lessons learnt in recent trials in negative symptoms · • i am an employee of f. hoffmann – la...
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ISCTM ~ ECNP Joint Conference ▪ 1 September 2017 ▪ Paris ▪ France
Lessons learnt in recent trials in negative symptoms
D. Umbricht, N. Schooler, D. Fraguas, A. Khan, A. Kott, D. Daniel, C. Arango
ISCTM Paris, September 1st, 2017
1
Disclosures
• I am an employee of F. Hoffmann – La Roche • I hold stocks of F. Hoffmann – La Roche,
Novartis, and Basilea
• The views and opinions expressed in this presentation only present the personal views of Dr. Umbricht and not those of F. Hoffmann – La Roche, Ltd.
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 2
Outline
• Results of a survey among experienced trialists • Some lessons learnt from the bitopertin phase 3
trials • Results of a meta-analysis of recent negative
symptom trials • Monotherapy or adjunctive treatment?
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 3
Definitions* • Prominant or dominant negative symptoms
– High negative symptoms but also a “substantial burden from psychotic symptoms including hallucinations and delusions” ØExample: A score of ≥4 on at least 3, or ≥5 on at least 2, of the 7
negative subscale items of the Positive and Negative Syndrome Scale (PANSS) (Stauffer et al 2012).
• Predominant negative symptoms – High negative symptoms, but mild and stable positive
symptoms (and low EPS and depression) ØExample: A score of ≥4 on at least 3, or ≥5 on at least 2, of the 7
negative subscale items of the Positive and Negative Syndrome Scale plus a PANSS positive score of <19, a Barnes Akathisia score of <2, a Simpson–Angus score of <4, and a Calgary Depressive Scale score of <9 (Stauffer et al 2012)
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 4
*Marder et al, 2013
Results of a survey among experienced trialists
• 12 colleagues interviewed • 8 from industry, 4 from academia • Responsible for 1-4 trials, average 2, in total
23 trials (9 academia, 14 industry) • Methods
– First a questionnaire* was sent out – Followed up by personal interviews**
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 5
*Developed by Nina Schooler, Celso Arango and Daniel Umbricht **Conducted by Nina Schooler and Daniel Umbricht
Key ‘hot’ topics
• Patient population/Inclusion criteria • Scales/Assessments • Role of informant • Role of a psychosocial «platform» in a trial
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 6
Patient population/Inclusion criteria • Predominant versus dominant negative symptoms
– General agreement that inclusion criteria may have been ‘overengineered’ with too much a focus on keeping positive symptoms low excluding a large number of subjects from studies
– General agreement that substantial positive symptoms should be allowed as long as they are stable and not ‘disruptive’
– Possible solution: Stratify predominant/dominant neg sx patients
• Severity of negative symptoms – Concern that including only patients with relatively high negative
symptoms selects more ‘treatment resistant’ and least engaged patients
– Solution: Include patients with less severe negative symptoms, stratify by severity
• Duration of illness – Focus on patients earlier in their illness
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 7
Effects of neg sx inclusion criteria
ISCTM ~ ECNP Joint Conference ▪1 September
2017 ▪Paris ▪ France 8
0.25
0.31
0.35
0.33
0.32
0.40
0.23
0.36
Correlation between changes from BL in
positive and negative subscales
• More restrictive baseline symptom severity thresholds yielded a considerably smaller sample size and higher negative and lower positive symptoms at baseline.
• Unadjusted negative symptom change greater with more restrictive criteria; • When adjusted for baseline severity the magnitude of change comparable across subsets. • The amount of variance in negative symptom change attributed to positive symptom change also comparable
across subsets. Dunayevich et al, European Neuropsychopharmacology(2014) 24, 1615–1621
Change in neg sx (NSFS*) tends to be greater when positive symptoms are “relatively” lower - independent of negative symptom level**
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 9
Pos Sx > Neg Sx Neg Sx > Pos Sx
NSFS* at baseline
N= 861
N= 62
N= 203
N= 174
N= 107
N= 376
* NSFS= PANSS Negative Symptom Factor Score (Marder factor; item scoring 0-6)) ** Data from phase 3 bitopertin suboptimally controlled symptoms studies
Change in neg sx (NSFS*) tends to be greater when positive symptoms are lower - independent of negative symptom level**
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 10
Pos Sx <14 Pos Sx = 14-18 Pos Sx > 18
NSFS* at baseline
N= 101 N= 361
N= 53
N= 159
N= 34
N= 149
* NSFS= PANSS Negative Symptom Factor Score (Marder factor; item scoreing 0-6) ** Data from phase 3 bitopertin suboptimally controlled symptoms studies
N= 471
N= 165
N= 300
Change in positive sx (PNSFS*) tends to be greater when positive symptoms are higher - independent of negative symptom level**
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 11
Pos Sx <14 Pos Sx = 14-18 Pos Sx > 18
NSFS at baseline
N= 101 N= 361
N= 53
N= 159
N= 34
N= 149
* PSFS= PANSS Positive Symptom Factor Score (Marder factor; item scoring 0-6) ** Data from phase 3 bitopertin suboptimally controlled symptoms studies
N= 165
N= 300
IRT analysis, Bitopertin P3 negative sx studies: Key ‘avolition’ items of PANSS NSFS perform best around or
below mean
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 12
Ø Analysis supports the view that patients with less severe neg sx should be enrolled
N=1878 Analysis performed by A. Khan, NeurocogTrials
N2 Emotional Withdrawal N4. Passive/apathetic social withdrawal N1. Blunted affect
G16. Active social avoidance G7. Motor retardation N6. Lack of spontaneity and flow of conversation N3. Poor rapport
Item information
Mean NSFS at baseline
IRT analysis, Bitopertin P3 neg sx studies: Key ‘avolition’ items of PANSS NSFS perform best around or
below mean
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 13
Ø Analysis supports the view that patients with less severe neg sx should be enrolled
200 200 200
200
Analysis performed by A. Khan, NeurocogTrials
N2 Emotional Withdrawal N4. Passive/apathetic social withdrawal N1. Blunted affect
G16. Active social avoidance G7. Motor retardation N6. Lack of spontaneity and flow of conversation N3. Poor rapport
N=1878 Item information
NSFS distribution at baseline
IRT analysis of NSA, Bitopertin P3 neg sx studies
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 14
75
N=1783
Analysis performed by A. Khan, NeurocogTrials
NSA Total Score Distribution at baseline
Item information
Individual items of NSA-16 perform the best around or below mean (IRT analysis, Bitopertin P3 neg sx studies)
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 15 Analysis performed by A. Khan, NeurocogTrials
Prolonged time to respond Restricted speech quantity Impoverished speech content Inarticulate speech
Emotion: Reduced range Affect: Reduced modulation of intensity Affect: Reduced display on demand Reduced social drive
NSA Total Score Distribution at baseline
N=1783 Item information
Individual items of NSA-16 perform the best around or below mean (IRT analysis, Bitopertin P3 neg sx studies)
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 16 Analysis performed by A. Khan, NeurocogTrials
Poor rapport with interviewer Sexual interest Poor grooming and hygiene Reduced sense of purpose
Reduced interests Reduced daily activity Reduced expressive gestures Slowed movements
Additional topics Role of Informant
– Deemed unreliable as informant, more important for compliance – Insistence on informant may limit patients to lower functioning patients, potentially excluding
patients who live independently and may respond best
Scales/Assessments – Include scales that measure avolition and expressive deficits separately (CAINS, BNSS), keep
PANSS for legacy reason – Most colleagues in favor of either centralized ratings, video taping/independent assessment
or ‘Blended’ approaches with site rater responsible for enrollment, CR or videotaped interviews used for outcome
– Some scepticism that CR could not capture all nuances of negative symptoms also expressed
Role of a psychosocial «platform» in a trial – Biggest difference between academic and industry
• Colleagues from academia in favor of a psychosocial platform, also to increase number of visits to provide a «low level» psychosocial platform
• Colleagues from industry were less enthusiastic, favored ‘clean’ studies with fewer visits
Biomarkers – If biomarkers were considered, effort-choice tasks recommended to characterize patients
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 17
Drivers of placebo response in negative symptoms trials
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 18
Larger Placebo Response in Antipsychotic Trials Obscures True Treatment Effect
19
Factors associated with placebo response • Year of study • Number of sites • Percentage of university or VA settings
Line A = Mean drug response Line B = Identity line i.e. size of drug response (vertical axis) equal to
the placebo response (horizontal axis); vertical deviation from this identity line shows the drug-placebo difference.
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Agid et al, Am J Psychiatry 2013; 170:1335–1344
Placebo Response >40% Obscures Treatment Effect in MDD Meta-analysis of adjunctive treatment in MDD
Placebo (+SoC) response >40% showed a trend to lower risk ratio of response to the adjunctive drug vs. placebo (Iovieno & Papaksotas 2012)
20
Res
pons
e R
ate
(RR
)
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Response* Rates (ITT population) in Bitopertin Phase 2 and Phase 3 Trials in Negative Symptoms of Schizophrenia
21
61%
58% 56%
44%
61% 58%
60% 58%
30%
35%
40%
45%
50%
55%
60%
65%
Resp
onse
Rat
e
Placebo Bitopertin 10mg
Phase 2 Trial -------------------------- Phase 3 Trials ---------------------------
* Response defined as ≥ 20% improvement on the NSFS ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Categorization of patients Responding to any
intervention
• Active + • Placebo + • Not informative
Responding to active, but not placebo
• Active + • Placebo ± • Informative
Not responding to any intervention
• Active - • Placebo - • Not informative
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 22
30% >-7.25
25% >-8
20% >-9.3
15% >-9
10% >-10.5
5% >-14
≤-3.75
≤-3.3
≤-3
≤-2.3
≤-2
≤-1.2
Adapted from Borsook, Becerra and Fava, Transl Psychiatry. 2013
Low Placebo response High Placebo response
Identify sites that show high or low average placebo response and remove all data including data from patients on active treatment, assuming that average placebo response is indexing category of patients recruited at that site ® composition of patients contains more patients in the green group with filter narrowing
Effect of Sites with “Normal” PBO Response: NS, 10mg, MMRM Week 24, Bitopertin Phase 3 neg sx studies
Treatment<<Favors>> Placebo
30% >-7.25 25% >-8 20% >-9.3 15% >-9 10% >-10.5 5% >-14
≤-3.75 ≤-3.3 ≤-3 ≤-2.3 ≤-2 ≤-1.2
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 23 Results in “Normal” Pbo response sites better than the overall population in all NS studies
Correlation between Number of Study Sites and Placebo Response* Rates (ITT population) in Bitopertin Phase 2 and
Phase 3 Trials in Negative Symptoms of Schizophrenia
24
61%
58% 56%
44%
R² = 0.92
30%
35%
40%
45%
50%
55%
60%
65%
40 50 60 70 80 90 100 110
Plac
ebo
Resp
onse
Number of Sites
Placebo
Linear (Placebo)
Phase 2 Trial
Phase 3 Trials
* Response defined as ≥ 20% improvement on the NSFS ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Correlation between Number of Study Sites and Placebo Response* Rates (ITT population) in Bitopertin Phase 2 and
Phase 3 Trials in Negative Symptoms of Schizophrenia
25
61%
58% 56%
44%
R² = 0.92
30%
35%
40%
45%
50%
55%
60%
65%
40 50 60 70 80 90 100 110
Plac
ebo
Resp
onse
Number of Sites
PlaceboBitopertin 10mgLinear (Placebo)Linear (Bitopertin 10mg)
Phase 2 Trial
Phase 3 Trials
* Response defined as ≥ 20% improvement on the NSFS ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Investigating predictors of placebo response in phase 3 bitopertin neg sx trials
• Erratic ratings • Change in the first four weeks
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 26
<.0001
<.0001
<.0001 <.0001
<.0001 <.0001 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=199) Not affected subjects (N=149) Affected subjects (N=16)
Protocol WN25308
Erratic ratings of NSFS in placebo treated patients– change of at least 20% in opposite directions across 2 consecutive visits associated with
greater placebo response at patient level
ES = 0.09
Analysis performed by A. Kott and X. Wang, Bracket
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 27
0.4974
0.0075
0.0035
<.0001
<.0001
0.0174
-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=202) Not affected subjects (N=162) Affected subjects (N=17)
Protocol WN25309
Erratic ratings of NSFS in placebo treated patients– change of at least 20% in opposite directions across 2 consecutive visits associated with
greater placebo response at patient level
ES = 0.04
Analysis performed by A. Kott and X. Wang, Bracket
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
28
0.0123
0.0009
0.0023
0.0003 0.0007 0.0042
-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=197) Not affected subjects (N=142) Affected subjects (N=20)
Protocol NN25310
Erratic ratings of NSFS in placebo treated patients– change of at least 20% in opposite directions across 2 consecutive visits associated with
greater placebo response at patient level
ES = 0.04
Analysis performed by A. Kott and X. Wang, Bracket
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 29
0.0001
<.0001
<.0001 <.0001
<.0001 0.0001
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24
Erratic ratings of NSFS in placebo treated patients – change of at least 20% in opposite directions across 2 consecutive visits
associated with greater placebo response at site level*
Study week
Study Placebo response (N=199) Not affected subjects (N=161) @ 73 sites Affected subjects (N=38; 19%) @ 19 sites
Protocol WN25308
ES = 0.11
*sites with at least one patient with erratic ratings in any treatment arm
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 30
Analysis performed by A. Kott and X. Wang, Bracket
0.1286
0.0042 0.0031
<.0001
<.0001 <.0001
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=202) Not affected subjects (N=154) @ 72 sites Affected subjects (N=48; 23%) @ 24 sites
Protocol WN25309
Erratic ratings of NSFS in placebo treated patients – change of at least 20% in opposite directions across 2 consecutive visits
associated with greater placebo response at site level*
ES = 0.14
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 31
*sites with at least one patient with erratic ratings in any treatment arm
Analysis performed by A. Kott and X. Wang, Bracket
0.0323
0.001
0.0006 0.0013 0.0082 0.0894
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=197) Not affected subjects (N=152) @ 79 sites Affected subjects (N=45; 27%) @ 26 sites
Protocol NN25310
Erratic ratings of NSFS in placebo treated patients – change of at least 20% in opposite directions across 2 consecutive visits
associated with greater placebo response at site level*
ES = 0.04
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 32
*sites with at least one patient with erratic ratings in any treatment arm
Analysis performed by A. Kott and X. Wang, Bracket
Placebo response – Improvement in NSFS above 95th percentile at week 4 at patient level
<.0001
<.0001 <.0001
<.0001
<.0001
<.0001
-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=199) Not affected subjects (N=187) Affected subjects (N=12)
Protocol WN25308
ES = 0.06
Analysis performed by A. Kott and X. Wang, Bracket
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 33
Placebo response – Improvement in NSFS above 95th percentile at week 4 at patient level
<.0001
<.0001 0.0001
0.0002 0.0004 0.0001
-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=202) Not affected subjects (N=195) Affected subjects (N=7)
Protocol WN25309
ES = 0.09
Analysis performed by A. Kott and X. Wang, Bracket
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 34
<.0001 <.0001
<.0001 <.0001
<.0001 <.0001 -18
-16
-14
-12
-10
-8
-6
-4
-2
0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=197) Not affected subjects (N=186) Affected subjects (N=11)
Protocol NN25310
Placebo response – Improvement in NSFS above 95th percentile at week 4 at patient level
ES = 0.11
Analysis performed by A. Kott and X. Wang, Bracket
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
35
<.0001
<.0001
<.0001
<.0001 <.0001 0.0156
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=199) Not affected subjects (N=169) @ 75 sites Affected subjects (N=30; 15%) @ 17 sites
Protocol WN25308
Placebo response – Improvement in NSFS above 90th percentile at week 4 at site level
ES = 0.07
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 36
*sites with at least one patient with improvement above 90th percentile in any treatment arm
Analysis performed by A. Kott and X. Wang, Bracket
0.0073
<.0001 <.0001
<.0001 <.0001
<.0001 -10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20
Placebo response – Improvement in NSFS above 90th percentile at week 4 at site level
24 Study week
Study Placebo response (N=202) Not affected subjects (N=174) @ 77 sites Affected subjects (N=28;13%) @ 19 sites
Protocol WN25309
ES = 0.09
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 37
*sites with at least one patient with improvement above 90th percentile in any treatment arm
Analysis performed by A. Kott and X. Wang, Bracket
<.0001
<.0001
<.0001 <.0001
<.0001 <.0001 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=197) Not affected subjects (N=165) @ 91 sites Affected subjects (N=32 ;16%) @ 14 sites
Protocol NN25310
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Placebo response – Improvement in NSFS above 90th percentile at week 4 at site level
ES = 0.20
38
*sites with at least one patient with improvement above 90th percentile in any treatment arm
Analysis performed by A. Kott and X. Wang, Bracket
Placebo response – Improvement in NSFS above 90th percentile at week 4 at site level
<.0001
<.0001
<.0001 <.0001
<.0001 <.0001 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0
Cha
nge
in M
arde
r Neg
ativ
e Fa
ctor
Sco
re
LSM
ean
+/- S
E
0 4 8 12 16 20 24 Study week
Study Placebo response (N=197) Not affected subjects (N=165) @ 91 sites Affected subjects (N=32) @ 14 sites
Protocol NN25310
ES = 0.20
ES of change in placebo response 0.04 to 0.2 potentially jeopardizing signal detection. These observations raise the issues of patient selection and assesssment quality. • Erratic ratings not compatible with known rate of change in patients Þ Supports the use of centralized or videotaped ratings and/or
performance based and ecologically momentary assessments
• Dramatic improvement post randomization not expected in true negative symptom patients
Þ Need for biomarkers and behavioral characterization (e.g. Effort choice task)
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 39
Meta-regression analysis of placebo response in neg sx trials*
• Eighteen clinical trials (12 academia, 6 industry) conducted in the last 15 years from seventeen publications, assessing the effect of 13 drugs versus placebo on negative symptom in 998 patients on stable AP background treatment
• Placebo response was significant (p<0.001) and clinically relevant (Cohen’s d: 2.91, 95% CI: 2.05 to 3.77), but there was significant heterogeneity and high risk of publication bias.
• Multivariable meta-regression analysis found that a higher placebo response was significantly and independently associated with – Higher numbers of arms in the trial (p=0.001) – More study sites (p<0.001) – Industry sponsorship (p=0.001)
• Severity of negative and positive symptoms at baseline were not associated with placebo response when controlling for other factors
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*Fraguas D, Díaz-Caneja CM, Pina-Camacho L, Umbricht D, Arango C: manuscript in preparation
Adjunctive versus monotherapy?
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 41
Adjunctive versus monotherapy?
Treatment Period 1 3 weeks
Wash out 14 days Treatment Period 2 3 weeks
Treatment Period 3 3 weeks
§ Proof-of-Mechanism (POM) study, randomized, double-blind, placebo-controlled, three-way crossover design
§ Six different treatment sequences (n=5) of PDE10 inhibitor RG7203 at 5 mg QD and 15 mg QD and placebo on top of stable antipsychotic treatment
§ N=24 (completers; 33 recruited) Schizophrenia patients with negative symptoms (mild/moderate)
§ At end of each treatment period imaging (monetary incentive delay task) and behavioral (effort choice task) assessment of reward anticipation and reward valuation
Wash out 14 days
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 42
MID Task: Increased discrimination between reward and non-reward at low dose in the context of an overall blunted
activation in drug conditions
Error areas represent the standard error of mean
Control Condition
Anticipation of low reward
Anticipation of high reward
43
p=0.039* p=0.053*
* two-sided p-value for paired t-test versus placebo
Figures show time-dependent fitted BOLD response
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Patients choose high effort high reward option significantly less often during treatment than during placebo
44 ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France
Multiple regression shows that overall activation but not differential activation (reward anticipation versus control) is related to effortful behavior
Effect of risperidone in healthy volunteers (N=21): Risperidone blunts the overall response in the MID task
p<0.01
• Do antipsychotics curtail potential benefits of adjunctive treatments for negative symptoms?
• In-hous preclinical data would support that
Ø “The preferred design is a double-blind comparison with placebo, especially since no standard treatment for negative symptoms is recognized…..(Möller et al, Working group on negative symptoms in schizophrenia, Psychopharmacology, 1994)
ISCTM ~ ECNP Joint Conference ▪1 September 2017 ▪Paris ▪ France 45
Conclusions • Patient selection
– Drop restrictions on level of positive symptoms, as long as they are not ‘disruptive’, and stratification into dominant vs predominant neg symptom patients
– Consider enrolling patients with moderate negative symptoms (i.e. 14 and up on NSFS [scoring 0-6])
– Include patients with shorter duration of illness – Consider patients who can live independently, that is have more potential for
improvment, i.e. consider dropping requirement of informant
• Assessments – Consider use of effort choice task to characterize patients – Consider centralized or videotaped independent ratings
• Study design/operational aspects – Keep site numbers low; in phase 3 consider separate safety studies – Keep number of arms to a minimum – Consider a monotherapy trial in patients who have predominant negative symptoms?
• Industry versus academic trials? Result of commercialization of drug development? How can we involve academia more?
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