AZD3241 PET MSA Trial, Phase 2, Randomized,12 Week Safety and Tolerability Trial With PET in MSA Patients

A 12-Week, Multicenter, Randomized, Parallel-Group Study to Assess the Safety, Tolerability, Pharmacokinetics, Biomarker Effects, Efficacy, and Effect on Microglia Activation, as Measured by Positron Emission Tomography, of AZD3241 in Subjects With Multiple System Atrophy

AZD3241 myeloperoxidase (MPO) inhibitor trial is assessing safety and tolerability, randomized trial, in patients with Multiple System Atrophy.

Study Overview

• Status: Completed
• Conditions: Multiple System Atrophy, MSA
• Intervention / Treatment: Drug: AZD3241; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria, 6020
    • Research Site
• Finland
  • Turku, Finland, 20520
    • Research Site
• France
  • Bordeaux Cedex, France, 33076
    • Research Site
  • Toulouse Cedex 9, France, 31059
    • Research Site
• Italy
  • Salerno, Italy, 84131
    • Research Site
• Sweden
  • Stockholm, Sweden, 141 86
    • Research Site
• United Kingdom
  • London, United Kingdom, W12 0NN
    • Research Site
  • London, United Kingdom, SE5 9RJ
    • Research Site
  • Oxford, United Kingdom, OX3 9DU
    • Research Site
• United States
  • California
    • Stanford, California, United States, 94305
      • Research Site
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8048
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33613
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48105-2945
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • New York
    • New York, New York, United States, 10016
      • Research Site
    • New York, New York, United States, 10032
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, age 30-80 years, inclusive, at screen.
2. Meet criteria for diagnosis of probable or possible MSA according to the consensus criteria (Gilman et al. 2008 ).
3. "High-affinity binder" or "mixed-affinity binder" for TSPO, as confirmed by prospective genotyping of TSPO polymorphism during screen.
4. Subjects must understand the nature of the study and must provide signed and dated written informed consent in accordance with local regulations before the conduct of any study-related procedures. The informed consent should reflect the protocol stipulations concerning the use of contraception.
5. Medical treatment of MSA and co-morbid medical conditions must be stable for at least 30 days prior to screen and between screen and baseline.
6. Written and oral fluency in the local language.
7. Able and willing to participate in all scheduled evaluations, abide by all study restrictions, and complete all required tests and procedures.
8. In the opinion of the investigator, the subject must be considered likely to comply with the study protocol and to have a high probability of completing the study.
9. Able to swallow tablets whole.

Exclusion Criteria:

1. Prior participation in any AZD3241 study.
2. Magnetic resonance imaging (MRI) performed during screen not consistent with diagnosis of MSA.
3. Received a PET scan within the last 12 months.
4. Negative Allen test in both hands, unless the brachial artery is used for arterial cannulation.
5. Subjects determined to be "low affinity binders" by TSPO genotyping.
6. Claustrophobia that would contraindicate a brain MRI scan or brain PET scan.
7. Pregnancy, lactation, or, if female of childbearing potential, positive serum β-hCG at screen or positive urine β-hCG at baseline (Day -1).
8. Initiation or change in pharmacologic therapy for symptoms of MSA within 30 days prior to screen or between screen and baseline (Day -1).
9. Significant neurological disease affecting the central nervous system (CNS), other than MSA
10. History of brain surgery for parkinsonism.
11. History of stem cell treatment.
12. Seizure disorder, unless well controlled and for which treatment has been stable for at least 30 days prior to screen and between screen and baseline (Day -1).
13. Presence of any clinically significant medical condition
14. History or presence of thyroid disease.
15. Any abnormal TSH or Free T4 test result at screen or baseline (Day -1).
16. History or presence of gastrointestinal disorders or other disease known to interfere with absorption, distribution, metabolism or excretion of drugs
17. History or presence of renal disease or impaired renal function.
18. A QT interval corrected according to the Fridericia procedure (QTcF) interval measurement > 450 msec at screen (single ECG) or baseline (Day -1) (mean of three ECG measurements) or a family history of long-QT syndrome.
19. Uncontrolled hypertension
20. History or presence of diabetes, unless glucose levels have been well controlled and for which treatment has been stable for at least 30 days prior to screen and between screen and baseline (Day -1).
21. History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma of the skin.
22. Any clinically important abnormality, as determined by the investigator, on physical examination or vital signs, ECG, or clinical laboratory test results other than abnormality due to a stable, well-controlled medical condition; or any abnormality that could be detrimental to the subject or could compromise the study.
23. Use of potent inhibitors of CYP3A4, Use of potent inducers of CYP3A4 and/or Use of drugs mainly metabolized by CYP3A4
24. Treatment with any investigational drug or device within 60 days or five half-lives prior to screen, whichever is longer, or between screen and baseline (Day -1).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AZD3241; Subjects will be randomized to one of the two doses of AZD3241 or placebo in a 1:1:1 ratio.	Drug: AZD3241; Drug: AZD3241 administered for 12 weeks orally as a tablet.; Other Names: AZD3241 to match placebo administered for 12 weeks.
Placebo Comparator: Placebo to match AZD3241; Subjects will be randomized to one of the two doses of AZD3241 or placebo in a 1:1:1 ratio.	Drug: Placebo; Placebo to match AZD3241 administered for 12 weeks orally as a tablet.; Other Names: Placebo to match AZD3241 administered for 12 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Striatum Brain Region: Change From Baseline in Microglia Activation Via Positron Emission Tomography(PET)	Striatum Brain region: Change from baseline in microglia activation via PET By [11C]PBR28 binding to translocator protein	Baseline (pre randomization) and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity	Myeloperoxidase (MPO) inhibition in plasma (change from baseline), on samples collected and analyzed, specific activity (activity/protein)	Baseline (Day -1) and week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Efficacy: Unified Multiple System Atropy Rating Scale, Change From Baseline (Total Score, Part 1 + Part 2)	Exploratory efficacy: Unified Multiple System Atropy Rating Scale, change from baseline (total Score, Part 1 + Part 2) : Score range 0 to 104, positive value indicates worsening symptoms	Baseline to final treatment visit

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2015
• Primary Completion (Actual): September 19, 2016
• Study Completion (Actual): September 19, 2016

Study Registration Dates

• First Submitted: March 9, 2015
• First Submitted That Met QC Criteria: March 9, 2015
• First Posted (Estimate): March 17, 2015

Study Record Updates

• Last Update Posted (Actual): September 25, 2017
• Last Update Submitted That Met QC Criteria: August 18, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Keywords: Multiple System Atrophy (MSA), PET imaging, myeloperoxidase (MPO) inhibitor
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Pathological Conditions, Anatomical; Autonomic Nervous System Diseases; Primary Dysautonomias; Hypotension; Atrophy; Multiple System Atrophy; Shy-Drager Syndrome
• Other Study ID Numbers: D0490C00023