Clinical Trial Results:
A Phase 2a Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel-group Safety and Tolerability Study of PQ912 in Subjects with Early Alzheimer’s Disease (SAPHIR)
Summary
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EudraCT number |
2014-001967-11 |
Trial protocol |
NL FI DE SE BE ES |
Global end of trial date |
22 Sep 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Apr 2018
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First version publication date |
12 Apr 2018
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PBD 01071
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02389413 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Probiodrug AG
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Sponsor organisation address |
Weinbergweg 22, Halle, Germany, 06120
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Public contact |
Suzanne Bruins, Probiodrug AG, 0049 3455559900, info@probiodrug.de
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Scientific contact |
Suzanne Bruins, Probiodrug AG, 0049 3455559900, info@probiodrug.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Apr 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Apr 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Sep 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study is to assess the safety and tolerability of multiple doses of PQ912 compared with placebo in subjects with early stage AD.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Council for Harmonisation E6 Good Clinical Practice guidelines and applicable national laws and regulatory requirements. Each patient who wanted to participate needed to have a study partner (friend or relative) who also consented to the study and needed to accompany the patient at each visit. A Safety Oversight Expert was responsible for making recommendations to the Steering Committee to either continue the study unchanged, or to continue with modifications or to (temporary) stop the study, based on observed safety.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Mar 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 19
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Country: Number of subjects enrolled |
Spain: 8
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Country: Number of subjects enrolled |
Sweden: 7
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Country: Number of subjects enrolled |
Belgium: 3
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Country: Number of subjects enrolled |
Finland: 24
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Country: Number of subjects enrolled |
France: 9
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Country: Number of subjects enrolled |
Germany: 50
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Worldwide total number of subjects |
120
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EEA total number of subjects |
120
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
25
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From 65 to 84 years |
94
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85 years and over |
1
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Recruitment
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Recruitment details |
Recruitment started in March 2015 and stopped in December 2016. | |||||||||||||||
Pre-assignment
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Screening details |
Procedures at screening included documentation of medical history, physical and neurological examination, assessment of vital signs, electrocardiogram (ECG), Mini Mental State Exam (MMSE), Geriatric Depression Scale (GDS), neuropsychological test battery, Magnetic Resonance Imaging (MRI) and EEG. Blood, urine and CSF samples were collected. | |||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||
Blinding implementation details |
To preserve the blinding of the study, batch numbers for placebo and PQ912 were the same. Emergency unblinding for (S)AEs could be done through Electronic Data Capture (EDC). This option was to be used only if the subject’s wellbeing required knowledge of the subject’s treatment assignment and only after the investigator had made an effort to contact the Sponsor (or delegate). All calls resulting in unblinding were to be recorded and reported by EDC.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||
Arm description |
Subjects receiving placebo administered orally, BID, 12 weeks | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Week 1: Matching Placebo tablets.
Weeks 2-12: Matching Placebo tablets.
The tablet strength of PQ912 is 200 mg, therefore subjects were required to take 2 tablets per dosing (in Week 1) or 4 tablets per dosing (in Weeks 2-12).
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Arm title
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PQ912 | |||||||||||||||
Arm description |
Subjects receiving PQ912 administered orally, BID, 12 weeks | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
PQ912
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Week 1: PQ912 400 mg BID (total daily dose 800 mg).
Weeks 2-12: PQ912 800 mg BID (total daily dose 1600 mg).
The tablet strength of PQ912 is 200 mg, therefore subjects were required to take 2 tablets per dosing (in Week 1) or 4 tablets per dosing (in Weeks 2-12).
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects receiving placebo administered orally, BID, 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PQ912
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Reporting group description |
Subjects receiving PQ912 administered orally, BID, 12 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects receiving placebo administered orally, BID, 12 weeks | ||
Reporting group title |
PQ912
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Reporting group description |
Subjects receiving PQ912 administered orally, BID, 12 weeks |
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End point title |
Safety primary composite endpoint | |||||||||||||||||||||
End point description |
The safety primary composite endpoint was based on:
• Discontinuation of a subject due to SAE
• Discontinuation of a subject due to AE with severity ≥ grade 3 according to CTCAE
• Discontinuation of a subject due to an extreme laboratory parameter
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End point type |
Primary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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Statistical analysis title |
Composite Safety | |||||||||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||||||||||||||
P-value |
= 0.027 | |||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.02 | |||||||||||||||||||||
upper limit |
0.18 | |||||||||||||||||||||
Notes [1] - RR was not possible since 1 cell was zero. |
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Statistical analysis title |
Discontinuation subject due to SAE | |||||||||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | |||||||||||||||||||||
P-value |
= 0.027 | |||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.02 | |||||||||||||||||||||
upper limit |
0.18 | |||||||||||||||||||||
Notes [2] - RR was not possible since 1 cell was zero . |
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Statistical analysis title |
Discontinuation subject due to AE ≥ CTCAE Grade 3 | |||||||||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | |||||||||||||||||||||
P-value |
= 0.027 | |||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.02 | |||||||||||||||||||||
upper limit |
0.18 | |||||||||||||||||||||
Notes [3] - RR was not possible since 1 cell was zero. |
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Statistical analysis title |
Discontinuation subject due to extreme lab value | |||||||||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | |||||||||||||||||||||
P-value |
= 1 | |||||||||||||||||||||
Method |
Fisher exact | |||||||||||||||||||||
Parameter type |
Risk difference (RD) | |||||||||||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0 | |||||||||||||||||||||
upper limit |
0 | |||||||||||||||||||||
Notes [4] - RR was not possible since both cells were zero. |
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End point title |
Tolerability primary composite endpoint | |||||||||||||||
End point description |
A composite tolerability endpoint composed of:
1) The number of subjects who experienced a dose adjustment, defined as a reduction of dose from 800 BID to 400 BID, and
2) The number of subjects experiencing non-adherence to randomized treatment, defined as using less than 75% of the prescribed dose in 4 consecutive weeks including at least one week with less than 50%, or three or more consecutive days in total or seven days of interrupted use during the full 12 weeks.
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End point type |
Primary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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Statistical analysis title |
Composite tolerability | |||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.001 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
4.5
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
2 | |||||||||||||||
upper limit |
10.11 | |||||||||||||||
Statistical analysis title |
Dose adjustment during treatment period | |||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
= 1 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
0.31 | |||||||||||||||
upper limit |
3.28 | |||||||||||||||
Statistical analysis title |
Non-adherence to randomised treatment | |||||||||||||||
Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
120
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||
P-value |
< 0.001 | |||||||||||||||
Method |
Fisher exact | |||||||||||||||
Parameter type |
Risk ratio (RR) | |||||||||||||||
Point estimate |
13
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
3.23 | |||||||||||||||
upper limit |
52.35 |
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End point title |
Number of SAEs | ||||||||||||
End point description |
The number of SAEs occurring during the study was recorded.
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End point type |
Secondary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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No statistical analyses for this end point |
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End point title |
Number of AEs with severity ≥ grade 3 according to CTCAE | ||||||||||||
End point description |
The number of AEs with severity ≥ grade 3 according to CTCAE occurring during the study was recorded.
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End point type |
Secondary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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No statistical analyses for this end point |
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End point title |
Time to dose adjustment (time in days after randomisation) | |||||||||||||||
End point description |
The time to dose adjustment (time in days after randomisation) was recorded during the study. Dose adjustment, i.e. reduction, was defined as a reduction of dose from 800 mg BID to 400 mg BID. If applicable, median survival time is reported. Median survival time cannot be assessed because less than 50 % of subjects showed an event before the end of study. In this case, 0 = NA.
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End point type |
Secondary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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Attachments |
Time to dose adjustment |
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No statistical analyses for this end point |
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End point title |
Time to non-adherence (time in weeks after randomisation) | |||||||||||||||
End point description |
Time to non-adherence (time in weeks after randomisation) was recorded during the study. Non-adherence was defined as using <75% of the prescribed dose in 4 consecutive weeks including at least 1 week with <80%, or ≥3 consecutive days in total or 7 days of interrupted use during the full 12 weeks. If applicable, median survival time is reported. Median survival time cannot be assessed because less than 50 % of subjects showed an event before the end of study. In this case, 0 = NA.
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End point type |
Secondary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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Attachments |
Untitled (Filename: Figure 14.4.2.jpg) |
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No statistical analyses for this end point |
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End point title |
Time to non-adherence, dose adjustment, discontinuation due to SAE, AE-CTCAE3+ or extreme lab (time in weeks after randomisation). | |||||||||||||||
End point description |
Time to non-adherence, dose adjustment, discontinuation due to SAE, AE-CTCAE3+ or extreme laboratory values were recorded during the study. Dose adjustment, i.e. reduction, was defined as a reduction of dose from 800 mg BID to 400 mg BID. Non-adherence was defined as using <75% of the prescribed dose in 4 consecutive weeks including at least 1 week with <80%, or ≥3 consecutive days in total or 7 days of interrupted use during the full 12 weeks. If applicable, median survival time is reported. In this case, 0 = NA.
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End point type |
Secondary
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End point timeframe |
From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
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Attachments |
Time to event |
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No statistical analyses for this end point |
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End point title |
Glutaminyl cyclase (QC) activity in cerebrospinal fluid (CSF) | |||||||||||||||||||||
End point description |
QC activity is the primary target of the QC inhibitor PQ912.
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End point type |
Secondary
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End point timeframe |
CSF samples for biomarker assessment were obtained at screening and V5/End-of-treatment (EoT) visits.
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Statistical analysis title |
QC activity | |||||||||||||||||||||
Statistical analysis description |
An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
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Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
67
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Analysis specification |
Pre-specified
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Analysis type |
superiority [5] | |||||||||||||||||||||
P-value |
< 0.001 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
mean difference in log-transformed value | |||||||||||||||||||||
Point estimate |
-0.454
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.507 | |||||||||||||||||||||
upper limit |
-0.4 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.027
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Notes [5] - 65 subjects were included in this Per Protocol (PP) analysis. |
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End point title |
Target Occupancy (TO) [6] | ||||||||||
End point description |
The target of PQ912, the QC enzyme, is present in the CSF and its activity can be measured ex vivo in CSF samples. Based on the measured QC activities pre- and post-dosing the TO can be calculated. The TO will give important information about the dose-relatedness of QC inhibition as a prerequisite for any effect on disease related pathological pathways and on cognition. TO was calculated for CSF samples taken within 24 hours after last intake at Visit 5/EOT, where the corresponding QC activity at screening was available. Measurement of QC activity in vitro required a sample dilution and is sensitive to substrate concentration relative to Michaelis Menten constant (Km).
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End point type |
Secondary
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End point timeframe |
CSF samples for biomarker assessment were obtained at screening and V5/End-of-treatment (EoT) visits.
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: TO was not calculated for the placebo group. |
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No statistical analyses for this end point |
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End point title |
pGlu-A-beta oligomer | |||||||||||||||||||||
End point description |
The production of the toxic species pGlu-A-beta might be reduced by using the QC inhibitor PQ 912 and was therefore selected as biomarker in this study.
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End point type |
Secondary
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End point timeframe |
CSF samples for biomarker assessment were obtained at screening and V5/E0T visits.
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Notes [7] - 25 subjects were analysed at baseline and for change over time, 26 subjects were analysed at EoT |
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Statistical analysis title |
pGlu-A-beta oligomer | |||||||||||||||||||||
Statistical analysis description |
The data was dichotomized (yes/no LLOQ), reported in cross tables for baseline and EOT assessments per group and analysed using Mantel Haenszel statistics with treatment andV5/EOT as variables and V1 as confounder.
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Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
67
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [8] | |||||||||||||||||||||
P-value |
= 0.369 | |||||||||||||||||||||
Method |
Mantel-Haenszel | |||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||
Point estimate |
1.76
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
0.51 | |||||||||||||||||||||
upper limit |
6.04 | |||||||||||||||||||||
Notes [8] - 68 subjects were included in this PP analysis |
|
||||||||||||||||||||||
End point title |
Neurogranin | |||||||||||||||||||||
End point description |
Neurogranin is a biomarker associated with synaptic dysfunction. Increases are seen in patients with AD.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
CSF samples for biomarker assessment were obtained at screening and V5/EoT visits.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [9] - 41 subjects were analysed at baseline and EoT, 40 subjects were analysed for change over time |
||||||||||||||||||||||
Statistical analysis title |
Neurogranin | |||||||||||||||||||||
Statistical analysis description |
An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
|
|||||||||||||||||||||
Comparison groups |
Placebo v PQ912
|
|||||||||||||||||||||
Number of subjects included in analysis |
67
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [10] | |||||||||||||||||||||
P-value |
= 0.194 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
mean difference in log-transformed value | |||||||||||||||||||||
Point estimate |
-0.021
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.054 | |||||||||||||||||||||
upper limit |
0.011 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.016
|
|||||||||||||||||||||
Notes [10] - 64 subjects were included in this PP analysis |
|
||||||||||||||||||||||
End point title |
YKL40 | |||||||||||||||||||||
End point description |
YKL-40, a marker of astrocyte activation (inflammation), has been shown to be increased in subjects with AD and mild cognitive impairment due to AD, compared to matched controls and is evaluated for its potential as therapeutic marker.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
CSF samples for biomarker assessment were obtained at screening and V5/EoT visits.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Notes [11] - 41 subjects were analysed at baseline and EoT, 40 subjects were analysed for change over time |
||||||||||||||||||||||
Statistical analysis title |
YKL40 | |||||||||||||||||||||
Statistical analysis description |
An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
|
|||||||||||||||||||||
Comparison groups |
Placebo v PQ912
|
|||||||||||||||||||||
Number of subjects included in analysis |
67
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [12] | |||||||||||||||||||||
P-value |
= 0.025 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
mean difference in log-transformed value | |||||||||||||||||||||
Point estimate |
-0.032
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.059 | |||||||||||||||||||||
upper limit |
-0.004 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.014
|
|||||||||||||||||||||
Notes [12] - 64 subjects were included in this PP analysis |
|
||||||||||||||||||||||
End point title |
Relative theta power | |||||||||||||||||||||
End point description |
It has been widely established that in AD, eyes closed resting state EEG shows distinct changes reflecting abnormalities of brain oscillatory activity. In the earliest phase of AD, especially in late onset AD as opposed to young onset AD (< 65 years), the EEG can be normal. With progression of the disease, there is a gradual, diffuse slowing of brain activity. First, theta power increases and beta power decreases, followed by slowing and diminished reactivity of the alpha peak frequency. In later stages, alpha power decreases and finally delta power increases. An increase in relative theta power is thus regarded as the most sensitive oscillatory activity marker in the earliest stages of AD.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
EEG endpoints were assessed at screening and V5/EoT visits.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Relative theta power | |||||||||||||||||||||
Statistical analysis description |
An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
|
|||||||||||||||||||||
Comparison groups |
Placebo v PQ912
|
|||||||||||||||||||||
Number of subjects included in analysis |
76
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [13] | |||||||||||||||||||||
P-value |
= 0.002 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
mean difference in log-transformed value | |||||||||||||||||||||
Point estimate |
-0.07
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.114 | |||||||||||||||||||||
upper limit |
-0.026 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.022
|
|||||||||||||||||||||
Notes [13] - 74 subjects were included in this PP analysis |
|
||||||||||||||||||||||
End point title |
One Back Test | |||||||||||||||||||||
End point description |
The One Back Test is designed to assess working memory.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Neuropsychological endpoints were assessed at screening, baseline and V5/EoT visits.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
One Back Test | |||||||||||||||||||||
Statistical analysis description |
An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
|
|||||||||||||||||||||
Comparison groups |
Placebo v PQ912
|
|||||||||||||||||||||
Number of subjects included in analysis |
91
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other [14] | |||||||||||||||||||||
P-value |
= 0.144 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
mean difference in log-transformed value | |||||||||||||||||||||
Point estimate |
-0.027
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.063 | |||||||||||||||||||||
upper limit |
0.009 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.018
|
|||||||||||||||||||||
Notes [14] - 88 subjects were included in this PP analysis |
|
||||||||||||||||||||||
End point title |
Detection Test | |||||||||||||||||||||
End point description |
The Detection Test is designed to assess psychomotor speed.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Neuropsychological endpoints were assessed at screening, baseline and V5/EoT visits.
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Detection Test | |||||||||||||||||||||
Statistical analysis description |
An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
|
|||||||||||||||||||||
Comparison groups |
Placebo v PQ912
|
|||||||||||||||||||||
Number of subjects included in analysis |
91
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other [15] | |||||||||||||||||||||
P-value |
= 0.397 | |||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||
Parameter type |
mean difference in log-transformed value | |||||||||||||||||||||
Point estimate |
-0.025
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.083 | |||||||||||||||||||||
upper limit |
0.033 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.029
|
|||||||||||||||||||||
Notes [15] - 88 subjects were included in this PP analysis |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From screening to end of study. Screening to randomization: between 4 and 12 weeks. Randomization to end of study: 16 weeks.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Note: the frequency threshold is => 3 subjects (2.5%) reporting in total.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects receiving placebo administered orally, BID, 12 weeks. All non-serious adverse events reported here are treatment-emergent. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PQ912
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects receiving PQ912 administered orally, BID, 12 weeks. All non-serious adverse events reported here are treatment-emergent. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
05 Dec 2014 |
Reason for amendment: Protocol has been updated after comments from regulatory authorities
Main changes:
- Statistical considerations section updated to be aligned with protocol
- Baseline MRI, EEG and Lumbar Puncture moved to Screening MRI, EEG and Lumbar Puncture
- Added to the protocol that treatment with Standard of Care AD treatment may be started during the course of the study in case of clinical worsening
- Hepatitis A and C assessments in blood added
|
||
12 Feb 2015 |
Reason for amendment: Protocol has been updated after comments from regulatory authorities.
Main changes:
- Definition of primary safety endpoint (composite endpoint) made more clear
- Added information on the power calculations
- Clarified that in Sweden no study partner would be used
- Clarification on dose-adjustments during the study
- GnRH and TRH measurements were added |
||
08 Dec 2015 |
Reason for amendment: to improve recruitment/eligibility and changed on request of regulatory authorities
Main changes:
- The per patient screening period extended
- To allow for re-screening
- Tau/A-beta ratio added to inclusion criteria
- Use of Souvenaid is allowed
- Added: precautionary measures due to photo toxicity
- Added prohibited mediation for inclusion |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |