Cli linical Tria ials For r Treatment Resistant t Neuropsychiatric ic Conditions: le lessons fr from tr treatment res esistant sc schizophrenia Prof Oliver Howes oliver.howes@kcl.ac.uk 1
Disclosures • Oliver Howes is a psychiatrist and clinical academic at the Maudsley Hospital NHS Trust & KCL and ICL, UK • He has received investigator-initiated research grants, and/or spoken at events for: • Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Janssen/J&J, Leyden-Delta, Lundbeck, Otsuka, Servier, Sunovion, Roche • Neither Dr Howes nor his family have shares/other investments in or are employed by biopharmaceutical companies
Acknowledgements Rick Adams, Paul Allen, Ilinca Angelescu, Abhi Ashok, David Baumeister, Gareth Barker, Katie Beck, Sagnik Bhattacharyya, David Bonsall, Michael Bloomfield, Peter Bloomfield, Ilaria Bonoldi, Faith Borgan, Subrata Bose, Stefan Brugger, Ines Carreira, Paul Chadwick, Paula Dazzan, Marta DiForti, Jacek Donocik, Val Curran, Fern Day, Enrico D’Ambrosio , Tarik Dahoun, Arsime Demjaha, Alice Egerton, Karl Friston, Sean Froudist-Walsh, Paolo Fusar-Poli, Fiona Gaughran, Siobhan Gee, Cristian Gobjila, Roger Gunn, Guy Hindley, Conrad Iyegbe, Stephen Kaar, Sameer Jauhar, Shitij Kapur, Matthew Kempton, Euitae Kim, John Lally, Dave Lythgoe, Tiago Marques, James MacCabe, Robert McCutcheon, Philip McGuire, Mitul Mehta, Andreina Mendez, Yuya Mizuno, Elias Mouchliantis, Celia Morgan, Robin Murray, Sridhar Natesan, Chiara Nosarti, Matthew Nour, Ellis Onwordi, Emanule Osimo, Anna Pacelli, Fiona Pepper, Emanuelle Peters, Toby Pillinger, IIlan Rabiner, Tiago Reis-Marques,Jon Roiser, Maria Rogdaki, Jon Roiser, Anai Sarkis, Kat Shatalina, Sudharka Selvaraj, Sukhi Shergill, Lade Smith, James Stone, Paul Shotbolt, Paul Stokes, David Taylor, Federico Turkheimer, Mark Ungless, Lucia Valmaggia, Isabel Valli, Lisa Wells, Mattia Veronese, Steve Williams, Matt Williams, Toby Winton-Brown, Dominic Withers, Jolanta Zanelli The patients and volunteers
Outline • Concept of treatment resistance • Problems with current approach: example of schizophrenia • TRRIP consensus • Other issues and recommendations
Concept Treatment resistance Correct Adequate Diagnosis treatment Non- response Pillinger & Howes In Sub
Problem 1: clinical guidelines Howes et al AJPsych 2017
Problem 2: clinical trial definitions Lessons from clozapine network meta-analyses
How many defined treatment resistance? • 50%: no clear definition • 95%: used different or no clear definition Howes et al AJPsych 2017
Methods for Defining TRS Summary of criteria used across 42 clinical trials of treatment resistant schizophrenia NS – Not specified. CPZ – Chlorpromazine equivalents - Only two studies (5%) utilized the same criteria. Howes et al. Am J Psychiatry. 2017
Patients thought to be treatment resistance…. • 35-44% of patients had sub-therapeutic antipsychotic levels Sub-therapeutic levels McCutcheon et al 2015 McCutcheon et al 2017
Can you bring in your medication?
Are they comparing like with like?
In most trials Treatment resistance Not operationalised Correct Adequate Diagnosis treatment Non- response Not operationalised Howes et al 2017
Similar problems in other disorders.. Depression Persistent HAM-D-17 90 score ≥ 17 GSRD 89 2 ≥4 weeks ‘Optimal dose of the Not defined prescribed antidepressant (at least as high as the lowest dose defined as effective in the product data sheet’ APA 91,92 Not defined ≥8 weeks. Review dose ‘upper limit of a ‘assess…treatment adherence’ ‘minimal or no improvement in numerically at 4-8 weeks, consider medication dose’ symptoms’ dose increase RANZCP 93 2 ≥3 weeks ‘at the recommended ‘ensure that the patient has been taking their medication ‘lack of improvement’ therapeutic dose’ as prescribed’ Bipolar Affective Disorder Depression 2 8 Adequate therapeutic ‘include continuous and rigorous ‘failure to reach sustained remission’ : (antipsychotic/mood- doses medication adherence’ Hidalgo- stabiliser) Mazzei et al., 2019 98 (consensus definition) Obsessive Compulsive Disorder AACAP 14 2 drug trials: either 2 Drug: 10 weeks Maximum Not defined ‘persistent and substantial OCD trials of SSRI, or 1 trial CBT: 8-10 total sessions, recommended or symptomatology’ of SSRI and 1 trial of or 6-8 sessions of maximum tolerated clomipramine exposure and response doses 1 trial of CBT prevention Reviewed in Pillinger & Howes In Sub
Outline • Concept of treatment resistance • Problems with current approach: example of schizophrenia • TRRIP consensus • Other issues and recommendations
AIMS • Operationalise criteria • Provide reporting benchmarks • Operationalise reporting criteria Howes et al AJPsych 2017
TRRIP approach: Minimum and optimum criteria Sub-typing by symptom and time course: positive, negative, cognitive Treatment resistance Operationalise Early vs late • Duration • Type Correct Adequate • Number Diagnosis treatment • Dose • Adherence (PK/PD) Non- Operationalise response • Duration • Severity • Function/ impact
Outline • Concept of treatment resistance • Problems with current approach: example of schizophrenia • TRRIP consensus • Other issues and recommendations
Placebo or active comparator? Favours active comparator Favours placebo Some benefit from treatment Signal detection may be easier More representative of practice Differences in side-effect profile may favour comparator Easier to recruit Less risk of unblinding Atkinson et al J Clin Psych 2007; Pickar et al AJPsych 2003
Recommendations for future trials • Operationalise inclusion criteria: non-response and treatment • Careful attention to prior treatment: prospective run-in • Active comparator • Length will probably need to be longer
Example: DAYBREAK LU AF3700 study LU AF3700 Prospective Randomisation antipsychotic treatment Olanzapine/ risperidone single-blind, double-blind, 6 weeks 10 weeks ClinicalTrials.gov Identifier: NCT02717195
DAYBREAK study Treatment resistance DSM-5: SZ 1 retrospective Rx: Correct Adequate over 6 weeks Diagnosis treatment 1 prospective Rx ?adherence Non- response PANSS total>79 CGI>3
DAYBREAK study
LU AF3700 pharmacology and the pathophysiology of TRS D1 and D2 antagonist • No in vivo evidence that D1 signaling is altered in TRS • Limited in vivo evidence D1 antagonism is involved in therapeutic action of clozapine Howes et al JAMA Psych 2012; Potkin et al Mol Psych 2003 https://investor.lundbeck.com/news-releases/news-release-details/lundbeck- Nordstrom et al AJPsych 1995 updates-clinical-phase-iii-study-lu-af35700-treatment
DA & treatment resistance 0.016 p=0.02; DA synthesis capacity/ min 0.015 ES=1.12 0.014 0.013 0.012 0.011 0.01 0.009 0.008 Controls Responders Treatment resistant Demjaha et al, AJPsych 2012; Jauhar et al Mol Psych 2018
Recommendations for future trials • Operationalise inclusion criteria: non-response and treatment • Careful attention to prior treatment: prospective run-in and adherence monitoring • Active comparator • Length of trial likely will need to be longer • Understand pathophysiology of treatment resistance • Phase Ib trials of target engagement
Summary Treatment resistance: • Poorly defined in clinical criteria • Variably defined in RCTs • Some RCTs conflate resistance with intolerability • Inadequate treatment a major issue: definition and choice in some disorders Potential solutions: TRRIP approach: operationalize criteria, prospective run-in Better pharmacodynamic understanding of resistance Academic and pre-competitive consortia Consensus approach to definitions and reporting for other disorders
Extra slides
Variation in criteria
Variation in criteria: including treatment intolerant
Duration Minimum: At least 12 weeks Optimum: At least 12 weeks; specify duration of treatment resistance
Functioning Treatment resistant patients should be determined to be have at least moderate functional impairment, measured using a validated scale (for example, Social and Occupational Functioning Scale).
Dosage Treatment resistant patients will have been treated with a dose of medication equivalent to at least 600 mg of chlorpromazine per day. Record minimum and mean(SD) dosage for each drug
But in non- treatment resistant patients….. Leucht et al 2013
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