E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064060 |
E.1.2 | Term | Multiple system atrophy |
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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 evaluate the effect of AZD3241 on disease progression in patients with MSA using scales covering historical review, motor function, autonomic examination, and global disability.
For Stage 1, the primary objective is to evaluate the safety and tolerability of AZD3241 in order to select a dose for treatment of MSA patients in Stage 2. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the effect of AZD3241 on brain neurodegeneration using magnetic resonance imaging (MRI)
Safety objective: To evaluate the safety and tolerability of AZD3241.
Exploratory objectives: 1. To explore the pharmacokinetics (PK) of AZD3241 2. To explore the effects of AZD3241 on α synuclein levels in plasma 3. To evaluate the effect of AZD3241 on myeloperoxidase (MPO) activity in plasma 4. To collect and store DNA samples that may be used for future, exploratory genetic research aimed at identifying/exploring genetic variations that may affect PK and pharmacodynamics (including biomarkers), safety, and tolerability related to AZD3241. In addition, susceptibility genes and genes related to underlying disease may be explored. The results of the pharmacogenetic analyses will be reported separately from the Clinical Study Report (CSR).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study-specific procedures 2. Diagnosis of probable or possible MSA in accordance with consensus criteria (Gilman et al 2008) excluding patients with MSA-C without Parkinsonism
Criteria for the diagnosis of probable MSA - Autonomic failure involving urinary incontinence (inability to control the release of urine from the bladder, with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic, and - Poorly levodopa-responsive Parkinsonism (bradykinesia with rigidity, tremor, or postural instability), or - A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction) Criteria for the diagnosis of possible MSA - Parkinsonism (bradykinesia with rigidity, tremor, or postural instability), or - A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction), and - At least 1 feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency, or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure decline that does not meet the level required in probable MSA), and - At least one of the additional features shown below Additional features of possible MSA Possible MSA-P or MSA-C - Babinski sign with hyperreflexia - Stridor Possible MSA-P - Rapidly progressive Parkinsonism - Poor response to levodopa - Postural instability within 3 years of motor onset - Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction - Dysphagia within 5 years of motor onset - Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum - Hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in putamen, brainstem, or cerebellum Possible MSA-C - Parkinsonism (bradykinesia and rigidity) - Atrophy on MRI of putamen, middle cerebellar peduncle, or pons - Hypometabolism on FDG-PET in putamen - Presynaptic nigrostriatal dopaminergic denervation on single photon emission computed tomography or positron emission tomography 3. Females or males aged ≥40 years and ≤75 years. Females must be of non-childbearing potential, confirmed at enrolment by fulfilling any of the criteria: - Females >50 years of age who have been amenorrheic for 12 months or more and have not used exogenous hormonal treatment, - Females who are permanently or surgically sterilised or postmenopausal. Permanent sterilisation includes hysterectomy and/or bilateral oopherectomy and/or bilateral salpingectomy, but excludes bilateral tubal occlusion. Women will be considered postmenopausal if they are amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: (i) Women under 50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range (ii) Women over 50 years of age would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments. 4. Males should be willing to use barrier contraception (ie, condoms) from the first day of dosing until 3 months after the last dose of IP 5. Treatment for symptoms of MSA (Parkinsonism, autonomic dysfunction, etc) should be stable for at least 1 month prior to enrolment (Visit 1) 6. UMSARS Part IV ≤3 7. Documented diagnosis less than 3 years 8. Patients who are ambulatory 9. Patient must be able to understand and be willing to comply with study procedures, restrictions and requirements as judged by the Investigator. In addition, for inclusion in the optional genetic research (DNA sampling), patients need to fulfil the following criterion: 1. Provision of informed consent for optional exploratory genetic research.
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E.4 | Principal exclusion criteria |
1. Patients with: idiopathic Parkinson’s disease, other Parkinson plus syndromes (eg, progressive supranuclear palsy), or secondary Parkinsonism (eg, medication induced) 2. Patients with speech problems as assessed by a score of ≥3 on UMSARS Part I, Question 1 3. Patients with swallowing problems as assessed by a score of ≥3 on UMSARS Part I, Question 2 4. Patients with walking problems as assessed by a score of ≥3 on UMSARS Part I, Question 7 5. Patients with falling/postural instability problems as assessed by a score of ≥3 on UMSARS Part I, Question 8 6. Patients with severe orthostatic symptoms as assessed by a score of ≥3 on UMSARS Part I, Question 9 7. Patients with urinary function problems as assessed by a score of ≥3 on UMSARS Part I, Question 10 8. Use of monoamine oxidase B (MAO-B) inhibitors, metoclopramide, CYP3A4 inhibitors, or CYP3A4 inducers within 1 month of randomisation; patients receiving such medications at enrolment should undergo a 1-month (4-week) washout period prior to randomisation 9. Current significant major or unstable respiratory disease, heart disease, cerebrovascular disease, haematological disease, hepatic disease, renal disease, gastrointestinal disease, or other major disease as judged by the Investigator 10. History of any clinically significant disease or disorder other than MSA which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient’s ability to participate in the study 11. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks prior to the first administration of IP as judged by the Investigator 12. Significant abnormalities on the clinical examination (excluding findings of MSA), that may interfere with the study or present a safety risk to the patient, as judged by the Investigator 13. Any clinically significant abnormalities in clinical chemistry, haematology, or urinalysis results as judged by the Investigator 14. Having known or suspected systemic infection (eg, hepatitis B virus, hepatitis C virus, human immunodeficiency virus, tuberculosis) as judged by the Investigator 15. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with the interpretation of QTc interval changes. This includes patients with any of the following: - Clinically significant PR (PQ) interval prolongation - Intermittent second or third degree atrioventricular block - Incomplete, full or intermittent bundle branch block (QRS <110 msec with normal QRS and T wave morphology is acceptable if there is no evidence of left ventricular hypertrophy) - Abnormal T wave morphology, particularly in the protocol-defined primary lead 16. Prolonged QTcF >450 msec or shortened QTcF <340 msec or a family history of long QT syndrome 17. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator 18. Known or suspected history of drug abuse as judged by the Investigator 19. History of hypersensitivity to drugs with a similar chemical structure or class to AZD3241 20. History of intolerance or hypersensitivity to mannitol 21. History of severe allergy/hypersensitivity or symptoms/signs of ongoing allergy/ hypersensitivity as judged by the Investigator 22. History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs 23. Plasma donation within 1 month of enrolment or any blood donation/blood loss >500 mL during the 3 months prior to enrolment 24. Participation in another clinical study with an IP during the past 12 weeks that is anticipated to interfere with the objectives of the study as judged by the Investigator 25. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff, contract research organisation [CRO], or staff at the study site) 26. Previous randomisation or treatment in present study. In addition, any of the following is regarded as a criterion for exclusion from the optional genetic research: 1. Previous allogenic bone marrow transplant 2. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The change from baseline to Month 12 in UMSARS I+II score (for evaluation of primary objective). |
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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 | Yes |
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 | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
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 | Information not present in EudraCT |
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 |
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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
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The end of the study is defined as “the last visit of the last patient undergoing the study.” |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |