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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


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


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


    Genetic Absence Epilepsy Rats from Strasbourg

    Levetiracetam

    Values given are means ± S.D. (n=8)


    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


    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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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
    Carisbamate Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:Suppression of the Photoparoxismal Response

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


    Retigabine
    Retigabine Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:>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


    Most common adverse events 10 incidence
    Most Common Adverse Events Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:(>10% Incidence)


    Discontinuations due to adverse events
    Discontinuations Due to Adverse Events Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    *Dose-related


    Current pharmacologic therapy in epilepsy
    Current pharmacologic therapy in epilepsy Eslicarbazerpine (ESL) in Refractory Partial 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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    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? Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    NeuroPace “RNS” Trial

    Medtronic, “Sante” Trial


    Medtronic SANTE Trial Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    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


    Electrode (4 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:contacts)

    Stimulating Electrode, 4 contacts


    Deep brain stimulation study
    Deep Brain Stimulation Study Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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 Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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


    Rns with leads
    RNS with Leads Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:


    RNS Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:


    Anthony Murro, M.D. Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    Medical College of Georgia


    Other drugs devices on the way
    Other drugs/devices on the way Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • Drugs:

      • Ganaxalone

      • ICA-105665

      • Perampanel (E2007)

      • T2000: (non-sedating barbiturate)

      • YKP3089

      • Huperzine

      • NPY gene transfer

    • Devices

      • Drug Delivery Pumps

      • Seizure detection/prevention


    Conclusion
    Conclusion Eslicarbazerpine (ESL) in Refractory Partial Epilepsy:

    • 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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