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Indication: As adjunctive therapy for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients 2 years of age and older
CADTH recommends that Epidiolex should be reimbursed by public drug plans as adjunctive therapy for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients aged 2 years and older if certain conditions are met.
Epidiolex should only be covered for the treatment of patients who are aged 2 years and older with seizures caused by TSC despite receiving other antiseizure medications.
Epidiolex should only be reimbursed in patients who have at least 8 seizures over a 28-day period that are not controlled despite receiving 2 or more antiseizure medications if it is prescribed by physicians with experience in the diagnosis and management of patients living with TSC and if the cost of Epidiolex is reduced. Epidiolex should not be reimbursed for use in combination with mTOR inhibitors or recreational or medicinal cannabis.
TSC is a rare genetic disease that causes noncancerous tumours (known as tubers) to grow in many parts of the body, most commonly in the brain, heart, lungs, kidneys, skin, and eyes. Tubers that form in the brain often cause different types of seizures, which can be frequent, severe, and even fatal. TSC affects 1 in 5,000 to 10,000 births; however, the number of people with seizures caused by TSC is unknown.
Although many antiseizure medications are available, there is still a need for safe treatments that further reduce the number and severity of seizures for patients who have seizures that are not controlled by their current medication.
Treatment with Epidiolex is expected to cost approximately $12,631, $20,036, $32,730, and $45,672 annually for patients aged 2 to 6 years, 7 to 11 years, 12 to 17 years, and 18 years and older, respectively.
The CADTH Canadian Drug Expert Committee (CDEC) recommends that cannabidiol be reimbursed as adjunctive therapy for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients aged 2 years and older only if the conditions listed in Table 1 are met.
TSC is a rare, multisystem disorder in which seizures of varying types are the most common neurologic manifestation of the disease, affecting up to 70% of patients. TSC-associated seizures generally begin during the first year of life and progress aggressively over time, resulting in substantial disease-related morbidity and potential early mortality.
One phase III, double-blind, randomized controlled trial (RCT) (CARE6; N = 224) demonstrated that, in patients with TSC-associated epilepsy that was not completely controlled by their current antiseizure medication (ASM), treatment with cannabidiol resulted in added clinical benefit in TSC-associated seizure frequency compared with placebo. In the CARE6 trial, the mean percent reduction from baseline in TSC-associated seizures was 48.6% for patients who received cannabidiol 25 mg/kg/day and 26.5% for patients who received placebo. This was associated with a difference in mean percent reduction in seizure frequency from baseline at 16 weeks of 31.0% (95% confidence interval [CI], 13.9% to 43.3%; P = 0.0009) in favour of cannabidiol. In addition, the proportion of patients with a reduction in seizure frequency of 50% or more was 36.0% for patients receiving cannabidiol and 22.4% for those receiving placebo (odds ratio [OR] = 1.95; 95% CI, 0.95 to 4.00). In clinical practice, 20% to 30% of patients with seizures associated with TSC are expected to have a strong response to treatment with cannabidiol (i.e., 50% reduction), which was demonstrated in the cannabidiol treatment group.
Patients identified a need for new, effective therapies that reduce seizure frequency and severity, which ultimately impact overall quality of life (QoL). Additionally, treatments that are associated with fewer side effects were desirable to patients. Based on the evidence reviewed, CDEC concluded that cannabidiol may meet some of these needs, including reduction in seizure frequency; however, there was insufficient evidence to evaluate the effect of cannabidiol on seizure severity, total seizure freedom, and health-related QoL (HRQoL) and cognition.
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 $295,503 per quality-adjusted life-year (QALY) compared with usual care alone. At this ICER, cannabidiol is not cost-effective at a willingness-to-pay (WTP) threshold of $50,000 per QALY gained for patients aged 2 years and older with TSC and a history of epilepsy that is inadequately controlled by their current ASM. A price reduction is required for cannabidiol to be considered cost-effective at a $50,000 per QALY gained threshold.
Reimbursement Conditions and Reasons.
TSC is a rare genetic disorder resulting in the formation of benign tumours in many different organs, primarily in the brain, heart, lungs, kidneys, skin, and eyes. Although Canadian-specific estimates are lacking, TSC is estimated to occur in 1 of 5,000 to 10,000 live births and has a prevalence of 8.8 cases per 100,000 people. Epileptic seizures of varying types are the most common neurologic manifestation of the disease, affecting upwards of 70% of patients. Seizures are also a significant cause of morbidity and mortality in patients with TSC. Uncontrolled epilepsy is among the most common causes of death in TSC, resulting from status epilepticus or sudden unexpected death in epilepsy (SUDEP). Clinically, the most effective prevention strategy for death related to epilepsy is to reduce the frequency of seizures.
TSC-associated seizures generally begin within the first year of life in most patients (62.5% to 73.0%) as infantile spasms characterized by sudden and brief extension or flexion of the extremities. Other seizure types associated with TSC include focal seizures, which occur in approximately two-thirds of patients who present with variable symptoms. These can evolve to a more generalized seizure, including tonic (brief tonic extension of the extremities, sometimes resulting in a fall), atonic (sudden loss of muscle tone resulting in a fall), or tonic-clonic (involving both stiffening and twitching or jerking of extremities) seizures, which can become refractory in two-thirds of patients.
Seizure burden in patients with TSC can be high; patients not receiving treatment report an average of 87 TSC-associated seizures per month. Patients with TSC-associated seizures often have severe impairment of daily functioning or a history of epilepsy-related injuries. As a result, TSC-associated epilepsy has a severe impact on patients’ QoL. Patients with TSC and early onset of seizures experience greater impairment in intellectual development than those without seizures and the early appearance of seizures usually results in severe forms of intellectual disability. TSC is a chronic, lifelong condition. Although the prognosis for many people living with TSC has improved in recent years and life expectancy has increased, careful monitoring of all organ systems and development is critical. Most patients require multidisciplinary care at tertiary institutions as a result of their seizures and/or aspects of TAND.
TSC may present at any age and is often diagnosed based on specific clinical criteria and/or genetic testing. Major clinical diagnostic criteria include 3 or more hypomelanotic macules at least 5 mm in diameter, 3 or more angiofibromas or fibrous cephalic plaques, 2 or more ungual fibromas, shagreen patch, multiple retinal hamartomas, multiple cortical tubers and/or radial migration lines, 2 or more subependymal nodules, subependymal giant cell astrocytoma, cardiac rhabdomyoma, lymphangioleiomyomatosis, and more than 2 angiomyolipomas. Minor diagnostic features of TSC include “confetti” skin lesions, more than 3 dental enamel pits, more than 2 intraoral fibromas, retinal achromatic patch, multiple renal cysts, nonrenal hamartomas, and sclerotic bone lesions. Without genetic confirmation, patients are considered to who have TSC if they have 2 major diagnostic features or 1 major feature and 2 minor diagnostic features. Possible TSC is considered in patients with either 1 major diagnostic feature or 2 or more minor diagnostic features. Two genes have been identified that can cause TSC: TSC1 and TSC2. Only 1 pathogenic variant in either of these genes is required for TSC to be present.
The goal of treatment in patients with TSC-related seizures is to prevent or control seizures, which may improve cognitive neurodevelopment and enhance HRQoL. There are limited options for disease-modifying medical therapies in TSC, and no Canadian guidelines exist for the management of TSC-related seizures. International guidelines broadly agree on the overall treatment strategy; antiepileptic drugs are the mainstay of current pharmacological treatment, consisting of sodium valproate, vigabatrin, levetiracetam, clobazam, lamotrigine, lacosamide, oxcarbazepine, topiramate, and carbamazepine in Canada. Additional nonpharmacological treatments for seizures related to TSC include a ketogenic diet, surgery for tumour removal, and vagus nerve stimulation.
Cannabidiol has been approved by Health Canada as adjunctive therapy for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, or TSC in patients aged 2 years and older. The antiseizure mechanism of cannabidiol is unknown, although it is structurally distinct from other ASMs. Cannabidiol reduces neuronal hyperexcitability through modulation of intracellular calcium via G protein–coupled receptor 55 and transient receptor potential vanilloid cation channel subfamily V member 1, and modulation of adenosine-mediated signalling through inhibition of adenosine transport via the equilibrative nucleoside transporter-1. It is available as an oral solution, and the dosage recommended in the product monograph is 2.5 mg/kg taken twice daily (5 mg/kg/day). After 1 week, the dosage should be increased to 5 mg/kg twice daily (10 mg/kg/day). Based on individual clinical response and tolerability, the dosage can be increased up to a maximum recommended dosage of 12.5 mg/kg twice daily (25 mg/kg/day).
To make its recommendation, the committee considered the following information:
Two patient groups provided input for this review: the CEA and TSCST. The CEA collected input from its 24 member associations on the knowledge and experience of patients, caregivers, clinicians, volunteers, and supporters. The input from TSCST was gathered from a survey of 11 patient and caregiver members that was conducted in September 2023.
Both patient groups emphasized the catastrophic nature of uncontrolled seizures in infants and children, which are linked to cognitive delays and physical disabilities and have a high correlation with mental illness, including depression and anxiety. Seizures occur so frequently that patients are unable to achieve milestones, learn, and even sleep. Patient groups note that seizures associated with TSC are typically hard to control and require constant monitoring and medication changes to try to find a combination that works to control, or at least reduce, the number of seizures. Patient groups noted that when someone has epilepsy, the whole family is affected, highlighting the tremendous burden of uncontrolled seizures on caregivers. Patients and caregivers experience anxiety around when and where the next seizure will occur and what impact it will have. Caregivers are often sleep deprived and constantly fatigued due to sleep interruptions or anxiety. Caregivers are also exposed to the sometimes highly unpleasant side effects, including mood swings, suicidal thoughts, memory loss, problems with concentration, fatigue, exhaustion, depression, and sexual dysfunction, which are exacerbated by various medications.
Both patient groups emphasized the importance of total seizure freedom or reduction in seizure frequency in improving overall QoL. Patient groups cited that seizure control improves more than just developmental milestones, but day-to-day life as well, leading to fewer postictal side effects, better sleep, and less fatigue, confusion, anxiety, and headaches, among others. Both patient groups also highlighted the physical and emotional wellbeing of both caregivers and patients, the ability to get an education or full-time employment, as well as the importance of social interactions in an otherwise isolating disease, which could all be improved by greater seizure control.
Because TSC is a lifelong disease, the experts noted that the main goals of treatment include seizure reduction and improved QoL, cognition, and behaviour without side effects that worsen comorbidities. Other goals include prevention of SUDEP, reduction in caregiver burden, and greater independence for patients.
Current pharmacological treatment for TSC-associated seizures includes ASMs, which the experts noted are generally directed at the specific types of seizure and is often age related. The experts highlighted that most patients present with infantile spasms, which are generally treated with first-line vigabatrin followed by corticosteroids. Focal seizures are often treated with sodium channel blockers (e.g., carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, phenytoin), whereas generalized seizures are often treated with broad-spectrum agents (e.g., valproate, clobazam, topiramate, levetiracetam, brivaracetam). Treatments targeting the mTOR pathway, such as everolimus and sirolimus, are used to treat some tumours associated with TSC; however, there is controversy about whether they improve seizure frequency and neuropsychiatric comorbidities. In addition, mTOR inhibitors require chronic use and have potential serious side effects that require close monitoring. Interruption of the use of mTOR inhibitors can lead to tumour regrowth or seizure worsening, and the long-term effects of mTOR inhibition on TSC are still uncertain.
Despite many currently available ASMs, response is highly variable, and patients continue to have severe and debilitating seizures. The clinical experts highlighted that cannabidiol does not address the underlying disease process any more than other conventional ASMs; however, the distinct mechanism of action of cannabidiol could be complementary to other ASMs. Current treatments are often associated with side effects, including sedation or liver toxicity, that can worsen comorbidities such as those related to behaviour and may require constant monitoring.
The clinical experts noted that patients with TSC-associated seizures who are most in need of intervention would be those whose seizures remain uncontrolled by their current therapies or those who have behavioural issues on their current treatments. The experts considered that the patients who would be most likely to benefit from cannabidiol are those with intellectual disabilities and developmental delays. Patients with neuropsychiatric comorbidities could also benefit from cannabidiol because it may improve neuropsychiatric symptoms, whereas other available ASMs may worsen these symptoms. The experts also noted that eligible patients would be easily identifiable by clinicians based on the patients’ number and type of seizures as well as comorbidities. The clinical experts emphasized that caution and monitoring should be taken in treating patients with a history of depression or with liver disease, particularly for patients taking concomitant valproate. Dose adjustment may be required in patients who are taking concomitant clobazam and mTOR inhibitors because of the increased levels of desmethylclobazam and mTOR due to the administration of cannabidiol. In addition, the safety of cannabidiol in pregnancy has not been established, which would be a consideration for patients of childbearing age.
The clinical experts highlighted that measures of seizure frequency and severity remain the most important consideration of treatment. Additional assessments in real-world practice include hospitalizations, rescue medication use, and side effects of treatment. The clinical experts also agreed that, although important, QoL measurements, caregiver burden, increase in independence, and clinical global impression are not commonly used in clinical practice, although the subjective experience of patients is used to inform treatment decisions. The clinical experts highlighted that despite the 50% responder threshold used in the trial, even a 25% to 30% reduction in seizure frequency may be beneficial if there is reduction in the most severe and disabling type of seizures (i.e., tonic-clonic seizures).
Initially, patients with TSC-associated seizures would be seen as often as every 3 months to monitor treatment and perform any medication adjustments, although patients are usually seen every 6 months. For patients who are seizure free, annual assessments would be conducted. When deciding to discontinue treatment, the clinical experts agreed that treatment would be discontinued in patients who experience severe adverse events (SAEs), such as elevation of liver enzymes of more than 5 times the limit, severe sedation, nausea, and allergic reaction. Worsening of neuropsychiatric side effects, such as depression, should also be a reason for discontinuation. The clinical experts also stated that some medications can interact with cannabidiol (e.g., valproic acid and clobazam) and may need to be adjusted before considering discontinuation. The experts noted that use of additional rescue medication would not prompt discontinuation of treatment because rescue medication is generally used to break a cluster of seizures or a continuous prolonged seizure.
No clinician group input was received by CADTH for this review.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Responses to Questions From the Drug Programs.
One phase III, placebo-controlled RCT (CARE6; N = 224) evaluated the reduction in seizure frequency using cannabidiol oral solution versus placebo as adjunctive therapy for the treatment of seizures in children and adults with TSC whose seizures were not completely controlled by their current ASMs. Patients were randomized 2:2:1:1 to cannabidiol 25 mg/kg/day (n = 75), cannabidiol 50 mg/kg/day (n = 73), and 2 matching dose-volume equivalent placebo groups (pooled n = 76) for 16 weeks. The cannabidiol 50 mg/kg/day group was not included in this report because it is not a recommended dosage per Health Canada. Following completion of the double-blind treatment period, patients then had the option to enter the long-term open-label extension (OLE) study.
Baseline characteristics were generally balanced across treatment groups. Mean age was 13.7 years (25 mg/kg/day: mean = 14.1 years; placebo: mean = 13.9 years); there were some baseline imbalances that were compatible with chance. All patients had TSC-associated seizures, with type 2 focal seizures occurring most frequently in patients in both groups (25 mg/kg/day: n = 46 [61.3%]; pooled placebo: n = 50 [65.8%]), followed by type 1 focal motor seizures (25 mg/kg/day: n = 29 [38.7%]; placebo: n = 33 [43.4%]). The mean number of TSC-associated seizures during the baseline period of 28 days was 77.95 (standard deviation [SD] = 83.39; range, 7.7 to 427.7) in the cannabidiol 25 mg/kg/day group and 89.22 (SD = 101.78; range, 8.0 to 558.0) in the placebo group. The median number of concurrent ASMs in each treatment group was 3 (range, 0 to 5), while the median number of previously taken ASMs was 4 (range, 0 to 15).
The primary end point of the CARE6 trial was the change from baseline in the number of TSC-associated seizures during the treatment period. The mean percentage reduction from baseline for the cannabidiol 25 mg/kg/day group was 48.6% (95% CI, 40.4% to 55.8%) and 26.5% (95% CI, 14.9% to 36.5%) for the placebo group. The relative treatment ratio of cannabidiol to placebo from the negative binomial regression analysis was 0.699 (95% CI, 0.567 to 0.861), which translated to an estimated relative reduction for cannabidiol 25 mg/kg/day compared to placebo of 31.0% (95% CI, 13.9% to 43.3%; P = 0.0009).
Results of subgroup analyses were consistent with the primary analysis, although the reductions in seizure frequency observed in patients who were also taking clobazam appeared larger than in those who were not taking clobazam (the 95% CIs overlapped).
The proportion of patients who had a 50% or more reduction from baseline in TSC-associated seizure frequency was the first key secondary end point of the CARE6 trial. In the double-blind treatment period, 27 patients (36.0%) in the cannabidiol 25 mg/kg/day group and 17 patients (22.4%) in the pooled placebo group experienced a 50% or more reduction in seizure frequency (OR = 1.95; 95% CI, 0.95 to 4.00; P = 0.0692). The difference in the proportion of patients who had a 50% or greater reduction in TSC-associated seizure frequency between the cannabidiol 25 mg/kg/day group compared to the pooled placebo group was 13.6% (95% CI, −0.7% to 28.0%).
The proportion of patients who had a reduction in TSC-associated seizure frequency of at least 25% and the proportion who had seizure freedom (100% reduction in seizure frequency) were secondary end points of the CARE6 trial. During the treatment period, 43 patients (57.3%) and 33 patients (43.4%) in the cannabidiol 25 mg/kg/day and placebo groups, respectively, experienced a 25% or greater reduction in seizure frequency (OR = 1.75; 95% CI, 0.92 to 3.33). The difference in the proportion of patients who achieved a 25% or greater reduction in TSC-associated seizure frequency between the cannabidiol 25 mg/kg/day and placebo groups was 13.9% (95% CI, −1.9% to 29.7%). Only 1 (1.3%) patient in the cannabidiol 25 mg/kg/day group experienced seizure freedom during the treatment period.
HRQoL was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire in pediatric patients aged 2 to 18 years and the Quality of Life in Epilepsy (QOLIE)-31-P questionnaire in patients aged 19 years and older. For both measures, the overall scores were calculated from 0 to 100, with higher scores representing better HRQoL.
An overall QoL score for the QOLCE was available for 45 patients in the cannabidiol 25 mg/kg/day group at baseline and 42 patients at the end of treatment. For the placebo group, 50 patients had an overall QOLCE QoL score at baseline and 47 at the end of treatment. At the end of treatment, the least squares (LS) mean change from baseline was 3.1 points (95% CI, −0.6 to 6.7 points) and 1.6 points (95% CI, −1.8 to 4.9 points) in the cannabidiol and placebo groups, respectively. The LS mean difference between groups in change from baseline was 1.5 points (95% CI, −3.3 to 6.3 points).
The QOLIE-31-P was completed by 13 patients in the cannabidiol 25 mg/kg/day group and 10 patients in the placebo group at baseline and by 14 patients in the cannabidiol 25 mg/kg/day group and 12 patients in the placebo group at the end of treatment. At the end of treatment, the LS mean change from baseline was −1.4 points (95% CI, −16.2 to 13.5 points) and 2.3 points (95% CI, −15.0 to 19.7 points) in the cannabidiol and placebo groups, respectively. The LS mean difference between groups in change from baseline was −3.7 points (95% CI, −16.6 to 9.2 points).
During the baseline period, the mean number of days of rescue medication use in the cannabidiol 25 mg/kg/day group and placebo group was 2.14 days (SD = 2.19 days) and 2.32 (SD = 3.20 days), respectively. The mean number of days of rescue medication use during the treatment period was 0.79 days (SD = 2.47 days) in the cannabidiol 25 mg/kg/day group and 0.55 days (SD = 1.40 days) in the placebo group, representing a mean change from baseline of 0.19 days (SD = 2.84 days) and −0.92 days (SD = 1.86 days), respectively. The mean difference in reduction from baseline in rescue medication use days between the cannabidiol 25 mg/kg/day group and the placebo group was 0.96 days (95% CI, −0.65 to 2.56 days).
During the baseline period, no patients in the cannabidiol 25 mg/kg/day group had status epilepticus compared to 3 patients (3.9%) in the placebo group. The proportion of patients who reported episodes of status epilepticus during the treatment period was 6.7% in the cannabidiol 25 mg/kg/day group and 9.2% in the placebo group.
At the end of treatment, the mean adaptive behaviour composite score in the cannabidiol 25 mg/kg/day and placebo groups was 50.7 points (SD = 22.24 points) and 51.5 points (SD = 25.57 points), respectively, representing a LS mean change from baseline of −0.0 points (95% CI, −1.6 to 1.5 points) for cannabidiol 25 mg/kg/day, and −0.0 points (95% CI, −1.6 to 1.5 points) for placebo. The difference in LS mean change from baseline was 0.0 points (95% CI, −2.2 to 2.1 points).
At least 1 treatment emergent adverse event (TEAE) was reported by 70 patients (93.3%) in the cannabidiol 25 mg/kg/day group and by 72 patients (94.7%) in the pooled placebo group. The most frequently occurring TEAEs (10% of patients or more) in the cannabidiol 25 mg/kg/day group were diarrhea (23; 30.7%); decreased appetite (15; 20.0%); pyrexia (14; 18.7%); vomiting (13; 17.3%); increased gamma-glutamyl transferase (12; 16.0%), alanine aminotransferase (ALT) (9; 12.0%), and aspartate aminotransferase (AST) (8; 10.7%); somnolence (10; 13.3%); and cough (8; 10.7%). In the pooled placebo groups, the most frequently occurring TEAEs were diarrhea (13; 17.1%), nasopharyngitis (12; 15.8%), upper respiratory tract infection (10; 13.2%), and decreased appetite (9; 11.8%).
A total of 28 patients (12.5%) in the CARE6 trial experienced a total of 44 SAEs, 16 (21.3%) in the 25 mg/kg/day group and 2 (2.6%) in the pooled placebo group. The most commonly reported individual SAEs in the cannabidiol 25 mg/kg/day group were increased ALT (2; 2.7%), increased AST (2; 2.7%), and status epilepticus, vomiting, and viral gastroenteritis (2; 2.7% each). Serious AEs in the placebo group only occurred in 2 patients (2.6%) and included pneumonia and status epilepticus (1; 1.3% each).
A total of 20 patients (8.9%) had TEAEs leading to discontinuation of treatment, 8 (10.7%) in the 25 mg/kg/day group and 2 (2.6%) in the pooled placebo group. The most common reason for discontinuing treatment in the cannabidiol group was rash (2; 2.7%). All other reasons for discontinuation occurred in only 1 patient (1.3%). The 2 patients in the placebo group discontinued treatment due to TEAEs of ataxia (1 patient) and agitation (1 patient).
There were no deaths reported during the CARE6 trial.
AEs of special interest to this review were hepatocellular injury and hypersensitivity reactions. In the cannabidiol 25 mg/kg/day group, 1 patient (1.3%) had liver injury and 1 patient (1.3%) had a type IV hypersensitivity reaction. These were listed as SAEs, and both led to discontinuation of treatment.
The phase III CARE6 trial was the only study included in this review. Randomization was stratified by age. Because of the known interaction between clobazam and cannabidiol, failure to stratify by clobazam use was a limitation; however, the CARE6 trial was initiated before the importance of this interaction was known. It remains unclear what impact this may have had on the distribution of patients in the trial and how the results may have been impacted. There were some baseline imbalances; however, the clinical experts consulted by CADTH noted that there is substantial disease heterogeneity in this population, and they agreed that the differences could be due to chance. There were also differences across the cannabidiol 25 mg/kg/day and placebo groups in discontinuation of study treatment (13.3% versus 1.3%), primarily due to AEs (10.7% versus 0.0%). Although the CARE6 trial was a double-blind RCT, this may have revealed treatment assignment; however, it is unclear what effect this would have on the results of the study.
Most outcomes in the CARE6 trial were related to seizure frequency, which was measured by countable seizures of various types. In consultation with clinical experts, there is some subjectivity and error in how patients and caregivers may classify these; however, the seizure types defined for the trial are generally countable and should not ultimately bias the results. Based on discussion with the clinical experts consulted by CADTH, subgroups of interest to this review included clobazam use and the number of concurrent and prior ASMs. Results generally supported the primary analysis, although they were not statistically powered to detect within-group or between-group differences. In addition, wide overlapping 95% CIs reflected uncertainty in the effect estimates and were likely due to the small sample sizes, thus the results should be viewed as supportive evidence for the overall effect of cannabidiol.
Outcomes related to HRQoL were considered important to patients and were captured as other secondary end points of CARE6. The QOLCE and QOLIE-31-P were considered reliable and valid measures for epilepsy in TSC, although the clinical experts consulted by CADTH noted that these are not used in routine clinical practice. The use of rescue medication and change in rescue medication use days was an exploratory outcome of CARE6. Most patients required the use of rescue medication at some point during the treatment period. Rescue medication usage was not accounted for in the primary or key secondary end point analyses, thus it remains unclear whether there was any impact of rescue medication on the results. As noted by the clinical experts, the use of rescue medication would not prompt discontinuation of therapy.
Two dosages of cannabidiol were evaluated in the CARE6 trial: 25 mg/kg/day and 50 mg/kg/day. However, the maximum recommended Health Canada–approved dosage of cannabidiol for TSC-associated seizures is 12.5 mg/kg twice daily (25 mg/kg/day), so the cannabidiol 50 mg/kg/day dose was not of interest to this review.
The CARE6 trial was an international multicenter study, but there were no Canadian sites included. As part of the inclusion and exclusion criteria for the CARE6 trial, patients were required to have a clinical diagnosis of TSC. Genetic confirmation was not required, which was noted by the clinical experts consulted by CADTH to be consistent with clinical practice. The included population had a high seizure burden and particularly drug-resistant epilepsy demonstrated by the 28-day baseline seizure frequency (range, 8 to 558 days) and the number of prior (range, 0 to 15) and concurrent (range, 0 to 5) ASMs. The clinical experts consulted by CADTH noted that the included population was reflective of clinical practice, highlighting that there is often variability in seizure burden across patients. However, it was highlighted that not all patients with TSC have such high disease burden, thus the enrolled population may have been restrictive, selecting for patients with more refractory epilepsy and higher disease burden. In addition, there was heterogeneity in the concomitant ASMs received by patients in the CARE6 trial. The clinical experts consulted by CADTH noted that this is in line with clinical practice and varies by patient based on response, intolerance, and various contraindications.
Outcomes in the CARE6 trial were considered clinically relevant and important to patients, mainly focusing on measures of seizure frequency, which is the focus of epilepsy treatment in routine clinical practice. An additional consideration as noted by patient groups and the clinical experts consulted by CADTH is reduction in seizure severity, which was not explicitly measured in the CARE6 trial. The clinical experts consulted by CADTH highlighted that a reduction in the frequency of seizures may not necessarily be associated with a reduction in severity.
The duration of the CARE6 trial at 16 weeks was considered appropriate for measuring response to treatment and observing changes in seizure frequency. However, because the effects of cannabidiol on HRQoL and TANDs were also outcomes of interest to this review and the secondary nature of these outcomes, the small sample sizes for completion of various measures and the short duration of the CARE6 trial are difficult to interpret. As such, these outcomes should only be viewed as supportive of the overall effect of 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 the RCT started as high-certainty evidence and it could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
The selection of outcomes for the 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: the percent change from baseline in the number of TSC-associated seizures at week 16, the proportion of patients who responded to treatment (i.e., achieving target reductions of 25% or 50% more) or had seizure freedom (100% reduction in seizure frequency) at week 16, improved HRQoL as assessed by the change from baseline in QOLCE and QOLIE-31-P scores at week 16, the proportion of patients who had episodes of status epilepticus at week 16, the change from baseline in rescue medication use days at week 16, the change from baseline in Vineland II Adaptive Behavior Scale at week 16, the proportion of patients with at least 1 SAE, and the proportion of patients with hepatocellular injury.
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 the certainty of evidence assessment was the presence of a clinically important reduction in seizure frequency (percent change in seizure frequency) on thresholds informed from clinical expert opinion, treatment guidelines, and clinical trials, as well as HRQoL and patient-reported outcome (QOLCE, QOLIE-31-P, Vineland II) assessments informed by the literature where available. Other targets for the certainty of evidence assessment were the presence or absence of any (non-null) effect for the proportion of patients achieving 25%, 50% or 100% reductions in seizure frequency, the proportion of patients who had episodes of status epilepticus, and changes from baseline in rescue medication use.
One open-label, single-arm, long-term extension of the CARE6 study (CARE6 OLE) was summarized to provide evidence regarding long-term safety and efficacy of cannabidiol. Upon completion of the double-blind phase of the CARE6 study, 199 patients who had completed the double-blind phase were invited to receive open-label cannabidiol during the OLE period for a maximum duration of 4 years (124 from cannabidiol 25 mg/kg/day and 50 mg/kg/day groups and 75 from the placebo group). The primary outcome of the CARE6 OLE study was to evaluate the AE profile (long-term safety and tolerability) of cannabidiol. Secondary outcomes of interest to this review were in line with the outcomes evaluated during the double-blind period of the CARE6 study.
In the OLE study, maintenance of efficacy was assessed in 156 patients treated for 37 to 48 weeks to account for differences in sample sizes with increasing time. The median percent reduction in TSC-associated seizure frequency from baseline was −66.27% (interquartile range [IQR], −86.70% to −18.64%) during weeks 37 to 48 of treatment, and a median −55.22% (IQR, −81.70% to −13.47%) change throughout the entire OLE treatment period (n = 199).
The number of patients who achieved a 50% or greater reduction in TSC-associated seizure frequency at 37 to 48 weeks of treatment was 93 (60%) and 106 (53%), respectively, throughout the entire OLE treatment phase. There were no notable differences in the proportion of patients achieving a 50% or greater reduction in TSC-associated seizure frequency between patients who had been treated with cannabidiol and patients receiving placebo during the double-blind phase of the study (60.0% and 59.0%, respectively).
Patients experienced a reduction in overall QOLIE-31-P (patient aged ≥ 19 years) total score relative to the prerandomization baseline of the double-blind phase, with a mean change from baseline of −9.0 points (SD = 17.99 points) for all evaluable patients (n = 9 of 199) and −7.4 points (SD = 18.57 points) for patients aged 19 years or older (n = 8) at OLE end of treatment. Based on a change from the double-blind phase baseline to OLE end of treatment, a reduction in the mean QOLIE-31-P total score was observed in the cannabidiol cohort (−14.8 points; SD = 20.60 points; n = 5) and the placebo cohort (−1.8 points; SD = 13.2 points; n = 4). For patients aged 19 years and older (n = 8), mean QOLIE-31-P total score reduction was −13.1 points (SD = 23.39 points; n = 4) in cannabidiol cohort versus −1.8 points (SD = 13.12 points; n = 4) in the placebo cohort.
Based on change from the double-blind baseline to OLE end of treatment, a reduction in mean number of days of rescue medication use was −0.44 days (SD = 4.09 days) in the total population (n = 55 of 199): −0.10 days (SD = 4.73 days) in the cannabidiol cohort (n = 35 of 124) and −1.02 days (SD = 2.64 days) in placebo cohort (n = 20 of 75).
The number of patients with episodes of status epilepticus was 5 (2.5%) during the baseline period and 20 (10.1%) during the OLE treatment period. The number of patients who experienced status epilepticus was similar between patients treated with cannabidiol versus placebo during the double-blind phase of the CARE6 study.
A total of 192 patients (96.5%) treated with cannabidiol had 1 or more AEs during the OLE study. The most common TEAEs were diarrhea (46.7%), seizure (29.6%), and pyrexia (24.1%). SAEs were reported in 56 patients with TSC (28.1%), with the most common SAEs experienced being seizure (8%), status epilepticus (5%), and dehydration (3%).
There were 18 patients (9%) with TSC that stopped treatment due to AEs, with the most common AEs leading to discontinuation being seizure (2%) and diarrhea (2%). One patient died 2 months after starting the open-label treatment of cannabidiol, although this was considered unrelated to cannabidiol.
There was no active comparator or placebo group in the CARE6 OLE study, thus the safety and the efficacy data could not be used to draw any conclusion in relation to an appropriate comparator. The open-label design may also bias the reporting of subjective end points, including AEs, SAEs, and TEAEs. Because completion of a pivotal trial was an eligibility criterion for the extension study, patients who discontinued those trials due to AEs or lack of response were excluded. This could result in a population of patients who were more tolerant of cannabidiol, which can lead to a selection bias because patients who do not respond to treatment are less likely to continue. Having a patient population more tolerant of cannabidiol can also lead to biased estimates related to AEs, potentially resulting in fewer and less severe AEs being reported. The sample size of the CARE6 OLE study (N = 199) may not be sufficient to detect rare AEs. Only 17.1% of patients completed the study, and there was wide variation in follow-up duration for individuals. For several outcomes, the sample size was very small and not representative of all patients who started the OLE period.
The CARE6 OLE study enrolled patients from multiple sites in different countries, but there were no study sites in Canada. No evidence indicating a difference between the study population and patients in Canada was identified in consultation with the clinical experts. The median number of dosing days was 369.5 days (range, 95.0 to 1,462 days) which provides longer follow-up for AE assessment versus the double-blind phase of the CARE6 study; however, the proportion of patients who adhered to cannabidiol during the longer follow-up was not reported. Thus, the study drug exposure among patients in the OLE study was uncertain. Approximately half the patients (46.7%) were taking the 50 mg/kg/day dose, which is not an approved dosing level and could have impacted the results. The remaining patients were taking the 25 mg/kg/day dose, which is the highest dose suggested in the product monograph.
No indirect evidence on the comparative efficacy or safety of cannabidiol in patients with TSC-associated seizures was submitted by the sponsor.
No studies addressing gaps in the systematic review evidence were submitted by the sponsor.
Summary of Economic Evaluation.
CADTH identified the following limitations in the sponsor’s base case: the full indicated population for TSC was not modelled, the Non-Insured Health Benefits (NIHB) population was inappropriately calculated, cannabidiol drug costs are uncertain and likely underestimated, and the proportion of patients eligible for public drug plan coverage is uncertain and may be underestimated.
CADTH conducted reanalyses of the budget impact analysis by aligning the eligible population with the Health Canada indication for TSC, adopting a maintenance dose of 23 mg/kg/day among patients treated with cannabidiol, and using 100% adherence in the calculation of drug costs. Based on the CADTH base case, the estimated budget impact associated with the reimbursement of cannabidiol as adjunctive therapy for the treatment of seizures associated with TSC is expected to be $3,930,164 in year 1, $9,134,576 in year 2, and $15,275,760 in year 3, for a 3-year budgetary impact of $28,340,500.
CADTH conducted scenario analyses to address remaining uncertainty. If the reimbursement of cannabidiol is restricted to patients with drug-refractory TSC-associated epilepsy, the 3-year budget impact associated with reimbursing cannabidiol is expected to be $14,174,180. Assuming that the price of cannabidiol is reduced by 63%, the price reduction at which cannabidiol plus usual care would be considered cost-effective at a WTP threshold of $50,000 per QALY gained, the 3-year budget impact associated with reimbursing cannabidiol is expected to be $10,542,666. The estimated budget impact is highly sensitive to narrowing the eligible population to an ASM-refractory subgroup as well as 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 29, 2024
Regrets: 3 expert committee members did not attend.
Conflicts of interest: None
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Indication: As adjunctive therapy for the treatment of seizures associated with tuberous sclerosis complex (TSC) in patients 2 years of age and older
Sponsor: Jazz Pharmaceuticals Canada, Inc.
Final recommendation: Reimburse with conditions
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