Attention Deficit Hyperactivity Disorder
Conditions
Brief summary
The primary objectives are to investigate the effect of atomoxetine on impulsivity after single dose and at steady state measured by the total score of Barrett Impulsiveness Scale version 11 (BIS-11) and Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale. The secondary objective is to evaluate the safety of atomoxetine.
Interventions
DRUGZentiva®
Zentiva®, oral, tablet
DRUGPlacebo
Placebo, oral, tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Male and female subjects, 18-45 years of age at the time of consent meeting diagnostic criteria of Attention Deficit Hyperactivity Disorder (ADHD) per Diagnostic and Statistical Manual of Mental Disorders (DSM-5) at screening visit and currently undergoing diagnostic assessment and/or treatment for ADHD * Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. * A diagnosis of the moderate symptoms of ADHD confirmed with combined score of 4 or higher in Clinical Global Impression-ADHD-Severity (CGI-ADHD-S) at Screening; Hyperactivity/Impulsivity subscale min 8 (at least moderate for impulsivity measure with ADHD checklist) * Able and willing to discontinue the use of any psychotropic medications for treatment of ADHD symptoms, as well as of all relevant co-medication for comorbid conditions during the study * Women of childbearing potential (WOCBP) \[1\] must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria and instructions on the duration of their use is provided in the patient information. 1. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation.
Exclusion criteria
* Per DSM-5, had ever met diagnostic criteria for schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, delusional disorder or major depressive disorder (MDD) with psychotic features at the time of screening. * Diagnosis of any mental disorder (according to DSM-5) that was primary focus of treatment within 6 months prior to Screening or at Baseline (as per clinical discretion of the investigator). --The following are not excluded: Substance Induced Mood Disorder, Major Depressive Disorder in remission, Generalized Anxiety Disorder in remission, Post-Traumatic Stress Disorder in remission, recreational/occasional substance use as long as willing to stop for duration of the study, Borderline Personality Disorder. * Any psychiatric disorder, including the ones mentioned under #1, that in the opinion of the investigator would compromise participants' safety and/or validity of the data. * Current or recent (in the 6 months prior to screening) suicidal ideation or behaviour of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-SSRS). * Any finding in the medical examination (including blood pressure (BP), pulse rate (PR), temperature, or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator. * Repeated measurement of systolic blood pressure outside the range of 90 to 145 millimetre of mercury (mmHg), diastolic blood pressure outside the range of 45 to 90 mmHg, or pulse rate outside the range of 45 to 95 beats per minute (bpm). * A marked baseline prolongation of QT/QTc interval (\[QT/QTc = Time between start of the Q-wave and the end of the T-wave in an electrocardiogram / QT interval corrected for heart rate using the method of Fridericia (QTcF) or Bazett (QTcB)\] such as QTc intervals that are repeatedly greater than 450 milliseconds (ms) in males or repeatedly greater than 470 ms in females) or any other relevant electrocardiogram (ECG) finding at screening. * A history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome). * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) After Single Dose (at Day 1) | Analysis based on the observation period: days 0 to 1, change from baseline calculated for Day 1. | The BIS-11 evaluates impulsiveness via 30 items scored on a 4-point scale (Rarely/Never = 1; Occasionally = 2; Often = 3; Almost Always/Always = 4). Total scores range from 30 (least impulsive) to 120 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the BIS-11 score at baseline as a covariate and the treatment arm as fixed factor. |
| Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) at Steady State (at Day 14) | Analysis based on the observation period: days 0 to 14, change from baseline calculated for Day 14. | The BIS-11 evaluates impulsiveness via 30 items scored on a 4-point scale (Rarely/Never = 1; Occasionally = 2; Often = 3; Almost Always/Always = 4). Total scores range from 30 (least impulsive) to 120 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the BIS-11 score at baseline as a covariate and the treatment arm as fixed factor. |
| Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale After Single Dose (at Day 1) | Analysis based on the observation period: days 0 to 1, change from baseline calculated for Day 1. | The S-UPPS-P assesses impulsivity across five traits using 20 items scored on a 4-point scale (Agree Strongly = 1; Agree Some = 2; Disagree Some = 3; Disagree Strongly = 4). Total scores range from 20 (least impulsive) to 80 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the S-UPPS-P score at baseline as a covariate and the treatment arm as fixed factor. |
| Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale at Steady State (at Day 14) | Analysis based on the observation period: days 0 to 14, change from baseline calculated for Day 14. | The S-UPPS-P assesses impulsivity across five traits using 20 items scored on a 4-point scale (Agree Strongly = 1; Agree Some = 2; Disagree Some = 3; Disagree Strongly = 4). Total scores range from 20 (least impulsive) to 80 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the S-UPPS-P score at baseline as a covariate and the treatment arm as fixed factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Treatment Emergent Adverse Events and Serious Adverse Events | From first drug administration on Day 1 until Day 16 + 4 days (REP), up to 20 days. | Treatment emergent adverse events are adverse events that occurred after treatment administration up to 4 days after the last dose of study drug. |
Countries
Germany
Participant flow
Recruitment details
This was a multi-center, randomized, double-blind, placebo controlled parallel-group trial in participants with attention deficit hyperactivity disorder (ADHD). Eligible participants were randomized in a 1:1 ratio to receive either placebo or atomoxetine during a 2-week double-blind treatment period.
Pre-assignment details
63 male and female participants (32 atomoxetine, 31 placebo) were randomized and 62 participants were treated. Out of these, 58 completed the planned treatment and trial per protocol; 2 were erroneously randomized and discontinued (one treated and one not treated); 3 discontinued due to other reasons. All participants were free to withdraw at any time and were closely monitored.
Participants by arm
| Arm | Count |
|---|---|
| Atomoxetine Day 1 and Day 8:
After fasting for at least 10 hours overnight, participants received a single dose of Atomoxetine consisting of two 40 mg capsules (totaling 80 mg) in the morning at the trial site.
Day 2 to Day 7:
Participants took a single dose of Atomoxetine consisting of one 40 mg capsule in the morning at home.
Day 9 to Day 14:
Participants took a single dose of Atomoxetine consisting of two 40 mg capsules (totaling 80 mg) in the morning at home. | 31 |
| Placebo (Matching Atomoxetine) Day 1 and Day 8:
After fasting for at least 10 hours overnight, participants received a single dose of placebo (matching Atomoxetine) in the morning at the trial site.
Day 2 to Day 7:
Participants took a single dose of placebo (matching Atomoxetine) in the morning at home.
Day 9 to Day 14:
Participants took a single dose of placebo (matching Atomoxetine) in the morning at home. | 31 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Exclusion criteria not met | 1 | 0 |
| Overall Study | Not treated | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo (Matching Atomoxetine) | Total | Atomoxetine |
|---|---|---|---|
| Age, Continuous | 27.4 Years STANDARD_DEVIATION 4.4 | 26.4 Years STANDARD_DEVIATION 4 | 25.4 Years STANDARD_DEVIATION 3.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 48 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 27 Participants | 54 Participants | 27 Participants |
| Sex: Female, Male Female | 17 Participants | 32 Participants | 15 Participants |
| Sex: Female, Male Male | 14 Participants | 30 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 31 | 0 / 31 |
| other Total, other adverse events | 28 / 31 | 23 / 31 |
| serious Total, serious adverse events | 0 / 31 | 0 / 31 |
Outcome results
Primary
Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) After Single Dose (at Day 1)
The BIS-11 evaluates impulsiveness via 30 items scored on a 4-point scale (Rarely/Never = 1; Occasionally = 2; Often = 3; Almost Always/Always = 4). Total scores range from 30 (least impulsive) to 120 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the BIS-11 score at baseline as a covariate and the treatment arm as fixed factor.
Time frame: Analysis based on the observation period: days 0 to 1, change from baseline calculated for Day 1.
Population: All randomized participants who received one dose of the study drug (placebo or atomoxetine) on Day 1 and had study data available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atomoxetine | Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) After Single Dose (at Day 1) | -0.8 Score on a scale |
| Placebo (Matching Atomoxetine) | Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) After Single Dose (at Day 1) | -0.4 Score on a scale |
Comparison: Change from baseline was analyzed with an ANCOVA model with the BIS-11 score at baseline as covariate and treatment as fixed factor.95% CI: [-2.6, 1.7]ANCOVA
Primary
Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) at Steady State (at Day 14)
The BIS-11 evaluates impulsiveness via 30 items scored on a 4-point scale (Rarely/Never = 1; Occasionally = 2; Often = 3; Almost Always/Always = 4). Total scores range from 30 (least impulsive) to 120 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the BIS-11 score at baseline as a covariate and the treatment arm as fixed factor.
Time frame: Analysis based on the observation period: days 0 to 14, change from baseline calculated for Day 14.
Population: All randomized participants who received at least 90% (not more than one missed dose) of the planned doses of the study drug (placebo or atomoxetine) up to Day 14 and had study data available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atomoxetine | Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) at Steady State (at Day 14) | -2.3 Score on a scale |
| Placebo (Matching Atomoxetine) | Change From Baseline in Total Score of Barratt Impulsiveness Questionnaire v.11 (BIS-11) at Steady State (at Day 14) | -0.1 Score on a scale |
Comparison: Change from baseline was analyzed with an ANCOVA model with the BIS-11 score at baseline as covariate and treatment as fixed factor.95% CI: [-4.6, 0.3]ANCOVA
Primary
Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale After Single Dose (at Day 1)
The S-UPPS-P assesses impulsivity across five traits using 20 items scored on a 4-point scale (Agree Strongly = 1; Agree Some = 2; Disagree Some = 3; Disagree Strongly = 4). Total scores range from 20 (least impulsive) to 80 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the S-UPPS-P score at baseline as a covariate and the treatment arm as fixed factor.
Time frame: Analysis based on the observation period: days 0 to 1, change from baseline calculated for Day 1.
Population: All randomized participants who received one dose of the study drug (placebo or atomoxetine) on Day 1 and had study data available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atomoxetine | Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale After Single Dose (at Day 1) | 0.0 Score on a scale |
| Placebo (Matching Atomoxetine) | Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale After Single Dose (at Day 1) | -0.1 Score on a scale |
Comparison: Change from baseline was analyzed with an ANCOVA model with the S-UPPS-P score at baseline as covariate and treatment as fixed factor.95% CI: [-2.1, 2.4]
Primary
Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale at Steady State (at Day 14)
The S-UPPS-P assesses impulsivity across five traits using 20 items scored on a 4-point scale (Agree Strongly = 1; Agree Some = 2; Disagree Some = 3; Disagree Strongly = 4). Total scores range from 20 (least impulsive) to 80 (most impulsive), calculated by summing item scores. Higher scores indicate greater impulsiveness. The data used in the analysis of covariance (ANCOVA) were estimated regardless of whether participants used rescue or other concomitant medications, or experienced nausea/vomiting. For participants who discontinued treatment early (receiving \<90% of planned doses), their data were included in the analysis only up to the point of discontinuation. Reported summary data was based on an ANCOVA with the S-UPPS-P score at baseline as a covariate and the treatment arm as fixed factor.
Time frame: Analysis based on the observation period: days 0 to 14, change from baseline calculated for Day 14.
Population: All randomized participants who received at least 90% (not more than one missed dose) of the planned doses of the study drug (placebo or atomoxetine) up to Day 14 and had study data available.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Atomoxetine | Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale at Steady State (at Day 14) | -0.2 Score on a scale |
| Placebo (Matching Atomoxetine) | Change From Baseline in Total Score of Short Urgency, Perseverance, Premeditation, and Sensation Seeking-Positive Urgency Impulsive Behavior Scale (S-UPPS-P) Impulsive Behavior Scale at Steady State (at Day 14) | -1.0 Score on a scale |
Comparison: Change from baseline was analyzed with an ANCOVA model with the S-UPPS-P score at baseline as covariate and treatment as fixed factor.95% CI: [-1.3, 3.1]ANCOVA
Secondary
Percentage of Patients With Treatment Emergent Adverse Events and Serious Adverse Events
Treatment emergent adverse events are adverse events that occurred after treatment administration up to 4 days after the last dose of study drug.
Time frame: From first drug administration on Day 1 until Day 16 + 4 days (REP), up to 20 days.
Population: All participants who were treated with at least one dose of study drug (i.e. placebo or atomoxetine).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Atomoxetine | Percentage of Patients With Treatment Emergent Adverse Events and Serious Adverse Events | Treatment-emergent adverse events | 90.3 Percentage (%) of participants |
| Atomoxetine | Percentage of Patients With Treatment Emergent Adverse Events and Serious Adverse Events | Treatment-emergent serious adverse events | 0 Percentage (%) of participants |
| Placebo (Matching Atomoxetine) | Percentage of Patients With Treatment Emergent Adverse Events and Serious Adverse Events | Treatment-emergent adverse events | 80.6 Percentage (%) of participants |
| Placebo (Matching Atomoxetine) | Percentage of Patients With Treatment Emergent Adverse Events and Serious Adverse Events | Treatment-emergent serious adverse events | 0 Percentage (%) of participants |