Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT01714310
• Collaborator: National Institute of Mental Health (NIMH) (NIH), Shire (Industry)
• Enrollment: 34
• Location: 1
• Arms: 3
• Duration (Months): 41
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This project will characterize children and adolescents with severe mood dysregulation (SMD) and conduct a pilot study of combination pharmacotherapy as a basis for future intervention trials.

Eligible participants assessed for SMD will have 4 weeks open titration with lisdexamfetamine (LDX) to optimal dose, followed by double-blind randomization to fluoxetine (N=25) or placebo (N=25) in combination with optimized LDX for an additional 8 weeks. Participants will be monitored for clinical response and adverse events.

Specific aims are:

#1: To define youth meeting SMD criteria in terms of psychiatric comorbidity, neurocognitive functioning, and a potential "bio-signature" derived from electroencephalography (EEG).

Specific hypotheses to be tested include: 1) that SMD participants will differ in comparison to non-SMD individuals in our pre-existing database on patterns of a) psychiatric comorbidity, b) symptoms, c) behavioral ratings, and d) neurocognitive functioning, and 2) that a distinct EEG bio-signature will be confirmed in individuals formally diagnosed with SMD.

#2: To conduct a preliminary study of sequential pharmacotherapy for SMD with a stimulant followed by randomized, placebo-controlled selective serotonin re-uptake inhibitor (SSRI) therapy to evaluate the feasibility of recruitment and enrollment and assess the suitability of the proposed combination treatment as a basis for future clinical investigations.

Specific hypotheses to be tested include: 1) that significant improvement in Clinical Global Impression - Improvement -SMD (CGI-I-SMD) scores and other secondary measures are evident after open-label LDX titration; 2) that participants randomized to fluoxetine will demonstrate additional significant improvement in CGI-I-SMD scores and other secondary measures in comparison to participants randomized to placebo; 3) that combination LDX and SSRI therapy is safe and well tolerated, and 4) that EEG profiles will normalize with treatment.

Condition or Disease	Intervention/Treatment	Phase
Severe Mood Dysregulation	Drug: lisdexamfetamine; Drug: Placebo; Drug: fluoxetine	Phase 2

Detailed Description

Background

The increased frequency of diagnosed pediatric bipolar disorder has emerged as one of the greatest controversies in child and adolescent psychiatry. Beginning with reports that 20% of prepubertal of children with Attention-Deficit/Hyperactivity Disorder (ADHD) met criteria for juvenile mania, a view arose that bipolar children were more irritable than euphoric and more chronic than episodic, compared with the typical adult. Concurrently, there was a 4 to 6-fold increase in inpatient discharges and 40-fold increase in office-based visits for pediatric bipolar disorder, although many of these failed to meet formal Diagnostic and Statistical Manual (DSM) criteria. Concerns have been raised that any child with impulsive, volatile behavior is apt to be diagnosed as bipolar.

Some attempted to inform valid symptomatic boundaries by proposing a differentiation of narrow versus broad pediatric bipolar phenotypes. The narrow phenotype was defined by strict DSM criteria for mania or hypomania, including discrete episodes of grandiosity and euphoria. In contrast, the broad phenotype, also referred to as severe mood dysregulation (SMD), was defined by chronic, non-episodic illness lacking hallmark symptoms of grandiosity and euphoria, but typified by severe irritability and hyperarousal. Work at the National Institute of Mental Health (NIMH) demonstrated that patterns of adolescent irritability are stable and distinct, with episodic irritability leading to mania and simple phobia, and chronic irritability leading to diagnosed depression and ADHD. On structured assessment, children with SMD were highly comorbid for major depression (20%), anxiety (64%), oppositional defiant disorder (83%), and ADHD (87%). Others also found increased rates of ADHD and anxiety. In addition, the broad and narrow phenotypes could be differentiated according to electroencephalography (EEG) measures. SMD youth have impaired face emotion recognition deficits correlated with dysfunctional family relationships and were less influenced by emotional distracters during tasks of attention. A recent study revealed patterns of amygdala hypoactivation similar to depression, further supporting links between chronic irritability and subsequent depressive episodes.

In response to the perceived over-diagnosis of pediatric DSM bipolar disorder, acknowledgment that the "classic" adult bipolar phenotype does occur in prepubertal youth, and increased recognition that SMD is a distinct behavioral and/or biological syndrome, the DSM-5 Child Disorders Workgroup proposed a new diagnostic category named temper dysregulation disorder with dysphoria (TDD). Criteria for TDD were largely based on SMD, however, the requirement for hyperarousal was removed and minor changes were made in age of onset and exclusion criteria. Unlike SMD, TDD lacks any demonstrated scientific basis or history of prior research. As such, it seems prudent at this time to continue research on the better-established SMD category with an expectation that any information derived will have ready applicability as work on TDD progresses.

One preliminary report suggests that SMD has a lifetime prevalence of 3.3% among those ages 9-19. Recent longitudinal studies further indicate that children with SMD have increased rates of adult mood and anxiety disorders, substance abuse, suicidality, and poorer overall functioning. Given this significant morbidity, it is essential that the investigators increase understanding of children with chronic irritability and affective instability. Impulsive aggression in childhood has been identified as a significant public health concern that cuts across currently defined diagnostic categories. These youth demonstrate increased difficulties with school adjustment, peer interactions, cognitive deficits, problem-solving, and physical abuse - a developmental trajectory predictive of significant adult dysfunction.

Current community practice emphasizes use of second-generation antipsychotic agents for children with impulsive aggression. While risperidone has proven effective for irritability associated with pervasive developmental disorders [25,26] and second-generation antipsychotics have been effective in pediatric bipolar disorder, these agents are associated with significant weight gain and other metabolic effects. Use of these medications is associated with decreased utilization of psychosocial interventions. Given the relationship of SMD with ADHD, anxiety, and unipolar depression, investigations of drugs from other classes with targeted effects and better side effect profiles, such as mood stabilizers, antidepressants, and stimulants, are certainly warranted. In fact, the DSM-5 Workgroup has specifically called for clinical trials stating it is "critically important" to assess whether stimulants and SSRIs should be first line treatments in SMD-affected youth. The only published medication trial in SMD youth is a double-blind placebo controlled study of lithium conducted by the intramural group at NIMH, which failed to demonstrate effects. Other informative investigations include small positive studies of methylphenidate versus placebo for ADHD plus oppositional defiant disorder and aggression, open-label stimulant followed by adjuvant divalproex vs. placebo for ADHD and aggression, and stimulant augmentation with double-blind risperidone versus placebo in ADHD with treatment resistant aggression. These studies are notably heterogeneous in design and choice of outcome measures. No clear predictors of response have been reported.

Most existing SMD research has been conducted by a single intramural group at NIMH. It is imperative that investigations of SMD be expanded to other research groups to ensure that results generalize to broad clinical settings. Additional research is required to delineate clinical phenomenology that will inform subsequent efforts at diagnostic classification. Further work is also necessary to establish the appropriate foundation for future clinical interventions research. This should include pilot studies of various medication classes that might prove useful in management of SMD, as well as examination of various outcome measures that are likely to be useful in both medication and psychosocial intervention trials.

Overview

The study will include comprehensive phenotyping of 65 patients meeting criteria for SMD, including assessment of comorbid psychopathology, language disorder, neurocognition, and EEG. Potential endophenotypes and diagnostic boundaries will be assessed in relation to our large existing database of children and adolescents with internalizing and externalizing disorders, as well as non-clinical controls. Eligible participants with SMD will proceed to a pilot study of sequential pharmacotherapy with an initial 4-week titration of open label lisdexamfetamine (LDX) followed by 8 weeks adjunctive therapy with randomized fluoxetine or placebo. Statistical analyses will address diagnostic boundaries of SMD compared with other disorders and emphasize initial determinations of the potential efficacy and tolerability of stimulant and SSRI treatments for SMD. There will be an added emphasis on effect size estimates and determination of optimal outcome measures in anticipation of future large-scale studies.

Project Visits and Procedures

Following baseline visit (week 0), eligible participants will undergo undergo open-label stepwise titration with one week each of low, medium, and high dose LDX during study weeks 1, 2, and 3. The study physician may modify titration due to emergent side effects following routine practice standards.

At the end of study week 3, the clinician will determine "optimal" stimulant dose based on review of parent and teacher-completed Conners Global Index scales and all available adverse event and side effects data, using procedures similar to those used in other studies. Participants will remain on this optimal stimulant dose for the remainder of the study, unless side effects necessitate some downward dose adjustment.

At study week 4, participants who fail to achieve CGI-I-SMD score < 4 will be randomized to double blind adjunctive treatment with either fluoxetine or placebo.

A forced dose, stepwise, upward titration of one week each of 5, 10, and 20 mg fluoxetine/placebo will occur at during week 5, 6, and 7. The treating physician may modify this titration schedule in response to emergent side effect following routine practice standards. Participants will remain on their week 7 doses of fluoxetine/placebo until the study's final visit, unless side effects necessitate some downward titration.

Side effects, adverse events, and medication compliance will be assessed at each visit. Major outcome assessments will occur at baseline (week 0) , end of week 4, and end of week 12.

Arrangements will be made to transfer participants to standard clinical care following week 12.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Initial arm for open-label titration of lisdexamfetamine followed by randomization of participants who retain eligibility to double blind adjunctive fluoxetine or placebo.Initial arm for open-label titration of lisdexamfetamine followed by randomization of participants who retain eligibility to double blind adjunctive fluoxetine or placebo.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Adjunctive fluoxetine Participants previously titrated with open-label lisdexamfetamine randomized to adjunctive fluoxetine at end of study week 4.	Drug: lisdexamfetamine; Titration and open label treatment from baseline visit for 12 week study.; Other Names: Vyvanse ; Drug: fluoxetine; Initiated at end of study week 4 and continued to study week 12.; Other Names: Prozac
Placebo Comparator: Adjunctive placebo Participants previously titrated with open-label lisdexamfetamine randomized to adjunctive placebo at end of study week 4.	Drug: lisdexamfetamine; Titration and open label treatment from baseline visit for 12 week study.; Other Names: Vyvanse ; Drug: Placebo; Initiated at end of study week 4 and continued to study week 12.
Other: Open Lisdexamfetamine Titration All participants initially titrated with open-label lisdexamfetamine from baseline to end of study week 4.	Drug: lisdexamfetamine; Titration and open label treatment from baseline visit for 12 week study.; Other Names: Vyvanse

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impression-Severity-Severe Mood Dysregulation [Baseline through week 12.]

   A dimensional clinician rating of overall SMD related impairment, modified by the National Institute of Mental Health to assess specific domains pertinent to Severe Mood Dysregulation. Minimum score = 1. Maximum score = 7. Higher scores means greater impairment.

Secondary Outcome Measures

1. ADHD-IV Rating Scale [Baseline through week 12.]

   A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity.

2. Conners Parent Global Index [Baseline through week 3.]

   Parent completed dimensional measure of ADHD symptoms, with score range from 0 - 30 and higher scores indicating more severe symptoms.

3. Conners Global Index Emotional Lability Subscale - Parent Report [Baseline to week 3.]

   A sub scale of the Conners Global Index, with scores ranging from 0 - 12, with higher scores indicating more impairment.

4. Conners Global Index Restless-Impulsive Subscale Parent Report [Baseline through week 3.]

   A dimensional parent report measure of restless-impulsive symptoms, with scores ranging from 0 to 21, and higher scores indicating greater impairment.

5. Conners Teacher Global Index [Baseline through week 3.]

   Teacher completed dimensional measure of ADHD symptoms, with scores ranging from 0 - 30, and higher scores indicating more severe impairment.

6. Affective Reactivity Index - Parent Report [Baseline through week 12.]

   A parent completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.

7. Revised Modified Overt Aggression Scale - Total Score [Baseline through week 12.]

   A parent rated retrospective dimensional assessment of oppositional and aggressive behaviors, with scores ranging from 0-40, and higher scores indicating greater severity.

8. Clinical Global Impression - Improvement [Percentage improved at week 4 for Open Lisdexamfetamine group and at week 12 for fluoxetine and placebo groups.]

   Percentage improved by treatment group

9. Height [Baseline through week 12.]

   A dimensional measure assessed in cms.

10. Weight [Baseline through week 12.]

    Weight in kg.

11. Pulse [Baseline through week 12.]

    Heart rate in beats per minute.

12. Systolic Blood Pressure [Baseline through week 12.]

    Systolic Blood Pressure measured in mmHG

13. Diastolic Blood Pressure [Baseline through week 12.]

    Diastolic Blood pressure measured in mmHG.

Other Outcome Measures

1. Pediatric Anxiety Rating Scale [Baseline through week 12.]

   Clinician completed dimensional assessment of anxiety symptoms.

2. Children's Depression Rating Scale [Baseline through week 12.]

   Clinician completed dimensional rating of depressive symptoms.

3. Affective Reactivity Index Child Report [Baseline through week 12.]

   Dimensional self-report of irritability, with total score 1-12, and higher scores indicating greater severity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male and female participants, ages 7-17 years.

2. Abnormal mood (specifically anger, sadness, and/or irritability), present at least half of the day most days and of sufficient severity to be noticeable in the child's environment (e.g. parents, teachers, peers).

3. Hyperarousal, as defined by at least three of the following symptoms: insomnia, agitation, distractibility, racing thoughts or flight of ideas, pressured speech, intrusiveness.

4. Compared to his/her peers, the child exhibits markedly increased reactivity to negative emotional stimuli that is manifest verbally and/or behaviorally. For example, the child responds to frustration with extended temper tantrums (inappropriate for age and/or precipitating event), verbal rages, and/or aggression toward people or property. Such events occur, on average, at least three times a week.

5. Criteria 2, 3, and 4 are currently present and have been present for at least 12 months without any symptom free periods exceeding two months.

6. The onset of symptoms must be prior to age 12 years.

7. The symptoms are severe in at least one setting (e.g. violent outbursts, extreme verbal abuse, assaultiveness at home, school, or with peers). In addition. There are at least mild symptoms (distractibility, intrusiveness) in a second setting.

8. Score > 9 on either the Inattentive or Hyperactive/Impulsive subscales of the baseline ADHD-RS.

9. Score < 12 on the irritability subscale of the Aberrant Behavior Checklist. -

Exclusion Criteria:

1. As evidenced in the mania section of the Kiddie-Schedule for Affective Disorders and Schizophrenia, the individual exhibits any of these cardinal bipolar symptoms in distinct periods lasting more than 1 day, and therefore meets criteria for bipolar disorder not otherwise specified (NOS):

1. Elevated or expansive mood. ii) Grandiosity or inflated self esteem. iii) Decreased need for sleep. iv) Increase in goal-directed activity (this can result in the excessive involvement in pleasurable activities that have a high potential for painful consequences).

1. Meets criteria for schizophrenia, schizophreniform, schizoaffective illness, PTSD, or conduct disorder.

2. T-score greater than/equal to 60 on baseline Social Responsiveness Scale

3. Meets criteria for substance use disorder in the three months prior to baseline.

4. Full scale intelligence < 70.

5. The symptoms are due to the direct physiological effects of drug abuse, or to a general medical or neurological condition.

6. Currently pregnant or lactating, or sexually active without using an acceptable method of contraception.

7. Failed an adequate trials (defined as four weeks of consecutive treatment at the minimally effective dose) or severe ill effects while on therapeutic doses of SSRI therapy.

8. Hypersensitivity or severe adverse reaction to methylphenidate.

9. History of fainting after exercise, syncope, a young family with sudden cardiac death, or known structural heart defect.

10. A serious history of adverse reactions (psychosis, severely increased activation compared to baseline) to methylphenidate or amphetamines.

11. Any chronic medical condition that requires medication that is contraindicated with SSRI or stimulant therapy, or any serious chronic or unstable medical disorder.

12. Medical contraindication to treatment with SSRI or stimulant therapy. -

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Semel Institute	Los Angeles	California	United States	90095

Sponsors and Collaborators

• University of California, Los Angeles
• National Institute of Mental Health (NIMH)
• Shire

Investigators

• Principal Investigator: James J McGough, M.D., University of California, Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: James McGough, Professor of Clinical Psychiatry, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT01714310
• Other Study ID Numbers: U01MH093582; U01MH093582
• First Posted: Oct 25, 2012
• Last Update Posted: Feb 26, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by James McGough, Professor of Clinical Psychiatry, University of California, Los Angeles: severe mood dysregulation; irritability; lisdexamfetamine; fluoxetine; newly recognized syndrome
• Additional relevant MeSH terms: Lisdexamfetamine Dimesylate; Fluoxetine

Study Results

Participant Flow

Pre-assignment Detail	At completion of open lisdexamfetamine, participants who achieved Clinical Global Impression Severity (CGI-S) SMD score < 4 were deemed sufficiently improved, and not randomized to adjunctive treatment. N=4 participants were sufficiently improved and completed study participation at study week 4, prior to randomization

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at study week 4 and continuing to study week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at study week 4 and continuing through study week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing to the end of study week 4.
Period Title: Open Lisdexamfetamine Titration
STARTED	0	0	34
COMPLETED	0	0	30
NOT COMPLETED	0	0	4
Period Title: Open Lisdexamfetamine Titration
STARTED	12	14	0
COMPLETED	10	11	0
NOT COMPLETED	2	3	0

Baseline Characteristics

Arm/Group Title	Open Lisdexamfetamine	Fluoxetine	Placebo	Total
Arm/Group Description	All eligible participants initially titrated to optimal dose open lisdexamfetamine from baseline through week 3.	Randomized participants who competed open-label lisdexamfetamine titration from baseline through week 3, who continued to meet eligibility criteria, and then proceeded to adjunctive fluoxetine therapy from week 4 through week 12.	Randomized participants who competed open-label lisdexamfetamine titration from baseline through week 3, who continued to meet eligibility criteria, and then proceeded to adjunctive placebo from week 4 through week 12.	Total of all reporting groups
Overall Participants	34	12	14	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.24 (2.58)	9.97 (2.30)	10.22 (2.74)	NA (NA)
Sex: Female, Male (Count of Participants)
Female	13 38.2%	5 41.7%	5 35.7%	23 38.3%
Male	21 61.8%	7 58.3%	9 64.3%	37 61.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 17.6%	5 41.7%	0 0%	11 18.3%
Not Hispanic or Latino	28 82.4%	7 58.3%	14 100%	49 81.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 2.9%	0 0%	0 0%	1 1.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 2.9%	0 0%	0 0%	1 1.7%
White	27 79.4%	8 66.7%	13 92.9%	48 80%
More than one race	5 14.7%	4 33.3%	1 7.1%	10 16.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Wechsler Abbreviated Scale of Intelligence (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	103.16 (14.30)	105.58 (15.56)	101.69 (14.34)	NA (NA)
Clinical Global Impression SMD Severity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.82 (.52)	4.75 (.46)	4.83 (.72)	NA (NA)
Affective Reactivity Index Parent Report (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.91 (2.47)	10.00 (1.95)	8.57 (2.17)	NA (NA)

Outcome Measures

1. Primary Outcome

Title	Clinical Global Impression-Severity-Severe Mood Dysregulation
Description	A dimensional clinician rating of overall SMD related impairment, modified by the National Institute of Mental Health to assess specific domains pertinent to Severe Mood Dysregulation. Minimum score = 1. Maximum score = 7. Higher scores means greater impairment.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Compares groups lisdexamfetamine plus fluoxetine vs. lisdexamfetamine plus placebo over 12 week trial. Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine starting at baseline (week 0) and continuing through study week.
Measure Participants	12	14	34
Baseline	4.91 (.53)	3.62 (.48)	4.30 (.32)
Week 4	4.42 (.34)	4.57 (.31)	4.31 (.19)
Week 5	4.15 (.36)	3.51 (.32)
Week 6	3.67 (.34)	3.90 (.33)
Week 7	3.61 (.37)	3.59 (.34)
Week 8	3.42 (.39)	3.37 (.34)
Week 10	3.45 (.42)	3.11 (.35)
Week 12	3.51 (.38)	3.30 (.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.58
	Comments	Group: F=.31, df=1/140
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.85
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=.03, df=1/140

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.26
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=1.28, df=1/140

2. Secondary Outcome

Title	ADHD-IV Rating Scale
Description	A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at end of study week 4 6 continuing through week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at end of study week 4 and continuing through week.	All eligible participants initially titrated to optimal dose open lisdexamfetamine at study visits 2-6.
Measure Participants	12	14	34
Baseline	34.50 (1.97)	34.31 (1.87)	34.20 (1.15)
Week 4	14.92 (1.97)	18.64 (1.82)	16.59 (1.21)
Week 12	16.29 (2.10)	11.93 (1.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.97
	Comments	Group: F=0.00, df=1/44
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline through week 12) and time2 (weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0002
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=136.22, df=1/44

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=64.90, df=1/44

3. Secondary Outcome

Title	Conners Parent Global Index
Description	Parent completed dimensional measure of ADHD symptoms, with score range from 0 - 30 and higher scores indicating more severe symptoms.
Time Frame	Baseline through week 3.

Outcome Measure Data

Analysis Population Description

Participants were assessed on this measure only during the Open Lisdexamfetamine phase. Some participant discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing tp week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 and continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	0	0	34
Baseline	15.91 (.82)
Week 1	9.54 (.82)
Week 2	10.60 (.85)
Week 3	8.60 (.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Lisdexamfetamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Time: F=41.85, df=1/89, p<.0001.
	Method	Mixed Models Analysis
	Comments	Linear regression of outcome change over time within single group.

4. Secondary Outcome

Title	Conners Global Index Emotional Lability Subscale - Parent Report
Description	A sub scale of the Conners Global Index, with scores ranging from 0 - 12, with higher scores indicating more impairment.
Time Frame	Baseline to week 3.

Outcome Measure Data

Analysis Population Description

Participants were assessed on this measure only during the Open Lisdexamfetamine phase. Some participants discontinues as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through week 4.
Measure Participants	0	0	34
Baseline	8.81 (.52)
Week 1	5.90 (.52)
Week 2	6.33 (.53)
Week 3	5.45 (.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Lisdexamfetamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Time: F=26.65, df=1/92, p <.0001.
	Method	Mixed Models Analysis
	Comments	Linear regression of outcome change over time within single group.

5. Secondary Outcome

Title	Conners Global Index Restless-Impulsive Subscale Parent Report
Description	A dimensional parent report measure of restless-impulsive symptoms, with scores ranging from 0 to 21, and higher scores indicating greater impairment.
Time Frame	Baseline through week 3.

Outcome Measure Data

Analysis Population Description

Participants were assessed on this measure only during the Open Lisdexamfetamine phase. Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 though week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine at study visits 2-6.
Measure Participants	0	0	34
Baseline	15.91 (.82)
Week 1	9.55 (.82)
Week 2	10.60 (.85)
Week 3	8.60 (.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Lisdexamfetamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Time: F=40.35, df=1/89, p < .0001.
	Method	Mixed Models Analysis
	Comments	Linear regression of outcome change over time within single group.

6. Secondary Outcome

Title	Conners Teacher Global Index
Description	Teacher completed dimensional measure of ADHD symptoms, with scores ranging from 0 - 30, and higher scores indicating more severe impairment.
Time Frame	Baseline through week 3.

Outcome Measure Data

Analysis Population Description

Participants were assessed on this measure only during the Open Lisdexamfetamine phase. Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	0	0	34
Baseline	18.13 (1.87)
Week 1	13.21 (1.87)
Week 2	10.18 (1.93)
Week 3	8.31 (1.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Open Lisdexamfetamine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Time: F=26.36, df=1/29, p <.0001.
	Method	Mixed Models Analysis
	Comments	Linear regression of outcome change over time within single group.

7. Secondary Outcome

Title	Affective Reactivity Index - Parent Report
Description	A parent completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	10.00 (.96)	8.57 (.88)	9.29 (.92)
Week 4	7.58 (.96)	7.71 (.88)	6.87 (.59)
Week 5	6.58 (.96)	6.21 (.88)
Week 6	6.42 (.96)	5.32 (.90)
Week 7	6.69 (1.00)	6.49 (1.00)
Week 8	6.49 (1.00)	5.62 (.90)
Week 10	6.74 (1.07)	4.89 (.97)
Week 12	6.39 (1.00)	5.30 (.94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.44
	Comments	Group: F=.60, df=1/157
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=22.39, df=1/157

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.04
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=4.40, df=1/157

8. Secondary Outcome

Title	Revised Modified Overt Aggression Scale - Total Score
Description	A parent rated retrospective dimensional assessment of oppositional and aggressive behaviors, with scores ranging from 0-40, and higher scores indicating greater severity.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	22.23 (4.44)	33.68 (4.08)	26.03 (2.61)
Week 4	14.44 (4.30)	25.35 (3.98)	17.93 (2.67)
Week 5	13.72 (4.31)	20.60 (4.19)
Week 6	10.00 (4.20)	20.55 (3.98)
Week 7	13.19 (4.45)	21.89 (4.32)
Week 8	14.09 (4.45)	21.33 (4.08)
Week 10	12.61 (4.60)	17.68 (4.47)
Week 12	14.29 (4.45)	18.34 (4.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.05
	Comments	Group: F=3.81, df=1/145
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
Other Statistical Analysis		No significant group*time interactions. Group trend likely due to baseline differences.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.0001
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Tie: F=15.28, df=1/145

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=5.42, df=1/145

9. Secondary Outcome

Title	Clinical Global Impression - Improvement
Description	Percentage improved by treatment group
Time Frame	Percentage improved at week 4 for Open Lisdexamfetamine group and at week 12 for fluoxetine and placebo groups.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at study week 4 and continuing to study week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at study week 4 and continuing through study week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	10	11	34
Count of Participants [Participants]	7 20.6%	7 58.3%	8 57.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.76
	Comments
	Method	Chi-squared
	Comments	Chi Square = .10, df=1, p=.76

10. Secondary Outcome

Title	Height
Description	A dimensional measure assessed in cms.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	140.25 (3.82)	144.63 (3.53)	142.37 (2.12)
Week 1	140.05 (3.81)	144.76 (3.53)	142.35 (2.12)
Week 2	139.95 (3.82)	144.81 (3.53)	142.43 (2.12)
Week 3	140.26 (3.82)	144.88 (3.53)	142.59 (2.12)
Week 4	140.56 (3.82)	144.54 (3.53)	142.59 (2.12)
Week 5	140.11 (3.82)	144.82 (3.53)
Week 6	140.21 (3.82)	145.44 (3.53)
Week 7	140.55 (3.82)	145.14 (3.53)
Week 8	140.81 (3.82)	144.98 (3.53)
Week 10	140.83 (3.82)	145.30 (3.54)
Week 12	140.98 (3.82)	145.60 (3.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.38
	Comments	Group: F=.78, df=1/220
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline through week 12) and time2 (weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.42
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=.66, df=1/220

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.13
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=.66, df=1/220

11. Secondary Outcome

Title	Weight
Description	Weight in kg.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	37.96 (5.26)	47.26 (4.87)	42.59 (3.16)
Week 1	37.29 (5.26)	46.39 (4.87)	41.83 (3.16)
Week 2	36.96 (5.26)	45.56 (4.87)	41.29 (3.16)
Week 3	36.55 (5.26)	45.06 (4.87)	40.73 (3.16)
Week 4	36.20 (5.26)	45.22 (4.87)	40.67 (3.16)
Week 5	36.08 (5.26)	44.80 (4.87)
Week 6	35.73 (5.26)	44.34 (4.87)
Week 7	35.30 (5.26)	44.72 (4.87)
Week 8	35.08 (5.26)	44.08 (4.87)
Week 10	34.61 (5.26)	44.16 (4.87)
Week 12	34.73 (5.26)	43.05 (4.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.21
	Comments	Group: F=1.56, df=1/222
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=63.11, df=1/222

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.0004
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=12.86, df=1/222

12. Secondary Outcome

Title	Pulse
Description	Heart rate in beats per minute.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	82.28 (3.26)	84.64 (3.22)	80.84 (2.30)
Week 1	95.08 (3.16)	85.21 (2.91)	88.15 (2.13)
Week 2	88.25 (3.15)	81.64 (2.91)	84.33 (2.13)
Week 3	96.32 (3.26)	85.79 (3.01)	90.71 (2.26)
Week 4	93.08 (3.15)	83.21 (2.91)	88.45 (2.23)
Week 5	94.16 (3.26)	83.00 (3.23)
Week 6	87.33 (3.15)	90.55 (3.12)
Week 7	91.94 (3.55)	90.00 (3.22)
Week 8	87.17 (3.40)	85.10 (3.00)
Week 10	95.83 (3.55)	82.90 (3.52)
Week 12	92.75 (3.55)	90.62 (3.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments	Group: F=5.42, df=1/223
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.18
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=1.77, df=1/223

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.49
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=.47, df=1/223

13. Secondary Outcome

Title	Systolic Blood Pressure
Description	Systolic Blood Pressure measured in mmHG
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	107.85 (4.01)	106.68 (3.92)	107.40 (2.69)
Week 1	99.42 (3.89)	111.71 (3.60)	106.03 (2.53)
Week 2	104.83 (3.89)	110.36 (3.60)	107.48 (2.53)
Week 3	109.20 (4.01)	109.89 (3.70)	110.73 (2.67)
Week 4	112.00 (3.89)	110.07 (3.60)	111.77 (2.65)
Week 5	109.57 (4.01)	104.20 (3.93)
Week 6	111.58 (3.89)	108.98 (3.80)
Week 7	112.04 (4.31)	112.80 (3.92)
Week 8	111.20 (4.31)	110.94 (3.96)
Week 10	112.25 (4.31)	105.67 (4.23)
Week 12	116.15 (4.31)	113.90 (3.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.90
	Comments	Group: F=.02, df=1/223
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.21
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=1.60, df=1/223

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.73
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=.12, df=1/223

14. Secondary Outcome

Title	Diastolic Blood Pressure
Description	Diastolic Blood pressure measured in mmHG.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

Some participants discontinued as trial progressed.

Arm/Group Title	Fluoxetine	Placebo	Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 continuing to week 12.	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at week 4 continuing through week 12.	All eligible participants initially titrated to optimal dose open lisdexamfetamine beginning at baseline (week 0) and continuing through study week 4.
Measure Participants	12	14	34
Baseline	68.86 (2.36)	66.40 (2.34)	67.39 (1.56)
Week 1	71.33 (2.27)	69.50 (2.10)	69.15 (1.45)
Week 2	66.00 (2.27)	66.79 (2.10)	66.63 (1.45)
Week 3	68.74 (2.36)	62.82 (2.18)	67.21 (1.56)
Week 4	71.17 (2.27)	66.21 (2.10)	69.31 (1.53)
Week 5	71.17 (2.36)	65.17 (2.34)
Week 6	69.58 (2.27)	70.61 (2.25)
Week 7	68.14 (2.58)	70.64 (2.34)
Week 8	68.06 (2.46)	68.40 (2.17)
Week 10	70.81 (2.58)	67.06 (2.56)
Week 12	77.11 (2.58)	70.05 (2.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.15
	Comments	Group: F=2.05, df=1/223
	Method	Mixed Models Analysis
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.59
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time: F=.29, df=1/223

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.14
	Comments	Partial linear regression using mixed model, assessing outcome variable over time (baseline to study week 12) and time2 (study weeks 4-12).
	Method	Mixed Models Analysis
	Comments	Time2: F=2.15, df=1/223

15. Other Pre-specified Outcome

Title	Pediatric Anxiety Rating Scale
Description	Clinician completed dimensional assessment of anxiety symptoms.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Other Pre-specified Outcome

Title	Children's Depression Rating Scale
Description	Clinician completed dimensional rating of depressive symptoms.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Other Pre-specified Outcome

Title	Affective Reactivity Index Child Report
Description	Dimensional self-report of irritability, with total score 1-12, and higher scores indicating greater severity.
Time Frame	Baseline through week 12.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Baseline through study week 12.
Adverse Event Reporting Description	Adverse events were collected via structured ratings, including the Columbia Suicide Severity Rating Scale and the Side Effects Rating Scale.
Arm/Group Title	Fluoxetine		Placebo		Open Lisdexamfetamine
Arm/Group Description	All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive fluoxetine at week 4 and continuing though week 12.		All participants initially enrolled in open lisdexamfetamine treatment, followed by randomization to adjunctive placebo at study week 4 and continuing through week 12.		All eligible participants initially titrated to optimal dose open lisdexamfetamine from baseline through week 4.
All Cause Mortality
	Fluoxetine		Placebo		Open Lisdexamfetamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/14 (0%)		0/34 (0%)
Serious Adverse Events
	Fluoxetine		Placebo		Open Lisdexamfetamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/14 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Fluoxetine		Placebo		Open Lisdexamfetamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)		10/14 (71.4%)		30/34 (88.2%)
Cardiac disorders
Heart skips beats	0/12 (0%)	0	2/14 (14.3%)	2	0/34 (0%)	0
Racing heart	0/12 (0%)	0	2/14 (14.3%)	2	2/34 (5.9%)	2
Chest pain	1/12 (8.3%)	1	0/14 (0%)	0	2/34 (5.9%)	2
Gastrointestinal disorders
Stomach pain/ache	0/12 (0%)	0	1/14 (7.1%)	1	4/34 (11.8%)	5
Nausea/vomiting	1/12 (8.3%)	1	1/14 (7.1%)	1	2/34 (5.9%)	3
Diarrhea	2/12 (16.7%)	2	1/14 (7.1%)	1	3/34 (8.8%)	3
Constipation	3/12 (25%)	3	0/14 (0%)	0	0/34 (0%)	0
Heartburn	1/12 (8.3%)	1	0/14 (0%)	0	0/34 (0%)	0
General disorders
Feeling drowsy/sleep	1/12 (8.3%)	2	1/14 (7.1%)	1	4/34 (11.8%)	5
Dry mouth	0/12 (0%)	0	3/14 (21.4%)	3	4/34 (11.8%)	6
Restless/uncomfortable urge to move	1/12 (8.3%)	1	2/14 (14.3%)	4	1/34 (2.9%)	2
Decreased appetite	7/12 (58.3%)	24	6/14 (42.9%)	11	21/34 (61.8%)	51
Nervous system disorders
Headache	1/12 (8.3%)	1	1/14 (7.1%)	1	5/34 (14.7%)	8
Excessive sweating	0/12 (0%)	0	1/14 (7.1%)	1	3/34 (8.8%)	3
Tremor/shakiness	0/12 (0%)	0	0/14 (0%)	0	1/34 (2.9%)	2
Tics	2/12 (16.7%)	2	3/14 (21.4%)	3	4/34 (11.8%)	7
Bites fingernails	3/12 (25%)	5	2/14 (14.3%)	6	5/34 (14.7%)	7
Psychiatric disorders
Wish to be dead	1/12 (8.3%)	3	2/14 (14.3%)	2	0/34 (0%)	0
Suicidal ideation without intent	1/12 (8.3%)	1	0/14 (0%)	0	0/34 (0%)	0
Trouble sleeping	1/12 (8.3%)	1	4/14 (28.6%)	6	9/34 (26.5%)	15
Sleeplessness	1/12 (8.3%)	6	2/14 (14.3%)	4	4/34 (11.8%)	9
Nightmares	0/12 (0%)	0	2/14 (14.3%)	3	1/34 (2.9%)	1
Euphoria	1/12 (8.3%)	1	1/14 (7.1%)	1	1/34 (2.9%)	1
Talks less with others	1/12 (8.3%)	1	2/14 (14.3%)	2	1/34 (2.9%)	1
Prone to crying	0/12 (0%)	0	3/14 (21.4%)	3	6/34 (17.6%)	9
Renal and urinary disorders
Frequent urination	0/12 (0%)	0	0/14 (0%)	0	1/34 (2.9%)	2

Limitations/Caveats

Study was designed as an initial feasibility and proof of concept trial. Initial power analysis suggested need to randomize N=50 participants. Recruitment was much more difficult than expected, leading to small sample size.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.