1. What’s new in clinical Trials
Jacqueline A French MD
NYU Epilepsy Center

2. Current issues to discuss
Why do we do clinical trials?
What to expect from a trial
Drugs/Devices currently in development

3. Why do we do clinical trials?
The American Public looks to its government for assurance that therapies developed to treat diseases are both SAFE and EFFECTIVE
The Food and Drug Administration (FDA) is charged with ensuring that safety and effectiveness are proven before a drug is put on pharmacy shelves, or before a device is marketed
They are also responsible for LABELING drugs so that the public is aware of risks and benefits
There are very strict rules that govern the conduct of clinical trials to determine safety and efficacy (effectiveness)

4. Who does clinical trials?
Early trials may be done by researchers at Universities
Most drugs and devices (even if the idea comes from research labs or the National Institutes of Health (NIH) will be tested by companies that eventually will sell the product
The cost of developing a new drug is $800 million to 2 Billion and takes years
Companies need to partner with clinical researchers and doctors to perform good trials

5. The course of drug development
Pre-Clinical testing
10,
(compounds) (get to animal testing) (enter human tests)
Phase I
Testing in about 100 normal volunteers
Developer needs to get approval from FDA in the form of an NDA (new drug application)
Phase II/III
Tests to determine if therapy is safe and effective

6. The course of drug development
Phase II/III (continued)
For a drug, At least 2 trials with a control group (usually placebo)
Drug must be better than “placebo” (how much?)
Can see how frequent dose-related side effects are compared to placebo
For a device a single trial may be sufficient
Overall, pts exposed to drug, to look for “rare” side effects

7. The difficulty of clinical trials
Clinical trials cannot be exactly like clinical practice
Too much chance that events that occur by “chance” (good and bad) will be attributed to the novel intervention
Therefore, good clinical science requires that trials have a “control group”, that will provide data on what would have happened had the intervention NOT occurred
Studies without a control group usually over-estimate effectiveness of an intervention

8. DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL
DOSE 2 +AEDS
DOSE 1 +AEDS
1-2 AEDS
PLACEBO +AEDS
TAPER
(DOUBLE BLIND)
+ FOLLOW-UP
BASELINE
TITRA-
TION
TREATMENT

9. Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy: 50% Responder Rates
41%*
38%*
33%
(* P<0.05
vs PL)
% Patients
22%
Placebo LCS 200mg LCS 400mg LCS 600mg
Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

10. Pregabalin Most Frequent Adverse Events
Preferred Term
Placebo N=73
PGB 600 mg/d fixed dose N=137
PGB mg/d flexible dose N=131
N (%)
Dizziness
6 (8.2)
59 (43.1)
32 (24.4)
Ataxia
3 (4.1)
29 (21.2)
12 (9.2)
Weight gain*
5 (6.8)
28 (20.4)
25 (19.1)
Asthenia (weakness)
10 (13.7)
25 (18.2)
22 (16.8)
Somnolence
24 (17.5)
Vertigo
2 (2.7)
19 (13.9)
14 (10.7)
Diplopia
1 (1.4)
16 (11.7)
8 (6.1)
Amblyopia
14 (10.2)
3 (2.3)
Constipation
12 (8.8)
4 (3.1)
Tremor
0 (0.0)
*Weight gain AEs were not exclusively spontaneously reported. A query was generated for patients with a change in weight >7% to assess whether the body weight changes also needed to be reported as an AE.
Data on file, Pfizer Inc

11. Precautionary tale: Cinromide
Promising potential AED in 1980’s
Highly effective in open-label trial of Lennox-Gastaut , a very severe childhood epilepsy with multiple seizures/day : Over 50% of children had seizures reduced by half
No difference from placebo in randomized controlled trial (significant response in both arms)
The Group for the Evaluation of Cinromide in the Lennox-Gastaut Syndrome, Epilepsia, 30:

12. The difficulty of clinical trials
Thus, patients who volunteer for trials will have to accept possibility of randomization to placebo.
Without this type of trial, we would never be able to know if a drug is truly working
New trial designs: attempt to limit placebo exposure as much as possible

13. SINCE 1998 20 Lacosamide Rufinamide Pregabalin 10 Zonisamide
Number of Licensed Antiepileptic Drugs
Oxcarbazepine
Levetiracetam 5
Lamotrigine
Tiagabine
Topiramate
Gabapentin
Felbamate
1990
2000
2010
Calendar Year

14. DO WE NEED MORE NEW ANTIEPILEPTIC DRUGS?
Problem with current AEDs:
Seizure control
Newly diagnosed well treated
Still 40% with therapy resistance
New AEDs over last 20 years have not changed this equation!
Safety/tolerability
Some new (and old) AEDs still have important safety and tolerability problems

15. What’s new this year? Two new drugs approved
Vimpat (lacosamide) (refractory partial-onset seizures)
Inovelon (rufinamide) (seizures associated with Lennox-Gastaut)
Four drugs in late trials (all for refractory partial onset seizures)
Eslicarbazepine
Rikelta (brivaracetam)
Carisbamate
Retigabine
One drug in development for acute clusters
Two devices in late trials
Responsive Neurostimulator (RNS)
Deep Brain Stimulator (DBS)

16. BRIVARACETAM
Similar mechanism to Levetiracetam (KeppraTM) but much stronger in animal models
Also has sodium channel blocking activity
Should work in many seizure types, including myoclonus
FDA trials underway

17. Genetic Absence Epilepsy Rats from Strasbourg
Levetiracetam
Values given are means ± S.D. (n=8)

18. Genetic Absence Epilepsy Rats from Strasbourg
Values given are means ± S.D. (n=8)

19. SEIZURE-FREEDOM RATES
Responder Rates
RESPONDER RATES
SEIZURE-FREEDOM RATES
p = 0.001
55.8 60 60
p = 0.002
44.2 50 50 40
p = 0.047
32.0 40
% Patients
% Responders 30 30
16.7 20 20
8.0
4/50
7.7
4/52
7.7
4/52 10 10
1.9
1/54
PBO
(n=54)
BRV5
(n=50)
BRV20
(n=52)
BRV50
(n=52)
PBO
(n=54)
BRV5
(n=50)
BRV20
(n=52)
BRV50
(n=52)
Results from logistic regression (50% responder rate); ITT population
ITT population: n=208; 110M, 98F; age range 16–65 y; p-value versus PBO

20. Brivaracetam Adverse Events
PBO
BRV5
BRV20
BRV50
Patients (N) 54 50 52
Permanent study drug discontinuation
2 (3.7)
3 (6.0)
1 (1.9)
Patients with ≥1 AE, n (%)
29 (53.7)
26 (52.0)
29 (55.8)
28 (53.8)
Total AEs 59 72 56
AEs reported in ≥ 5% patients
Headache
Somnolence
Influenza
Dizziness
Neutropenia
Fatigue
4 (7.4)
3 (5.6)
4 (8.0)
1 (2.0)
2 (3.8)
3 (5.8)
4 (7.7)

21. Eslicarbazepine A “third generation” Carbamazepine (TegretolTM)
Improves on second generation (TrileptalTM)
Less effect on sodium
Smoother release may produce less side effects
Hopefully will work equally as well
Ready to submit to FDA

22. Double-Blind Placebo-Controlled Add-on Trial of Eslicarbazerpine (ESL) in Refractory Partial Epilepsy: 50% Responder Rates (n=143)
54%*
41%
(* P=0.008
vs PL)
% Patients
28%
Placebo ESL ESL
1200 mg/d mg/d
o.i.d b.i.d.
Bialer et al., Epilepsy Res 2007;73:1-52.

23. Carisbamate Mechanism of action unknown
Performed very well in suppressing epileptic activity as a result of flashing lights (photosensitivity)
Two double-blind, placebo controlled trials in partial epilepsy, one positive and one negative
Side effects mild
Clinical trials are ongoing

24. Carisbamate Suppression of the Photoparoxismal Response
Kasteleijn-Nolst Trenité et al, Epilepsy Res 2007;74:

25. Retigabine
Works on a NEW channel that other drugs don’t work on (Potassium channel)
Defect in potassium channel linked to one inherited form of epilepsy (benign neonatal seizures)
Trials completed, ready to submit to FDA for approval

26. Patients with >50% Seizure Reduction in Overall Treatment Period (Titration + Maintenance)
Study 302
Study 301
% Patients
179
181
178
152
153
Placebo
600
900
Placebo
1200 RTG
RTG
Intent-to-treat
*p< **p<0.001

27. Most Common Adverse Events (>10% Incidence)
% Patients
Placebo (N=331)
RTG 600 (N=181)
RTG 900 (N=178)
RTG 1200 (N=153)
Dizziness 10 17 26 40
Somnolence 13 14 31
Fatigue 5 15 16
Confusion 1 2
Dysarthria 12
Headache 11
Ataxia / gait disturbance 3
Urinary tract infection
Tremor 9
Vision blurred
<1
Nausea 6 7

28. Discontinuations Due to Adverse Events
Adverse event as primary reason for discontinuation
Placebo (N=331)
600 (N=181)
900 (N=178)
1200 (N=153) 8%
14%
26%
27%
Cause for discontinuation in >3% of patients
Dizziness*
Confusion*
Somnolence
Fatigue
*Dose-related

29. Current pharmacologic therapy in epilepsy
Preventive (antiepileptic medications):
Standard for nearly all patients
Not effective for an “acute” seizure
Abortive or rescue medications
Seizures in clusters
Prolonged seizures
One seizure after another (status epilepticus)

30. Options for abortive therapy
Current:
Rectal Diazepam (valium)
Mostly used in children
Often not feasible, or may be a delay in administration
Buccal or nasal preparations
Not FDA approved
Future
Intranasal Midazolam
Studies beginning soon

31. Advantages of Nasal Drug Delivery
Easy access with/without patient cooperation
Rapid and extensive absorption through the nasal mucosa
Convenient and easy administration
Needle-less
Further studies to see if effect is due to transneural transport may be needed
In a study by Hussain, et al in the Biological and Synthetic Membranes, 1989, IN administration in humans of lipophilic propranolol resulted in blood levels similar to those observed following IV administration (60 ng/ml)

32. Comparative Efficacy of IN MDZ vs IV DZP
N=47 children with febrile seizures (>10 min)
Main outcome measures: Time from arrival at hospital to drug administration
& time to seizure cessation
Observation period = 60 minutes
5 min
Dose = 0.2 mg/kg
Dose = 0.3 mg/kg
3.5 min
Objective: To compare the safety and efficacy of midazolam given intranasally with diazepam given intravenously in the treatment of children with prolonged febrile seizures. Design: Prospective randomized study. Setting: Pediatric emergency department in a general hospital. Subjects: 47 children aged six months to five years with prolonged febrile seizure (at least 10 minutes) during a 12 month period. Interventions: Intranasal midazolam (0.2 mg/kg) and intravenous diazepam (0.3 mg/kg). Main outcome measures: Time from arrival at hospital to starting treatment and cessation of seizures. Results: Intranasal midazolam and intravenous diazepam were equally effective. Overall, 23 of 26 seizures were controlled with midazolam and 24 out of 26 with diazepam. The mean time from arrival at hospital to starting treatment was significantly shorter in the midazolam group (3.5 (SD 1.8) minutes, 95% confidence interval 3.3 to 3.7) than the diazepam group (5.5 (2.0), 5.3 to 5.7). The mean time to control of seizures was significantly sooner (6.1 (3.6), 6.3 to 6.7) in the midazolam group than the diazepam group (8.0 (0.5), 7.9 to 8.3). No significant side effects were observed in either group. Conclusion: Seizures were controlled more quickly with intravenous diazepam than with intranasal midazolam, although midazolam was as safe and effective as diazepam. The overall time to cessation of seizures after arrival at hospital was faster with intranasal midazolam than with intravenous diazepam. The intranasal route can possibly be used not only in medical centers but in general practice and, with appropriate instructions, by families of children with recurrent febrile seizures at home.
8 min
6.1 min
Lahat E, et al. BMJ. 2000;321:83-86.

33. What should I ask my doctor about a new drug?
How many patients have been exposed to date?
What are the common dose-related side effects
Were there any irreversible side effects, or will the problems go away when I lower the dose?
Was this drug studied for my seizure type?
How well did the drug do compared to placebo?

34. Devices under study
NeuroPace “RNS” Trial
Medtronic, “Sante” Trial

35. Medtronic SANTE Trial
Stimulation of Anterior Thalamus for Epilepsy
Electrodes surgically placed in the thalamus, a deep part of the brain, on both sides
Stimulation every 5 minutes
Strength and duration of stimulation can be adjusted
Like Vagus nerve stimulator, patient can “trigger” stimulation for an aura or seizure

36. Electrode (4 contacts) Stimulating Electrode, 4 contacts
Greg: These 3 slides are from the ANTs patients. The first 2 show that focal discharges on the EEG can be seen focally on biopolar recordings from the ANTs electrodes (they are shown at a different gain in referential and bipolar montages. The last slide shows a delay from the right frontal to left frontal regions (across the callosum) to the ANTs: I.e. frontal regions to thalamus in this patient with a right frontal focus with rapid spread. The ANTs stimulator stopped her falls. This slide supports a proposed functional disruption of conduction from the frontal to more central regions, which might be responsible for the therapeutic effect (the stim. Was off the entire time these recordings were obtained).

37. Deep Brain Stimulation Study
Of the 87 study participants who completed the diaries through month 13, 40 % experienced a ≥ 50 % reduction in their baseline rate of seizures 13 months after implant.
During this same long-term follow-up period (last three months of data for each patient), median seizure frequency was reduced by approximately two-thirds, 9% of study participants had no seizures and 19 % experienced a >90 % reduction in seizure frequency.
The infection rate was 10.9 % and the rate of asymptomatic intracranial hemorrhage was 1.3 % per lead implant.
There was a significantly higher incidence of spontaneously self-reported depression, memory impairment, and anxiety in the active group compared to the control group during the blinded phase,

38. Responsive Neurostimulator
The RNS is designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms.
The RNS is placed within the skull and underneath the scalp by a surgeon. The RNS is then connected to one or two wires containing electrodes that are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start).
The RNS is designed to continuously monitor brain electrical activity from the electrodes and, after identifying the "signature" of a seizure's onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure.
Early trials are promising, and studies are ongoing

39. RNS with Leads

40. RNS

41. Medical College of Georgia
Anthony Murro, M.D.
Medical College of Georgia

42. Other drugs/devices on the way
Ganaxalone
ICA
Perampanel (E2007)
T2000: (non-sedating barbiturate)
YKP3089
Huperzine
NPY gene transfer
Devices
Drug Delivery Pumps
Seizure detection/prevention

43. Conclusion
Without volunteers for clinical trials, no new drugs or devices will be possible
Many new options are on the way, providing hope for all people with uncontrolled seizures