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What’s new in clinical Trials. Jacqueline A French MD NYU Epilepsy Center. Current issues to discuss. Why do we do clinical trials? What to expect from a trial Drugs/Devices currently in development. Why do we do clinical trials?.

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what s new in clinical trials

What’s new in clinical Trials

Jacqueline A French MD

NYU Epilepsy Center

current issues to discuss
Current issues to discuss
  • Why do we do clinical trials?
  • What to expect from a trial
  • Drugs/Devices currently in development
why do we do clinical trials
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)
who does clinical trials
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 12-15 years
  • Companies need to partner with clinical researchers and doctors to perform good trials
the course of drug development
The course of drug development
  • Pre-Clinical testing

10,000250 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
the course of drug development1
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, 1500-3000 pts exposed to drug, to look for “rare” side effects
the difficulty of clinical trials
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
double blind placebo controlled trial
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

slide9

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

pregabalin most frequent adverse events
Pregabalin Most Frequent Adverse Events

*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

slide11

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, 1989. Epilepsia, 30:422-429

the difficulty of clinical trials1
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
since 1998
SINCE 1998

20

Lacosamide

Rufinamide

Pregabalin

10

Zonisamide

Number of Licensed Antiepileptic Drugs

Oxcarbazepine

Levetiracetam

Lamotrigine

5

Tiagabine

Topiramate

Gabapentin

Felbamate

0

2010

1990

2000

Calendar Year

do we need more new antiepileptic drugs
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
what s new this year
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)
brivaracetam
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
slide17

Genetic Absence Epilepsy Rats from Strasbourg

Levetiracetam

Values given are means ± S.D. (n=8)

slide18

Genetic Absence Epilepsy Rats from Strasbourg

Values given are means ± S.D. (n=8)

responder rates
Responder Rates

SEIZURE-FREEDOM RATES

RESPONDER RATES

p = 0.001

55.8

60

60

p = 0.002

44.2

50

50

40

40

p = 0.047

32.0

% Patients

% Responders

30

30

16.7

20

20

8.0

4/50

7.7

4/52

7.7

4/52

10

1.9

1/54

10

0

0

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

eslicarbazepine
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
slide22
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 1200 mg/d

o.i.d b.i.d.

Bialer et al., Epilepsy Res 2007;73:1-52.

carisbamate
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
carisbamate suppression of the photoparoxismal response
CarisbamateSuppression of the Photoparoxismal Response

Kasteleijn-Nolst Trenité et al, Epilepsy Res 2007;74:193-200

retigabine
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
patients with 50 seizure reduction in overall treatment period titration maintenance
Patients with >50% Seizure Reduction in Overall Treatment Period(Titration + Maintenance)

Study 302

Study 301

% Patients

179

181

178

152

153

600

900

Placebo

1200 RTG

Placebo

RTG

Intent-to-treat

*p<0.005 **p<0.001

current pharmacologic therapy in epilepsy
Current pharmacologic therapy in epilepsy
  • Preventive (antiepileptic medications):
    • Standard for nearly all patients
    • Not effective for an “acute” seizure
  • Abortive or rescuemedications
    • Seizures in clusters
    • Prolonged seizures
    • One seizure after another (status epilepticus)
options for abortive therapy
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
advantages of nasal drug delivery
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
comparative efficacy of in mdz vs iv dzp
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

8 min

6.1 min

Lahat E, et al. BMJ. 2000;321:83-86.

what should i ask my doctor about a new drug
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?
devices under study
Devices under study

NeuroPace “RNS” Trial

Medtronic, “Sante” Trial

slide35

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

slide36

Electrode (4 contacts)

Stimulating Electrode, 4 contacts

deep brain stimulation study
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,
responsive neurostimulator
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
slide41

Anthony Murro, M.D.

Medical College of Georgia

other drugs devices on the way
Other drugs/devices on the way
  • Drugs:
    • Ganaxalone
    • ICA-105665
    • Perampanel (E2007)
    • T2000: (non-sedating barbiturate)
    • YKP3089
    • Huperzine
    • NPY gene transfer
  • Devices
    • Drug Delivery Pumps
    • Seizure detection/prevention
conclusion
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
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