Clinical Trial Results:
A Phase 2 Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study to Evaluate Pharmacodynamic Effects, Safety, Tolerability, and Pharmacokinetics of Multiple Oral Doses of TAK-831 in Adult Subjects With Schizophrenia
Summary
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EudraCT number |
2017-001739-38 |
Trial protocol |
GB |
Global end of trial date |
21 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
25 May 2022
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First version publication date |
25 May 2022
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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 |
TAK-831-2001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03359785 | ||
WHO universal trial number (UTN) |
U1111-1197-9766 | ||
Other trial identifiers |
NRES number: 17/YH/0196 | ||
Sponsors
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Sponsor organisation name |
Neurocrine Biosciences, Inc.
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Sponsor organisation address |
12780 El Camino Real, San Diego, United States, CA 92130
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Public contact |
Neurocrine Medical Information, Neurocrine Biosciences, Inc., medinfo@neurocrine.com
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Scientific contact |
Neurocrine Medical Information, Neurocrine Biosciences, Inc., medinfo@neurocrine.com
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Sponsor organisation name |
Takeda Development Centre Europe Ltd
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Sponsor organisation address |
61 Aldwych, London, United Kingdom, WC2B 4AE
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Public contact |
For contact information, see Neurocrine Biosciences, Inc., medinfo@neurocrine.com
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Scientific contact |
For contact information, see Neurocrine Biosciences, Inc., medinfo@neurocrine.com
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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 |
21 Dec 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Dec 2020
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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 |
To determine whether luvadaxistat (TAK-831) is superior to placebo in improving cerebellar function as measured with the average percentage of conditioned responses during the eyeblink conditioning (EBC) test.
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Protection of trial subjects |
The study was conducted in accordance with Takeda standards that meet regulations relating to Good Clinical Practice (GCP). The study was conducted in full compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use GCP guidelines and with the laws and regulations of the countries in which the study was conducted.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Jan 2018
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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 |
United States: 31
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Worldwide total number of subjects |
31
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EEA total number of subjects |
0
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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) |
31
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This 2-period cross-over study assessed the pharmacodynamic (PD) effects, safety, tolerability and pharmacokinetics (PK) of multiple oral doses of luvadaxistat given once daily (QD) in adult subjects with schizophrenia. Effects of 2 dose levels of luvadaxistat (500 milligrams [mg] and 50 mg) or placebo were assessed. | |||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
The study consisted of a screening period (30 days), treatment period 1 (8 days), washout (14 to 21 days), treatment period 2 (8 days) and a safety follow-up visit. 17 subjects were randomized to 1 of 2 sequences comparing luvadaxistat 500 mg to placebo and 14 subjects were randomized to 1 of 2 sequences comparing luvadaxistat 50 mg to placebo. | |||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (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 | |||||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Luvadaxistat 500 mg, then Placebo | |||||||||||||||||||||||||||||||||||
Arm description |
Subjects first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 1. | |||||||||||||||||||||||||||||||||||
Arm type |
Cross-over (experimental & placebo) | |||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Luvadaxistat
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Investigational medicinal product code |
TAK-831
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Other name |
NBI-1065844
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
In treatment period 1, subjects received luvadaxistat QD, administered as 5 oral tablets of 100 mg each.
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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 |
In treatment period 2, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.
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Arm title
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Placebo, then Luvadaxistat 500 mg | |||||||||||||||||||||||||||||||||||
Arm description |
Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 2. | |||||||||||||||||||||||||||||||||||
Arm type |
Cross-over (experimental & 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 |
In treatment period 1, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.
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Investigational medicinal product name |
Luvadaxistat
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Investigational medicinal product code |
TAK-831
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Other name |
NBI-1065844
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
In treatment period 2, subjects received luvadaxistat QD, administered as 5 oral tablets of 100 mg each.
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Arm title
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Luvadaxistat 50 mg, then Placebo | |||||||||||||||||||||||||||||||||||
Arm description |
Subjects first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 3. | |||||||||||||||||||||||||||||||||||
Arm type |
Cross-over (experimental & placebo) | |||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Luvadaxistat
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Investigational medicinal product code |
TAK-831
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Other name |
NBI-1065844
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
In treatment period 1, subjects received luvadaxistat QD, administered as 5 oral tablets of 10 mg each.
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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 |
In treatment period 2, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.
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Arm title
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Placebo, then Luvadaxistat 50 mg | |||||||||||||||||||||||||||||||||||
Arm description |
Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 4. | |||||||||||||||||||||||||||||||||||
Arm type |
Cross-over (experimental & 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 |
In treatment period 1, subjects received placebo QD, administered as 5 oral placebo (matching luvadaxistat) tablets.
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Investigational medicinal product name |
Luvadaxistat
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Investigational medicinal product code |
TAK-831
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Other name |
NBI-1065844
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
In treatment period 2, subjects received luvadaxistat QD, administered as 5 oral tablets of 10 mg each.
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Baseline characteristics reporting groups
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Reporting group title |
Luvadaxistat 500 mg, then Placebo
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Reporting group description |
Subjects first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 1. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo, then Luvadaxistat 500 mg
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Reporting group description |
Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Luvadaxistat 50 mg, then Placebo
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Reporting group description |
Subjects first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 3. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo, then Luvadaxistat 50 mg
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Reporting group description |
Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 4. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Luvadaxistat 500 mg, then Placebo
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Reporting group description |
Subjects first received luvadaxistat 500 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 1. | ||
Reporting group title |
Placebo, then Luvadaxistat 500 mg
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Reporting group description |
Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 500 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 2. | ||
Reporting group title |
Luvadaxistat 50 mg, then Placebo
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Reporting group description |
Subjects first received luvadaxistat 50 mg orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received matching placebo orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 3. | ||
Reporting group title |
Placebo, then Luvadaxistat 50 mg
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Reporting group description |
Subjects first received matching placebo orally QD for 8 days during treatment period 1. After a washout of 14 to 21 days, subjects then received luvadaxistat 50 mg orally QD for 8 days during treatment period 2. Also referred to as treatment sequence 4. | ||
Subject analysis set title |
Luvadaxistat 50 mg
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who received luvadaxistat 50 mg orally QD for 8 days during either treatment periods 1 or 2 of the study.
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Subject analysis set title |
Placebo (reference for luvadaxistat 50 mg)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment in this arm corresponds to subjects who received 50 mg luvadaxistat in the alternative treatment period (ie, subjects receiving 50 mg and 500 mg luvadaxistat were analyzed separately and placebo treatment was not pooled).
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Subject analysis set title |
Luvadaxistat 500 mg
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who received luvadaxistat 500 mg orally QD for 8 days during either treatment periods 1 or 2 of the study.
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Subject analysis set title |
Placebo (reference for luvadaxistat 500 mg)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment in this arm corresponds to subjects who received 500 mg luvadaxistat in the alternative treatment period (ie, subjects receiving 50 mg and 500 mg luvadaxistat were analyzed separately and placebo treatment was not pooled).
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End point title |
Change From Baseline in Average Percent of Conditioned Responses During the EBC Test at Day 8 | ||||||||||||||||||||
End point description |
EBC is a method used to investigate cerebellar-dependent learning. In EBC, a conditioned stimulus, a tone precedes but co-terminates with an unconditioned stimulus, an airpuff to the eyelid. Learning is demonstrated when an eyeblink (the conditioned response) occurs prior to the onset of the unconditioned stimulus. The percentage can range from 0% (no conditioned learning has occurred) to 100% (all responses are conditioned). Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as least squares (LS) mean change from baseline at Day 8, determined using an analysis of variance (ANOVA). The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
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End point type |
Primary
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End point timeframe |
Baseline and Day 8 of each treatment period
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Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in percent of conditioned responses during the EBC test at Day 8.
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Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
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Number of subjects included in analysis |
22
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.2401 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
0.278
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Confidence interval |
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level |
90% | ||||||||||||||||||||
sides |
1-sided
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lower limit |
-0.246 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.376
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Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in percent of conditioned responses during the EBC test at Day 8.
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Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
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Number of subjects included in analysis |
22
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.9053 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
-0.766
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Confidence interval |
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level |
90% | ||||||||||||||||||||
sides |
1-sided
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lower limit |
-1.513 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.547
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End point title |
Change From Baseline in the Mean Mismatch Negativity (MMN) at Day 8 | ||||||||||||||||||||
End point description |
MMN is an event related potential (ERP) evoked in response to unattended changes in background stimulation. MMN reflects an automatic process of detecting a mismatch between a deviant stimulus and a sensory-memory trace. Smaller amplitudes of MMN have been consistently identified in schizophrenia subjects. MMN amplitude was measured at midline frontal electrode (Fz) of electroencephalogram (EEG). Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
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End point type |
Secondary
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End point timeframe |
Baseline and Day 8 of each treatment period
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Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in MMN amplitude at Day 8.
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Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
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Number of subjects included in analysis |
25
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.0497 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
-0.908
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
- | ||||||||||||||||||||
upper limit |
-0.211 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.527
|
||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in MMN amplitude at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
30
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.8517 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
0.748
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
- | ||||||||||||||||||||
upper limit |
1.67 | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.702
|
|
|||||||||||||||||||||
End point title |
Change From Baseline in the Mean P300 Amplitude at Day 8 | ||||||||||||||||||||
End point description |
The P300 wave is an ERP component that is elicited by the presentation of a novel, behaviorally relevant target stimulus embedded among irrelevant stimuli in a manner similar to MMN but requiring active listening and responding from subjects. Auditory stimuli are presented in an oddball paradigm consisting of 1 standard tone and 1 target tone. Subjects are instructed to push a button as quickly as possible when they hear the target tone but not when they hear the standard tone. P300 reflects allocation of attention and activation of immediate memory. P300 amplitude was measured at midline parietal electrode (Pz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Day 8 of each treatment period
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in P300 target amplitude at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
24
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.9185 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
-2.627
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
-5.02 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
1.74
|
||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in P300 target amplitude at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
28
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.7193 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
-1.493
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
-4.878 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
2.5
|
|
|||||||||||||||||||||
End point title |
Change From Baseline in the Mean Auditory Steady State Response (ASSR) at Day 8 | ||||||||||||||||||||
End point description |
ASSRs are evoked oscillatory responses that are entrained to the frequency and phase of temporally modulated stimuli. Individuals with schizophrenia experience subjective sensory anomalies and objective deficits on assessment of sensory function. These deficits can be produced by abnormal signaling in the sensory pathways and sensory cortex or by later-stage disturbances in the cognitive processing of such inputs. ASSR can be used to assess the integrity of sensory pathways including cortical processing. The ASSR applied a frequency stimulus of 40 hertz (Hz) and was measured at midline central electrode (Cz) of EEG. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 8, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Day 8 of each treatment period
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in ASSR at 40 Hz stimulation at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
25
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.0561 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
18.417
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
3.87 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
10.7
|
||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in ASSR at 40 Hz stimulation at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
29
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.4954 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
0.208
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
-24.409 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
17.6
|
|
|||||||||||||||||||||
End point title |
Change from Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 7 | ||||||||||||||||||||
End point description |
BACS is a cognition assessment battery and includes brief assessments of reasoning and problem solving, verbal fluency, attention, verbal memory, working memory and motor speed. The primary measure from each test is standardized by creating z-scores whereby the mean of the test session of a healthy person is set to 0 and the standard deviation set to 1. A composite score was calculated by averaging the 4 measures from the BACS used in the study and then calculating a z-score of the composite. The composite z-score indicates how much higher or lower the subject’s cognition is compared to a healthy person. Baseline was defined as the last observation prior to the dose of study treatment in the corresponding period. Results are reported as LS mean change from baseline at Day 7, determined using an ANOVA. The PD set consisted of all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-dose PD result.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Day 7 of each treatment period
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline on the BACS composite score at Day 7.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
24
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.799 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
-2.495
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
-6.426 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
2.83
|
||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline on the BACS composite score at Day 7.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
30
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.004 | ||||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
5.771
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
3.132 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
2.01
|
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline in the Mean Plasma Concentrations of D-serine and L-serine at Day 8 | ||||||||||||||||||||||||||||||
End point description |
Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and L-serine were measured. Results are reported as LS mean change from baseline at Day 8, determined using a mixed model for repeated measures (MMRM). The PK analysis set included all randomized subjects who received at least 1 dose of study treatment and who had any available plasma concentration data.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Samples were collected on Day 1 (pre-dose and 3 to 6 hours post-dose), Day 7 (pre-dose and 3 to 6 hours post-dose) and Day 8 (pre-dose).
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||||||||||||
Statistical analysis description |
Change from baseline in plasma concentrations of D-serine at Day 8.
|
||||||||||||||||||||||||||||||
Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
24
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
0.0411
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||||||||||||
lower limit |
0.03 | ||||||||||||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||||||||
Dispersion value |
0.00836
|
||||||||||||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||||||||||||
Statistical analysis description |
Change from baseline in plasma concentrations of D-serine at Day 8.
|
||||||||||||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
30
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
0.0377
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||||||||||||
lower limit |
0.0264 | ||||||||||||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||||||||
Dispersion value |
0.00861
|
||||||||||||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||||||||||||
Statistical analysis description |
Change from baseline in plasma concentrations of L-serine at Day 8.
|
||||||||||||||||||||||||||||||
Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
24
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
= 0.0219 | ||||||||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
1.21
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||||||||||||
lower limit |
0.466 | ||||||||||||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||||||||
Dispersion value |
0.562
|
||||||||||||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||||||||||||
Statistical analysis description |
Change from baseline in plasma concentrations of L-serine at Day 8.
|
||||||||||||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
30
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||
P-value |
= 0.8782 | ||||||||||||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||||||||||||
Point estimate |
-0.784
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
90% | ||||||||||||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.65 | ||||||||||||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||||||||||||
Dispersion value |
0.658
|
|
|||||||||||||||||||||
End point title |
Change From Baseline in the Mean Plasma D-serine to Total Serine Ratio at Day 8 | ||||||||||||||||||||
End point description |
Blood samples were collected at pre-specified timepoints and plasma concentrations of D-serine and total serine were measured. Plasma D-serine to total serine ratios were then calculated. Results are reported as LS mean change from baseline at Day 8, determined using a MMRM. The PK analysis set included all randomized subjects who received at least 1 dose of study treatment and who had any available plasma concentration data.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline and Day 8 of each treatment period
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 50 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in plasma D-serine to total serine ratio at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 50 mg v Placebo (reference for luvadaxistat 50 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
24
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.0206 | ||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
0.00234
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
0.000925 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.00107
|
||||||||||||||||||||
Statistical analysis title |
Luvadaxistat 500 mg Compared with Placebo | ||||||||||||||||||||
Statistical analysis description |
Change from baseline in plasma D-serine to total serine ratio at Day 8.
|
||||||||||||||||||||
Comparison groups |
Luvadaxistat 500 mg v Placebo (reference for luvadaxistat 500 mg)
|
||||||||||||||||||||
Number of subjects included in analysis |
30
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.0006 | ||||||||||||||||||||
Method |
MMRM | ||||||||||||||||||||
Parameter type |
LS Mean Difference | ||||||||||||||||||||
Point estimate |
0.00499
|
||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
level |
90% | ||||||||||||||||||||
sides |
1-sided
|
||||||||||||||||||||
lower limit |
0.00321 | ||||||||||||||||||||
upper limit |
- | ||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||||||
Dispersion value |
0.00135
|
|
|||||||||||||||||||||||||||||||
End point title |
Mean Plasma Concentration of Luvadaxistat | ||||||||||||||||||||||||||||||
End point description |
Blood samples were collected at pre-specified timepoints and plasma concentrations of luvadaxistat were measured. The PK analysis set included all randomized subjects who received at least 1 dose of study treatment and who had any available luvadaxistat plasma concentration data. Here 'n' refers to number of subjects analyzed at each timepoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Samples were collected on Day 1 (pre-dose and at 0.25 to 2 hours and 3 to 6 hours post-dose), Day 7 (pre-dose and at 0.25 to 2 hours and 3 to 6 hours post-dose) and Day 8 (pre-dose).
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
8-day treatment period for each of treatment periods 1 and 2 (separated by washout of up to 21 days) and up to 30 days follow-up after last dose of study treatment. Up to a maximum of 67 days for overall timeframe.
|
||||||||||||||||||||||||||||
Adverse event reporting additional description |
Treatment-emergent adverse events were defined as adverse events that occurred after the first dose of study treatment and up to 30 days after the last dose or early termination. The safety analysis set included all randomized subjects who received at least 1 dose of study treatment.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects who received matching placebo orally QD for 8 days during either treatment periods 1 or 2 of the study. Placebo treatment was pooled for subjects receiving 50 mg and 500 mg luvadaxistat. | ||||||||||||||||||||||||||||
Reporting group title |
Luvadaxistat 500 mg
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Reporting group description |
Subjects who received luvadaxistat 500 mg orally QD for 8 days during either treatment periods 1 or 2 of the study. | ||||||||||||||||||||||||||||
Reporting group title |
Luvadaxistat 50 mg
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Reporting group description |
Subjects who received luvadaxistat 50 mg orally QD for 8 days during either treatment periods 1 or 2 of the study. | ||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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08 Sep 2017 |
• The primary reason for this amendment was to revise pregnancy avoidance and contraception requirements. |
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11 Oct 2017 |
• The primary reason for this amendment was to revise luvadaxistat doses to be administered (from 400 mg and 40 mg to 500 mg and 50 mg) and procedures, dose justification and update clinical experience. |
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30 May 2018 |
• The primary reason for this amendment was to eliminate the functional magnetic resonance imaging blood oxygen level-dependent imaging component. In addition to the change in study design, inclusion/exclusion criteria were modified, study treatment distribution, including subject randomization process was modified to include interactive response technology and changes were made in the schedule of assessments.
The clinical site in the UK where the study was initiated (Amendment 11 October 2017) was chosen based on its imaging capabilities. Since imaging was no longer to be conducted, a new study site (in the US) with an appropriate subject population and expertise for the modified study protocol was chosen to conduct the study. The study was initiated (Amendment 11 October 2017) at the previous site and 1 subject was enrolled and completed all assessments. The data from this subject was excluded from the current analysis as only those subjects participating in this study at the site in the US under Amendment 30 May 2018 were included.
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17 Dec 2018 |
• The primary reason for this amendment was to modify exclusion criterion 17 to separate the prespecified exclusion criteria from those based on investigator opinion. Those exclusion which were subject to investigator opinion remained in exclusion criterion 17, while those that were measurable were moved to exclusion criteria 18 through 23.
• In addition, an exploratory objective that did not have a corresponding endpoint was removed, revised the exclusion duration for any investigational drug to be consistent with the relevant exclusion criterion, clarified study design and added guidance for rescreening subjects, corrected inconsistency in randomization description and updated time of 12-lead electrocardiogram collection for ease of collection. |
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19 Sep 2019 |
• The primary reasons for this amendment were to modify inclusion criterion 10 to revise the maximum dose of quetiapine as add-on hypnotic from 100 mg to 300 mg as this increased dose was not expected to interfere with the primary and secondary endpoints and modify exclusion criterion 6 to allow rescreening of marijuana positive subjects at screening and to allow for increasing subject recruitment.
• In addition, exclusion criteria were updated to capture corrections in Amendment 17 December 2018 informed to the sites via administrative letters and statistical procedure gave precedence to the statistical analysis plan over protocol to correct the inconsistencies. |
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09 Jan 2020 |
• The primary reason for this amendment was to modify inclusion criterion 3 to revise the maximum subject age from 50 to 60 years of age, to allow for increasing subject recruitment. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
One subject was excluded from the study entirely (enrolled at a site in the UK), due to a new version of the protocol being used (Amendment 30 May 2018). Thus, only data from the site in the US were included in the current analysis. |