comparators (placebo & active) in parkinson disease … · cabergoline 85 - ropinirole 45 -...
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COMPARATORS (PLACEBO & ACTIVE)
IN PARKINSON DISEASE TRIALS
Pr Olivier RASCOL
Clinical Investigation Center (CIC1436)
Department of Clinical Pharmacology
Department of Neurosciences
NS-PARK/F-CRIN Network
NeuroToul/COEN Center of Excellence for Neurodegeneration
TOULOUSE University Hospital, FRANCE
Disclosure: Prof Rascol has served and serves as a scientific advisor for most pharmaceutical
companies developing treatments for Parkinson disease including: AbbVie, Accorda, Adamas,
Britannia, Civitas, Lundbeck, Merck, MundiPharma, NeuroDerm, ONO, Osmotica, Oxford
Biomedica, Pfiezer, Sanofi, Servier, Teva, UCB, XenoPort, Zambon
Trois grands principes «méthodologiques»
dans les essais cliniques
1 - Principe de « comparaison »
Pour tenir compte de l’évolution spontanée, effet placebo,
choix d’un comparateur (placebo ou produit de référence), procédures d’insu (aveugle)…
2 - Principe de « comparabilité »
Les groupes doivent être comparables en dehors du médicament reçu: Tirage au sort (hasard)
3 - Principe de « signification »
Nécessité d’un test statistique pour « exclure » le rôle du hasard
« Placebo »: « I shall please »
• The placebo effect can be defined as any genuine psychological or physiological effect which is attributable to receiving a substance or undergoing a procedure, but is not due to the inherent powers of that substance or procedure
The Placebo Effect: Dissolving the Expectancy Versus Conditioning Debate. Stewart-Williams, Steve; Podd, John Psychological Bulletin, Vol 130(2), Mar 2004, 324-340. doi: 10.1037/0033-2909.130.2.324
• Placebo are considered physiologically inactive • The placebo effect means the combined physical and emotional change occuring with inert treatment
Références internationales
Déclaration d’Helsinki (1964) :
Principes éthiques sur la recherche
médicale impliquant des êtres humains
Placebo and ethics
Intrastriatal GDNF infusion: Open label pilot trial (Gill et al, Nat Med 2003)
Intrastriatal GDNF infusion: Placebo - controlled RCT (Lang et al, Ann Neurol 2006)
Placebo GDNF
EXAMPLE:
INTRA-STRIATAL GDNF INFUSION
Benedetti et al 2011
PLACEBO: A COMPLEX AND FASCINATING ISSUE…
Pharmacological displacement of PET [11C] raclopride binding by amphetamine-
induced endogenous dopamine release (Carlsson et al, 1997; Piccini et al, 2003)
baseline amphetamine
L-DOPA effect on [11C] raclopride binding
baseline Levodopa
Adapted from Lidstone et al
20100
De la Fuente-Fernandez et al, 2001: • 4 PET (3 sc apomorphine, 1 placebo) • DA release : 17% reduction in [11C]raclopride binding corresponding to a >200% increase in extracellular DA concentration • Equivalent to amphetamine effect in normal subjects
Placebo diplaces [11C] raclopride binding in the brain of patients with PD
From Lidstone
et al 2010
baseline Levodopa Placebo
Placebo mimics L-DOPA changes in [11C] raclopride binding in the brain of PD patients
THE MESOLIMBIC DOPAMINE SYSTEM AND REWARD EXPECTATION
Dopamine neurons fire in response to unexpected rewards but not to predicable rewards => dopamine signals occur in response to the reward prediction error
Neuron activity is • maximal at p=0.5 • declines at p= 0.25 or p=0.75 • virtually 0 at p=0 or p=1
DA release is associated with reward prediction in the ventral striatum (n. accumbens)
Lidstone et al 2010
Different DA release in: • VENTRAL STRIATUM (motivation, goal-directed behaviour, reward anticipation) • DORSAL STRIATUM (voluntary movement)
Importance of expectation in the placebo response in PD patients
Goetz et al, 2008
Overal placebo response rate (> 50% UPDRS improvement) = 16% (range 0-55%) Stablility over time
The placebo response in PD
Rascol et al, 2010
• There were 8/30 (27%) « placebo- responders » (patients who switched ON after placebo)
• « Placebo-responders » exhibited a mean reduction in UPDRS III >40%
Acute single challenge
Diederich and Goetz, 2008
Expectation and clinical outcomes in patients with PD
• Dyskinesia placebo-associated improvement (>25% reduction UPDRS 32+33) : 178/484 patients (37%) Older age, lower baseline UPDRS, lower L-DOPA dose
• Dyskinesia placebo-associated worsening (>25% reduction UPDRS 32+33) : 37/484 patients (8%) Lower baseline dyskinesia score
• No correlation between placebo-associated changes in dyskinesia and parkinonism scores => non DA mechanisms ?
Goetz 2008
Placebo response of non-motor
symptoms in PD
P = 0.01
Richard et al, 2012 Barone et al, 2009
Beck Depressive Inventory Hamilton rating scale for depression
RCT
EARLY STIM is an open-label non-blind RCT
- EARLYSTIM was conducted in patients with motor complications
- EARLYSTIM was assessing a surgical intervention
- EARLYSTIM used a subjective outcome (PDQ39) as primary enpoint…
« To overcome the difficulties of blinding in neurostimulatioin studies, we
introduced the blinded review of motor scores with the use of video
recordings »…
=> Single-blindness cannot address the bias related to patients’
expectations
=> Motor score was not EARLYSTIM primary outcome…
« Best medical management »
STN DBS ON
Different expectations…
Probable positive placebo
effect in the DBS arm
(Expectation)
It is most likely that the positive benefit reported in
EARLYSTIM has been artificially increased due to
the lack of blinding
Probable negative nocebo effect
in the medical treatment arm
(Disappointment)
Less benefit
Risk ? The real
difference might
be 50% less than
the reported
EARLYSTIM
8 PDQ39 units…
RCT
ON
ON
EARLYSTIM could (and should) have used a double-
blind design
STN DBS ON
STN DBS OFF
Physical exercise: Which placebo? Blinding ?
NON PHARMACOLOGICAL INTERVENTIONS
ACTIVE COMPARATORS • Why an active comparator ?
– Ethics – Trial “internal” validity? – Efficacy? Safety? – Regulatory issues (EMEA vs FDA)? – Pricing?
• Which one ? – A “reference” comparator – From the same or a different pharmacological class? – Cheap or expensive ?
• With or without a third placebo arm? • Technical issues?
– Non-inferiority (=> Power and sample size) – Blinding (double dummy, different titration & daily dose) – Access to the active comparator and its placebo…
« PREVENTING » MOTOR COMPLICATIONS USING
EARLY DA AGONISTS MONOTHERAPY
«Efficacious»
L-dopa
cabergoline
85 - Ropinirole
45 - L-dopa
Patient numbers
0.0
0.2
0.4
0.6
0.8
1.0
Time since start of study (years)
ropinirole
*
p<0.0001
2.82 hazard ratio
(95% CI [1.78,
4.44]) 0 1 2 3 4 5 143
73
125
67
111
62
101
56
179
89
Dyskin
ésie
s
L-dopa
L-dopa
pramipexole
% D
YS
KIN
ES
IA
days
pramipexole
L-dopa L-dopa
months
L-dopa
pergolide
Rinne et al, 1998
Oertel et al, 2006 PSG, 2000
Rascol et al, 2000
A
Hazard ratio (95% CI) = 1.29 (1.0, 1.65)
P-value = 0.038
Stocchi et al, Ann Neurol 21010
STRIE-PD: INITIATING L-DOPA+CARBIDOPA
(SINEMET°) vs L-DOPA+CARBIDOPA
+ENTACAPONE (STALEVO°)
3 ARM TRIALS (tested medication + reference drug + placebo)
Titration Phase de Maintenance 0
-1.0
-2.0
-3.0
-4.0
Red
ucti
on
du
tem
ps
passé O
FF
(h
/j)
Semaine: 1
2 3 4 5 6 7 0 2 8 12 16 4
Am
élio
rati
on
Pramipexole (n=200)
Placebo (n=100)
Rotigotine (n=201) (CLEOPATRA: Poewe et al,2007)
-2,0
-1,5
-1,0
-0,5
0,0
Ch
an
ge f
rom
baselin
e (
ho
urs
)
Rasagiline
Entacapone
Placebo
***p<0.001 vs placebo
-1.18 -1.20
-0.40
*** ***
(LARGO, Rascol et al,2005)
3 ARM TRIALS (tested medication + reference drug + placebo)
A
Placebo Istradefylline 40 mg/d
EntacaponeO
FF
from
Base
lin
e
-2
-1
0
Baseline Week 4 8 12 16 Endpoint
*
**
**
**
A
Placebo Istradefylline 40 mg/d
EntacaponeO
FF
from
Base
lin
e
-2
-1
0
Baseline Week 4 8 12 16 Endpoint
*
**
**
**
Study NCT00199394 6002-EU-007
(Istradefylline / Entacapone / placebo: Rascol et al 2007
3 ARM TRIALS (tested medication + reference drug + placebo)
Design (Hauser et al, 2015):
5 arms, 6 months, DB,
PBO-controlled RCT in
1022 PD patients with
wearing-off
“Failure” of the preladenent Phase III program
RCT
(1:1:1:1:1 ratio)
Rasagiline 1 mg QD (active control)
Preladenant 2, 5, 10 mg BID
Placebo
Diederich and Goetz, 2008
COMPARATORS
(Placebo &/or Active) :
A complex but major
methodological issue when
designing a clinical trial in
Parkinson disease