Trial Design 2013 - The Northeast ALS Consortium

The Northeast ALS Consortium
ALS and the Clinical Trial Process
Jeremy M. Shefner, MD, PhD
Professor and Chair of Neurology
Associate VP for Clinical and
Translational Research
SUNY Upstate Medical University
Bottleneck in Drug Development
Industry
?
Academic
Labs
In vitro
In vivo
Phase I
Multiple drug candidates
Preclinical Testing
Phase II
Small pool of patients
Limited resources
Phase III
Time for development
New Drugs and Devices Approved by US
Food and Drug Administration by Sector,
1998-2004
Moses, H. et al. JAMA 2005;294:1333-1342.
Clinical Trial Definitions

Phase I





Designed to evaluate safety, tolerability, pharmacokinetics
(how a drug behaves in the body)
May be performed with normal volunteers or subjects with
disease
Doses that have no effect, maximum tolerated dose
determined here
Placebos are almost always a part of these trials
Phase II


Gain more information on dosing issues and tolerability
Look for signal of drug activity



This is a specific problem in ALS; no validated targets, disease
markers
Placebo control often used, but not always
Phase III


Definitive evaluation of drug efficacy and tolerability
Always involve use of placebo
Phase 1 Studies
These are the “first in human” studies
 Primary purposes:

 To
assess safety and tolerability
 To assess the maximum tolerated dose
 To learn about pharmacokinetics

Two main designs
 Predetermined
dose escalation in small
numbers of subjects
 Continual Reassessment Method
Pharmacokinetics
How is a drug absorbed?
 Where does it go?

 Does
it get into the brain?
How long does it stay there?
 How does the body eliminate it?

 Kidneys
 Liver

What other drugs interact with it?
Phase 2

Goals





Preliminary evidence of effect on target
EXPLORATORY
Go-no go decision
Confirmatory trial can follow later
Risks


Select an intervention that truly does not work
Discard an intervention that truly does work
Phase 2








Variable designs and goals
In target population
Not intended to definitely show that drug
“works”
Moderate in size and duration
Often have placebo group
Range of doses
Often look at intermediate
effects/biomarkers
Statistically more flexible
Phase 3
Confirmatory
 Definite efficacy trial
 Further safety experience
 Large, simple
 High power
 Avoid falsely concluding that drug
works

Phase 3
Study population clearly defined
 Study measures well understood
 Clear criteria for “success”
 Should lead to change in practice, not
“just” publication

What makes a successful trial?
–
–
–
–
–
–
A drug with good preclinical science
Adequate pharmacokinetic information
The appropriate dose
An easily measured outcome relevant to
disease progression
An effective design
Sample size and power that depend on the
trial goals.
Dose is important both in early and
late design stages


Need dose ranging in vitro and animal studies,
assessing both no effect levels and toxic doses
If possible, need multiple dose human studies, also
to maximum tolerated dose (MTD)


MTD can be established in volunteers, usually with small
sample sizes
MTD is often not determined in ALS studies
Expense
 Sample size requirements
 Lack of appropriate animal toxicology

Dosing Questions That Still Remain




Stroke– how much aspirin is ideal?
Multiple sclerosis- how much interferon, copaxone is
best?
Myasthenia Gravis- steroids, immunomodulation,
thymectomy lack adequate studies
Anticonvulsants: older drugs with dosing
information; newer ones are less clear
Phase 2A dose ranging study of
Arimoclomol in subjects with ALS


80 subjects, treated with placebo or three doses of
arimoclomol
Study duration: 12 weeks
Serum Concentrations of Arimoclomol
Male and Female Subjects Combined
Male and Female Composite
Plasma Arimoclomol Conc, ng/mL
1000
75 mg
150 mg
300 mg
100
10
Baseline
Week 4
1
0
4
8
12
0
4
8
12
Time, Hour
From: Cudkowicz, Shefner et al., 2008
Arimoclomol Penetrates the Human
Blood:Brain Barrier: CSF levels
180
Arimoclomol (ng/mL)
160
3 hr
6 hr
140
120
100
80
60
40
20
0
Placebo
From: Cudkowicz, Shefner et al., 2008
75 mg
150 mg
300 mg
Study Conclusions





Arimoclomol was deemed safe and well tolerated
Arimoclomol crossed the blood brain barrier and
displayed a dose dependent increase in CSF levels
Preliminary serum arimoclomol pharmacokinetics
show no accumulation or auto-induction.
However, no MTD was reached, and higher doses
were thought most appropriate for further study.
Higher doses were not supported by available
preclinical toxicology
For this reason, a phase IIb study in ALS was not
performed
In Late Phase Studies, Dose selection
can Determine Outcome

Minocycline in ALS
 Preclinical
science supported an action
against cell death
 Phase I/II trial (Gordon, 2004)
100 mg per day not associated with drug
related negative effects (adverse events, or
AEs), no change in efficacy measures
 400 mg/day, in crossover study with placebo,
associated with GI AEs (p=0.057), and faster
progression

Minocycline in ALS
A Phase III trial performed using lead-in phase, then
randomization of 412 subjects to placebo or 400
mg/day for 9 months
Slope during
lead-in
ALSFRS-R
VC
MMT
-0.81 (0.05)
-2.31 (0.16)
-0.19 (0.01)
Conclusion ?
From Gordon, et al., 2007
On Treatment Slope
Placebo
Minocycline
-1.07 (0.07)
-3.01 (0.20)
-0.26 (0.02)
-1.30 (0.07)
-3.48 (0.21)
-0.30 (0.02)
P
0.005
0.111
0.112
Other examples of problems related to dose
selection in ALS Trials

Topiramate
 800
mg/d caused massive weight loss,
associated loss of strength- would a lower dose
have shown a signal?

Creatine
 5-10
mg/d not well matched to mouse datawould higher doses have been effective?

Celecoxib
 800
mg/day was ineffective- no toxicity was
seen; should higher doses have been studied?
Safety
Always monitored, regardless of phase
 Side effects can be uncommon
 Often discovered only in Phase 3 or
post –marketing
 General population may be different
than those in trial

Outcome Measures in ALS

Clinically Relevant Endpoints
 How

a patient feels, functions, or survives
Surrogate Endpoints
A
laboratory value, image, or objective
assessment intended to substitute for or
predict a clinically relevant outcome


Some Biomarkers
Mechanistic, Pharmacokinetic Endpoints
 Direct
measurement of drug levels or effect on
identified physiological process
 Not necessarily clinically relevant, not a
surrogate for another endpoint
Survival as an Outcome in ALS

Useful only when events are likely to
occur
 ALS

Treatments other than the
experimental drug may have an effect
 Tracheostomy
ventilation
 NIPPV
 Feeding tube
and mechanical
Survival as an Outcome Measure in
ALS
MICE
From: Drachman et al., 2000
PEOPLE
From Lacomblez et al., 1996
How Could Biomarkers Help?


Could be less variable than clinical
measures
Could change more rapidly


Would allow smaller, shorter trials
Target based pharmacodynamic markers
establish whether drug hits the intended
target

Easier to discard drug classes
However
Biomarker research is a hot area, but
targets are still not obvious
 Disease progression biomarkers are
thus far not validated

MUNE
 EIM
 Biofluids


Target based biomarkers require an
accessible target
Other Hot Topics
The importance of trial design
 The therapeutic misconception

 Importance

of informed consent
Placebo control
 Historical
controls
 Prediction of likely progression

Expanded access
 Open
label follow on studies
 Expanded access prior to drug approval
Natural History Lead In

Goal is to reduce variance of outcome measure

Hypothesis is that individuals differ in rate of progression,
and that this rate is constant


By estimating rate of decline with lead in, can use this as
covariate in analysis, and reduce sample size.
Problems
Delays onset of active treatment
 Recruitment is difficult
 If decline is non linear, early decline may not predict
late decline

ALSFRS-R
Phase IIb Controlled Trial of TCH 346 in ALS
placebo
2.5 mg
7.5 mg
1.0 mg
15 mg
From Miller et al., 2007
week
Futility Designs

Normally, null hypothesis is that there is no
underlying effect of drug on disease

In a futility study, the null hypothesis is that it is non
futile to go forward with further investigation

Rejecting the null means concluding futility;
probability of rejecting the null depends on the type
I error rate, which is set by investigator

Often, if there is no difference between groups, non
futility will still be concluded
Avoiding Therapeutic
Misconception
High quality information
 Set realistic expectations
 Education
 Thoughtful communication

Historical Controls

Only appropriate if outcome measure
is stable over time- not true for survival
63% alive
Lacomblez, 1996
Celebrex
placebo
group: 90 of
99 (90%)
patients
alive at 1
year
Cudkowicz et al.,
2006
Historical Controls

ALSFRS has not systematically changed
over many studies and many years
0.85 units per month
Cudkowicz et al., 2006
0.84 units per month
Shefner et al., 2003
But, average ALSFRS decline in Empower study was about 1.1 points per month
Mean Change in ALSFRS Total Score
Open Label Trial of Coenzyme Q in
ALS
ALSFRS compared to placebo
group in Celecoxib study.
From Ferrante et al., 2005
Coenzyme Q10
Placebo
0
-2
-4
-6
-8
-10
0
2
4
Months
6
8
Expanded Access
For subjects who have completed a
clinical trial
 For the wider ALS community

 Prior
to phase 3
 Subsequent to phase 3
How can we improve our trials?
Pay attention to dose
 Demonstrate drug gets to target
 Make sure we are asking the right
questions
 Continue search for markers of drug
activity
 Continue search for biomarkers
indicative of disease activity
