Safety and Tolerability of Aripiprazole in Adolescents With Schizophrenia or Children and Adolescents With Bipolar I Disorder, Manic or Mixed Episode With or Without Psychotic Features.

A Long-term, Multicenter, Open-Label Study to Evaluate the Safety and Tolerability of Flexible-Dose Oral Aripiprazole (OPC-14597) as Maintenance Treatment in Adolescent Patients With Schizophrenia or Child and Adolescent Patients With Bipolar I Disorder, Manic or Mixed Episode With or Without Psychotic Features

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01122927

Acronym

ATTAIN 267

Enrollment

524

Registered

2010-05-13

Start date

2010-07-31

Completion date

2014-09-30

Last updated

2016-02-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Adolescent Schizophrenia, Child or Adolescent Bipolar I Disorder, Manic or Mixed Episode With or Without Psychotic Features

Keywords

schizophrenia, adolescent, bipolar

Brief summary

This is an open-label study consisting of a screening period, a conversion/titration phase (Phase 1), an open-label treatment phase (Phase 2), and a follow-up period. The study will enroll new subjects (hereafter referred as de novo subjects) with schizophrenia, or bipolar I disorder, manic or mixed episode with or without psychotic features, and rollover subjects with schizophrenia from 31-09-266 (hereafter referred to as Study 266). All de novo subjects must enter the screening period of the study. Subjects who are screened and are not required to go through Phase 1 will complete a Phase 2 baseline visit prior to their participation in Phase 2. Study Design: Treatment, Single Group Assignment, Open Label, Active Control, Safety/Efficacy Study

Interventions

DRUGAripiprazole

Aripiprazole (2-mg, 5-mg, 10-mg, 15-mg, 20-mg, 25-mg or 30-mg) pill taken orally once per day

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

10 Years to 17 Years

Healthy volunteers

Inclusion criteria

* Subjects 13-17 years old (Schizophrenia); Subjects 10-17 years old (Bipolar manic or mixed episode)\* \[\*Bulgaria will enroll Schizophrenia subjects only.\] * Subjects with a current diagnosis of schizophrenia, and a history of the illness (diagnosis or symptoms) for at least 6 months prior to screening (as per subject, family, or healthcare provider, or by previous medical records). * Subjects with a current diagnosis of bipolar I disorder, manic or mixed episode with or without psychotic features (diagnosis or symptoms) experiencing symptoms for at least 1 week prior to screening. \* \[\*These subjects will not be eligible to enroll in Bulgaria\] * Subjects who have shown previous response to antipsychotic treatment (other than clozapine) and are not resistant to treatment with other antipsychotics. * Subjects who are currently being treated with oral antipsychotics other than clozapine, and are not resistant to treatment with other antipsychotics. * Inpatient or outpatient status, with the exception of acute hospitalization due to psychiatric reasons at the time of screening or before Phase 2.

Exclusion criteria

* All subjects: diagnosis of schizoaffective disorder, autism, pervasive developmental disorder (PDD), OCD, or PTSD. * Subjects with schizophrenia: a current major depressive episode. * Subjects with bipolar manic or mixed episode: presenting with a clinical picture and/or history that is consistent with a diagnosis of bipolar II disorder or bipolar disorder not otherwise specified. * Subjects with delirium, dementia, amnesia or other cognitive disorders; subjects with psychotic symptoms that are better accounted for by another general medical condition(s) or direct effect of a substance (i.e., medication, illicit drug use, etc.). * Subjects with any neurological disorder, with the exception of Tourette's syndrome. * Subjects experiencing major depressive episode at the time of screening other than subjects diagnosed with bipolar I disorder mixed episode. * Subjects who are currently receiving clozapine or have received clozapine at any time in the past are ineligible for entry into the study. * Subjects who meet the DSM-IV-TR criteria for substance dependence (including alcohol and benzodiazepines, but excluding caffeine and nicotine) within the past 180 days prior to screening. * Subjects who have epilepsy, a history of seizures (except for a single childhood febrile seizure or post-traumatic seizure), or a history of severe head trauma or stroke, or have a history or current evidence of other unstable medical conditions. * Subjects with a history of subclinical hypothyroidism (TSH ≥ 4.0 mIU/L), known hypothyroidism, or hyperthyroidism (unless the condition has been stabilized with medications for at least 90 days prior to entry into Phase 1 or Phase 2). * Subjects who have a medical history of uncontrolled diabetes, labile or unstable diabetes (brittle diabetes), newly diagnosed diabetes, or clinically significant abnormal blood glucose levels (defined as fasting blood glucose ≥ 125 mg/dL).

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Adverse Events (AEs)	Adverse events were recorded from the time of the informed consent was signed throughout the 24 month treatment period until the follow-up visit 30 (± 3) days after the end of trial.	An AE was defined as any untoward medical occurrence in a participant or participant enrolled in a clinical trial and which did not necessarily have a causal relationship with the study medication. A treatment emergent adverse event (TEAE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study medication, whether or not considered to have a causal relationship with the study medication. A serious-AE or reaction was any untoward occurrence that, at any dose, was fatal, life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was any other medically significant event that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above.

Secondary

Measure	Time frame	Description
Incidence of Physical Examination Findings of Potential Clinical Relevance	Baseline to Month 24	The physical examination evaluation was one of the parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in the following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.
Incidence of Vital Signs of Potential Clinical Relevance	Baseline to Month 24	Vital signs are taken at Baseline, Weeks 1, 2, 3, 4, 6, 8, and Months 3, 4, 6, 9, 12, 15, 18, 21, 24 of Phase 2 (Visits beyond Month 12 only for de novo subjects). Assessments included orthostatic (supine and standing) blood pressure (BP), heart rate and body temperature. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria. Abnormal vital signs in participants were reported as SAE/AEs and are reported in the SAE/other AE section of this report.
Mean Change From Baseline by Week in Abnormal Involuntary Movement Scale (AIMS)	Baseline to Month 24	The AIMS Scale was an extrapyramidal symptoms (EPS) rating scale. The AIMS is a 12 item scale. The first 10 items e.g. facial and oral movements (items 1-4), extremity movements (items 5 and 6), trunk movements (item 7), investigators global assessment of dyskinesia (items 8 to 10). The first 10 items are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28.
Mean Change From Baseline by Week in Simpson-Angus Scale (SAS) Total Score	Baseline to Month 24	The SAS is a rating scale used to measure EPS. The SAS scale consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40.
Mean Change From Baseline by Week in Barnes Akathisia Rating Scale (BARS) Score	Baseline to Month 24	The BARS was an EPS rating scale. The BARS was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia).
Number of Participants With Cognitive Impairment for Each New York Assessment for Adverse Cognitive Effects of Neuropsychiatric Treatment (NY-AACENT)	Baseline to Month 24	The NY-AACENT is not a validated scale. It was included in this trial because of concerns that regulatory authorities (the European Committee for Medicinal Products for Human Use \[CHMP\] and the Paediatric Sub-Committee of the European Medicinal Agency \[PDCO\]) had regarding drug induced cognitive impairment. No validated scale addressing these issues was available at the time of the trial. The NY-AACENT was used to detect changes in cognitive function subsequent to pharmacological or similar treatments for neurological or psychiatric problems. It was specifically designed to be used in pediatric populations (ages 12 to 17), but could have been utilized with other age groups, as appropriate.
Baseline and Post-Baseline Tanner Staging	Baseline to Last Visit	Tanner staging was completed together with the physical examination by the same trial-affiliated clinician in the most inconspicuous manner for the participant as possible. Tanner staging assessment consisted of 2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis development, and testes development) for boys. A participant who reached Stage 5 (both in pubic hair and genitalia) did not need to continue with Tanner Staging assessment and the Tanner Staging scales of this participant were imputed as 5 for all of the following scheduled time points up to and including the completion visit/ET visit. The clinician arrived at a single score summarizing the domains (not individual domain scores) when evaluating the participant. The total shift data for last visit is presented below.
Mean Change From Baseline for Columbia-Suicide Severity Rating Scale (C-SSRS) in Suicidal Ideation Intensity Total Score	Baseline to Month 24	Suicidality was defined as reporting at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any type of suicidal behaviors (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). Suicidal ideation was defined as reporting any type of suicidal ideation. The suicidal ideation intensity total score is the sum of intensity scores of 5 items (frequency, duration, controllability, deterrents, and reasons for ideation). The score of each intensity item ranges from 0 (none) to 5 (worst) which leads to the range of the total score from 0 to 25. A missing score of any item resulted in a missing total score. If no suicidal ideation was reported, a score of 0 was given to the intensity scale.
Incidence of Suicidality, Suicidal Behavior and Suicidal Ideation	Baseline to Month 24	Suicidality was defined as reporting at least one occurrence of any suicidal behavior or suicidal ideation. Suicidal behavior was defined as reporting any type of suicidal behaviors (actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior). Suicidal ideation was defined as reporting any type of suicidal ideation. The below reported N value is the number of participants with specified suicidal ideation/behavior at the given time point.
Percentage of Participants Who Discontinued Due to All Adverse Events	Baseline to Month 24	The percentage of participants who discontinued due to all causes other than sponsor terminating the trial was measured from the date of entering the open-label treatment phase to the date of ET for discontinued participants in the open-label treatment phase (ie, time to discontinuation = date of discontinuation \[or date of completion for completed participants\] - date of participant entering the open-label treatment phase + 1). If the participants completed the trial or were discontinued due to the sponsor terminating the trial, they were censored at the time of completion or trial termination, respectively.
Incidence of Laboratory Values of Potential Clinical Relevance	Baseline to Month 24	The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria. Abnormal laboratory values in participants were reported as SAE/AEs and are reported in the SAE/other AE section of this report.
Mean Change From Baseline in PANSS Positive Subscale Score	Baseline to Month 24	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS positive subscale score was the sum of the rating scores for the 7 positive scale items from the PANSS panel. The 7 positive symptom constructs are delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
Mean Change From Baseline in PANSS Negative Subscale Score	Baseline to Month 24	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS negative subscale score was the sum of the rating scores for the 7 negative scale items from the PANSS panel. The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Subscale ranges from 7 (absence of symptoms) to 49 (extremely severe symptoms).
Mean Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score	Baseline to Month 24	The severity of illness for each participant was rated using the CGI-S scale. To assess CGI-S, the study physician answered the following question: Considering your total clinical experience with this particular population, how mentally ill is the participant at this time? Response choices included: 0 = not assessed; 1 = normal, not ill at all; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants.
Mean Change in Clinical Global Impression-Improvement (CGI-I) Score	Baseline to Month 24	The efficacy of trial medication were rated for each participant using the CGI-I scale. The study physician must rate the participant's total improvement whether or not it is due entirely to drug treatment. All responses were compared to the participant's condition at baseline. Response choices include: 0 = not assessed; 1 =very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 =minimally worse; 6 = much worse; and 7 = very much worse.
Mean Change From Baseline in Young Mania Rating Scale (YMRS) Score	Baseline to Month 24	The YMRS consists of 11 items assessing the core symptoms of mania and was used to assess participants with bipolar I disorder, manic and mixed episodes with or without psychotic features: elevated mood, increased motor activity - energy, sexual interest, sleep, irritability, speech (rate and amount), language - thought disorder, content, disruptive - aggressive behavior, appearance, and insight. Each item had 5 or 9 grades of severity, with lower scores indicating milder symptoms. The number of raters within each trial center was to be kept to a minimum. The YMRS Total Score (range 0 to 44) is the sum of the rating scores for 11 items for assessing the core symptoms of mania. A missing value for any YMRS assessment item(s) could have resulted in a missing YMRS Total Score. A higher YMRS Total Score represents greater severity. In this study, 94 participants had bipolar disorder, this explains the N=94 in the table below and these were de novo participants.
Mean Change From Baseline in Clinical Global Impression Scale - Bipolar (CGI-BP) Version Severity Score	Baseline to Month 24	The CGI-BP scale refers to the global impression of the subject with respect to bipolar disorder. The scale rated the subject's Severity of Illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and Change From Preceding Phase (CGI-BP-Improvement: mania, depression, and overall bipolar illness) based on a 7- or 8-point scale. Severity of Illness (CGI-BP-Severity) was rated at all visits. At each visit other than Day 0 (Baseline), the Change From Preceding Phase (CGI-BP-Improvement) was judged with respect to participant's condition at Baseline. The CGI-BP Severity Scores (range 1 to 7), as well as CGI-BP Improvement Scores (range 1 to 7) are single-item rating scores, with higher scores representing greater severity or less improvement. Data for 94 de novo participants were available with bipolar disorder.
Mean Change From Baseline in Clinical Global Impression Scale - Bipolar Version Improvement Score	Baseline to Month 24	The CGI-BP scale refers to the global impression of the subject with respect to bipolar disorder. The scale rated the subject's Severity of Illness (CGI-BP-Severity: mania, depression, and overall bipolar illness) and Change From Preceding Phase (CGI-BP-Improvement: mania, depression, and overall bipolar illness) based on a 7- or 8-point scale. Severity of Illness (CGI-BP-Severity) was rated at all visits. At each visit other than Day 0 (Baseline), the Change From Preceding Phase (CGI-BP-Improvement) was judged with respect to participant's condition at Baseline. The CGI-BP Severity Scores (range 1 to 7), as well as CGI-BP Improvement Scores (range 1 to 7) are single-item rating scores, with higher scores representing greater severity or less improvement. Only 94 participants had data at Baseline to explain the N=94 in the table below and these were de novo participants.
Mean Change From Baseline in General Behavior Inventory (GBI) Scale Total Score for Mania and Depression in Both Parent/Guardian and Subject Version of the Scale	Baseline to Month 24	The GBI is a self-report inventory with 73 items focusing on mood-related behaviors, including depressive, hypomanic, and biphasic symptoms. For this trial, two 20-item subscales were utilized: one was completed by the parent/guardian or legal representative, as applicable for local laws, and the other was completed by the participant. Responses were given on a 4-point Likert scale, with 0 being never or hardly ever and 3 being very often or almost constantly. The GBI Total Score for mania (range 0 to 30) is the sum of scores for items 1 to 10 and the GBI Total Score for depression (range 0 to 30) is the sum of scores for items 11 to 20 in the GBI Parent/Guardian or Subject Version panel. Scores from the Parent/Guardian and participant Versions were summarized separately. A missing value for any GBI assessment items could have resulted in a missing GBI Total Score. High scores represent greater psychopathology. Data was only available for 80 de novo participants with bipolar disorder.
Mean Change From Baseline in the Attention Deficit Hyperactive Disorders Rating (ADHD-RS-IV) Scale Score	Baseline to Month 24	The ADHD-RS-IV is a reliable and easy-to-administer instrument both for diagnosing ADHD in children and adolescents and for assessing treatment response. Containing 18 items, the scale was linked directly to DSM-IV-TR diagnostic criteria for ADHD. There were 3 versions of the scale: a parent questionnaire on home behaviors (English), a parent questionnaire on home behaviors (Spanish), and a teacher questionnaire on classroom behaviors. For this trial, the parent questionnaire on home behaviors (English) was utilized. The ADHD-RS-IV Total Score (range 0 to 54) is the sum of rating scores for 18 items, with higher scores representing greater severity. A missing value for any ADHD-RS-IV assessment items could have resulted in a missing ADHD-RS-IV Total Score. Data were only available for 82 participants with bipolar disorder and these were de novo participants.
Mean Change From Baseline in Children's Global Assessment Scale (CGAS) in Bipolar (de Novo Participants)	Baseline to Month 24	The CGAS is a 100-point rating scale measuring psychological, social, and school functioning for children aged 6 to 17. It was adapted from the Adults Global Assessment Scale. The Global Assessment Scale was a rating scale for evaluating the overall functioning of a participant during a specified time period on a continuum from psychological or psychiatric sickness to health. The CGAS is a valid and reliable tool for rating a child's general level of functioning on a health-illness continuum. The CGAS was developed by Schaffer and colleagues to provide a global measure of severity of disturbance in children and adolescents. The CGAS Score (range 1 to 100) is a single-item score for rating a child's general level of functioning on a health-illness continuum, with higher scores representing better functioning.
Mean Change From Baseline in Positive and Negative Symptoms Score (PANSS) Total Score	Baseline to Month 24	The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).

Countries

Bulgaria, Croatia, Hungary, India, Malaysia, Philippines, Poland, Romania, Russia, Serbia, Taiwan, Ukraine, United States

Participant flow

Recruitment details

This trial was conducted in 524 participants at 118 trial sites in the following 13 countries: Bulgaria, Croatia, Hungary, India, Malaysia, Philippines, Poland, Romania, Russia, Serbia, Taiwan, Ukraine, and the United States.

Pre-assignment details

524 participants entered this trial (297 participants in the conversion phase and 510 participants in the open-label treatment phase). In the latter, 362 were de novo participants (283 participants entered into the conversion phase) and 148 rolled over from Trial NCT01149655.

Participants by arm

Arm	Count
All Study Participants Participants who entered open-label treatment phase had received oral aripiprazole at a target dose of 10 to 30 mg/day, with a minimum dose of 5 mg/day, based on individual participant's response and tolerability considerations.	524
Total	524

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1 - Conversion Phase	Adverse Event	3	0
Period 1 - Conversion Phase	Met Withdrawal Criteria	1	0
Period 1 - Conversion Phase	Physician Decision	2	0
Period 1 - Conversion Phase	Protocol Deviation	1	0
Period 1 - Conversion Phase	Withdrawal by Subject	7	0
Period 2- Open-label Treatment Phase	Adverse Event	0	33
Period 2- Open-label Treatment Phase	Lack of Efficacy	0	7
Period 2- Open-label Treatment Phase	Lost to Follow-up	0	21
Period 2- Open-label Treatment Phase	Met Withdrawal Criteria	0	9
Period 2- Open-label Treatment Phase	Physician Decision	0	12
Period 2- Open-label Treatment Phase	Sponsor Discontinued Trial	0	165
Period 2- Open-label Treatment Phase	Withdrawal by Subject	0	65

Baseline characteristics

Characteristic	All Study Participants
Age, Continuous	15.2 Years STANDARD_DEVIATION 1.6
Sex: Female, Male Female	316 Participants
Sex: Female, Male Male	208 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	40 / 297	194 / 510
serious Total, serious adverse events	2 / 297	49 / 510

Outcome results

Primary

Number of Participants With Adverse Events (AEs)

An AE was defined as any untoward medical occurrence in a participant or participant enrolled in a clinical trial and which did not necessarily have a causal relationship with the study medication. A treatment emergent adverse event (TEAE) was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study medication, whether or not considered to have a causal relationship with the study medication. A serious-AE or reaction was any untoward occurrence that, at any dose, was fatal, life-threatening, required inpatient hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was any other medically significant event that, based on appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the outcomes listed above.

Time frame: Adverse events were recorded from the time of the informed consent was signed throughout the 24 month treatment period until the follow-up visit 30 (± 3) days after the end of trial.

Population: All participants who had received at least one dose of oral aripiprazole.

Arm	Measure	Group	Value (NUMBER)
Open-label Treatment Phase	Number of Participants With Adverse Events (AEs)	Participants with TEAEs	349 Participants
Open-label Treatment Phase	Number of Participants With Adverse Events (AEs)	Participants with serious TEAEs	49 Participants
Open-label Treatment Phase	Number of Participants With Adverse Events (AEs)	Participants with severe TEAEs	33 Participants
Open-label Treatment Phase	Number of Participants With Adverse Events (AEs)	Discontinued due to AEs	32 Participants

Secondary

Baseline and Post-Baseline Tanner Staging

Tanner staging was completed together with the physical examination by the same trial-affiliated clinician in the most inconspicuous manner for the participant as possible. Tanner staging assessment consisted of 2 domains (pubic hair and breast development) for girls and 3 domains (pubic hair, penis development, and testes development) for boys. A participant who reached Stage 5 (both in pubic hair and genitalia) did not need to continue with Tanner Staging assessment and the Tanner Staging scales of this participant were imputed as 5 for all of the following scheduled time points up to and including the completion visit/ET visit. The clinician arrived at a single score summarizing the domains (not individual domain scores) when evaluating the participant. The total shift data for last visit is presented below.

Time frame: Baseline to Last Visit

Population: All those participants who had received at least one dose of oral aripiprazole during the open-label treatment phase.

Arm	Measure	Group	Value (NUMBER)
Open-label Treatment Phase	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 4) (N= 134)	0 participants
Open-label Treatment Phase	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 1) (N= 1)	1 participants
Open-label Treatment Phase	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 5) (N= 327)	0 participants
Open-label Treatment Phase	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 2) (N= 9)	4 participants
Open-label Treatment Phase	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 3) (N= 39)	2 participants
Tanner Score at Baseline of 2	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 4) (N= 134)	7 participants
Tanner Score at Baseline of 2	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 3) (N= 39)	9 participants
Tanner Score at Baseline of 2	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 2) (N= 9)	5 participants
Tanner Score at Baseline of 2	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 5) (N= 327)	3 participants
Tanner Score at Baseline of 2	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 1) (N= 1)	0 participants
Tanner Score at Baseline of 3	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 3) (N= 39)	28 participants
Tanner Score at Baseline of 3	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 1) (N= 1)	0 participants
Tanner Score at Baseline of 3	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 2) (N= 9)	0 participants
Tanner Score at Baseline of 3	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 4) (N= 134)	33 participants
Tanner Score at Baseline of 3	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 5) (N= 327)	18 participants
Tanner Score at Baseline of 4	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 5) (N= 327)	102 participants
Tanner Score at Baseline of 4	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 1) (N= 1)	0 participants
Tanner Score at Baseline of 4	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 4) (N= 134)	94 participants
Tanner Score at Baseline of 4	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 3) (N= 39)	0 participants
Tanner Score at Baseline of 4	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 2) (N= 9)	0 participants
Tanner Score at Baseline of 5	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 3) (N= 39)	0 participants
Tanner Score at Baseline of 5	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 4) (N= 134)	0 participants
Tanner Score at Baseline of 5	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 1) (N= 1)	0 participants
Tanner Score at Baseline of 5	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 5) (N= 327)	204 participants
Tanner Score at Baseline of 5	Baseline and Post-Baseline Tanner Staging	Last Visit (Post-Baseline score of 2) (N= 9)	0 participants

Secondary

Incidence of Laboratory Values of Potential Clinical Relevance

The laboratory values were one of the parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria. Abnormal laboratory values in participants were reported as SAE/AEs and are reported in the SAE/other AE section of this report.