Clinical Trial Results:
A randomized controlled clinical trial for assessing the effectiveness of pharmacogenetic information obtained with NEUROFARMAGEN in the treatment of patients with mental disorders
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Summary
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EudraCT number |
2013-002228-18 |
Trial protocol |
ES |
Global end of trial date |
05 Dec 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Jun 2022
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First version publication date |
11 Jun 2022
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Other versions |
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Summary report(s) |
Perez 2017 PMID 28705252 AB-GEN-2013 Summary AB-GEN-2013 Clinical Study Report AB-GEN-2013 Statistical Report |
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 |
AB-GEN-2013
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02529462 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AB-BIOTICS S.A.
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Sponsor organisation address |
Av. De la Torre Blanca, 57, Sant Cugat del Vallès, Spain, 08172
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Public contact |
Ariana Salavert, AB-BIOTICS, 0034 935946024, salavert@ab-biotics.com
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Scientific contact |
Ariana Salavert, AB-BIOTICS, 0034 935946024, salavert@ab-biotics.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 |
17 Mar 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Oct 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Dec 2016
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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 assess NEUROFARMAGEN test effectiveness in selecting drug treatments for mental disorders (major depressive disorder, bipolar disorder, schizophrenia and obsessive-compulsive disorder) by the proportion of patients achieving sustained response over a period of six months. Sustained response is considered when the patient gets a PGI-I of 2 points or less in two consecutive assessments after the last change in treatment.
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Protection of trial subjects |
The study was assessed by the IRB of Hospital Clínic de Barcelona as the centralized reference IRB,
as well as the IRB of each participating hospital. The study was conducted in compliance with Good Clinical Practice requirements and the Declaration of Helsinki. Written informed consent was obtained from all participants before enrolment.
An electronic case report form (eCRF) with remote access was designed with security protocols. This system met general and specific good clinical practice guidelines and the highest possible computerised system validation requirements with restricted and personalised access for each user (data manager, monitor, investigators, etc.). All data was collected and managed in strict compliance with Organic Law 15/1999 of 13 December, on Personal data protection.
The eCRF did not identify subjects by their name or initials or any other variable that may lead to their identification, such as their date of birth. The only acceptable identification that appeared on the eCRF or other documents was the unique subject identification number.
Patients were informed Tthat his/her participation in the study is completely free and voluntary and that he/she can withdraw from the study at any time.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jul 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
Spain: 316
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Worldwide total number of subjects |
316
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EEA total number of subjects |
316
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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) |
272
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From 65 to 84 years |
42
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85 years and over |
2
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Recruitment
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Recruitment details |
Five hundred and twenty patients (both outpatients and inpatients) were enrolled from 18 hospitals and associated mental health centers in Spain from July 29, 2014 to June 15, 2015. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Screening visit (week -4): fulfillment of eligibility criteria, collection of saliva sample to obtain the pharmacogenetic data. N = 520. Randomization visit (week 0): fulfillment of the entry criteria. N = 316 | |||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
520 [1] | |||||||||||||||||||||
Number of subjects completed |
316 | |||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Incorrectly randomized: 105 | |||||||||||||||||||||
Reason: Number of subjects |
Not meeting eligibility criteria: 99 | |||||||||||||||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: This trial had a screening visit (pre-baseline, week -4) to recruit patient meeting eligibility criteria and willing to participate, who needed to provide a saliva sample to genotype them so that those falling in the intervention group at the baseline (randomization, week 0) could have their pharamcogenetic information available. That is why 520 entered the study at the screening visit but only 316 still met eligibility criteria and were randomized at baseline. |
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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 |
Single blind [2] | |||||||||||||||||||||
Roles blinded |
Subject, Monitor | |||||||||||||||||||||
Blinding implementation details |
Both patients and telephone interviewers who assessed the main variable were blind to the patient allocation (intervention or control group). The treating psychiatrists had access to the results of NEUROFARMAGEN at baseline for the patients in the study group, and at the final visit for the control patient group.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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NEUROFARMAGEN-guided treatment (intervention group) | |||||||||||||||||||||
Arm description |
In the intervention group, the treating psychiatrists had the results of the NEUROFARMAGEN genetic test as supporting information to help them select the treatment for the patient. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
NEUROFARMAGEN (pharmacogenetic test)
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Investigational medicinal product code |
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Other name |
NEUROPHARMAGEN
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Pharmaceutical forms |
Mouthwash
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Routes of administration |
Other use
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Dosage and administration details |
The product under investigation (NEUROFARMAGEN) is a pharmacogenetic test developed by AB-BIOTICS that enables the analysis of genetic polymorphisms related to the pharmacokinetics and pharmacodynamics of multiple psychoactive drugs. A saliva sample of the patients, obtained by means of a liquid saliva collector, was needed to genotype them and obtain a pharmacogenetic report. In the intervention arm, treating psychiatrists had access to the pharmacogenetic results to guide the choice the the patient's pharmacological treatment.
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Arm title
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Treatment as Usual (Control group) | |||||||||||||||||||||
Arm description |
In the control patient group, patients were selected and prescribed pharmacological treatment to treat major depression in accordance with routine clinical practice. | |||||||||||||||||||||
Arm type |
No intervention | |||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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| Notes [2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: Both patients and phone interviewers who assessed the main variable were blind to the patient allocation (intervention or control group). The treating psychiatrists/investigators, who assessed patients' clinical status in this trial, had access to the results of NEUROFARMAGEN at baseline for the patients in the study group so that they could prescribe a treatment according to NEUROFARMAGEN. Thus, it is a single blinded trial with a second evaluators for the main variable who is also blind. |
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Baseline characteristics reporting groups
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Reporting group title |
NEUROFARMAGEN-guided treatment (intervention group)
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Reporting group description |
In the intervention group, the treating psychiatrists had the results of the NEUROFARMAGEN genetic test as supporting information to help them select the treatment for the patient. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Treatment as Usual (Control group)
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Reporting group description |
In the control patient group, patients were selected and prescribed pharmacological treatment to treat major depression in accordance with routine clinical practice. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intention-to-Treat (ITT)
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The intention-to-treat (ITT) population analysed 316 patients and the per protocol (PP) population
analysed 237 patients. The percentage of participants not randomised and lost to follow-up was
higher than expected. For this reason, the low number of patients included in PP population did
not ensure that the test had high statistical power. Thus, the results reported herein are based on
the ITT population.
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End points reporting groups
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Reporting group title |
NEUROFARMAGEN-guided treatment (intervention group)
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Reporting group description |
In the intervention group, the treating psychiatrists had the results of the NEUROFARMAGEN genetic test as supporting information to help them select the treatment for the patient. | ||
Reporting group title |
Treatment as Usual (Control group)
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Reporting group description |
In the control patient group, patients were selected and prescribed pharmacological treatment to treat major depression in accordance with routine clinical practice. | ||
Subject analysis set title |
Intention-to-Treat (ITT)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intention-to-treat (ITT) population analysed 316 patients and the per protocol (PP) population
analysed 237 patients. The percentage of participants not randomised and lost to follow-up was
higher than expected. For this reason, the low number of patients included in PP population did
not ensure that the test had high statistical power. Thus, the results reported herein are based on
the ITT population.
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End point title |
Sustained response to treatment (accordig to PGI-I) | ||||||||||||||||||||||||
End point description |
The PGI-I scale (Patient Global Impression of Improvement) reports the patient's own assessment of improvement after the therapeutic interventions. It is a single-item questionnaire that assesses the change experienced using a 7-point Likert scale that runs from 1 (very much better) to 7 (very much worse). A sustained response will be considered when the patient reports a PGI-I score of 2 or less, on at least two consecutive assessments, maintained until the end of the follow-up.
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End point type |
Primary
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End point timeframe |
12 weeks
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Statistical analysis title |
Sustained Response at 12 weeks | ||||||||||||||||||||||||
Statistical analysis description |
Differences between the intervention and control groups with regards to the number of patients with at least two consecutive evaluations by phone interview with a PGI-I score of 2 or less after the last change of treatment.
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Comparison groups |
Treatment as Usual (Control group) v NEUROFARMAGEN-guided treatment (intervention group)
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Number of subjects included in analysis |
294
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||||||||
Method |
Chi-squared | ||||||||||||||||||||||||
Confidence interval |
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End point title |
Response to treatment (according to PGI-I) | ||||||||||||||||||
End point description |
The PGI-I scale (Patient Global Impression of Improvement) reports the patient's own assessment of improvement after the therapeutic interventions. It is a single-item questionnaire that assesses the change experienced using a 7-point Likert scale that runs from 1 (very much better) to 7 (very much worse). A patient was considered a responder when reporting a PGI-I score of 2 or less (i.e. "much better"/"very much better").
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Response at 12 weeks | ||||||||||||||||||
Comparison groups |
NEUROFARMAGEN-guided treatment (intervention group) v Treatment as Usual (Control group)
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Number of subjects included in analysis |
280
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
< 0.05 | ||||||||||||||||||
Method |
Chi-squared | ||||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||||
Point estimate |
1.62
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
1 | ||||||||||||||||||
upper limit |
2.61 | ||||||||||||||||||
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End point title |
Response to treatment (according to HDRS-17) | ||||||||||||
End point description |
HDRS-17 rates the clinical severity of depression. It has 17 questions, each with three to five possible answers, with scores ranging from 0 to 2 or from 0 to 4, respectively. The total score ranges from 0 to 52 and cut-off scores can be used to classify the depressive disorder. The analysis of the response to treatment according the the HDRS-17 sought to find statystical differences between study groups in terms of score change in this scale from baseline to the end of the study.
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Response at 12 weeks | ||||||||||||
Comparison groups |
NEUROFARMAGEN-guided treatment (intervention group) v Treatment as Usual (Control group)
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Number of subjects included in analysis |
280
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.1 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
1.57
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.18 | ||||||||||||
upper limit |
3.32 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.89
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End point title |
Burden of Side Effects | ||||||||||||
End point description |
The Burden domain consists of 1 questions with scores ranging from 0 (no side effects / no impairment) to 6 (intolerable / unable to function / present all of the time). The aim was to compare the number of subjects in the study and control groups with a score equal or lower than 2 (i.e., tolerated pharmacological treatment).
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End point type |
Secondary
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End point timeframe |
12 weeks
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Statistical analysis title |
Response at 12 weeks | ||||||||||||
Comparison groups |
NEUROFARMAGEN-guided treatment (intervention group) v Treatment as Usual (Control group)
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Number of subjects included in analysis |
281
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.56
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-1 | ||||||||||||
upper limit |
-0.12 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.22
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Adverse events information [1]
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Timeframe for reporting adverse events |
Adverse events regardless of causality were collected for all patients from the time of signature of informed consent (screening visit, week -4) throughout the follow-up period (end of the study, week 12).
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Adverse event reporting additional description |
All Adverse Events (AEs) starting after baseline were recorded on the case report form by the investigators, and included: start date, severity, causality with the drug, actions taken with regards to treatment, date and resolution of AE, unexpected and/or serious AE.
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||
Dictionary version |
16.0
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| Frequency threshold for reporting non-serious adverse events: 5% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Adverse events are reported in table 25 and table 26 of the Clinical Trial Report (attached document) |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| Main limitations: - majority of patients of Caucasian origin - primary variable measured with a simple patient-rated scale (PGI-I) | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/2870525 http://www.ncbi.nlm.nih.gov/pubmed/29728861 http://www.ncbi.nlm.nih.gov/pubmed/31480800 |
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