Clinical Trials Register

Summary
EudraCT Number:	2015-000075-27
Sponsor's Protocol Code Number:	HPN-100-021
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-11-16
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
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2015-000075-27

A.3

Full title of the trial

A Randomised, Controlled, Open-Label Parallel Arm Study of the Safety, Pharmacokinetics and Ammonia Control of RAVICTI® (Glycerol Phenylbutyrate [GPB]) Oral Liquid and Sodium Phenylbutyrate (NaPBA) in Phenylbutyrate Treatment Naïve Patients with Urea Cycle Disorders (UCDs)

A.3.1

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

A study to compare RAVICTI® against Sodium Phenylbutyrate (NaPBA) in the treatment of Urea Cycle Disorders (UCDs) in patients who have not received Phenylbutyrate treatment before.

A.4.1

Sponsor's protocol code number

HPN-100-021

A.5.4

Other Identifiers

Name:

IND Number

Number:

073480

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Horizon Therapeutics, LLC
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	Horizon Therapeutics, LLC
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	Horizon Therapeutics, LLC
B.5.2	Functional name of contact point	Director, Clinical Drug Development
B.5.3	Address:
B.5.3.1	Street Address	150 South Saunders Road
B.5.3.2	Town/ city	Lake Forest
B.5.3.3	Post code	IL, 60045
B.5.3.4	Country	United States
B.5.4	Telephone number	001224804 3202
B.5.5	Fax number	0012242413151
B.5.6	E-mail	ccanavan@horizonpharma.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	RAVICTI
D.2.1.1.2	Name of the Marketing Authorisation holder	Horizon Pharma Ireland Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/733 to 739
D.3 Description of the IMP
D.3.1	Product name	RAVICTI
D.3.2	Product code	N/A
D.3.4	Pharmaceutical form	Oral liquid
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Glycerol phenylbutyrate
D.3.9.1	CAS number	611168-24-2
D.3.9.2	Current sponsor code	HPN-100
D.3.9.3	Other descriptive name	GLYCEROL PHENYLBUTYRATE
D.3.9.4	EV Substance Code	SUB96043
D.3.10	Strength
D.3.10.1	Concentration unit	g/ml gram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.1
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	AMMONAPS Tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum International AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	AMMONAPS Tablets
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
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	sodium phenylbutyrate
D.3.9.1	CAS number	1716-12-7
D.3.9.2	Current sponsor code	NaPBA
D.3.9.3	Other descriptive name	SODIUM PHENYLBUTYRATE
D.3.9.4	EV Substance Code	SUB12586MIG
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	500
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	AMMONAPS Granules
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum International AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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	AMMONAPS Granules
D.3.4	Pharmaceutical form	Granules
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasogastric use (Noncurrent) Gastroenteral use Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	sodium phenylbutyrate
D.3.9.1	CAS number	1716-12-7
D.3.9.2	Current sponsor code	NaPBA
D.3.9.3	Other descriptive name	SODIUM PHENYLBUTYRATE
D.3.9.4	EV Substance Code	SUB12586MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	940
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Urea Cycle Disorders (UCDs)

E.1.1.1

Medical condition in easily understood language

Genetic disease that affects how the body gets rid of waste from excess protein in the diet

E.1.1.2

Therapeutic area

Body processes [G] - Metabolic Phenomena [G03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10013373
E.1.2	Term	Disorders of urea cycle metabolism
E.1.2	System Organ Class	100000161833

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the safety, tolerability, pharmacokinetics (PK) and ammonia control of RAVICTI and NaPBA in UCD subjects not currently treated with phenylacetic acid (also referred to as phenylacetate; PAA) prodrugs.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Signed informed consent given by the subject or the subject’s parent/legal guardian for those under 18 years of age or the age of consent by local regulation
• Male and female subjects with a suspected or confirmed UCD diagnosis of any subtype, except NAGS deficiency
- Suspected diagnosis is defined as having experienced an HAC or a documented high ammonia of ≥100 µmol/L
- Confirmed diagnosis is determined via enzymatic, biochemical, or genetic testing
• Requires nitrogen binding agents according to the judgment of the Investigator
• ≥ 2 months of age and older
• All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception from signing the informed consent throughout the duration of the study and for 30 days after the last dose of study drug. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active.

E.4

Principal exclusion criteria

• Subject has received chronic treatment with an oral phenylbutyrate (RAVICTI, NaPBA, Pheburane, or other) longer than 14 consecutive days within one year prior to enrollment
- Temporary use of oral PBA for acute management of a hyperammonemic crisis in the past is acceptable.
• Any concomitant illness (e.g. malabsorption or clinically significant liver or bowel disease) which would preclude the subject’s safe participation, as judged by the Investigator
• Have undergone liver transplantation, including hepatocellular transplant
• Subjects on NaBz at Baseline will be excluded if they are viewed by the Investigator as being unable to undergo NaBz transition to a PAA prodrug during the Initial Treatment Period
• Known hypersensitivity to PBA or any excipients of the NaPBA/PBA formulations
• Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed at the Baseline Visit prior to the start of study drug.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study is the Rate of Treatment Success: Efficacy

E.5.1.1

Timepoint(s) of evaluation of this end point

The efficacy endpoint will be evaluated during the Initial Treatment Period

E.5.2

Secondary end point(s)

1) Efficacy
a) Initial Treatment Period Endpoints (RAVICTI vs NaPBA)
• Drug discontinuation due to any reason
b) Transition, Maintenance, and Safety Extension Periods (RAVICTI)
• Control of plasma ammonia
• Annualized rate of HAC

2) Safety and Tolerability
• Assessment of AEs
• Standard clinical laboratory tests
• Amino acid panel
• Rate of drug discontinuation due to AEs

3) Clinical Outcome Assessments
• Rate of treatment success in the Initial Treatment Period
• Subject preference for study drug (Arm 2 after exposure to both RAVICTI and NaPBA)
• Palatability of study drug (Hedonic Scale)
• Changes in CGI scales (Investigator)
• Neuropsychological assessments: CBCL or ABCL or ASR
• EQ-5D-5L health status quality of life assessment

E.5.2.1

Timepoint(s) of evaluation of this end point

a) Initial Treatment Period (RAVICTI vs NaPBA)
• Drug discontinuation due to any reason
• Amino acid panel
• Standard clinical laboratory tests
• Assessment of AEs
• Rate of Treatment Success
• EQ-5D-5L health status quality of life assessment

b) Transition, Maintenance, and Safety Extension Periods (RAVICTI)
• Control of plasma ammonia
• Annualized rate of HAC
• Amino acid panel
• Standard clinical laboratory tests
• Neuropsychological assessments: CBCL or ABCL or ASR
• EQ-5D-5L health status quality of life assessment
• Subject preference for study drug (Arm 2 after exposure to both RAVICTI and NaPBA)
• Assessment of AEs
• Changes in CGI scales (Investigator)
• Palatability of study drug (Hedonic Scale)
• Rate of drug discontinuation due to AEs

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

Belgium

Italy

Spain

Switzerland

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

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:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

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

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

Subjects with diminished capacity may be enrolled in the study. Consent will be sought from parents/ guardians as appropriate

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

On completion of study participation subjects will be assigned to treatment at the discretion of the investigator.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-10

P. End of Trial
P.	End of Trial Status	Completed

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