What’s new in clinical Trials

Jacqueline A French MDNYU 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?• 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?

• 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

• Pre-Clinical testing 10,000 250 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 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• 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

BASELINE TITRA-TION

1-2 AEDS PLACEBO +AEDS

DOSE 1 +AEDS

DOSE 2 +AEDS

TAPER(DOUBLE BLIND)+ FOLLOW-UP

TREATMENT

Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy:50% Responder Rates

Double-Blind Placebo-Controlled Add-on Trial of Lacosamide (LCS) in Refractory Partial Epilepsy:50% Responder Rates

0

20

40

60

22%

41%*38%*

% P

atie

nts

33%

Placebo LCS 200mg LCS 400mg LCS 600mg

(* P<0.05 vs PL)

Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007

10

*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.

Pregabalin Most Frequent Adverse Events

Adverse Event

Preferred Term

PlaceboN=73

PGB600 mg/d fixed dose

N=137

PGB 150-600 mg/d flexible dose

N=131N (%) N (%) 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 6 (8.2) 24 (17.5) 25 (19.1)

Vertigo 2 (2.7) 19 (13.9) 14 (10.7)

Diplopia 1 (1.4) 16 (11.7) 8 (6.1)

Amblyopia 1 (1.4) 14 (10.2) 3 (2.3)

Constipation 3 (4.1) 12 (8.8) 4 (3.1)

Tremor 0 (0.0) 12 (8.8) 4 (3.1)

Data on file, Pfizer Inc

Precautionary tale: CinromidePrecautionary 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 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

20000

5

10

20

Zonisamide

FelbamateGabapentin

Topiramate

Oxcarbazepine

Tiagabine

Levetiracetam

Pregabalin

Calendar Year

Nu

mb

er o

f L

icen

sed

An

tiep

ilep

tic

Dru

gs

Lamotrigine

1990 2010

LacosamideRufinamide

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?

• 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

• 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

reference 0-20 20-40 40-60 60-80 80-100 100-1200

100

200

300

400

500

Control5.4 mg/kg i.p.17.0 mg/kg i.p.170 mg/kg i.p.

periodMinutes of testing

Me

an

du

ratio

n o

f S

WD

s (s

)

Values given are means ± S.D. (n=8)

Genetic Absence Epilepsy Rats from Strasbourg

Levetiracetam

Genetic Absence Epilepsy Rats from Strasbourg

reference 0-20 20-40 40-60 60-80 80-100 100-1200

100

200

300

400

500

Control

2.1 mg/kg i.p.

6.8 mg/kg i.p.

68 mg/kg i.p.

periodMinutes of testing

Mea

n du

ratio

n of

SW

Ds

(s)

Values given are means ± S.D. (n=8)

Responder Rates Responder Rates

SEIZURE-FREEDOM RATESRESPONDER RATES

Results from logistic regression (50% responder rate); ITT populationResults from logistic regression (50% responder rate); ITT populationITT population: n=208; 110M, 98F; age range 16–65 y; ITT population: n=208; 110M, 98F; age range 16–65 y; pp-value versus PBO-value versus PBO

PBO(n=54)

BRV5(n=50)

BRV20(n=52)

BRV50(n=52)

0

10

20

30

40

50

60

16.7

p = 0.04732.0

p = 0.00244.2

p = 0.00155.8

% R

esp

on

de

rs

PBO(n=54)

BRV5(n=50)

BRV20(n=52)

BRV50(n=52)

0

60

% P

atie

nts

1.91/54

8.04/50

7.74/52

7.74/52

10

20

30

40

50

Brivaracetam Adverse EventsBrivaracetam Adverse Events

PBO BRV5 BRV20 BRV50

Patients (N) 54 50 52 52Permanent study drug discontinuation

2 (3.7) 3 (6.0) 1 (1.9) 0

Patients with ≥1 AE, n (%) 29 (53.7)26

(52.0)29

(55.8)28

(53.8)Total AEs 59 50 72 56

AEs reported in ≥ 5% patients

Headache

Somnolence

Influenza

Dizziness

Neutropenia

Fatigue

4 (7.4)

4 (7.4)

4 (7.4)

3 (5.6)

1 (1.9)

2 (3.7)

4 (8.0)

1 (2.0)

4 (8.0)

1 (2.0)

4 (8.0)

0

2 (3.8)

3 (5.8)

0

0

2 (3.8)

2 (3.8)

1 (1.9)

3 (5.8)

1 (1.9)

4 (7.7)

0

3 (5.8)

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)

28%

41%

% P

atie

nts

54%*

Placebo ESL ESL 1200 mg/d 1200 mg/d o.i.d b.i.d.

(* P=0.008 vs PL)

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

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

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

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)

44%**

18%

39%**

31%*

17%

0

10

20

30

40

50

60

Intent-to-treat

Study 302 Study 301

*p<0.005 **p<0.001

% P

atie

nts

179 181 178 152 153

Placebo 600 900 Placebo 1200 RTGRTG

% Patients

Placebo(N=331)

RTG 600 (N=181)

RTG 900(N=178)

RTG 1200(N=153)

Dizziness 10 17 26 40

Somnolence 13 14 26 31

Fatigue 5 17 15 16

Confusion 1 2 5 14

Dysarthria 1 5 2 12

Headache 16 11 17 12

Ataxia / gait disturbance 2 3 5 12

Urinary tract infection 5 1 2 12

Tremor 3 2 9 11

Vision blurred 2 <1 5 11

Nausea 5 6 7 10

Most Common Adverse Events (>10% Incidence)

Discontinuations Due to Adverse Events

Adverse event as primary reason for discontinuationPlacebo(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

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)

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

• Easy access with/without patient cooperation

• Rapid and extensive absorption through the nasal mucosa

• Convenient and easy administration

• Needle-less

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

Dose = 0.3 mg/kg

Dose = 0.2 mg/kg

N=47 children with febrile seizures (>10 min)

3.5 min

5 min

6.1 min8 min

Main outcome measures: Time from arrival at hospital to drug administration & time to seizure cessation

Observation period = 60 minutes

Comparative Efficacy of IN MDZ vs IV DZP

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

Medtronic, “Sante” Trial

NeuroPace “RNS” Trial

Medtronic SANTE TrialStimulation 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

Stimulating Electrode, 4 contactsElectrode (4 contacts)

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• 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

Anthony Murro, M.D.Medical College of Georgia

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

• 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