Multiple System Atrophy, MSA
Conditions
Keywords
Multiple System Atrophy (MSA), PET imaging, myeloperoxidase (MPO) inhibitor
Brief summary
AZD3241 myeloperoxidase (MPO) inhibitor trial is assessing safety and tolerability, randomized trial, in patients with Multiple System Atrophy.
Interventions
DRUGAZD3241
Drug: AZD3241 administered for 12 weeks orally as a tablet.
DRUGPlacebo
Placebo to match AZD3241 administered for 12 weeks orally as a tablet.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Striatum Brain Region: Change From Baseline in Microglia Activation Via Positron Emission Tomography(PET) | Baseline (pre randomization) and Week 12 | Striatum Brain region: Change from baseline in microglia activation via PET By \[11C\]PBR28 binding to translocator protein |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | Baseline (Day -1) and week 12 | Myeloperoxidase (MPO) inhibition in plasma (change from baseline), on samples collected and analyzed, specific activity (activity/protein) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Efficacy: Unified Multiple System Atropy Rating Scale, Change From Baseline (Total Score, Part 1 + Part 2) | Baseline to final treatment visit | 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 |
Countries
Austria, Finland, France, Italy, Sweden, United Kingdom, United States
Participant flow
Recruitment details
124 subjects were screened, 22 of these were rescreened. A total of 61 subjects were assigned a treatment allocation through randomization. Two of ineligible subjects were never dispensed investigational product. One ineligible randomized subject was discontinued prior to dosing and refused to supply further data.
Pre-assignment details
Protocol was administratively changed to allow reduction of sample size from 64 in this study population. A total of 59 completed screening and were randomized, but only 58 completed randomization and were dosed with study medication.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo to match AZD3241 dosed twice daily | 19 |
| AZD3241 300 mg AZD3241 300 mg dosed twice daily | 19 |
| AZD3241 600 mg AZD3241 600 mg dosed twice daily | 20 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Dose Escalation Week 1 | Adverse Event | 1 | 2 | 1 |
| Dose Escalation Week 1 | Determined not eligible | 1 | 1 | 1 |
| Dose Escalation Week 2 | Determined not eligible | 1 | 1 | 1 |
| Dose Escalation Week 2 | Protocol Violation | 0 | 1 | 0 |
| Treatment Weeks 3 to 12 | Adverse Event | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | AZD3241 300 mg | AZD3241 600 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 59.3 Years STANDARD_DEVIATION 7.9 | 59.9 Years STANDARD_DEVIATION 6.1 | 58.0 Years STANDARD_DEVIATION 8.5 | 59 Years STANDARD_DEVIATION 7.5 |
| Diagnostic Category Possible MSA | 1 Participants | 4 Participants | 8 Participants | 13 Participants |
| Diagnostic Category Probable MSA | 18 Participants | 15 Participants | 12 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 16 Participants | 18 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Genotype TSPO - High Affinity Binding | 12 Participants | 10 Participants | 16 Participants | 38 Participants |
| Genotype TSPO- Low Affinity Binding | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Genotype TSPO - Mixed affinity binding | 7 Participants | 9 Participants | 4 Participants | 20 Participants |
| Multiple System Atropy Subtype MSA - C | 12 Participants | 9 Participants | 13 Participants | 34 Participants |
| Multiple System Atropy Subtype MSA - P | 7 Participants | 10 Participants | 7 Participants | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) White | 16 Participants | 15 Participants | 16 Participants | 47 Participants |
| Sex: Female, Male Female | 7 Participants | 5 Participants | 5 Participants | 17 Participants |
| Sex: Female, Male Male | 12 Participants | 14 Participants | 15 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 19 | 15 / 19 | 15 / 20 |
| serious Total, serious adverse events | 1 / 19 | 1 / 19 | 1 / 20 |
Outcome results
Primary
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
Time frame: Baseline (pre randomization) and Week 12
Population: PET analysis population (Paired baseline and week 12 PET scans)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Striatum Brain Region: Change From Baseline in Microglia Activation Via Positron Emission Tomography(PET) | -0.23 ml/cc | Standard Deviation 0.61 |
| AZD3241 300 mg | Striatum Brain Region: Change From Baseline in Microglia Activation Via Positron Emission Tomography(PET) | 0.12 ml/cc | Standard Deviation 0.83 |
| AZD3241 600 mg | Striatum Brain Region: Change From Baseline in Microglia Activation Via Positron Emission Tomography(PET) | -0.35 ml/cc | Standard Deviation 1.25 |
Comparison: Change from baseline within treatment armp-value: 0.13ANOVA
Comparison: Change from baselinep-value: 0.91ANOVA
Comparison: Change from baselinep-value: 0.68ANOVA
Comparison: Secondary objective - comparison to placebop-value: 0.32ANOVA
Comparison: Secondary objectivep-value: 0.45ANOVA
Secondary
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)
Time frame: Baseline (Day -1) and week 12
Population: efficacy population, restricted to subjects with paired samples analyzed within 6 months of collection
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Placebo | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | 1 hour post dose (WEEK 12 | 0.12 ratio |
| Placebo | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | Pre dose (week 12) | 0.12 ratio |
| Placebo | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | 2 to 6 hours post dose (week 12) | 0.04 ratio |
| AZD3241 300 mg | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | 1 hour post dose (WEEK 12 | -0.10 ratio |
| AZD3241 300 mg | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | Pre dose (week 12) | -0.12 ratio |
| AZD3241 300 mg | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | 2 to 6 hours post dose (week 12) | -0.15 ratio |
| AZD3241 600 mg | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | Pre dose (week 12) | -0.12 ratio |
| AZD3241 600 mg | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | 2 to 6 hours post dose (week 12) | -0.18 ratio |
| AZD3241 600 mg | Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity | 1 hour post dose (WEEK 12 | 0.10 ratio |
Other Pre-specified
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
Time frame: Baseline to final treatment visit
Population: Efficacy population: with baseline (Day -1) and post baseline assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Exploratory Efficacy: Unified Multiple System Atropy Rating Scale, Change From Baseline (Total Score, Part 1 + Part 2) | 4.7 Score change from baseline |
| AZD3241 300 mg | Exploratory Efficacy: Unified Multiple System Atropy Rating Scale, Change From Baseline (Total Score, Part 1 + Part 2) | 3.6 Score change from baseline |
| AZD3241 600 mg | Exploratory Efficacy: Unified Multiple System Atropy Rating Scale, Change From Baseline (Total Score, Part 1 + Part 2) | 2.6 Score change from baseline |