SRC Inhibition as a Potential Target for Parkinson's Disease Psychosis

NCT03661125 | Unknown Early Phase 1 FDA Drug

• 1 other identifier: 247303
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Parkinson's disease is often characterised by movement symptoms such as rigidity and bradykinesia, however, there are a number of non-motor symptoms that can have a significant impact on quality of life. One of the most common non-motor symptoms of Parkinson's disease is visual hallucinations (where someone sees things that don't exist outside their mind). . Recent findings led to the approval of a drug called Pimavanserin as a treatment for PD psychosis in the USA. Based on other recent studies, we believe that Saracatinib, a drug that interacts within the same system as Pimavanserin, is a potential treatment for PD psychosis. Saracatinib has shown to reduce the intensity of the psychedelic effect induced by psilocybin (a naturally occurring psychedelic found in psilocybe mushrooms) and attenuate social cognition and brain changes in healthy volunteers. The aim of this study is to test the effects of 14 days dosing of saracatinib or placebo on 30 volunteers with PD psychosis. We aim to to use neuroimaging combined with psychopharmacology to provide evidence that a putative new treatment approach can modulate abnormal visual cortex activation in patients with PD psychosis. If positive, this proof of mechanism study would provide a strong platform to pursue symptom modification studies with Saracatinib.

Conditions

Parkinson Disease Psychosis

Outcome Measures

Primary Outcomes (1)

• Difference between study drug and placebo in BOLD activity in the ventral visual stream during visual recognition vs. the control task measure using fMRI

  Using functional magnetic resonance imaging (fMRI) to look at the effect of saracatinib in attenuating the reduced response in the ventral visual stream on the visual recognition tasks, compared to placebo.

  2 months (two treatment arms)

Secondary Outcomes (2)

• Difference between study drug and placebo in BOLD activity in the occipito-temporal region during the visual processing task (Kanisza illusion)

  2 months (two treatment arms)

• Change in Mismatch negativity (MMN) in microvolts (mV) and connectivity with the posterior cingulate hub of the default mode network

  2 months (two treatment arms)

Other Outcomes (4)

• Seed-based connectivity from the Regions of Interest (ROI) within the inferotemporal cortex.

  2 months (two treatment arms)

• Difference between study drug and placebo in MMN amplitude at FZ on EEG.

  2 months (two treatment arms)

• Test a prediction error model for the effects of Saracatinib on brain activity during a mismatch negativity paradigm on the EEG.

  2 months (two treatment arms)

Study Arms (2)

Saracatinib or placebo

EXPERIMENTAL

In the first arm of the study, participants will be randomised into either the group that receives Saracatinib (study drug) or the Placebo.

Drug: Saracatinib; Drug: Placebo Oral Tablet

Placebo or Saracatinib (Cross-over)

EXPERIMENTAL

The groups will now cross over i.e. the group that had the study drug in the first arm will get the placebo in the second arm and the group that had the placebo in the first arm will have the study drug in the second arm.

Drug: Saracatinib; Drug: Placebo Oral Tablet

Interventions

Saracatinib DRUG

AZD0530 (Saracatinib) 50 mg Tablet Pink Round 7.0 mm ADM P/5406/49. Two tablets to be taken every morning for 14 days.

Placebo or Saracatinib (Cross-over); Saracatinib or placebo

Placebo Oral Tablet DRUG

Placebo AZD0530 (Saracatinib) 50 mg Tablet Pink Round 7.0 mm ADM P/5406/37. Two tablets to be taken every morning for 14 days.

Placebo or Saracatinib (Cross-over); Saracatinib or placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Understand the study procedures and agree to participate by providing written informed consent.
• Have a confirmed diagnosis of Parkinson's disease using internationally accepted UK brain bank criteria.
• Be male or female
• Be right handed
• Aged 40 years or over
• Be judged to be in good health by the investigator, based on clinical evaluations including laboratory safety tests, medical history, physical examination, 12 lead ECG and vital signs measurements performed at screening and prior to administration of the initial dose of study drug.
• Have a score of at least 22 on the Montreal Cognitive Assessment (MoCA).
• Have a diagnosis of idiopathic PD with moderate severity
• Have a combined score of at least 6 or an individual score of at least 4 on the neuropsychiatric inventory (NPI \[20\]) 23 items A (delusions) and/or B (hallucinations).

You may not qualify if:

• Is a female of child bearing potential
• Is currently taking anticholinergic medication
• Is currently taking any medication known to be a moderate or potent CYP3A4 inducer or inhibitor.
• Has an ongoing disability, medical or neurological history, cognitive impairment, or conditions that in the opinion of the investigator may interfere with study conduct or clinical assessments.
• Refuses to be withdrawn from quetiapine (see section 4.7).
• Has a family history of psychosis in a first degree relative
• Has poor peripheral arterial/venous access or recent wrist trauma that will restrict ability to gain venous access.
• Is currently using prescription or non-prescription drugs and herbal supplements, which are deemed to affect the integrity of the study, within 7 days or 5 half-lives (whichever is longer) prior to the first dose of trial medication. As an exception, paracetamol or acetaminophen may be used at doses of 1 g/day.
• Has a history of sensitivity to any of the study medications or any of the excipient constituents.
• Has a history of febrile illness within 5 days prior to the first dose
• Has a hairstyle which would affect EEG recording.
• Has any condition possibly affecting drug absorption (eg, gastrectomy).
• Has a history of regular alcohol consumption exceeding 14 units/week (6 glasses of 13.0% wine (175ml), 6 pints of 4.0% lager or ale (568ml), 5 pints of 4.5% cider (568 ml) or 14 glasses of 10.0% spirits (25ml)) within 6 months of screening.
• Uses tobacco- or nicotine-containing products in excess of the equivalent of 5 cigarettes per day.
• Uses caffeine containing products of the equivalence of 5 cups of regular filter coffee per day

Sponsors & Collaborators

• King's College London: lead
• AstraZeneca: collaborator
• King's College Hospital NHS Trust: collaborator

Study Sites (1)

Mitul Mehta

London, Camberwell, SE5 8AF, United Kingdom

RECRUITING

Related Publications (6)

• Nygaard HB, Wagner AF, Bowen GS, Good SP, MacAvoy MG, Strittmatter KA, Kaufman AC, Rosenberg BJ, Sekine-Konno T, Varma P, Chen K, Koleske AJ, Reiman EM, Strittmatter SM, van Dyck CH. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimers Res Ther. 2015 Apr 14;7(1):35. doi: 10.1186/s13195-015-0119-0. eCollection 2015.

  PMID: 25874001 BACKGROUND

• Chang A, Fox SH. Psychosis in Parkinson's Disease: Epidemiology, Pathophysiology, and Management. Drugs. 2016 Jul;76(11):1093-118. doi: 10.1007/s40265-016-0600-5.

  PMID: 27312429 BACKGROUND

• Ffytche DH, Creese B, Politis M, Chaudhuri KR, Weintraub D, Ballard C, Aarsland D. The psychosis spectrum in Parkinson disease. Nat Rev Neurol. 2017 Feb;13(2):81-95. doi: 10.1038/nrneurol.2016.200. Epub 2017 Jan 20.

  PMID: 28106066 BACKGROUND

• Byock I. Taking Psychedelics Seriously. J Palliat Med. 2018 Apr;21(4):417-421. doi: 10.1089/jpm.2017.0684. Epub 2018 Jan 22.

  PMID: 29356590 BACKGROUND

• Carter OL, Pettigrew JD, Burr DC, Alais D, Hasler F, Vollenweider FX. Psilocybin impairs high-level but not low-level motion perception. Neuroreport. 2004 Aug 26;15(12):1947-51. doi: 10.1097/00001756-200408260-00023.

  PMID: 15305143 BACKGROUND

• Meppelink AM, de Jong BM, Renken R, Leenders KL, Cornelissen FW, van Laar T. Impaired visual processing preceding image recognition in Parkinson's disease patients with visual hallucinations. Brain. 2009 Nov;132(Pt 11):2980-93. doi: 10.1093/brain/awp223. Epub 2009 Sep 15.

  PMID: 19755518 BACKGROUND

MeSH Terms

Interventions

saracatinib

Study Officials

• Mitul Mehta

  King's College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Miriam Vignando

CONTACT

+44 (0) 7492634351; miriam.vignando@kcl.ac.uk

Sonali Dave

CONTACT

07906990964; sonali.dave@kcl.ac.uk

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2018
• First Posted: September 7, 2018
• Study Start: April 11, 2019
• Primary Completion: September 1, 2021
• Study Completion: September 1, 2021
• Last Updated: August 13, 2019

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)