Clinical Trials Register

Summary
EudraCT Number:	2011-002221-21
Sponsor's Protocol Code Number:	SPD503-312
Clinical Trial Type:	Outside EU/EEA
Date on which this record was first entered in the EudraCT database:	2011-08-30
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED

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A. Protocol Information

A.2

EudraCT number

2011-002221-21

A.3

Full title of the trial

A Phase 3, Double-blind, Randomized, Multi-center, Placebo controlled, Dose-optimization Study Evaluating the Safety, Efficacy, and Tolerability of Once daily Dosing with Extended-release Guanfacine Hydrochloride in Adolescents Aged 13-17 years Diagnosed With Attention-deficit/Hyperactivity Disorder (ADHD)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to assess the safety and efficacy of Guanfacine hydrochloride in adolescents aged 13-17 with Attention Deficit/Hyperactivity Disorder.

A.4.1

Sponsor's protocol code number

SPD503-312

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/186/2010

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Shire Development Inc
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Shire Development Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Shire Pharmaceutical Development Ltd
B.5.2	Functional name of contact point	Clinical Programs Leadership
B.5.3	Address:
B.5.3.1	Street Address	Hampshire International Business Park
B.5.3.2	Town/ city	Basingstoke
B.5.3.3	Post code	RG24 8EP
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441256894000
B.5.5	Fax number	441256894707
B.5.6	E-mail	cpmailbox@shire.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	INTUNIV
D.2.1.1.2	Name of the Marketing Authorisation holder	Shire Development Inc
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Guanfacine Hydrochloride
D.3.2	Product code	SPD503
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Guanfacine Hydrocloride
D.3.9.1	CAS number	29110-48-3
D.3.9.2	Current sponsor code	SPD503
D.3.9.3	Other descriptive name	N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Guanfacine Hydrochloride
D.3.9.1	CAS number	29110-48-3
D.3.9.2	Current sponsor code	SPD503
D.3.9.3	Other descriptive name	N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Guanfacine Hydrochloride
D.3.9.1	CAS number	29110-48-3
D.3.9.2	Current sponsor code	SPD503
D.3.9.3	Other descriptive name	N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Guanfacine Hydrocloride
D.3.9.1	CAS number	29110-48-3
D.3.9.2	Current sponsor code	SPD503
D.3.9.3	Other descriptive name	N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 4
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Attention-Deficit/Hyperactivity Disorder (ADHD)

E.1.1.1

Medical condition in easily understood language

Attention-Deficit/Hyperactivity Disorder (ADHD)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10068451
E.1.2	Term	ADHD, combined type
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10068453
E.1.2	Term	ADHD, predominantly inattentive type
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10068452
E.1.2	Term	ADHD, predominantly hyperactive-impulsive type
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10064104
E.1.2	Term	ADHD
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of once daily dosing with optimized SPD503 compared with placebo in the treatment of adolescents aged 13-17 years with a diagnosis of ADHD as measured by the Attention deficit/Hyperactivity Disorder Rating Scale (ADHD-RS-IV).

E.2.2

Secondary objectives of the trial

1. To evaluate the effect on the Clinical Global Impressions – Severity of
Illness (CGI-S) Scale.
2. To evaluate the effect on the Clinical Global Impressions – Global
Improvement (CGI-I) Scale.
3. To evaluate the changes in functional impairment as measured by the Weiss Functional Impairment Rating Scale-Parent (WFIRS-P).
4. To evaluate the safety and tolerability based on treatment-emergent adverse events (TEAEs), clinical laboratory results, electrocardiogram (ECG) results, vital signs, and results from the Brief Psychiatric Rating Scale for Children (BPRS-C), a structured side-effect questionnaire (SSEQ), and the Columbia Suicide Severity Rating Scale (C-SSRS).
5. To evaluate the tolerability based on the Pediatric Daytime Sleepiness Scale (PDSS).
6. To develop a population pharmacokinetic model of
SPD503.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, aged 13-17 years at the time of consent/assent (screening only).
2. Subject’s parent or legally authorized representative (LAR) must provide signature of informed consent, and there must be documentation of assent by the subject indicating that the subject is aware of the investigational nature of the study and the required procedures and restrictions in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidance E6 (1996) and applicable regulations before completing any study-related procedures at screening.
3. Subject meets Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD, combined subtype, hyperactive/impulsive subtype, or inattentive sub-type based on a detailed psychiatric evaluation using the Kiddie Schedule for Affective Disorders and Schizophrenia – Present and Lifetime version (K SADS PL) at screening (re-confirm if baseline visit is >35 days from screening).
4. Subject has a minimum ADHD-RS-IV total score of 32 at baseline.
5. Subject has a minimum CGI-S score of 4 at baseline.
6. Subject is functioning at an age-appropriate level intellectually, as deemed by the Investigator.
7. Subject and parent/LAR understand, are able, willing and likely to fully comply with the study procedures and restrictions defined in this protocol.
8. Subject is able to swallow intact tablets.
9. All females must have a negative serum beta human Chorionic Gonadotropin (hCG) pregnancy test at screening and a negative urine pregnancy test at baseline. Female subjects must abstain from sexual activity that could result in pregnancy or agree to use acceptable methods of contraception.
10. Subject has a supine and standing blood pressure (BP) measurement within the 95th percentile for age, gender, and height.

E.4

Principal exclusion criteria

1. Subject has a current, controlled (requiring a prohibited medication or behavioral modification program) or uncontrolled, comorbid psychiatric diagnosis except Oppositional Defiant Disorder (ODD), including any severe comorbid Axis II disorders or severe Axis I disorders such as post traumatic stress disorder (PTSD), bipolar illness, psychosis, pervasive developmental disorder, obsessive-compulsive disorder (OCD), substance abuse disorder, or other symptomatic manifestations or lifetime history of bipolar illness, psychosis, or conduct disorder that, in the opinion of the Investigator, contraindicate SPD503 treatment or confound efficacy or safety assessments.
2. Subject has any condition or illness including clinically significant abnormal screening laboratory values which, in the opinion of the Investigator, represents an inappropriate risk to the subject and/or could confound the interpretation of the study.
3. Subject has a known history or presence of structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (e.g., clinically significant heart block), exercise-related cardiac events including syncope and pre-syncope, or clinically significant bradycardia.
4. Subject has clinically significant ECG findings as judged by the Investigator with consideration of the central ECG interpretation.
5. Subject with orthostatic hypotension or a known history of controlled or uncontrolled hypertension.
6. Current use of any prohibited medication, including herbal supplements that affect blood pressure, heart rate, have central nervous system (CNS) effects, or affect cognitive performance, such as sedating antihistamines and decongestant sympathomimetics (inhaled bronchodilators are permitted) or a history of chronic use of sedating medications (i.e., antihistamines) at baseline.
7. Subject has a history of alcohol or other substance abuse or dependence, as defined by DSM IV-TR (with the exception of nicotine) within the last six months.
8. Subject has taken another investigational product within 30 days prior to baseline.
9. Subject is significantly overweight based on Center for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts at screening. Significantly overweight is defined as a BMI >95th percentile for this study.
10. Body weight of less than 34.0kg or greater than 91.0kg at screening.
11. Subject has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride or any components found in SPD503.
12. Clinically important abnormality on urine drug and/or alcohol screen (excluding the subject’s current ADHD stimulant if applicable).
13. Subject is female and is pregnant or currently lactating.
14. Subject failed screening or was previously enrolled in this study.
15. Subject is currently considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or has a prior history of, or is currently demonstrating active suicide ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.
16. History of failure to respond to an adequate trial (consisting of an appropriate dose and adequate duration of therapy), in the opinion of the Investigator, of an α2-agonist for the treatment of ADHD.
17. Subject has a history of a seizure disorder (other than a single childhood febrile seizure occurring before the age of 3 years) or the presence of a serious tic disorder (including Tourette’s Syndrome).

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is the change from baseline (Day 0) for the ADHD-RS-IV total score at Week 13 (Visit 13).

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 13

E.5.2

Secondary end point(s)

The secondary endpoints are ADHD-RS-IV hyperactivity/impulsivity and inattentiveness subscale scores, CGI-S scores, CGI-I scores, and WFIRS P results.
Safety endpoints include results of vital signs, ECG results, TEAEs, clinical laboratory results, PDSS, BPRS-C, SSEQ, and C-SSRS results.

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 13

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

Will this trial be conducted at a single site globally?

E.8.4

Will this trial be conducted at multiple sites globally?

E.8.6 Trial involving sites outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Yes

E.8.6.3

Specify the countries outside of the EEA in which trial sites are planned

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of trial is defined as the safety follow-up visit i.e. 7 days post last dose of IMP, for the last subject

E.8.9 Initial estimate of the duration of the trial

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

280

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

280

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2011-08-30.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Due to population age of trial subjects, adults/parental consent forms have been generated

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

280

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

There is no planned additional care for subjects after the trial

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Not applicable
G.4.3.4	Network Country	United States

H.4 Third Country in which the Trial was first authorised
H.4.1	Third Country in which the trial was first authorised:	United States

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