A Phase IIa, Multi-Centre, Double-Blind, Randomised, Placebo-Controlled, Parallel Group 12-Month Treatment, Adaptive Design Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of AZD3241 in Patients with Multiple System Atrophy
- Conditions
- Multiple system atrophyMedDRA version: 12.1Level: LLTClassification code 10064060Term: Multiple system atrophy
- Registration Number
- EUCTR2009-018157-23-GB
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 135
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 (P
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method