Transcript What’s new in clinical Trials

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?
• 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
(compounds)
250
(get to animal testing)
10
(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 overestimate effectiveness of an intervention
DOUBLE-BLIND PLACEBOCONTROLLED TRIAL
DOSE 2 +AEDS
DOSE 1 +AEDS
1-2 AEDS
BASELINE
PLACEBO +AEDS
TITRATION
TREATMENT
TAPER
(DOUBLE BLIND)
+ FOLLOW-UP
Double-Blind Placebo-Controlled Add-on Trial
of Lacosamide (LCS) in Refractory Partial Epilepsy:
50% Responder Rates
60
41%*
% Patients
38%*
40
33%
(* P<0.05
vs PL)
22%
20
0
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
Placebo
N=73
PGB
600 mg/d
fixed dose
N=137
PGB
150-600 mg/d
flexible dose
N=131
N (%)
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)
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)
Adverse Event
Preferred Term
Asthenia (weakness)
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.
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 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
Number of Licensed Antiepileptic Drugs
SINCE 1998
20
Lacosamide
Rufinamide
Pregabalin
10
Zonisamide
Oxcarbazepine
Levetiracetam
Lamotrigine
Tiagabine
Topiramate
Gabapentin
Felbamate
5
0
1990
2000
Calendar Year
2010
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 LennoxGastaut)
• 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
Genetic Absence Epilepsy Rats from Strasbourg
Mean duration of SWDs (s)
500
Levetiracetam
400
300
Control
5.4 mg/kg i.p.
17.0 mg/kg i.p.
170 mg/kg i.p.
200
100
0
reference 0-20
period
Values given are means ± S.D. (n=8)
20-40
40-60
60-80
Minutes of testing
80-100 100-120
Genetic Absence Epilepsy Rats from Strasbourg
Mean duration of SWDs (s)
500
400
300
Control
2.1 mg/kg i.p.
6.8 mg/kg i.p.
68 mg/kg i.p.
200
100
0
reference 0-20
period
Values given are means ± S.D. (n=8)
20-40
40-60
60-80 80-100 100-120
Minutes of testing
Responder Rates
RESPONDER RATES
p = 0.001
55.8
60
40
50
% Patients
% Responders
60
p = 0.002
44.2
50
p = 0.047
32.0
30
20
SEIZURE-FREEDOM RATES
16.7
40
30
20
10
10
0
1.9
1/54
8.0
4/50
7.7
4/52
7.7
4/52
BRV20
(n=52)
BRV50
(n=52)
0
PBO
BRV5
(n=54) (n=50)
BRV20
(n=52)
BRV50
(n=52)
PBO
BRV5
(n=54) (n=50)
Results from logistic regression (50% responder rate); ITT population
ITT population: n=208; 110M, 98F; age range 16–65 y; p-value versus PBO
Brivaracetam Adverse Events
Patients (N)
Permanent study drug
discontinuation
Patients with ≥1 AE, n (%)
Total AEs
PBO
BRV5
BRV20
BRV50
54
50
52
52
2 (3.7)
3 (6.0)
1 (1.9)
0
26
(52.0)
50
29
(55.8)
72
28
(53.8)
56
29 (53.7)
59
AEs reported in ≥ 5% patients
Headache
4 (7.4)
4 (8.0)
2 (3.8)
1 (1.9)
Somnolence
4 (7.4)
1 (2.0)
3 (5.8)
3 (5.8)
Influenza
4 (7.4)
4 (8.0)
0
1 (1.9)
Dizziness
3 (5.6)
1 (2.0)
0
4 (7.7)
Neutropenia
1 (1.9)
4 (8.0)
2 (3.8)
0
Fatigue
2 (3.7)
0
2 (3.8)
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)
% Patients
54%*
41%
(* P=0.008
vs PL)
28%
Placebo
ESL
1200 mg/d
o.i.d
ESL
1200 mg/d
b.i.d.
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)
Study 302
Study 301
% Patients
60
50
44%**
39%**
40
31%*
30
20
18%
17%
10
0
179
181
178
Placebo
600
900
152
Placebo 1200 RTG
RTG
Intent-to-treat
*p<0.005
153
**p<0.001
Most Common Adverse Events
(>10% Incidence)
% Patients
Dizziness
Somnolence
Fatigue
Confusion
Dysarthria
Headache
Ataxia / gait disturbance
Urinary tract infection
Tremor
Vision blurred
Nausea
Placebo
(N=331)
RTG 600
(N=181)
RTG 900
(N=178)
RTG 1200
(N=153)
10
13
5
1
1
16
2
5
3
2
5
17
14
17
2
5
11
3
1
2
<1
6
26
26
15
5
2
17
5
2
9
5
7
40
31
16
14
12
12
12
12
11
11
10
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
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
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?
• 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
NeuroPace “RNS” Trial
Medtronic, “Sante” Trial
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
Stimulating
Electrode, 4 (4
contacts
Electrode
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