1 Project overview

1.1 Background

There is limited data on real-world outcomes associated with use of prescription cannabidiol (CBD) therapy. The purpose of this study was to describe the use of emergency healthcare services, time to first emergency healthcare service use, and change in anti-seizure medication (ASM) use over the first 12-months of prescription CBD therapy.

1.2 Methods

This was a single-center, prospective cohort study of patients prescribed CBD by a neurology clinic provider and fulfilled through the center’s specialty pharmacy from January 2019 through April 2020. Patients enrolled in a clinical trial for CBD or for whom the insurance approval process was not completed by the center’s specialty pharmacy were excluded. Descriptive statistics were used to summarize the data with results presented as medians with interquartile ranges (IQR). Pediatric age was defined as less than 18 years.

1.3 Outcomes

Clinical Characteristics

  • Demographic characteristics of study population (age, sex, race, ethnicity, insurance type, height/weight)
  • Prior AED therapies trialed (number, type)
  • Previous non-pharmacological treatments trialed (dietary, surgical, VNS, DBS)
  • Number of drug-drug interactions at baseline
  • Obtainment of baseline HFP
  • Route of administration
  • Number and type of concurrent AED therapies upon Epidiolex initiation
  • Number and type of drug-drug interactions present upon Epidiolex initiation
  • Outcome of drug interaction management upon Epidiolex initiation

Treatment Outcomes

  • Liver function lab results over the first 12-months of Epidiolex therapy
  • Adverse events reported during the first 12-months of Epidiolex therapy
  • Describe the use of emergency healthcare services over the first 12-months of Epidiolex therapy
  • Time to first emergency healthcare service use during the first 12-months of Epidiolex therapy
  • Change in ASM use over the first 12-months of Epidiolex therapy
  • Evaluate adherence, discontinuation rates, and reasons for non-adherence and discontinuation of Epidiolex during the first 12-months post-initiation

2 Exclusions

Exclusions
N

N=160
Reason for exclusion 160
    Participation in clinical trial 1.2% ( 2)
    Receiving medication through manufacturer 0.6% ( 1)
    Receiving from external specialty pharmacy 10.6% ( 17)
    VSP did not complete PA process 2.5% ( 4)
    No exclusion criteria met. Patient should be INCLUDED in the study. 85.0% (136)
N is the number of non-missing values. Numbers after proportions are frequencies.

3 Descriptive statistics

3.1 Demographics

Demographics
N
Adult
N=44
Pediatric
N=92
Combined
N=136
Age at start of prescription therapy 136 21.2 27.5 43.9  (32.8 ±13.3) 4.6 10.0 13.8  ( 9.5 ± 5.1) 8.6 13.8 20.9  (17.1 ±13.9)
Patient age category 136
    Adult 100% (44) 0% ( 0) 32% (44)
    Pediatric 0% ( 0) 100% (92) 68% (92)
Gender 136
    Female 57% (25) 47% (43) 50% (68)
    Male 43% (19) 53% (49) 50% (68)
Race 136
    White 86.4% ( 38) 83.7% ( 77) 84.6% (115)
    Black or African American 11.4% ( 5) 10.9% ( 10) 11.0% ( 15)
    Other Asian 0.0% ( 0) 1.1% ( 1) 0.7% ( 1)
    Decline to Answer 2.3% ( 1) 0.0% ( 0) 0.7% ( 1)
    Unknown 0.0% ( 0) 4.3% ( 4) 2.9% ( 4)
Insurance type 136
    Commercial 22.7% (10) 19.6% (18) 20.6% (28)
    Medicare 45.5% (20) 0.0% ( 0) 14.7% (20)
    Medicaid 31.8% (14) 72.8% (67) 59.6% (81)
    Tricare 0.0% ( 0) 7.6% ( 7) 5.1% ( 7)
    Other 0.0% ( 0) 0.0% ( 0) 0.0% ( 0)
Height (cm) 122 153 164 173  (163 ± 15) 102 130 147  (126 ± 30) 120 146 163  (139 ± 31)
Weight (kg) 136 49 62 76  (67 ±24) 17 29 38  (34 ±23) 24 37 60  (44 ±28)
Route of administration 136
    By mouth (PO) 93.2% ( 41) 78.3% ( 72) 83.1% (113)
    G-tube 6.8% ( 3) 18.5% ( 17) 14.7% ( 20)
    Other 0.0% ( 0) 3.3% ( 3) 2.2% ( 3)
a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. x ± s represents X ± 1 SD.   N is the number of non-missing values. Numbers after proportions are frequencies.

3.1.1 Age, height and weight

3.1.1.1 Pediatric

3.1.1.2 Adult

3.2 Medications

3.2.1 Previous ASM

Previous ASM by age group
N
Adult
N=44
Pediatric
N=92
Combined
N=136
Number of previous medications 136 8.0 11.5 14.0  (11.5 ± 4.0) 5.0 6.0 8.0  ( 6.7 ± 3.1) 5.0 7.0 11.0  ( 8.2 ± 4.1)
Number of previous medications 136
    2 0.0% ( 0) 4.3% ( 4) 2.9% ( 4)
    3 0.0% ( 0) 7.6% ( 7) 5.1% ( 7)
    4 2.3% ( 1) 12.0% (11) 8.8% (12)
    5 4.5% ( 2) 19.6% (18) 14.7% (20)
    6 0.0% ( 0) 12.0% (11) 8.1% (11)
    7 11.4% ( 5) 13.0% (12) 12.5% (17)
    8 9.1% ( 4) 7.6% ( 7) 8.1% (11)
    9 6.8% ( 3) 2.2% ( 2) 3.7% ( 5)
    10 4.5% ( 2) 10.9% (10) 8.8% (12)
    11 11.4% ( 5) 3.3% ( 3) 5.9% ( 8)
    12 13.6% ( 6) 3.3% ( 3) 6.6% ( 9)
    13 2.3% ( 1) 1.1% ( 1) 1.5% ( 2)
    14 11.4% ( 5) 2.2% ( 2) 5.1% ( 7)
    15 4.5% ( 2) 0.0% ( 0) 1.5% ( 2)
    16 6.8% ( 3) 0.0% ( 0) 2.2% ( 3)
    17 4.5% ( 2) 0.0% ( 0) 1.5% ( 2)
    18 4.5% ( 2) 1.1% ( 1) 2.2% ( 3)
    21 2.3% ( 1) 0.0% ( 0) 0.7% ( 1)
a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. x ± s represents X ± 1 SD.   N is the number of non-missing values. Numbers after proportions are frequencies.

3.2.2 Previous non-pharmacological treatments trialed

Previous non-pharm
N
Adult
N=44
Pediatric
N=92
Combined
N=136
Previous non-pharmacological treatments trialed 68
    Deep brain stimulation (DBS) 3.6% ( 1) 0.0% ( 0) 1.5% ( 1)
    Ketogenic diet 10.7% ( 3) 55.0% (22) 36.8% (25)
    Surgery 0.0% ( 0) 7.5% ( 3) 4.4% ( 3)
    Surgery, Ketogenic diet 0.0% ( 0) 5.0% ( 2) 2.9% ( 2)
    Surgery, Vagal nerve stimulation (VNS) 21.4% ( 6) 5.0% ( 2) 11.8% ( 8)
    Surgery, Vagal nerve stimulation (VNS), Ketogenic diet 14.3% ( 4) 5.0% ( 2) 8.8% ( 6)
    Vagal nerve stimulation (VNS) 21.4% ( 6) 10.0% ( 4) 14.7% (10)
    Vagal nerve stimulation (VNS), Ketogenic diet 28.6% ( 8) 12.5% ( 5) 19.1% (13)
N is the number of non-missing values. Numbers after proportions are frequencies.

3.2.3 Drug-drug interactions at baseline

Interactions
N

N=136
Number of drug-drug interactions 136 1.0 1.0 3.0  (1.7 ±1.5)
Number of drug-drug interactions 136
    0 19.9% (27)
    1 33.8% (46)
    2 20.6% (28)
    3 12.5% (17)
    4 7.4% (10)
    5 3.7% ( 5)
    6 2.2% ( 3)
a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. x ± s represents X ± 1 SD.   N is the number of non-missing values. Numbers after proportions are frequencies.

3.2.4 Concurrent medications at start

Concurrent medications
N

N=136
Number of concurrent medications 136 2.0 3.0 4.0  (2.7 ±1.3)
Number of concurrent medications 136
    0 2.9% ( 4)
    1 14.7% (20)
    2 27.9% (38)
    3 25.0% (34)
    4 24.3% (33)
    5 3.7% ( 5)
    6 1.5% ( 2)
a b c represent the lower quartile a, the median b, and the upper quartile c for continuous variables. x ± s represents X ± 1 SD.   N is the number of non-missing values. Numbers after proportions are frequencies.

3.3 Drug Drug interactions at baseline management

Management
N
Adult
N=44
Pediatric
N=92
Combined
N=136
Was management of a possible drug interaction performed at baseline (prior to starting prescription CBD)? 136
    No 25% ( 11) 17% ( 16) 20% ( 27)
    Yes 75% ( 33) 83% ( 76) 80% (109)
What type of drug interaction was managed? 109
    Pharmacokinetic 9.1% ( 3) 25.0% (19) 20.2% (22)
    Pharmacodynamic 42.4% (14) 36.8% (28) 38.5% (42)
    Both 48.5% (16) 38.2% (29) 41.3% (45)
N is the number of non-missing values. Numbers after proportions are frequencies.

4 Previous and concurrent medications

4.1 Figure

4.2 Previous medications

4.3 Concurrent medications

5 Previous non-pharmacological treatments trialed

5.1 Totals

5.2 Intersection

Pediatric

6 Number and type of drug-drug interactions present upon Epidiolex initiation

7 Outcome of drug interaction management

7.1 Agents and outcomes

Outcomes of drug interaction management
Agent n.agent Outcome n pct.outcome
clobazam 63 other agent stopped 1 1.6%
other agent dose change 5 7.9%
no medication change needed, pharmacist provided counseling only 57 90.5%
benzodiazepine (such as clonazepam, diazepam, lorazepam, midazolam) 58 no medication change needed, pharmacist provided counseling only 58 100.0%
antiepileptic medication not noted above 55 other agent stopped 3 5.5%
no medication change needed, pharmacist provided counseling only 52 94.5%
valproic acid 26 other agent dose change 1 3.8%
no medication change needed, pharmacist provided counseling only 25 96.2%
artisinal CBD 18 other agent stopped 18 100.0%
antihistamine (such as cetirizine, diphenhydramine, loratadine, fexofenadine) 9 no medication change needed, pharmacist provided counseling only 9 100.0%
antipsychotic 6 no medication change needed, pharmacist provided counseling only 6 100.0%
phenobarbital 5 no medication change needed, pharmacist provided counseling only 5 100.0%
antidepressant 4 no medication change needed, pharmacist provided counseling only 4 100.0%
fluoxetine no medication change needed, pharmacist provided counseling only 4 100.0%
other no medication change needed, pharmacist provided counseling only 4 100.0%
muscle relaxer 2 no medication change needed, pharmacist provided counseling only 2 100.0%
promethazine no medication change needed, pharmacist provided counseling only 2 100.0%
carbamazepine 1 no medication change needed, pharmacist provided counseling only 1 100.0%
cyproheptadine no medication change needed, pharmacist provided counseling only 1 100.0%
meclizine no medication change needed, pharmacist provided counseling only 1 100.0%
mTor inhibitor (everolimus, tacrolimus) no medication change needed, pharmacist provided counseling only 1 100.0%

7.2 Agents

Summary of agents
Overall
(N=260)
Agent
clobazam 63 (24.2%)
benzodiazepine (such as clonazepam, diazepam, lorazepam, midazolam) 58 (22.3%)
antiepileptic medication not noted above 55 (21.2%)
valproic acid 26 (10.0%)
artisinal CBD 18 (6.9%)
antihistamine (such as cetirizine, diphenhydramine, loratadine, fexofenadine) 9 (3.5%)
antipsychotic 6 (2.3%)
phenobarbital 5 (1.9%)
antidepressant 4 (1.5%)
fluoxetine 4 (1.5%)
other 4 (1.5%)
muscle relaxer 2 (0.8%)
promethazine 2 (0.8%)
carbamazepine 1 (0.4%)
cyproheptadine 1 (0.4%)
meclizine 1 (0.4%)
mTor inhibitor (everolimus, tacrolimus) 1 (0.4%)

7.3 Outcomes

Summary of outcomes
Overall
(N=260)
Outcome
no medication change needed, pharmacist provided counseling only 232 (89.2%)
other agent stopped 22 (8.5%)
other agent dose change 6 (2.3%)

7.4 PK/ PD

Characteristic N N = 2601
new_di_type 260
Pharmacodynamic 184 (70.8%)
Pharmacokinetic 76 (29.2%)
1 n (%)

8 Obtainment of baseline hepatic function panel (HFP)

8.1 Figure

9 Liver function labs during Epidiolex treatment

Characteristic N N = 2981
AST result 298
High 99 (33.2%)
In range 186 (62.4%)
Low 12 (4.03%)
Not available 1 (0.34%)
ALT result 298
High 83 (27.9%)
In range 201 (67.4%)
Low 11 (3.69%)
Not available 1 (0.34%)
Undetectable 2 (0.67%)
Bili result 298
High 37 (12.4%)
In range 229 (76.8%)
Low 6 (2.01%)
Not available 6 (2.01%)
Undetectable 20 (6.71%)
1 n (%)

10 Discontinuation

10.1 Discontinuation summary

Characteristic N N = 1361
Did the patient discontinue medication 136
No 105 (77.2%)
Yes 31 (22.8%)
Time to discontinuation 31
Mean (SD) 148.0 (108.6)
Median (IQR) 117.0 (68.0 - 216.0)
Range 13.0 - 349.0
Missing 105
1 n (%)

10.2 Figure

10.3 DC reasons

10.3.1 Reasons for DC

The denominator here is 31

value n pct
Major side effects/complication 12 38.7%
Common side effects 11 35.5%
No response/sub-optimal response to therapy 11 35.5%
Non-compliance 2 6.5%
NULL/Data not available 2 6.5%
Patient Decision (Not related to side effects/financial limitations) 2 6.5%
Deceased 1 3.2%

10.3.2 AEs listed as reason for DC

Here, the denominator is 16: the number of people reporting side effects as a reason for discontinuation (Major side effects/complication or Common side effects)

new n pct
Agitation/ irritability 4 25%
Other mood change 4 25%
Aggression 3 18.8%
Increased seizure frequency 3 18.8%
Other 3 18.8%
Somnolence 3 18.8%
Other behavioral change 2 12.5%
Self-injurious behavior 2 12.5%
Sleep disturbance 2 12.5%
Elevated transaminases 1 6.2%
Gastrointestinal upset 1 6.2%
Lethargy 1 6.2%
Musculoskeletal 1 6.2%
Other lab abnormality 1 6.2%
Rash 1 6.2%
Sialorrhea 1 6.2%
Suicidal ideation 1 6.2%

11 Adverse Events During Treatment

Denominator here is the total number of AEs reported.

new n pct
Total 149 -
Somnolence 44 29.5%
Gastrointestinal upset 21 14.1%
Lethargy 12 8.1%
Agitation/ irritability 9 6%
Appetite change 8 5.4%
Sleep disturbance 8 5.4%
Gait disturbance 7 4.7%
Other 7 4.7%
Aggression 6 4%
Sialorrhea 5 3.4%
Elevated transaminases 4 2.7%
Other behavioral change 3 2%
Other mood change 3 2%
Depression 2 1.3%
Mental status change 2 1.3%
Musculoskeletal 2 1.3%
Other lab abnormality 2 1.3%
Rash 2 1.3%
Dizziness 1 0.7%
Increased seizure frequency 1 0.7%

12 Adherence

12.1 Summary

Characteristic N N = 1361
Patient PDC 128
Mean (SD) 0.95 (0.11)
Median (IQR) 0.99 (0.95 - 1.00)
Range 0.18 - 1.00
Reason for low adherence 8
Patient was unreachable 1 (12.5%)
Adverse effects which interrupted therapy 2 (25.0%)
Medication provided during inpatient hospitalization 1 (12.5%)
Did not start therapy at time of initiation 1 (12.5%)
Transfer to outside pharmacy prior to returning 1 (12.5%)
Medications weaned without need for further refill 1 (12.5%)
Did not take amount prescribed 1 (12.5%)
Fills 136
Mean (SD) 10.64 (3.86)
Median (IQR) 12.50 (9.75 - 13.00)
Range 1.00 - 15.00
Number of gap days 136
Mean (SD) 14.35 (34.37)
Median (IQR) 1.50 (0.00 - 16.00)
Range 0.00 - 275.00
PDC denominator 136
Mean (SD) 295.67 (107.25)
Median (IQR) 347.00 (305.00 - 356.00)
Range 0.00 - 366.00
1 n (%)

13 Emergency Healthcare Utilization

13.1 Categorical

Characteristic N N = 1361
Total number of hospitalizations 30
1 19 (63.3%)
2 9 (30.0%)
3 1 (3.33%)
5 1 (3.33%)
Total number of ER or urgent care visits 29
1 20 (69.0%)
2 7 (24.1%)
3 1 (3.45%)
4 1 (3.45%)
1 n (%)

13.2 Continuous

Characteristic N N = 136
Total number of hospitalizations 30
Mean (SD) 1.5 (0.9)
Median (IQR) 1.0 (1.0 - 2.0)
Range 1.0 - 5.0
Total number of ER or urgent care visits 29
Mean (SD) 1.4 (0.7)
Median (IQR) 1.0 (1.0 - 2.0)
Range 1.0 - 4.0

13.3 Time to healthcare utilization

Characteristic N Medication shipped: p-value1 Overall, N = 136
After 3 days, N = 107 Within 3 days, N = 29
time.to.hosp 30 0.5
Mean (SD) 121.0 (102.6) 140.1 (80.9) 125.4 (97.0)
Median (IQR) 113.0 (26.0 - 176.0) 98.0 (92.0 - 168.5) 103.5 (38.2 - 178.5)
Range 5.0 - 318.0 79.0 - 283.0 5.0 - 318.0
time.to.er 29 >0.9
Mean (SD) 109.7 (106.2) 111.2 (90.5) 109.9 (102.1)
Median (IQR) 79.0 (29.8 - 160.0) 69.0 (61.0 - 196.0) 69.0 (31.0 - 196.0)
Range 0.0 - 348.0 12.0 - 218.0 0.0 - 348.0
1 Wilcoxon rank sum exact test; Wilcoxon rank sum test

14 Change in ASM Use

14.1 Categorical

Characteristic N N = 1361
Number of concurrent medications 136
0 4 (2.94%)
1 20 (14.7%)
2 38 (27.9%)
3 34 (25.0%)
4 33 (24.3%)
5 5 (3.68%)
6 2 (1.47%)
Number of Concurrent AEDs at time of Study Close 105
0 4 (3.81%)
1 19 (18.1%)
2 25 (23.8%)
3 34 (32.4%)
4 17 (16.2%)
5 6 (5.71%)
Change in number of concurrent medications 105
-3 1 (0.95%)
-2 3 (2.86%)
-1 19 (18.1%)
0 73 (69.5%)
1 9 (8.57%)
1 n (%)

14.2 Continuous

Characteristic N Medication shipped: p-value1 Overall, N = 136
After 3 days, N = 107 Within 3 days, N = 29
Number of concurrent medications 136 0.5
Mean (SD) 2.7 (1.3) 2.8 (1.2) 2.7 (1.3)
Median (IQR) 3.0 (2.0 - 4.0) 3.0 (2.0 - 4.0) 3.0 (2.0 - 4.0)
Range 0.0 - 6.0 0.0 - 5.0 0.0 - 6.0
Number of Concurrent AEDs at time of Study Close 105 0.8
Mean (SD) 2.5 (1.2) 2.6 (1.4) 2.6 (1.2)
Median (IQR) 3.0 (2.0 - 3.0) 3.0 (1.0 - 3.0) 3.0 (2.0 - 3.0)
Range 0.0 - 5.0 0.0 - 5.0 0.0 - 5.0
Change in number of concurrent medications 105 0.8
Mean (SD) -0.2 (0.6) -0.3 (0.8) -0.2 (0.7)
Median (IQR) 0.0 (0.0 - 0.0) 0.0 (0.0 - 0.0) 0.0 (0.0 - 0.0)
Range -2.0 - 1.0 -3.0 - 1.0 -3.0 - 1.0
1 Wilcoxon rank sum test