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AZD3241 PET MSA Trial, Phase 2, Randomized,12 Week Safety and Tolerability Trial With PET in MSA Patients

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ClinicalTrials.gov Identifier: NCT02388295
Recruitment Status : Completed
First Posted : March 17, 2015
Results First Posted : September 25, 2017
Last Update Posted : September 25, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Multiple System Atrophy, MSA
Interventions Drug: AZD3241
Drug: Placebo
Enrollment 59

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.

Arm/Group Title Placebo AZD3241 300 mg AZD3241 600 mg
Hide Arm/Group Description Placebo to match AZD3241 dosed twice daily AZD3241 300 mg dosed twice daily AZD3241 600 mg dosed twice daily
Period Title: Dose Escalation Week 1
Started 19 [1] 19 [1] 20 [1]
Completed 17 16 18
Not Completed 2 3 2
Reason Not Completed
Adverse Event             1             2             1
Determined not eligible             1             1             1
[1]
Number randomized to treatment
Period Title: Dose Escalation Week 2
Started 17 16 18
Completed 16 14 17
Not Completed 1 2 1
Reason Not Completed
Protocol Violation             0             1             0
Determined not eligible             1             1             1
Period Title: Treatment Weeks 3 to 12
Started 16 14 17
Completed 15 13 17
Not Completed 1 1 0
Reason Not Completed
Adverse Event             1             1             0
Arm/Group Title Placebo AZD3241 300 mg AZD3241 600 mg Total
Hide Arm/Group Description Placebo to match AZD3241 dosed twice daily AZD3241 300 mg dosed twice daily AZD3241 600 mg dosed twice daily Total of all reporting groups
Overall Number of Baseline Participants 19 19 20 58
Hide Baseline Analysis Population Description
Safety population, includes only 58 of 59 randomized subjects, those taking at least 1 dose of investigational product
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 19 participants 19 participants 20 participants 58 participants
59.3  (7.9) 59.9  (6.1) 58.0  (8.5) 59  (7.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 19 participants 20 participants 58 participants
Female
7
  36.8%
5
  26.3%
5
  25.0%
17
  29.3%
Male
12
  63.2%
14
  73.7%
15
  75.0%
41
  70.7%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 19 participants 20 participants 58 participants
Hispanic or Latino
1
   5.3%
0
   0.0%
0
   0.0%
1
   1.7%
Not Hispanic or Latino
16
  84.2%
16
  84.2%
18
  90.0%
50
  86.2%
Unknown or Not Reported
2
  10.5%
3
  15.8%
2
  10.0%
7
  12.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 19 participants 20 participants 58 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
1
   5.3%
2
  10.0%
3
   5.2%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   5.3%
0
   0.0%
0
   0.0%
1
   1.7%
White
16
  84.2%
15
  78.9%
16
  80.0%
47
  81.0%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
2
  10.5%
3
  15.8%
2
  10.0%
7
  12.1%
Multiple System Atropy Subtype   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 19 participants 20 participants 58 participants
MSA - P 7 10 7 24
MSA - C 12 9 13 34
[1]
Measure Description: Multiple System Atropy (MSA) Subtype, Parkinsonian (P) or Cerebellar (C)
Diagnostic Category   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 19 participants 20 participants 58 participants
Possible MSA 1 4 8 13
Probable MSA 18 15 12 45
[1]
Measure Description: Diagnostic Category for Multiple System Atropy (MSA); Possible or Probable were the eligible categories
Genotype   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 19 participants 19 participants 20 participants 58 participants
TSPO - High Affinity Binding 12 10 16 38
TSPO - Mixed affinity binding 7 9 4 20
TSPO- Low Affinity Binding 0 0 0 0
[1]
Measure Description: Translocator Protein binding (TSPO) : genotype (affinity for binding); Low Affinity Binding was exclusionary
1.Primary Outcome
Title Striatum Brain Region: Change From Baseline in Microglia Activation Via Positron Emission Tomography(PET)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
PET analysis population (Paired baseline and week 12 PET scans)
Arm/Group Title Placebo AZD3241 300 mg AZD3241 600 mg
Hide Arm/Group Description:
Placebo to match AZD3241 dosed twice daily
AZD3241 300 mg dosed twice daily
AZD3241 600 mg dosed twice daily
Overall Number of Participants Analyzed 14 13 16
Mean (Standard Deviation)
Unit of Measure: ml/cc
-0.23  (0.61) 0.12  (0.83) -0.35  (1.25)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo
Comments Change from baseline within treatment arm
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.13
Comments Not adjusted
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.38
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.24
Estimation Comments larger negative values (powered to detect -0.50)
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection AZD3241 300 mg
Comments Change from baseline
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.91
Comments not adjusted
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.03
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.25
Estimation Comments larger negative values (powered to detect -0.50)
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection AZD3241 600 mg
Comments Change from baseline
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.68
Comments [Not Specified]
Method ANOVA
Comments no adjustments
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.10
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.25
Estimation Comments larger negagtive values (powereed to detect -0.50)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, AZD3241 300 mg
Comments Secondary objective - comparison to placebo
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.32
Comments no adjustment
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.35
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.34
Estimation Comments Looking for negative direction to indicate treatment better than placebo
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, AZD3241 600 mg
Comments Secondary objective
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.45
Comments no adjustment
Method ANOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.28
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.36
Estimation Comments lookin for negative difference compared to placebo
2.Secondary Outcome
Title Myeloperoxidase (MPO) Inhibition in Plasma (Change From Baseline), Specific Activity
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
efficacy population, restricted to subjects with paired samples analyzed within 6 months of collection
Arm/Group Title Placebo AZD3241 300 mg AZD3241 600 mg
Hide Arm/Group Description:
Placebo to match AZD3241 dosed twice daily
AZD3241 300 mg dosed twice daily
AZD3241 600 mg dosed twice daily
Overall Number of Participants Analyzed 13 8 15
Least Squares Mean (90% Confidence Interval)
Unit of Measure: ratio
Pre dose (week 12)
0.12
(-0.10 to 0.50)
-0.12
(-0.22 to -0.03)
-0.12
(-0.18 to -0.05)
1 hour post dose (WEEK 12
0.12
(-0.30 to 0.54)
-0.10
(-0.58 to 0.39)
0.10
(-0.27 to 0.48)
2 to 6 hours post dose (week 12)
0.04
(-0.04 to 0.13)
-0.15
(-0.25 to -0.08)
-0.18
(-0.26 to -0.11)
3.Other Pre-specified Outcome
Title Exploratory Efficacy: Unified Multiple System Atropy Rating Scale, Change From Baseline (Total Score, Part 1 + Part 2)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Efficacy population: with baseline (Day -1) and post baseline assessment
Arm/Group Title Placebo AZD3241 300 mg AZD3241 600 mg
Hide Arm/Group Description:
Placebo to match AZD3241 dosed twice daily
AZD3241 300 mg dosed twice daily
AZD3241 600 mg dosed twice daily
Overall Number of Participants Analyzed 17 17 18
Least Squares Mean (90% Confidence Interval)
Unit of Measure: Score change from baseline
4.7
(2.5 to 6.8)
3.6
(1.4 to 5.7)
2.6
(0.5 to 4.7)
Time Frame 12 weeks of randomized treation plus a follow up period up to 14 days after last dose
Adverse Event Reporting Description Adverse events starting during screening period Before randomization or starting greater that 14 days after the last dose of study medication are not included in these tabulations.
 
Arm/Group Title Placebo AZD3241 300 mg AZD3241 600 mg
Hide Arm/Group Description Placebo to match AZD3241 dosed twice daily AZD3241 300 mg dosed twice daily AZD3241 600 mg dosed twice daily
All-Cause Mortality
Placebo AZD3241 300 mg AZD3241 600 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo AZD3241 300 mg AZD3241 600 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/19 (5.26%)      1/19 (5.26%)      1/20 (5.00%)    
Injury, poisoning and procedural complications       
Hip fracture * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Nervous system disorders       
Multipla System Atrophy * 1 [1]  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Respiratory, thoracic and mediastinal disorders       
Choking * 1 [2]  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
[1]
Subject found face down on bedding - considered disease related death
[2]
Subject found dead with cheese in throat
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 1%
Placebo AZD3241 300 mg AZD3241 600 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/19 (73.68%)      15/19 (78.95%)      15/20 (75.00%)    
Cardiac disorders       
atrial fibrilation * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Ear and labyrinth disorders       
Tinnitus * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Vertigo * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 1/20 (5.00%)  1
Eye disorders       
Diplopia * 1  0/19 (0.00%)  0 2/19 (10.53%)  2 0/20 (0.00%)  0
Gastrointestinal disorders       
Abdominal discomfort * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Abdominal pain upper * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Constipation * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 1/20 (5.00%)  1
Diarrhoea * 1  2/19 (10.53%)  2 1/19 (5.26%)  1 1/20 (5.00%)  2
Dysphagia * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Gastrooesophageal reflux disease * 1  1/19 (5.26%)  1 1/19 (5.26%)  1 1/20 (5.00%)  1
Salivary hypersecretion * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Toothache * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Nausea * 1  0/19 (0.00%)  0 1/19 (5.26%)  2 0/20 (0.00%)  0
General disorders       
Adverse drug reaction * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Discomfort * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Fatigue * 1  1/19 (5.26%)  1 3/19 (15.79%)  3 3/20 (15.00%)  4
Feeling jittery * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Gait disturbance * 1  2/19 (10.53%)  4 0/19 (0.00%)  0 0/20 (0.00%)  0
Influenza like illness * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Pain * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Pyrexia * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Infections and infestations       
Lower respiratory tract infection * 1  0/19 (0.00%)  0 1/19 (5.26%)  4 0/20 (0.00%)  0
Nasopharyngitis * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Rhinitis * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Urinary tract infection * 1  3/19 (15.79%)  3 5/19 (26.32%)  5 3/20 (15.00%)  3
Injury, poisoning and procedural complications       
Administration related reaction * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Fall * 1  1/19 (5.26%)  12 1/19 (5.26%)  1 4/20 (20.00%)  6
Procedural pain * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Thermal burn * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Investigations       
Lymphocyte count decreased * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Weight decreased * 1  1/19 (5.26%)  1 1/19 (5.26%)  1 0/20 (0.00%)  0
Weight increased * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Metabolism and nutrition disorders       
Decreased appetite * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 1/20 (5.00%)  1
Joint swelling * 1  1/19 (5.26%)  3 0/19 (0.00%)  0 1/20 (5.00%)  1
Muscle fatigue * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Musculoskeletal chest pain * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 2/20 (10.00%)  2
Musculoskeletal stiffness * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 1/20 (5.00%)  2
Myalgia * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 2/20 (10.00%)  2
Nervous system disorders       
Balance disorder * 1  1/19 (5.26%)  1 1/19 (5.26%)  1 0/20 (0.00%)  0
Clumsiness * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Dizziness * 1  2/19 (10.53%)  2 2/19 (10.53%)  2 2/20 (10.00%)  4
Dysarthria * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Headache * 1  4/19 (21.05%)  5 3/19 (15.79%)  6 2/20 (10.00%)  4
Hypokinesia * 1  1/19 (5.26%)  2 0/19 (0.00%)  0 0/20 (0.00%)  0
Lethargy * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Migraine with aura * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Presyncope * 1  0/19 (0.00%)  0 1/19 (5.26%)  2 2/20 (10.00%)  3
Radicular pain * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Restless leg syndrome * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Somnolence * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 1/20 (5.00%)  1
Syncope * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 1/20 (5.00%)  4
Psychiatric disorders       
Depressed mood * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Depression * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Depressive symptom * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Abnormal dreams * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Confusional state * 1  1/19 (5.26%)  1 0/19 (0.00%)  0 0/20 (0.00%)  0
Disorientation * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Panic attack * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Suicidal ideation * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Cough * 1  2/19 (10.53%)  2 0/19 (0.00%)  0 1/20 (5.00%)  1
Dyspnoea * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Epistaxis * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Sleep apnoe syndrome * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Skin and subcutaneous tissue disorders       
Eczema * 1  0/19 (0.00%)  0 1/19 (5.26%)  1 0/20 (0.00%)  0
Skin discolouration * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Skin lesion * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  2
Skin necrosis * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  1
Social circumstances       
Alcohol use * 1  0/19 (0.00%)  0 0/19 (0.00%)  0 1/20 (5.00%)  2
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA
Biomarker samples were included if testing done within 6 months of collection, recommendation changed to 3 months of collection during study. Included based on 6 months as per protocol to include as many samples as possible.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Jamie Mullen MD
Organization: AstraZeneca Pharmaceuticals LP
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02388295     History of Changes
Other Study ID Numbers: D0490C00023
First Submitted: March 9, 2015
First Posted: March 17, 2015
Results First Submitted: June 23, 2017
Results First Posted: September 25, 2017
Last Update Posted: September 25, 2017