Effectiveness of Vyvanse Compared to Concerta in Adolescents With Attention-deficit/Hyperactivity Disorder

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01552902
• Collaborator: (none)
• Enrollment: 549
• Locations: 95
• Arms: 3
• Actual Duration (Months): 25.6
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine effectiveness of Vyvanse compared to Concerta in adolescents with Attention-deficit/Hyperactivity Disorder (ADHD).

Condition or Disease	Intervention/Treatment	Phase
Attention-deficit/Hyperactivity Disorder	Drug: Lisdexamfetamine dimesylate; Drug: Methylphenidate Hydrochloride; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 549 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 4, Randomized, Double-blind, Multicenter, Parallel-group, Active-controlled, Forced-dose Titration, Safety and Efficacy Study of SPD489 (VYVANSE®) Compared With OROS-MPH (CONCERTA®) With a Placebo Reference Arm, in Adolescents Aged 13-17 Years With Attention-deficit/Hyperactivity Disorder (ADHD)
• Actual Study Start Date: Apr 3, 2012
• Actual Primary Completion Date: May 22, 2014
• Actual Study Completion Date: May 22, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lisdexamfetamine dimesylate	Drug: Lisdexamfetamine dimesylate; Daily oral dosing in the AM ranging from 30- 70 mg. 4 week forced dose titration, 2 week dose maintenance; Other Names: SPD489, Vyvanse, LDX
Active Comparator: Methylphenidate Hydrochloride	Drug: Methylphenidate Hydrochloride; Daily oral dosing in the AM ranging from 18-72 mg. 4 week force dose titration, 2 week dose maintenance; Other Names: Concerta, OROS-MPH
Placebo Comparator: Placebo	Drug: Placebo; Daily oral dosing in the AM for 6 weeks

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6 [Baseline, Week 6]

   The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms.

Secondary Outcome Measures

1. Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6 [Week 6]

   The Clinical Global Impressions Scale permits a global evaluation of the participant's severity of illness and improvement over time. The scale included a severity of illness item and a global improvement item. The investigator performed the CGI-I to rate the improvement of a participant's ADHD symptoms based on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse.). Percentage of participants with an improved measurement (response of very much improved and much improved) is reported.

Other Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [Baseline up to 3 days after last dose (last dose at Week 6)]

   An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of double-blind investigational product and up to 3 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

2. Change From Baseline in Blood Pressure at Week 6 [Baseline, Week 6]

3. Change From Baseline in Pulse Rate at Week 6 [Baseline, Week 6]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject must be 13-17 years of age, inclusive, at the time of consent.

• Subject must weigh more than 79.5lb.

• The parent/LAR must be available at approximately 7:00AM (±2 hours) to dispense the dose of investigational product for the study duration.

• Subject, who is a female, must have a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test and a negative urine pregnancy test and agree to comply with any applicable contraceptive requirements of the protocol.

• Subject has an ADHD-RS-IV total score ≥28.

• Subject is able to swallow a capsule.

• Subject does not have hypertension and has a resting sitting blood pressure less than or equal to 135/85mmHg.

Exclusion Criteria

• Subject has a current, controlled (with medications prohibited in this study) or uncontrolled, comorbid psychiatric diagnosis with significant symptoms such as any significant comorbid Axis II disorder or significant Axis I disorder (such as post traumatic stress disorder, psychosis, bipolar illness, pervasive developmental disorder, severe obsessive compulsive disorder, depressive or anxiety disorder.

• Diagnosis of conduct disorder. Oppositional defiant disorder is not exclusionary.

• Subject is considered a suicide risk, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded.

• Subject is underweight or overweight.

• Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition. Mild, stable asthma is not exclusionary.

• Subject has a history of seizures (other than infantile febrile seizures), a chronic or current tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder.

• Subject has a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place him/her at increased vulnerability to the sympathomimetic effects of a stimulant medication.

• Subject has a known family history of sudden cardiac death or ventricular arrhythmia.

• Subject has any clinically significant ECG or clinically significant laboratory abnormality.

• Subject has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone (TSH) and thyroxine (T4). Treatment with a stable dose of thyroid medication for at least 3 months is permitted.

• Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product.

• Subject has a documented allergy, hypersensitivity, or intolerance to MPH or to any excipients in the reference product.

• Subject has failed to fully respond to an adequate course(s) (dose and duration) of MPH or amphetamine therapy.

• Subject has a history of suspected substance abuse or dependence disorder (excluding nicotine). Subjects with a lifetime history of amphetamine, cocaine, or other stimulant abuse and/or dependence will be excluded.

• Subject has a positive urine drug result.

• Subject has previously participated in this study or another clinical study involving SPD489/NRP104.

• Subject has glaucoma.

• Subject is required to take or anticipates the need to take medications that have CNS effects or affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are monoamine oxidase inhibitors. Stable use of bronchodilator inhalers is not exclusionary.

• Subject is female and is pregnant or lactating.

• Subject is well controlled on his/her current ADHD medication.

• Subject has a pre-existing severe gastrointestinal tract narrowing.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harmonex Neuroscience Research, Inc.	Dothan	Alabama	United States	36303
2	Center for Advanced Improvement	Tucson	Arizona	United States	85719
3	Clinical Study Centers, LLC	Little Rock	Arkansas	United States	72211
4	Shanti Clinical Trials	Colton	California	United States	92324
5	Sun Valley Research Center	Imperial	California	United States	92251
6	Synergy Clinical Research Center	National City	California	United States	91950
7	Pacific Sleep Medicine, A Medical Corporation	Oceanside	California	United States	92054
8	Neuropsychiatric Research Center for Orange County	Orange	California	United States	92868
9	Peninsula Research Associates	Rolling Hills Estates	California	United States	90274
10	PCSD - Feighner Research	San Diego	California	United States	92108
11	University of California, San Francisco	San Francisco	California	United States	94143
12	Encompass Clinical Research	Spring Valley	California	United States	91978
13	Elite Clinical Trials	Wildomar	California	United States	92595
14	IMMUNOe International Research Center	Centennial	Colorado	United States	80112
15	MCB Clinical Research Centers, LLC	Colorado Springs	Colorado	United States	80910
16	Coastal Connecticut Research, LLC	New London	Connecticut	United States	06320
17	Florida Clinical Research Center, LLC	Bradenton	Florida	United States	34201
18	Amedica Research Institute, Inc	Hialeah	Florida	United States	33013
19	Clinical Neuroscience Solutions, Inc	Jacksonville	Florida	United States	32256
20	Sarkis Clinical Trials	Lake City	Florida	United States	32055
21	Florida Clinical Research Center, LLC	Maitland	Florida	United States	32751
22	Prevention & Strengthening Solutions, Inc.	Miami	Florida	United States	33169
23	Scientific Clinical Research, Inc.	North Miami	Florida	United States	33161
24	Medical Research Group of Central Florida	Orange City	Florida	United States	32763
25	Clinical Neuroscience Solutions, Inc.	Orlando	Florida	United States	32806
26	Compass Research, LLC	Orlando	Florida	United States	32806
27	Miami Research Associates	South Miami	Florida	United States	33143
28	Stedman Clinical Trials	Tampa	Florida	United States	33613
29	Atlanta Institute of Medicine & Research, Inc	Atlanta	Georgia	United States	30328
30	Clinical Research Center, University of Illinois at Chicago	Chicago	Illinois	United States	60608
31	Capstone Clinical Research	Libertyville	Illinois	United States	60048
32	Baber Research Group	Naperville	Illinois	United States	60563
33	Pedia Research, LLC	Newburgh	Indiana	United States	47630
34	Psychiatric Associates	Overland Park	Kansas	United States	66211
35	Pedia Research, LLC	Owensboro	Kentucky	United States	42301
36	Louisiana Resarch Associates, Inc.	New Orleans	Louisiana	United States	70114
37	Marc Hertzman, MD, PC	Rockville	Maryland	United States	20852
38	Rochester Center for Behavioral Medicine	Rochester Hills	Michigan	United States	48307
39	Clinical Neurophysiology Services, PC	Sterling Heights	Michigan	United States	48314
40	Behavioral Medical Center - Troy	Troy	Michigan	United States	48083
41	Comprehensive Psychiatric Associates	Gladstone	Missouri	United States	64118
42	Psychiatric Care & Research Center	O'Fallon	Missouri	United States	63368
43	St. Charles Psychiatric Associates - Midwest Research Group	Saint Charles	Missouri	United States	63301
44	Premier Psychiatric Research Institute, LLC	Lincoln	Nebraska	United States	68526
45	University of Nebraska Medical Center Dept Of Psychiatry	Omaha	Nebraska	United States	68198
46	Center for Psychiatry & Behavioral Medicine, Inc.	Las Vegas	Nevada	United States	89128
47	Center for Emotional Fitness	Cherry Hill	New Jersey	United States	08002
48	The NeuroCognitive Institute	Mount Arlington	New Jersey	United States	07856
49	Albuquerque Neuroscience, Inc.	Albuquerque	New Mexico	United States	87109
50	Brain Resource Center	New York	New York	United States	10023
51	Mount Sinai School of Medicine/Dept of Psychiaatry	New York	New York	United States	10029
52	Duke University medical Center/ Duke ADHD Program	Durham	North Carolina	United States	27705
53	PMG Research of Wilmington	Wilmington	North Carolina	United States	28401
54	University of Cincinnati College of Medicine/UCPC	Cincinnati	Ohio	United States	45219
55	The Ohio State University Nisonger Center	Columbus	Ohio	United States	43210
56	Tulsa Clinical Research, LLC	Tulsa	Oklahoma	United States	74104
57	Cyn3rgy Research	Gresham	Oregon	United States	97030
58	Oregon Center for Clinical Investigations Inc	Portland	Oregon	United States	97210
59	Summit Research Network	Portland	Oregon	United States	97210
60	Oregon Center for Clinical Investigations, Inc	Salem	Oregon	United States	97301
61	University Services	West Chester	Pennsylvania	United States	19380
62	Omega Medical Research	Warwick	Rhode Island	United States	02886
63	Rainbow Research, Inc.	Barnwell	South Carolina	United States	29812
64	Clinical Neuroscience Solutions, Inc.	Memphis	Tennessee	United States	38119
65	FutureSearch Trials of Dallas, LP	Dallas	Texas	United States	75231
66	Research Across America/Psychiatric Medical Associates	Dallas	Texas	United States	75234
67	Bayou City Research	Houston	Texas	United States	77007
68	Claghorn-Lesem Research Clinic, Ltd.	Houston	Texas	United States	77008
69	Clinical Trial Network	Houston	Texas	United States	77074
70	Texas Center for Drug Development, Inc.	Houston	Texas	United States	77081
71	Red Oak Psychiatry Associates, PA	Houston	Texas	United States	77090
72	Houston Clinical Trials, LLC	Houston	Texas	United States	77098
73	Westex Clinical Investigations	Lubbock	Texas	United States	79423
74	Clinical Trials of Texas, Inc.	San Antonio	Texas	United States	78229
75	Univ of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
76	Ericksen Research and Development - Westside Medical	Clinton	Utah	United States	84015
77	University of Virginia Child and Family Psychiatry Clinic	Charlottesville	Virginia	United States	22903
78	Northwest Clinical Research Center	Bellevue	Washington	United States	98007
79	Eastside Thereapeutic Resource	Kirkland	Washington	United States	98033
80	Summit Research Network (Seattle), LLC	Seattle	Washington	United States	98104
81	Rockwood Clinic, P.S.	Spokane	Washington	United States	99202
82	True North Clinical Research	Kentville	Nova Scotia	Canada	B4N 4K9
83	The Kids Clinic	Whitby	Ontario	Canada	L1N 2L1
84	Schwerpunktpraxis fur Entwicklung und Lernen	Bamberg		Germany	96047
85	Klinik Fur Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie	Frankfurt		Germany	15236
86	Universitatsklinikum Freiburg	Freiburg		Germany	79104
87	Kinderarztpraxis Dr. Kaiser und Dr. MarineBe	Hamburg		Germany	22415
88	Zentralinstitut fur Seelische Gesundheit	Mannheim		Germany	68159
89	Medizinisches Studienzentrum Wurzburg	Wurzburg		Germany	97070
90	Vadaskert Gyermekpszichiatriai Korhaz es Szakambulancia	Budapest		Hungary	H-1021
91	Bekes Megyei Pandy Kalman Korhaz	Gyula		Hungary	H-5700
92	Pecsi Megyei Jogu varos Egyesitett Egeszsegugyi Intezmenyek	Pecs		Hungary	H-7632
93	Szegedi Tudomanyegyetem	Szeged		Hungary	H-6725
94	Gillbergcentrum	Goteborg		Sweden	411 19
95	PRIMA Barn-och Vuxenpsykiatri Jarva	Spanga		Sweden	163 74

Sponsors and Collaborators

• Shire

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT01552902
• Other Study ID Numbers: SPD489-406; 2011-005452-34
• First Posted: Mar 13, 2012
• Last Update Posted: Jun 10, 2021
• Last Verified: May 1, 2021

• Keywords provided by Shire: ADHD
• Additional relevant MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity; Methylphenidate; Lisdexamfetamine Dimesylate

Study Results

Participant Flow

Recruitment Details	The study was conducted at 77 sites in the United States, Canada, and Europe.
Pre-assignment Detail	Of the 778 screened participants, 229 were screen failures and 549 were randomized to treatment. A total of 547 participants were treated and the reasons for 2 'randomized but not treated' participants included withdrawal by 1 participant in the Methylphenidate group and 1 participant with a protocol violation in the Lisdexamfetamine group.

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 milligram (mg) over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, Osmotic controlled oral release delivery system-methylphenidate [OROS-MPH]) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
Period Title: Overall Study
STARTED	110	218	219
COMPLETED	97	181	186
NOT COMPLETED	13	37	33

Baseline Characteristics

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate	Total
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).	Total of all reporting groups
Overall Participants	110	218	219	547
Age (Count of Participants)
<=18 years	110 100%	218 100%	219 100%	547 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.7 (1.37)	14.6 (1.38)	14.7 (1.42)	14.7 (1.40)
Sex: Female, Male (Count of Participants)
Female	34 30.9%	83 38.1%	69 31.5%	186 34%
Male	76 69.1%	135 61.9%	150 68.5%	361 66%
Attention-deficit/Hyperactivity Disorder (ADHD) Subtype (Count of Participants)
Predominantly Inattentive	40 36.4%	70 32.1%	71 32.4%	181 33.1%
Predominantly Hyperactive/Impulsive	2 1.8%	2 0.9%	4 1.8%	8 1.5%
Combined Subtype	68 61.8%	146 67%	144 65.8%	358 65.4%
Clinical Global Impressions - Severity of Illness (CGI-S) (Count of Participants)
Borderline mentally ill	1 0.9%	0 0%	0 0%	1 0.2%
Mildly ill	2 1.8%	4 1.8%	1 0.5%	7 1.3%
Moderately ill	60 54.5%	93 42.7%	115 52.5%	268 49%
Markedly ill	41 37.3%	106 48.6%	90 41.1%	237 43.3%
Severely ill	6 5.5%	15 6.9%	13 5.9%	34 6.2%
Attention-deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	36.1 (5.91)	37.2 (6.46)	36.9 (6.42)	36.9 (6.34)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6
Description	The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms.
Time Frame	Baseline, Week 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) was defined as all participants in the Safety set who had at least 1 post-baseline measurement of the ADHD-RS-IV. Not all FAS participants were evaluable for this outcome measure.

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
Measure Participants	93	175	181
Least Squares Mean (Standard Error) [units on a scale]	-17 (1.03)	-25.4 (0.74)	-22.1 (0.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lisdexamfetamine Dimesylate, Methylphenidate
	Comments	The least squares mean (LSM), the difference in LSM and its 95% confidence interval (CI), and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on Restricted maximum likelihood (REML) method of estimation and utilized an unstructured covariance.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0013
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -5.4 to -1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lisdexamfetamine Dimesylate
	Comments	The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-8.5
	Confidence Interval	(2-Sided) 95%; -11 to -6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Methylphenidate
	Comments	The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that includes treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	-5.1
	Confidence Interval	(2-Sided) 95%; -7.6 to -2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6
Description	The Clinical Global Impressions Scale permits a global evaluation of the participant's severity of illness and improvement over time. The scale included a severity of illness item and a global improvement item. The investigator performed the CGI-I to rate the improvement of a participant's ADHD symptoms based on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse.). Percentage of participants with an improved measurement (response of very much improved and much improved) is reported.
Time Frame	Week 6

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
Measure Participants	106	210	216
Number [percentage of participants]	50 45.5%	81.4 37.3%	71.3 32.6%

3. Other Pre-specified Outcome

Title	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
Description	An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of double-blind investigational product and up to 3 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time Frame	Baseline up to 3 days after last dose (last dose at Week 6)

Outcome Measure Data

Analysis Population Description

Safety set.

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
Measure Participants	110	218	219
Participants with TEAEs	49 44.5%	145 66.5%	129 58.9%
Participants with serious TEAEs	1 0.9%	1 0.5%	1 0.5%

4. Other Pre-specified Outcome

Title	Change From Baseline in Blood Pressure at Week 6
Time Frame	Baseline, Week 6

Outcome Measure Data

Analysis Population Description

Safety set. Not all Safety set participants were evaluable for this outcome measure.

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
Measure Participants	93	175	181
Systolic blood pressure	-1 (9.88)	1.5 (9.56)	2.4 (9.97)
Diastolic blood pressure	-0.1 (8.1)	3.4 (8.15)	3.5 (8.59)

5. Other Pre-specified Outcome

Title	Change From Baseline in Pulse Rate at Week 6
Time Frame	Baseline, Week 6

Outcome Measure Data

Analysis Population Description

Safety set. Not all Safety set participants were evaluable for this outcome measure.

Arm/Group Title	Placebo	Lisdexamfetamine Dimesylate	Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.	Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).	Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
Measure Participants	93	175	181
Mean (Standard Deviation) [Beats per minute]	2.4 (10.81)	6.7 (12.46)	8.2 (12.7)

Adverse Events

Time Frame	Baseline up to 3 days after last dose (last dose at Week 6)
Adverse Event Reporting Description	AEs occurred during the double-blind evaluation phase were considered as TEAEs if AEs had a start date on or after the first dose of double-blind study drug or a start date before the date of the first dose of double-blind study drug, but increased in severity on or after the date of the first dose of double-blind study drug. Safety Set.
Arm/Group Title	Placebo		Lisdexamfetamine Dimesylate		Methylphenidate
Arm/Group Description	2 placebo over encapsulated capsules once daily orally for 6 weeks.		Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance).		Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg [2*36 mg capsules] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance).
All Cause Mortality
	Placebo		Lisdexamfetamine Dimesylate		Methylphenidate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Lisdexamfetamine Dimesylate		Methylphenidate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/110 (0.9%)		1/218 (0.5%)		1/219 (0.5%)
Infections and infestations
Appendicitis	0/110 (0%)	0	0/218 (0%)	0	1/219 (0.5%)	1
Psychiatric disorders
Suicidal ideation	0/110 (0%)	0	1/218 (0.5%)	1	0/219 (0%)	0
Psychotic episode	1/110 (0.9%)	1	0/218 (0%)	0	0/219 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Lisdexamfetamine Dimesylate		Methylphenidate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/110 (29.1%)		113/218 (51.8%)		99/219 (45.2%)
Gastrointestinal disorders
Dry mouth	1/110 (0.9%)	1	16/218 (7.3%)	18	7/219 (3.2%)	7
Nausea	3/110 (2.7%)	3	11/218 (5%)	12	11/219 (5%)	11
Abdominal pain upper	2/110 (1.8%)	2	11/218 (5%)	11	8/219 (3.7%)	8
General disorders
Irritability	7/110 (6.4%)	7	11/218 (5%)	11	15/219 (6.8%)	16
Investigations
Weight decreased	0/110 (0%)	0	23/218 (10.6%)	23	11/219 (5%)	11
Metabolism and nutrition disorders
Decreased appetite	11/110 (10%)	11	69/218 (31.7%)	74	51/219 (23.3%)	52
Nervous system disorders
Headache	9/110 (8.2%)	13	33/218 (15.1%)	45	35/219 (16%)	40
Dizziness	0/110 (0%)	0	12/218 (5.5%)	12	11/219 (5%)	11
Psychiatric disorders
Insomnia	3/110 (2.7%)	3	17/218 (7.8%)	17	17/219 (7.8%)	20

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.