| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple system atrophy (MSA) |
|
| E.1.1.1 | Medical condition in easily understood language |
A rare, sporadic, progressive, adult-onset neurodegenerative
disorder of the central and autonomic nervous systems. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064060 |
| E.1.2 | Term | Multiple system atrophy |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To assess the safety and tolerability of AZD3241.
• To determine the effect of AZD3241 on microglia activation, as measured by [11C]PBR28 binding. |
|
| E.2.2 | Secondary objectives of the trial |
• To determine the biomarker effects of AZD3241
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
2 Optional Sub-studies-
1) PGt (Pharmacogenetic) analysis - a whole genome or exome analysis or targeted analyses of DNA polymorphisms may be conducted e.g., MPO, α-synuclein, and coenzyme Q2 genotype determination by sequencing.
Objective: Determination of the association between DNA and protein variation and the response to treatment with AZD3241.
2) CSF Sampling –
Objective: To determine the potential effect(s) of AZD3241 on surrogate marker(s) of MPO activity e.g., oxidized apolipoprotein A-1.
|
|
| E.3 | Principal inclusion criteria |
1. Males or females, aged 30-80 years.
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, confirmed by prospective genotyping of TSPO polymorphism.
4. Female subjects of childbearing potential must:
a. Have a negative serum β-hCG pregnancy test result at screen and a negative urine β-hCG test result at baseline, and
b. Agree not to become pregnant during participation in the study, and
c. Agree, if sexually active, to routinely use two methods of contraception during the study, for 40 days after the last dose of AZD3241, and for 3 months after the last administration of [11C]PBR28. One method must be a medically approved contraceptive. The other method must be condom use. Hormonal contraceptives sensitive to CYP3A4 induction are not permitted as a method of
contraception.
5. Postmenopausal females must have follicle-stimulating hormone (FSH) ≥ 38 mIU/mL at screen.
6. Males must agree to refrain from donating sperm during the study, for 100 days following the last dose of AZD3241, and for 3 months after the last administration of [11C]PBR28. Sexually active male subjects must:
a. Agree to use condoms during the study, for 100 days after the last dose of AZD3241, and for 3 months after the last administration of [11C]PBR28.
b. Agree to ensure that they and their partners are routinely using a
medically approved contraceptive method.
7. 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 (Day -1). Intermittently administered treatment may be
considered stable if the dose and dosing frequency have been unchanged
for the greater of 30 days or three dosing intervals (e.g., a treatment
given once a month must be at a stable dose and dosing frequency for 3
months).
8. Able to swallow tablets whole.
|
|
| E.4 | Principal exclusion criteria |
-Prior participation in any AZD3241 studies
-MRI performed during screen not consistent with MSA diagnosis
-ET scan or other procedure with administration of a radiopharmaceutical in the last 12 months
-Negative Allen test in both hands unless brachial artery used for
arterial cannulation
- Subjects determined as low affinity binders by TSPO genotyping
- Claustrophobia contraindicating brain MRI or PET scans
-Pregnancy, lactation or positive serum β-hCG at screen or positive
urine β-hCG at baseline
- Initiation or change in pharmacologic therapy for MSA symptoms
within 30 days prior to screen or between screen and baseline
- Other significant neurological disease affecting CNS , that may affect
motor or autonomic function or ability to complete the study including
Alzheimer's, idiopathic Parkinson's, other Parkinson plus syndromes or
secondary parkinsonism
- History of brain surgery for parkinsonism
- History of stem cell treatment
- Seizure disorder unless well controlled, for which treatment has been stable for at least 30 days prior to screen and between screen and
baseline
- Presence of any clinically significant medical condition that is clinically
unstable, is likely to deteriorate during the study, could put the patient
at risk because of participation, affect ability to complete the study or
influence study results
- History or presence of thyroid disease
- An abnormal TSH or FT4 test result at screen or baseline
- History or presence of GI or other disease or history of surgery known
to interfere with absorption, distribution, metabolism, or excretion of drugs
- Evidence of acute suicidal ideationHistory of suicidal behavior
- History of alcohol, drug abuse, dependence (except nicotine
dependence) within 1 year prior to screen
- Urine drug screen positive for a drug of abuse.
- Myocardial infarction; hospitalization for congestive heart failure or
symptoms of unstable angina; syncope not related to MSA within 1 year
prior to screen or between screen and baseline
- Moderate or severe congestive heart failure or known ejection fraction
< 40%
- History or presence of renal disease or impaired renal function
- Estimated creatinine clearance < 60 mL/min according to the
Cockcroft-Gault equation at screen
- A QT interval corrected by the Fridericia procedure (QTcF) > 450 msec at screen (single ECG measurement) or baseline (Day -1) (mean of three
ECG measurements), or a family history of long-QT syndrome
- Uncontrolled hypertension, 2 or more systolic readings > 220 mmHg or
diastolic readings > 105 mmHg
- History or presence of diabetes unless glucose levels have been well
controlled and treatment has been stable for at least 30 days prior to
screen and between screen and baseline
- HbA1c ≥ 6.5% at screen
- Clinically significant infection within 30 days prior to screen or
between screen and baseline
- History of cancer within the last 5 years except nonmetastatic basal
cell skin carcinoma
- Any clinically important abnormality on physical examination or vital
signs, ECG, or clinical laboratory test other than abnormality due to a
stable, well-controlled medical condition or any abnormality that could be detrimental to the subject or compromise the study
- Aspartate aminotransferase, alanine aminotransferase, or alkaline
phosphatase > 2 x upper limit of normal at screen or baseline
- Positive serologic findings for HIV, HBsAg or HCV antibodies
- History of 2 or more clinically important drug allergies
- Clinically significant blood clotting or bleeding disorder
- Use of antipsychotic medication within 3 months prior to screen or
between screen and baseline
- Use of any anticoagulant or oral glucocorticoid within 30 days prior to
baseline PET scan
- Use of metoclopramide, thyroid medication or regular use of narcotic
pain medication within 30 days prior to baseline
- Use of potent inhibitors of CYP3A4 or CYP1A2 within 14 days prior to
baseline
- Use of potent inducers of CYP3A4 or CYP1A2 or drugs mainly
metabolized by CYP3A4 or CYP2B6 that are sensitive to potential
induction by AZD3241 within 30 days prior to baseline
- Treatment with any investigational drug or device within 60 days or 5
half-lives prior to screen, whichever is longer, or between screen and
baseline
- Plasma donation within 1 month prior to screen or between screen and
baseline
- Blood donation/blood loss > 500 mL within 3 months prior to screen
- AstraZeneca employee or 1st degree relative, participating clinical trial
site employee
- Presence of MRI contraindications
PGt testing sub-study:
- Previous allogenic bone marrow transplant
- Non-leukocyte-depleted whole blood transfusion within 4 months prior
to testing CSF sampling sub-study:
- Any spinal malformations or other aspects (eg tattoos) or other clinical
findings (eg papilledema) that may complicate or contraindicate lumbar puncture
- Neoplasm or other space-occupying intracranial lesion on MRI
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1) [11C]PBR28 binding to translocator protein as measured by PET
2) Incidence of adverse events (AEs) and serious adverse events (SAEs) including frequency and severity
3) Change from baseline in vital signs (supine and standing blood pressure and pulse), oral temperature, weight, clinical laboratory tests, and ECG
4) Physical Exam
5) Suicidality as assessed by the Columbia-Suicide Severity Rating Scale (C SSRS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Screening and after 12 weeks of study medication
2) Screening, baseline, after 1, 2, 3, 4, 8, and 12 weeks of study medication and 14 ± 7 days after the last dose of study medication
3) Screening, baseline, after 1, 2, 3, 4, 8, and 12 weeks of study medication and 14 ± 7 days after the last dose of study medication
4) Screening and after 12 weeks of study medication
5) Screening, baseline, after 1, 2, 3, 4, 8, and 12 weeks of study medication and 14 ± 7 days after the last dose of study medication
|
|
| E.5.2 | Secondary end point(s) |
| Biomarker analysis - MPO activity |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Baseline and after 12 weeks of study medication
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Finland |
| France |
| Italy |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 21 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 21 |
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