of drop seizure–free days of 4.6 days (95% CI, 2.5 to 6.8 days), while treatment with cannabidiol 10 mg/kg/day was associated with an increase of 3.3 days (95% CI, 1.2 to 5.5 days).
In the CARE 4 trial, the mean number of drop seizure–free days increased in both treatment groups at the end of the treatment period. Compared to the volume-matched placebo group, treatment with cannabidiol 20 mg/kg/day was associated with a mean increase of 2.7 days (95% CI, 0.7 to 4.7 days).
The following outcomes were noted as being meaningful by the patient group and clinical experts consulted by CADTH, but not assessed in either the CARE 3 or CARE 4 trials: SUDEP rate, employment, and HRQoL of caregivers.
In the CARE 3 trial, at least 1 adverse event (AE) was reported among 93.9% of patients in the cannabidiol 20 mg/kg/day group, 83.6% of patients in the cannabidiol 10 mg/kg/day group, and 72.4% of patients in the pooled placebo groups.
In the CARE 4 trial, at least 1 AE was reported among 86.0% and 69.4% of patients in the cannabidiol 20 mg/kg/day group and volume-matched placebo group, respectively.
In the CARE 3 trial, at least 1 serious adverse event (SAE) was reported among 15.9% of patients in the cannabidiol 20 mg/kg/day group, 19.4% of patients in the cannabidiol 10 mg/kg/day group, and 10.5% of patients in the pooled 20 mg/kg/day and 10 mg/kg/day placebo groups.
In the CARE 4 trial, at least 1 SAE was reported among 23.3% and 4.7% of patients in the cannabidiol 20 mg/kg/day group and volume-matched placebo group, respectively.
In the CARE 3 trial, discontinuation of treatment due to AEs was reported among 7.3% of patients in the cannabidiol 20 mg/kg/day group, 1.5% of patients in the cannabidiol 10 mg/kg/day group, and 1.3% of patients in the pooled placebo group.
In the CARE 4 trial, discontinuation of treatment due to AEs was reported in 14.0% and 1.2% of patients in the cannabidiol 20 mg/kg/day group and the volume-matched placebo group, respectively.
There were no reported deaths in the CARE 3 trial. In the CARE 4 trial, 1 death (1.2% of patients) was recorded due to acute respiratory distress syndrome in the cannabidiol 20 mg/kg/day group.
Notable harms of interest were related to nervous system disorders (i.e., somnolence, status epilepticus, and sedation), hepatocellular injury or investigation (i.e., increased alanine aminotransferase [ALT] and aspartate aminotransferase [AST], bilirubin elevation and serum transaminase elevation), and gastrointestinal disorders (i.e., diarrhea, vomiting, and constipation).
In the CARE 3 trial, somnolence, status epilepticus, and sedation were reported in 30.5%, 4.9%, and 3.7% of patients, respectively, in the cannabidiol 20 mg/kg/day group; in 20.9%, 10.4%, and 3.0% of patients, respectively, in the cannabidiol 10 mg/kg/day group; and in 5.3%, 3.9%, and 1.3% of patients, respectively, in the pooled placebo group. Increased levels of ALT, AST, and serum transaminase were reported in 4.9%, 3.7%, and 1.2% of patients, respectively, in the cannabidiol 20 mg/kg/day group; in 4.5%, 3.7%, and 1.5% of patients, respectively, in the cannabidiol 10 mg/kg/day group; and in 1.3%, 1.3%, and 0% of patients, respectively, in the pooled placebo group. The following investigations were not reported in the CARE 3 trial: abnormal liver function test, acute hepatic failure, and hepatotoxicity. Diarrhea, vomiting, and constipation were reported in 14.6%, 12.2%, and 4.9% of patients, respectively, in the cannabidiol 20 mg/kg/day group; in 10.4%, 6.0%, and 4.5% of patients, respectively, in the cannabidiol 10 mg/kg/day group; and in 7.9%, 11.8%, and 3.9% of patients, respectively, in the pooled placebo group.
In the CARE 4 trial, somnolence, sedation, and status epilepticus were reported in 15.1%, 8.1%, and 1.2% of patients, respectively, in the cannabidiol 20 mg/kg/day group; and in 9.4%, 1.2%, and 1.2% of patients, respectively, in the volume-matched placebo group. The following hepatocellular injury and investigation AEs were reported in the cannabidiol 20 mg/kg/day group: increased ALT (9.3%), increased AST (7.0%), abnormal liver function test (4.7%), acute hepatic failure (3.5%), serum transaminase elevation (2.3%), hepatic failure (1.2%), and hepatotoxicity (1.2%). In the volume-matched placebo group, increased levels of ALT and AST were reported in 2.4% and 1.2% of patients, respectively. Diarrhea, vomiting, and constipation were reported in 18.6%, 10.5%, and 7.0% of patients, respectively, in the cannabidiol 20 mg/kg/day group; and in 8.2%, 16.5%, and 4.7% of patients, respectively, in the volume-matched placebo group.
The CARE 3 and CARE 4 trials were multicentre, randomized, double-blind, phase III RCTs. In both trials, patients were randomized centrally using interactive voice response system (IVRS) technology, which is typically adequate for concealing allocation until treatment assignment. IVRS technology was also used to dispense the investigational product allowing the treatment concealment for both patients and the investigator to remain blinded. Although the CARE 3 trial included 4 treatment types (cannabidiol 20 mg/kg/day, cannabidiol 10 mg/kg/day, volume-matched placebo 20 mg/kg/day, and volume-matched placebo 10 mg/kg/day), the study participants were randomized using a 1:1:1 randomization ratio to the cannabidiol 20 mg/kg/day treatment group, cannabidiol 10 mg/kg/day treatment group, and the placebo treatment group. The placebo group was split in half for patients to receive either the 20 mg/kg/day placebo or the 10 mg/kg/day placebo, and study results were reported based on the pooled placebo group. While this approach is acceptable, it relies on the assumption that randomization was successful in each group. Differences in baseline characteristics between cannabidiol 20 mg/kg/day, cannabidiol 10 mg/kg/day, and the pooled placebo groups were noted in the following factors: the proportion of patients reporting convulsive seizures longer than 30 minutes, and concomitant use of benzodiazepine derivatives at baseline. According to the clinical experts consulted by CADTH for the purpose of this review, it is unknown if the previously mentioned imbalances could influence treatment response given the rarity of LGS. At CADTH’s request, the sponsor reported that the assumptions related to splitting the placebo group and pooling results for analyses were not formally tested. However, the sponsor noted, as described in clinical study report for the CARE 3 trial, that post hoc sensitivity analyses were conducted on the primary outcome to determine if pooling the placebo group had an effect on the results. The analyses indicated that the efficacy response when cannabidiol 20 mg/kg/day was compared to placebo 20 mg/kg/day (and when the cannabidiol 10 mg/kg/day dose was compared to placebo 10 mg/kg/day) was similar to that for the doses versus the pooled placebo response. In the CARE 4 trial, the 1:1 randomization ratio and the randomization stratification factors appeared appropriate, and no notable baseline imbalances were observed between the cannabidiol 20 mg/kg/day group and the volume-matched placebo group.
In the CARE 3 trial, a higher proportion of patients in the cannabidiol 20 mg/kg/day group discontinued from the study compared to the cannabidiol 10 mg/kg/day and pooled placebo groups (approximately 12% versus approximately 3%). The higher discontinuation rate in the cannabidiol 20 mg/kg/day group appeared to be driven by AEs. In the CARE 4 trial, a higher proportion of patients in the cannabidiol 20 mg/kg/day group discontinued from the study compared to the volume-matched pooled placebo groups (9.3% versus 1.2%). The higher discontinuation rate in the cannabidiol 20 mg/kg/day group appeared to be driven by AEs. The application of the “missing not at random” assumption and sensitivity analysis exploring missing efficacy results due to treatment discontinuation suggests that bias due to uneven discontinuation was unlikely.
In both the CARE 3 and CARE 4 trials, all efficacy outcome measures were to be completed by the caregiver. To maintain consistency, the same caregiver, if patients had multiple caregivers, was to complete and answer the questionnaire and assessment. Seizure information in both studies was ascertained via patient or parent or caregiver report using an IVRS diary, while paper diaries were used to capture usage of the investigational product, concomitant medications, and AEs. Based on input from the clinical experts, patient and parent or caregiver reporting of seizures tended to be accurate for motor seizures; however, it was not very reliable or accurate for nonmotor seizures. Of note, seizure diaries are the standard method of collecting data for clinical trials, and the International League Against Epilepsy recommends the use of diaries for collecting seizure frequency data.19 Both the CARE 3 trial and the CARE 4 trial assessed HRQoL — an outcome deemed important by both patients and clinicians — using validated and reliable instruments: the QOLCE and the QOLIE-31-P. The double-blind nature of the trials minimized risk of bias in the measurement of subjective items of the QOLCE and QOLIE-31-P. However, comparative efficacy conclusions based on the HRQoL outcomes are limited because the QOLCE and the QOLIE-31-P were not part of the hierarchical testing procedure, and also because of the low completion rate across treatment groups. Total QOLCE scores were available for 47.6% and 36.3% of patients in the CARE 3 and CARE 4 trials, respectively, while total QOLI-31-P scores were available for 16.5% and 16.4% of patients in the CARE 3 and CARE 4 trials, respectively. Consequently, assessment of HRQoL in both trials is at high risk of attrition bias, although the extent and direction of the bias cannot be determined because it is not clear if the patients who completed the questionnaires were systematically different from those who did not. Of note, as the completion rates were similar between the treatment groups within the CARE 3 and CARE 4 trials, there is little risk of bias that attrition favoured any 1 treatment group.
Analysis of efficacy results in the CARE 3 and CARE 4 trials followed a defined statistical analysis plan. The primary and key secondary outcomes were addressed using a hierarchical gatekeeping procedure, which controlled for type 1 errors. The sponsor conducted additional sensitivity analyses of the primary efficacy outcome using the per-protocol analysis set, and testing the assumption that data were not missing at random. In all scenarios, the sensitivity analyses were consistent with the primary efficacy analysis.
The clinical experts consulted by CADTH for the purpose of this review were unable to assess if the results of the CARE 3 and CARE 4 trials were applicable to patients in the Canadian clinical setting. However, the clinical experts did note trial details that were applicable to the Canadian clinical setting, and others that were not representative of clinical practice in Canada. Briefly, the clinical experts noted that the treatment periods in the CARE 3 and CARE 4 trials were long enough to detect a meaningful treatment response on seizures in patients with LGS; however, it was uncertain if the treatment response observed could be sustained in the long term. Moreover, a longer study period would be required to detect a treatment response on cognitive functioning. In the Canadian setting, where the use of medicinal cannabis for adjunctive treatment of seizures associated with LGS can be accessed through the medical cannabis pathway supported by Health Canada, the clinical experts would not impose any sort of washout period before initiating pharmaceutical cannabidiol.
For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group. Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:
When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of certainty of evidence assessment was the presence of a clinically important reduction in the frequency of drop seizures (i.e., percentage change in the drop seizure frequency) and proportion of patients considered treatment responders (i.e., proportion of patients with ≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction in drop seizures) on thresholds informed by clinical expert opinion. Other targets for the certainty of evidence were the presence or absence of a non-null effect for the number of drop-seizure days, number of inpatient hospitalizations due to epilepsy, and HRQoL as measured by the QOLCE or QOLIE-31-P.
Table 3 summarizes the detailed GRADE summary of findings for cannabidiol versus placebo in the pivotal CARE 3 and CARE 4 trials with patients aged 2 years and older with LGS. For the GRADE assessments, findings from the CARE 3 and CARE 4 trials were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures.
Summary of Findings for Cannabidiol 10 mg/kg/day and Cannabidiol 20 mg/kg/day Versus Volume-Matched Placebo for Patients With Seizures Associated With LGS.
To inform the longer-term safety and tolerability of cannabidiol as an adjunctive treatment in children and adults with inadequately controlled LGS, the results of 1 open-label extension (OLE) study, the CARE 5 study, were summarized.
The CARE 5 study was a multicentre, single-arm, OLE, phase III study with the primary objective of evaluating the longer-term safety and tolerability of cannabidiol as an adjunctive treatment, which included children and adults with LGS (N = 366) who had completed the CARE 3 and CARE 4 core studies. The long-term efficacy of cannabidiol as an adjunctive treatment in patients aged 2 years or older with LGS was evaluated as the secondary objective of the CARE 5 study. Patients enrolled in the CARE 5 study received adjunctive cannabidiol in addition to their usual treatment, which consisted of a 2-week titration period, a maintenance period, and a 10-day taper period. Patients were titrated up to 10 mg/kg/day to 20 mg/kg/day cannabidiol using the recommended titration schedule. The participants continued at their 10 mg/kg/day to 20 mg/kg/day dose during the maintenance period. During the maintenance period, dose adjustments by the investigators were permitted if a patient experienced intolerance (dose decrease) or required better seizure control (dose increase) until the optimal dose was achieved. If deemed necessary by the investigator, a maximum dose of 30 mg/kg/day was permitted. Among patients whose dose had been decreased, dose increases were considered, provided there was adequate tolerance. Following the end-of-treatment or withdrawal visit (end-of-treatment visit occurred after a maximum of 6 years of treatment [312 weeks after visit 1], following early withdrawal from the study, or following an unscheduled end-of-treatment visit conducted no earlier than 730 days after visit 1), doses were tapered at home (10% per day for 10 days) until the end-of-taper-period visit. Participants could receive treatment for a maximum of 6 years (312 weeks after visit 1), depending on the protocols used in the country of enrolment.
The CARE 5 study was conducted across 75 sites in 8 countries (Australia, Spain, France, Israel, Netherlands, Poland, UK, and US). Approximately 78% of patients were recruited in the US. The average patient was aged 15.9 years (SD = 9.5) and was concurrently taking 3.4 ASMs (SD = 1.38). Of the 366 patients with LGS enrolled in the study, 66.4% completed the treatment period, 20.5% continued to the taper phase, and 18.3% completed the taper phase.
Efficacy end points were analyzed in the safety analysis set. The retention rates for the safety analysis set at weeks 37 to 48 (12 months), 85 to 96, 133 to 144 (36 months), 181 to 192, and 241 to 252 were 82% (299 of 366), 64% (236 of 366), 59% (216 of 366), 6% (22 of 366), and 2% (8 of 366), respectively. Missing data were addressed using the last observation carried forward method.
The proportions of patients with drop seizure–free status at weeks 37 to 48 (12 months), 133 to 144 (36 months), and 253 to 264 (66 months) were 7% (24 of 364), 8% (30 of 364), and 9% (34 of 364), respectively. Median percentage changes from baseline in drop seizure frequency during the same OLE periods from baseline of the core studies were −55.3% (interquartile range [IQR], −83.8% to −16.6%; n = 364), −59.1% (IQR, −85.7% to −15.2%; n = 364), and −59.4% (IQR, −87.1% to −16.0%; n = 364), respectively. Mean percentage changes in drop seizure frequency during the same periods of the OLE from baseline of the core studies were −34.9% (SD = 82.77; n = 364), −32.3% (SD = 106.11; n = 364), and −30.9% (SD = 127.21; n = 364), respectively. The proportions of patients who experienced a reduction in drop seizure frequency of 50% or greater during the same periods in the CARE 5 study were 53.8% (196 of 364), 56.3% (205 of 364), and 58% (211 of 364), respectively.
Among patients between the ages of 2 and 18 years, the mean change in overall quality of life score as measured by the QOLCE from baseline to last visit was 5.5 (SD = 13.71; n = 152). Among patients aged 19 years and older, the mean change in overall quality of life subscale weighted score on the QOLIE-31-P from baseline to last visit was 6.4 (SD = 28.63; n = 55).
A total of 353 participants (96.4%) with LGS reported experiencing 1 or more AEs during the CARE 5 study. The most common treatment-emergent AEs were convulsion (38.5%), diarrhea (38.3%), and pyrexia (34.4%). SAEs were reported by 157 participants (42.9%) with LGS. The most commonly reported SAEs were convulsion (12%), status epilepticus (11.5%), and pneumonia (7.1%). Discontinuation of treatment due to AEs was reported in 43 participants (11.7%) with LGS. The most common reasons for treatment discontinuation due to AEs were convulsion (1.9%), diarrhea (1.6%), and vomiting (1.4%). A total of 12 patients (3.3%) with LGS died during the study. Among those who died, SUDEP was recorded as the cause of death in 4 patients (1.1%).
The single-group, open-label, nonrandomized design of the CARE 5 OLE study makes interpretation of the long-term efficacy and safety of cannabidiol challenging. The lack of comparison with an active comparator and/or placebo precludes the ability to draw causal inference to assess the relative long-term therapeutic benefit or safety of cannabidiol. Although patient and caregiver self-counts of drop seizures and motor seizures were noted to be reliable based on input from the clinical experts consulted by CADTH for the purpose of this review, self-counting of other types of seizures are not accurate. Results for caregiver-reported and patient-reported outcomes were inconclusive due to the open-label design of the trial and the substantial decline in the number of patients available to provide assessment over time. Moreover, it is uncertain if the sample size (N = 366) was sufficient to detect rare AEs. As enrolment into the CARE 5 study was contingent upon the completion of a core study, thereby excluding patients who discontinued the CARE 3 or CARE 4 trials due to AEs or lack of response, it is possible that patients in the CARE 5 study represent a select population who were more tolerant of cannabidiol. Therefore, response bias cannot be ruled out. Finally, results may be biased due to attrition bias, as approximately one-third of patients did not complete the study, and there was wide variance in follow-up duration for individuals. None of the CARE 5 trial sites were in Canada. Due to the rarity of LGS and a lack of robust population-based studies on LGS in Canada, the clinical experts were unable to determine if the patient population included in the CARE 5 study was reflective of patients in the clinical practice setting across Canada. One clinical expert added that they do not, however, expect patients with LGS living in Canada to differ from those elsewhere. Adherence to the treatment regimen was not reported and, as such, overall exposure to cannabidiol during the OLE study period is uncertain.
No indirect treatment comparisons were included in this submission.
No studies addressing gaps in the evidence from the systematic review were included in this submission.
Summary of Economic Evaluation.
CADTH identified the following key limitations with the sponsor’s analysis:
CADTH reanalyses aligned the eligible population with the Health Canada indication for LGS, adopted a higher maintenance dose of cannabidiol, used mean weight in the calculation of drug costs, and assumed 100% adherence to treatment. In the CADTH base case, the budget impact of reimbursing cannabidiol for the treatment of seizures associated with LGS is expected to be $3,868,277 in year 1, $10,489,767 in year 2, and $15,071,851 in year 3, for a 3-year total of $29,429,895. If the reimbursement of cannabidiol is restricted to patients with drug-refractory LGS, the 3-year budget impact of reimbursing cannabidiol is expected to be $27,853,385. The estimated budget impact is highly sensitive to the price of cannabidiol.
Dr. James Silvius (Chair), Dr. Sally Bean, Mr. Dan Dunsky, Dr. Edward Xie, Mr. Bob Gagne, Dr. Ran Goldman, Dr. Peter Jamieson, Mr. Morris Joseph, Dr. Christine Leong, Dr. Kerry Mansell, Dr. Alicia McCallum, Dr. Srinivas Murthy, Dr. Trudy Huyghebaert, Dr. Danyaal Raza, and Dr. Peter Zed.
Meeting date: February 28, 2024
Regrets: One expert committee member did not attend.
Conflicts of interest: None
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Indication: As adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome in patients 2 years of age and older
Sponsor: Jazz Pharmaceuticals Canada, Inc.
Final recommendation: Reimburse with conditions
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