Study to assess the effect of AZD3241 in Multiple System Atrophy

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2014-004902-13-GB
• Date of registration: 24/12/2014
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: Study to assess the effect of AZD3241 in Multiple System Atrophy
• Scientific title: 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
• Date of first enrolment: 09/04/2015
• Target sample size: 64
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004902-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Finland, Sweden, United Kingdom, United States

Contacts

• Name: Information Desk
• Affiliation: AstraZeneca

• Name: Information Desk
• Affiliation: AstraZeneca

Key inclusion & exclusion criteria

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 ß-hCG pregnancy test result at screen and a negative urine ß-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 15 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 15 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 15 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 41
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 23

Exclusion criteria:
- Prior participation in any AZD3241 studies
- MRI performed during screen not consistent with MSA diagnosis
- PET 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 ß-hCG at screen or positive urine ß-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 ideation
- History 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
- QT interval measurement (central read) corrected according to the Fridericia procedure (QTcF) > 450 msec (mean of three ECG measurements) at screen or baseline, or 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 p

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Multiple system atrophy (MSA)
MedDRA version: 18.1 Level: PT Classification code 10064060 Term: Multiple system atrophy System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: AZD3241 100mg
Product Code: AZD3241
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: Not available
CAS Number: 890655-80-8
Current Sponsor code: AZD3241
Other descriptive name: IUPAC name: 1-(2-Isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d] pyrimidin-4-one
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: AZD3241 300mg
Product Code: AZD3241
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: Not available
CAS Number: 890655-80-8
Current Sponsor code: AZD3241
Other descriptive name: 1-(2-Isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo[3,2-d] pyrimidin-4-one
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

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)

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

Secondary Objective: • To determine the biomarker effects of AZD3241

Main Objective: • To assess the safety and tolerability of AZD3241.
• To determine the effect of AZD3241 on microglia activation, as measured by [11C]PBR28 binding.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1) Baseline and after 12 weeks of study medication

Secondary end point(s): Biomarker analysis - MPO activity

Secondary ID(s)

D0490C00023

Source(s) of Monetary Support

AstraZeneca

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 20/08/2017
• Date Completed: 29/09/2016
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-004902-13/results