Cli linical Tria ials For r Treatment Resistant t - - PowerPoint PPT Presentation

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Cli linical Tria ials For r Treatment Resistant t - - PowerPoint PPT Presentation

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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

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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

  • liver.howes@kcl.ac.uk

1

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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

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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

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Outline

  • Concept of treatment resistance
  • Problems with current approach: example of schizophrenia
  • TRRIP consensus
  • Other issues and recommendations
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Concept

Correct Diagnosis Adequate treatment Non- response Treatment resistance

Pillinger & Howes In Sub

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Problem 1: clinical guidelines

Howes et al AJPsych 2017

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Problem 2: clinical trial definitions Lessons from clozapine network meta-analyses

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How many defined treatment resistance?

  • 50%: no clear definition
  • 95%: used different or no

clear definition

Howes et al AJPsych 2017

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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

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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

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Can you bring in your medication?

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Are they comparing like with like?

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In most trials

Correct Diagnosis Adequate treatment Non- response Treatment resistance Not operationalised Not operationalised

Howes et al 2017

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Similar problems in other disorders..

Depression GSRD89 2 ≥4 weeks ‘Optimal dose of the prescribed antidepressant (at least as high as the lowest dose defined as effective in the product data sheet’ Not defined Persistent HAM-D-1790 score ≥ 17 APA91,92 Not defined numerically ≥8 weeks. Review dose at 4-8 weeks, consider dose increase ‘upper limit of a medication dose’ ‘assess…treatment adherence’ ‘minimal or no improvement in symptoms’

RANZCP93 2 ≥3 weeks ‘at the recommended therapeutic dose’ ‘ensure that the patient has been taking their medication as prescribed’ ‘lack of improvement’

Bipolar Affective Disorder Depression : Hidalgo- Mazzei et al., 201998 (consensus definition) 2 (antipsychotic/mood- stabiliser) 8 Adequate therapeutic doses ‘include continuous and rigorous medication adherence’ ‘failure to reach sustained remission’ Obsessive Compulsive Disorder AACAP14 2 drug trials: either 2 trials of SSRI, or 1 trial

  • f SSRI and 1 trial of

clomipramine 1 trial of CBT Drug: 10 weeks CBT: 8-10 total sessions,

  • r 6-8 sessions of

exposure and response prevention Maximum recommended or maximum tolerated doses Not defined ‘persistent and substantial OCD symptomatology’

Reviewed in Pillinger & Howes In Sub

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Outline

  • Concept of treatment resistance
  • Problems with current approach: example of schizophrenia
  • TRRIP consensus
  • Other issues and recommendations
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Howes et al AJPsych 2017

AIMS

  • Operationalise criteria
  • Provide reporting benchmarks
  • Operationalise reporting criteria
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TRRIP approach:

Correct Diagnosis Adequate treatment Non- response Treatment resistance Operationalise

  • Duration
  • Type
  • Number
  • Dose
  • Adherence

(PK/PD) Operationalise

  • Duration
  • Severity
  • Function/ impact

Minimum and optimum criteria Sub-typing by symptom and time course: positive, negative, cognitive Early vs late

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Outline

  • Concept of treatment resistance
  • Problems with current approach: example of schizophrenia
  • TRRIP consensus
  • Other issues and recommendations
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Placebo or active comparator?

Atkinson et al J Clin Psych 2007; Pickar et al AJPsych 2003 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

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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
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Example: DAYBREAK LU AF3700 study

Prospective antipsychotic treatment Randomisation LU AF3700 Olanzapine/ risperidone single-blind, 6 weeks double-blind, 10 weeks ClinicalTrials.gov Identifier: NCT02717195

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DAYBREAK study

Correct Diagnosis Adequate treatment Non- response Treatment resistance 1 retrospective Rx:

  • ver 6 weeks

1 prospective Rx DSM-5: SZ PANSS total>79 CGI>3 ?adherence

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DAYBREAK study

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LU AF3700 pharmacology and the pathophysiology of TRS

https://investor.lundbeck.com/news-releases/news-release-details/lundbeck- updates-clinical-phase-iii-study-lu-af35700-treatment

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 Nordstrom et al AJPsych 1995

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DA & treatment resistance

Demjaha et al, AJPsych 2012; Jauhar et al Mol Psych 2018

0.008 0.009 0.01 0.011 0.012 0.013 0.014 0.015 0.016 Controls Responders Treatment resistant

DA synthesis capacity/ min p=0.02; ES=1.12

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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
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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

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Extra slides

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Variation in criteria

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Variation in criteria: including treatment intolerant

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Duration

Minimum: At least 12 weeks Optimum: At least 12 weeks; specify duration of treatment resistance

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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).

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Dosage

Treatment resistant patients will have been treated with a dose of medication equivalent to at least 600 mg

  • f chlorpromazine per day.

Record minimum and mean(SD) dosage for each drug

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But in non-treatment resistant patients…..

Leucht et al 2013