Drug Trials Snapshots: Epidiolex
HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.
LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the EPIDIOLEX Package Insert for complete information.
EPIDIOLEX (cannabidiol)
EH-peh-DYE-oh-lex
Greenwich Research Ltd
Approval date: June 25, 2018
DRUG TRIALS SNAPSHOT SUMMARY:
What is the drug for?
EPIDIOLEX is a drug for the treatment of seizures in two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older.
Lennox-Gastaut and Dravet syndromes start during early childhood. They are associated with difficult to control seizures and various degrees of development disability.
How is this drug used?
EPIDIOLEX is a liquid solution that is taken twice daily by mouth to control seizures. It is usually taken with other drugs. The dose of EPIDIOLEX is based on the patient’s weight. EPIDIOLEX is started at a low dose. After one week, the dose can be increased weekly based on the patient’s response and ability to tolerate the drug.
What are the benefits of this drug?
Patients taking EPIDIOLEX along with other seizure medications had fewer seizures than patients taking placebo with other seizure medications.
What are the benefits of this drug (results of trials used to assess efficacy)?
The tables below summarize efficacy results for the evaluated subjects for Trials 1, 2, and 3. The main trial endpoint was the percent change from baseline (before the drug or placebo was begun) in the frequency of seizures.
Table 2: Change in Drop Seizure Frequency in Lennox–Gastaut Syndrome during the Treatment Period (Trials 1 and 2)
Drop Seizure Frequency | Placebo | EPIDIOLEX | EPIDIOLEX |
|---|---|---|---|
Trial 1 | N=85 | N/A | N=86 |
Baseline Period Median | 75 | N/A | 71 |
Median Percentage Change During Treatment | -22 | N/A | -44 |
p-value compared to placebo |
|
| 0.01 |
Trial 2 | N=76 | N=73 | N=76 |
Baseline Period Median | 80 | 87 | 86 |
Median Percentage Change During Treatment | -17 | -37 | -42 |
p-value compared to placebo |
|
EPIDIOLEX Prescribing Information
Table 3: Change in Convulsive Seizure Frequency in Dravet Syndrome during the Treatment Period (Trial 3)
Total Convulsive Seizure Frequency (per 28 Days) | Placebo | EPIDIOLEX |
|---|---|---|
Trial 3 | N=59 | N=61 |
Baseline Period Median | 15 | 12 |
Median Percentage Change During Treatment | -13 | -39 |
p-value compared to placebo |
| 0.01 |
EPIDIOLEX Prescribing Information
Were there any differences in how well the drug worked in clinical trials among sex, race and age?
- Sex: EPIDIOLEX worked similarly in males and females.
- Race: The majority of patients were White. The numbers of patients of other races were limited; therefore, differences in response among races could not be determined.
- Age: EPIDIOLEX worked similarly in patients below and above 18 years of age.
Were there any differences in how well the drug worked in clinical trials among sex, race and age groups?
The tables below summarize efficacy results by sex, race, age, and region. Racial subgroup differences were investigated between White race and all other races combined because the majority of patients were White, and there were relatively few patients of other races.
Table 4. Subgroup Analysis of the Primary Endpoint (Trial 1)
Subgroup | Treatment | N | Median | Median Difference (95%CI)* |
|---|---|---|---|---|
Sex | ||||
Male | 10 mg/kg | 40 | -36.08 | -16.86 (-31.34, -0.32) |
| 20 mg/kg | 45 | -39.62 | -22.09 (-39.78, -3.89) |
| Placebo | 44 | -17.17 |
|
Female | 10 mg/kg | 33 | -49.33 | -22.04 (-41.29, -5.75) |
| 20 mg/kg | 31 | -43.65 | -19.75 (-42.63, 6.35) |
| Placebo | 32 | -17.85 |
|
Race | ||||
White | 10 mg/kg | 62 | -36.69 | -16.81 (-28.46, -5.18) |
| 20 mg/kg | 67 | -39.62 | -15.74 (-29.81, -1.30) |
| Placebo | 69 | -19.13 |
|
Other | 10 mg/kg | 11 | -49.65 | -43.02 (-109.51, 19.09) |
| 20 mg/kg | 9 | -85.08 | -67.37 (-123.15, 1.68) |
| Placebo | 7 | 1.30 |
|
Age | ||||
2-5 years | 10 mg/kg | 8 | -39.69 | -22.68 (-56.60, 19.18) |
| 20 mg/kg | 9 | -29.55 | -10.58 (-62.35, 35.11) |
| Placebo | 9 | -13.37 |
|
6-11 years | 10 mg/kg | 24 | -49.41 | -28.92 (-49.07, -2.19) |
| 20 mg/kg | 25 | -25.74 | -15.16 (-41.19, 10.06) |
| Placebo | 24 | -17.17 |
|
12-17 years | 10 mg/kg | 19 | -46.74 | -26.44 (-44.30, -7.62) |
| 20 mg/kg | 20 | -50.18 | -27.05 (-51.09, 3.47) |
| Placebo | 20 | -26.94 |
|
18-55 years | 10 mg/kg | 22 | -18.16 | -2.31 (-22.90, 17.98) |
| 20 mg/kg | 22 | -44.65 | -29.35 (-50.30, -0.99) |
| Placebo | 23 | -8.90 |
|
*based on Hodges-Lehmann estimator
FDA Review
Table 5. Subgroup Analysis of the Primary Endpoint (Trial 2)
Subgroup |
Treatment |
N |
Median |
Median Difference (95% CI)* |
|---|---|---|---|---|
Sex | ||||
Male | 20 mg/kg | 45 | -46.43 | -10.29 (-30.52, 9.26) |
| Placebo | 43 | -21.66 |
|
Female | 20 mg/kg | 41 | -42.00 | -21.57 (-39.51, -5.24) |
| Placebo | 42 | -21.93 |
|
Race | ||||
White | 20 mg/kg | 75 | -42.00 | -17.92 (-32.25, -3.81) |
| Placebo | 79 | -21.66 |
|
Other | 20 mg/kg | 11 | -49.91 | -3.36 (-47.41, 45.20) |
| Placebo | 6 | -45.75 |
|
Age | ||||
2-5 years | 20 mg/kg | 11 | -50.68 | -8.55 (-49.19, 42.37) |
| Placebo | 12 | -28.29 |
|
6-11 years | 20 mg/kg | 26 | -40.73 | -22.16 (-50.49, 2.02) |
| Placebo | 27 | -14.04 |
|
12-17 years | 20 mg/kg | 19 | -45.81 | -27.28 (-59.50, 5.15) |
| Placebo | 18 | -26.54 |
|
18-55 years | 20 mg/kg | 30 | -39.89 | -13.32 (-32.04, 13.74) |
| Placebo | 28 | -22.35 |
|
*based on Hodges-Lehmann estimator
FDA Review
Table 6. Primary Efficacy Endpoint Analysis by Subgroups (Trial 3)
Subgroup | Treatment | N | Median | Median Difference (95% CI)* |
|---|---|---|---|---|
Sex | ||||
Male | 20 mg/kg | 35 | -37.14 | -19.63 (-41.85, 4.89) |
| Placebo | 27 | -9.52 |
|
Female | 20 mg/kg | 26 | -42.97 | -24.87 (-53.97, -0.30) |
| Placebo | 32 | -20.60 |
|
Race | ||||
White/Caucasian | 20 mg/kg | 44 | -38.57 | -21.52 (-41.46, -0.31) |
| Placebo | 50 | -20.60 |
|
Other | 20 mg/kg | 17 | -39.52 | -45.44 (-89.64, 5.61) |
| Placebo | 9 | 10.71 |
|
Age | ||||
2-5 years | 20 mg/kg | 18 | -54.86 | -29.58 (-60.63, 8.96) |
| Placebo | 17 | -39.37 |
|
6-12 years | 20 mg/kg | 23 | -28.57 | -29.86 (-63.48, 6.02) |
| Placebo | 24 | 12.43 |
|
13-18 years | 20 mg/kg | 20 | -49.33 | -18.19 (-40.48, 13.82) |
| Placebo | 18 | -24.73 |
|
*based on Hodges-Lehmann estimator
FDA Review
What are the possible side effects?
EPIDIOLEX may cause serious side effects including increase in liver enzymes, sleepiness, thoughts about suicide or dying, and severe allergic reactions.
The most common side effects of EPIDIOLEX are sleepiness, decreased appetite, diarrhea, increase in liver enzymes, lack of energy, and rash.
What are the possible side effects (results of trials used to assess safety)?
The table below summarizes adverse reactions in patients with seizures due to Lennox-Gastaut Syndrome and Dravet Syndrome in the combined trials (safety population).
Table 7. Adverse Reactions in Patients Treated with EPIDIOLEX in Controlled Trials
Adverse Reactions | EPIDIOLEX | Placebo | |
|---|---|---|---|
10 mg/kg/day | 20 mg/kg/day | ||
N=75 | N=238 | N=227 | |
Hepatic Disorders | |||
Transaminases elevated | 8 | 16 | 3 |
Gastrointestinal Disorders | |||
Decreased appetite | 16 | 22 | 5 |
Diarrhea | 9 | 20 | 9 |
Weight decreased | 3 | 5 | 1 |
Gastroenteritis | 0 | 4 | 1 |
Abdominal pain, discomfort | 3 | 3 | 1 |
Nervous System Disorders | |||
Somnolence | 23 | 25 | 8 |
Sedation | 3 | 6 | 1 |
Lethargy | 4 | 8 | 2 |
Fatigue, malaise, asthenia | 11 | 12 | 4 |
Insomnia, sleep disorder, poor quality sleep | 11 | 5 | 4 |
Irritability, agitation | 9 | 5 | 2 |
Aggression, anger | 3 | 5 | |
Drooling, salivary hypersecretion | 1 | 4 | |
Gait disturbance | 3 | 2 | |
Infections | |||
Infection, all | 41 | 40 | 31 |
Infection, viral | 7 | 11 | 6 |
Pneumonia | 8 | 5 | 1 |
Infection, fungal | 1 | 3 | 0 |
Infection, other | 25 | 21 | 24 |
Other | |||
Rash | 7 | 13 | 3 |
Hypoxia, respiratory failure | 3 | 3 | 1 |
EPIDIOLEX Prescribing Information
Were there any differences in side effects among sex, race and age?
- Sex: The risk of side effects was similar in males and females.
- Race: The majority of patients were White. The numbers of patients of other races were limited; therefore, differences in side effects among races could not be determined.
- Age: The risk of side effects was similar between patients below and above 18 years of age.
Were there any differences in side effects of the clinical trials among sex, race and age groups?
The table below summarizes the occurrence of the most common adverse reactions by subgroup.
Table 8. Subgroup Analysis of Adverse Reactions by Demographic Subgroup
Demographic Characteristics | Percent of Patients | Decreased Appetite | Somnolence, Sedation, Lethargy | ||||
|---|---|---|---|---|---|---|---|
EPIDIOLEX | PLACEBO | RR* | EPIDIOLEX | PLACEBO | RR* | ||
Sex | |||||||
Male | 54% | 23% | 4% | 5.5 | 32% | 9% | 3.4 |
Female | 46% | 16% | 6% | 2.9 | 33% | 14% | 2.4 |
Race | |||||||
White | 85% | 20% | 4% | 4.6 | 32% | 11% | 2.8 |
Black or African American | 4% | 20% | 0 | _ | 33% | 0 | _ |
Asian | 2% | 14% | 20% | 0.7 | 29% | 20% | 1.4 |
Other | 8% | 19% | 8% | 2.4 | 34% | 15% | 2.2 |
Age Group | |||||||
2 – 5 years | 16% | 16% | 5% | 3.0 | 35% | 8% | 4.5 |
6 – 11 years | 36% | 22% | 5% | 4.4 | 29% | 9% | 3.3 |
12 – 17 years | 25% | 20% | 2% | 11.4 | 34% | 21% | 1.6 |
> 18 years | 23% | 20% | 5% | 4.2 | 32% | 11% | 2.8 |
*RR = relative risk
FDA Review
WHO WAS IN THE CLINICAL TRIALS?
Who participated in the clinical trials?
The FDA approved EPIDIOLEX based on evidence from four clinical trials (Trial 1/NCT02224560, Trial 2/NCT02224690, Trial 3/NCT02091375, Trial 4/NCT02091375) of 550 patients with Lennox-Gastaut or Dravet syndromes. The trials were conducted at 58 sites in Europe and the United States.
Trials 1, 2, and 3 were used to evaluate the benefits of EPIDIOLEX. Demographics of these patients are presented in Table 10, under MORE INFO section. Trials 1, 2, 3, and 4 were used to evaluate safety. The safety population is presented below.
Figure 1 summarizes how many men and women were enrolled in the clinical trials used to evaluate safety.
Figure 1. Baseline Demographics by Sex (safety population)
FDA Review
Figure 2 summarizes the percentage of patients by race enrolled in the clinical trials used to evaluate safety.
Figure 2. Baseline Demographics by Race (safety population)
FDA Review
Table 1. Demographics of Safety Trials by Race
Race | Number of Patients | Percentage of Patients |
|---|---|---|
White | 470 | 86% |
Black or African American | 23 | 4% |
Asian | 12 | 2% |
Other | 45 | 8% |
FDA Review
Figure 3 summarizes the percentage of patients by age in the clinical trials used to evaluate safety.
Figure 3. Baseline Demographics by Age (safety population)
FDA Review
Who participated in the trials?
The table below summarizes demographics of all patients in the safety population.
Table 9. Demographic Characteristics of Patients in the Combined Clinical Trials
Demographic Characteristics | EPIDIOLEX | Placebo | TOTAL | |||
|---|---|---|---|---|---|---|
5 mg* | 10 mg | 20 mg | All | N=550 | ||
Sex, n (%) | ||||||
Male | 5 (50) | 39 (52) | 132 (55) | 176 (54) | 119 (52) | 295 (54) |
Female | 5 (50) | 36 (48) | 106 (45) | 147 (46) | 108 (48) | 255 (46) |
Race, n (%) | ||||||
White | 9 (90) | 60 (80) | 200 (84) | 269 (83) | 201 (89) | 470 (86) |
Black or African American | 0 | 7 (9) | 8 (3) | 15 (5) | 8 (4) | 23 (4) |
Asian | 0 | 1 (1) | 6 (3) | 7 (2) | 5 (2) | 12 (2) |
Other | 1 (10) | 7 (9) | 24 (10) | 32 (10) | 13 (6) | 45 (8) |
Age | ||||||
Mean + SD | 7.2 + 1.9 | 14 + 8.6 | 14.1 + 9.2 | 13.9 + 9.0 | 13.6 + 8.8 | 13.7 + 9.2 |
Median | 6.7 | 11.9 | 11.8 | 11.5 | 11.4 | 11.2 |
Min; Max | 5; 11 | 3; 38 | 3; 48 | 3; 48 | 2; 45 | 2; 48 |
Age Groups, n (%) | ||||||
2 - 5 years | 2 (20) | 10 (13) | 39 (16) | 51 (16) | 38 (17) | 89 (16) |
6 - 11 years | 8 (80) | 28 (37) | 81 (34) | 117 (36) | 79 (35) | 196 (36) |
12 -17 years | 0 | 18 (24) | 62 (26) | 80 (25) | 57 (25) | 137 (25) |
18 - 55 years | 0 | 19 (25) | 56 (23) | 75 (23) | 53 (23) | 128 (23) |
Ethnicity, n (%) | ||||||
Hispanic | 0 | 2 (3) | 8 (3) | 10 (3) | 1 ( | 11 (2) |
Non-Hispanic | 10 (100) | 73 (97) | 230 (97) | 313 (97) | 226 (99) | 539 (98) |
Region, n (%) | ||||||
United States | 8 (80) | 62 (83) | 170 (71) | 240 (74) | 171 (75) | 411 (75) |
Spain | 0 | 9 (12) | 11 (5) | 20 (6) | 12 (5) | 32 (6) |
France | 0 | 1 (1) | 12 (5) | 13 (4) | 6 (3) | 19 (3) |
United Kingdom | 2 (20) | 3 (4) | 15 (6) | 20 (6) | 11 (5) | 32 (6) |
Netherlands | 0 | 0 | 3 (1) | 3 (1) | 2 (1) | 5 (1) |
Poland | 0 | 0 | 27 (11) | 27 (8) | 25 (11) | 52 (9) |
* Not approved dose
Clinical Trial Data
The table below summarizes demographics of patients, in Trials 1, 2 and 3, used to assess efficacy. The intent to treat population is presented.
Table 10. Demographic Characteristics of the Intent-to-Treat (ITT) Population (Trials 1, 2, and 3)
Demographic Characteristics | EPIDIOLEX | Placebo | TOTAL | ||
|---|---|---|---|---|---|
10 mg | 20 mg | All | N=516 | ||
Sex, n (%) | |||||
Male | 40 (55) | 125 (56) | 172 (58) | 119 (52) | 295 (54) |
Female | 33 (45) | 98 (44) | 139 (46) | 108 (48) | 255 (46) |
Race, n (%) | |||||
White | 62(85) | 200 (84) | 269 (83) | 201 (89) | 470 (85) |
Black or African American | 4 (5) | 8 (3) | 15 (5) | 8 (4) | 23 (4) |
Asian | 1 (1) | 6 (3) | 7 (2) | 5 (2) | 12 (2) |
Other | 7 (9) | 24 (10) | 32 (10) | 13 (6) | 45 (8) |
Age | |||||
Mean + SD | 15.4 + 9.5 | 14.1 + 9.2 | 13.9 + 9.5 | 13.6 8.8 | 13.7 + 9.2 |
Median | 12.7 | 11.8 | 11.0 | 11.4 | 11.2 |
Min; Max | 3; 38 | 3; 48 | 3; 48 | 2; 45 | 2; 48 |
Age Groups, n (%) | |||||
2 - 5 years | 8 (11) | 39 (17) | 47 (16) | 38 (17) | 85 (16) |
6 - 11 years | 24 (33) | 71 (32) | 95 (32) | 72 (33) | 167 (32) |
12 -17 years | 19 (26) | 61 (27) | 80 (27) | 57 (26) | 137 (27) |
18 - 55 years | 22 (30) | 53 (24) | 75 (25) | 53 (24) | 128 (25) |
Ethnicity, n (%) | |||||
Hispanic | 2 (3) | 8 (4) | 10 (3) | 1 ( | 11 (2) |
Non-Hispanic | 71 (97) | 215 (96) | 286 (97) | 219 (99) | 505 (98) |
Region, n (%) | |||||
United States | 60 (82) | 156 (70) | 240 (74) | 171 (75) | 411 (75) |
Spain | 9 (12) | 11 (5) | 20 (6) | 12 (5) | 32 (6) |
France | 1 (1) | 12 (5) | 13 (4) | 6 (3) | 19 (3) |
United Kingdom | 3 (4) | 14 (6) | 20 (6) | 12 (5) | 22 (4) |
Netherlands | 0 | 3 (1) | 3 (1) | 2 (1) | 5 ( |
Poland | 0 | 26 (12) | 27 (8) | 25 (11) | 52 (9) |
Clinical Trial Data
How were the trials designed?
The benefits and side effects of EPIDIOLEX were evaluated in four clinical trials. Trials 1, 2, and 3 were used to evaluate both safety and benefits of EPIDIOLEX. Trial 4 was used for evaluation of safety only.
Trials 1 and 2 enrolled patients with seizures due to Lennox-Gastaut syndrome who were not controlled on their current treatment for seizures. In addition to their usual treatment for seizures, patients were randomly assigned to receive one of two doses of EPIDIOLEX or placebo twice daily. To reach the desired dose, the dose of EPIDOLEX and placebo were gradually increased every other day for 2 weeks. Patients remained on this dose for 12 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. The benefit of EPIDIOLEX was evaluated by measuring the change in the number of drop seizures from baseline for the patients receiving EPIDIOLEX in comparison to the patients who received placebo.
Trials 3 and 4 enrolled patients with seizures due to Dravet Syndrome that were not controlled on their current treatment for seizures. In Trial 3, patients were randomly assigned to receive EPIDIOLEX or placebo twice daily in addition to their usual treatment for seizures. To reach the desired dose, the dose of EPIDOLEX and placebo were gradually increased every other day for 2 weeks. Patients remained on this dose for 12 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. The benefit of EPIDIOLEX was evaluated by measuring the change in the number of convulsive seizures from baseline for the patients receiving EPIDIOLEX in comparison to the patients who received placebo.
In Trial 4, patients were randomly assigned to receive one of three different doses of EPIDIOLEX or placebo twice daily for 3 weeks. Neither the patients nor the health care providers knew which treatment was being given until after the trial was completed. Patients were evaluated primarily for side effects.
How were the trials designed?
The safety and efficacy of EPIDIOLEX were established in 4 randomized, double-blind, placebo-controlled trials. Patients with Lennox-Gastaut Syndrome and Dravet Syndrome, who had seizures that were not adequately controlled with concomitant antiepileptic drugs, were evaluated.
Trials 1 and 2 evaluated EPIDIOLEX for the treatment of seizures in patients aged 2 to 55 years with Lennox Gastaut Syndrome. Both trials had a 4-week baseline period followed by a 2-week titration period and 12-week maintenance period. During the 4-week baseline period, patients had at least 2 drop seizures per week. Patients were randomized to receive EPIDIOLEX or placebo in addition to their current antiepileptic drug regimen. In Trial 1, patients were randomized to receive EPIDIOLEX 20 mg/kg/day or placebo daily for 12 weeks. In Trial 2, patients were randomized to receive EPIDIOLEX 10 mg/kg/day, EPIDIOLEX 20 mg/kg/day, or placebo daily for 12 weeks. The primary efficacy endpoint of both trials was the percent change from baseline in the frequency of drop seizures over the 14-week treatment period.
Trial 3 evaluated EPIDIOLEX for the treatment of seizures in patients aged 2 to 18 years with Dravet Syndrome. This trial had a 4-week baseline period followed by a 2-week titration period and 12-week maintenance period. During the 4-week baseline period, patients had at least 4 convulsive seizures. Patients were randomized to receive EPIDIOLEX 20 mg/kg/day or placebo daily, in addition to their current antiepileptic drug regimen, for 12 weeks. The primary efficacy endpoint was the percent change from baseline in the frequency of convulsive seizures over the 14-week treatment period.
Trial 4 evaluated the safety profile of EPIDIOLEX in patients aged 4 to 10 years with Dravet Syndrome. This trial had a 4-week baseline period followed by a 3-week treatment period. During the 4-week baseline period, patients had less than 4 convulsive seizures. Patients were randomized to receive EPIDIOLEX 5 m/kg/day, EPIDIOLEX 10 mg/kg/day, EPIDIOLEX 20 mg/kg/day, or placebo twice daily in addition to their current antiepileptic drug regimen for 3 weeks.
GLOSSARY
CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.