Clinical Trials Register

Summary
EudraCT Number:	2016-001057-40
Sponsor's Protocol Code Number:	301OTC01
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-12-15
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

UK - MHRA

A.2

EudraCT number

2016-001057-40

A.3

Full title of the trial

A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Adults with Late-Onset OTC Deficiency

A.3.1

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

An early-phase clinical study of a virus transferring the gene for human Ornithine Transcarbamylase (OTC) in adults with late-onset OTC deficiency

A.4.1

Sponsor's protocol code number

301OTC01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02991144

A.5.4

Other Identifiers

Name:

IND Number

Number:

17190

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	Ultragenyx Pharmaceutical, 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	Ultragenyx Pharmaceutical, 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	Ultragenyx Pharmaceutical, Inc.
B.5.2	Functional name of contact point	Gene Therapy Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	840 Memorial Drive
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02139
B.5.3.4	Country	United States
B.5.4	Telephone number	+16177140705
B.5.6	E-mail	JRae@ultragenyx.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	No
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/3/16/1623
D.3 Description of the IMP
D.3.1	Product name	DTX301
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not yet assigned
D.3.9.3	Other descriptive name	DTX301
D.3.9.4	EV Substance Code	SUB184280
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	5000000000000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Classified as gene therapy medicinal product, EMA/CAT/803478/2015
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	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
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

Ornithine transcarbamylase deficiency

E.1.1.1

Medical condition in easily understood language

Inherited disorder causing accumulation of ammonia

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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	10071107
E.1.2	Term	Ornithine transcarbamylase deficiency
E.1.2	System Organ Class	100000004850

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 determine the safety of single intravenous (IV) doses of DTX301 in adults with late-onset OTC deficiency.

E.2.2

Secondary objectives of the trial

To establish a dose of DTX301 that has a clinically meaningful increase in the rate of ureagenesis to allow further clinical development.
To evaluate the efficacy of single IV doses of DTX301 in adults with late-onset OTC deficiency, in the setting of tapering or discontinuing ammonia scavenger medications.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Willing and able to provide written informed consent.
2. Males and females ≥18 years of age with documented diagnosis of late-onset (defined as first manifestation of signs and symptoms at ≥30 days of age) OTC deficiency, confirmed via enzymatic, biochemical, or molecular testing. This may include identification of a pathogenic mutation, pedigree analysis, liver OTC activity that is <20% of normal activity, or elevated urinary orotate (>20 μmol/mmol creatinine) after an allopurinol challenge test.
3. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 μmol/L.
4. Subject’s OTC deficiency is stable as evidenced by either a) no clinical symptoms of hyperammonemia OR b) plasma ammonia level <100 μmol/L within the 4 week period preceding the Screening visit.
5. Subject's plasma ammonia level on Day 1 (predose) is <100 μmol/L, for patients who historically maintain normal ammonia levels, and the subject is clinically stable OR subject's plasma ammonia level on Day 1 (predose) is < 200 μmol/L, for patients who historically are not able to fully control ammonia levels with baseline management, and the subject is clinically stable. If the Day 1 (predose) ammonia level is inconsistent with the subject's clinical status, the ammonia level may be repeated to
ensure accurate results.
6. On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks.
7. Willing to taper or discontinue ammonia scavengers during the study if deemed safe by the investigator.
8. No known allergic reaction to any component of DTX301.
9. Willing and able to comply with study procedures and requirements, including periodic inpatient hospitalizations, frequent blood draws, and urine collections over a 24-hour period.
10. Hematology and coagulation panel results are within the normal range or, if outside the normal range, deemed not clinically significant in the opinion of the investigator.
11. Males and all females of childbearing potential must be willing to use effective contraception at the time of administration of gene transfer and for the 52 weeks following administration of DTX301 to prevent the potential transmission of the AAV vector. For male subjects, appropriate contraceptive methods include the use of a condom with spermicide. For female subjects, appropriate contraceptive methods include the use of a condom with spermicide plus at least 1 of the following:
a. Oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device;
b. Use of a diaphragm or cervical/vault cap;
c. Previous female sterilization (surgical bilateral oophorectomy [with or without hysterectomy] or tubal ligation) at least 6 weeks prior to DTX301 administration. In case of an oophorectomy alone, the reproductive status of the subject must have been confirmed by follow-up hormone level assessment.
NOTE: Abstinence is an acceptable form of birth control; however, appropriate contraception must be used if the subject becomes sexually active. A condom with spermicide is required to be used by all sexually active vasectomized males in the study in order to prevent potential transmission of the vector via seminal fluid.
NOTE: Females of childbearing potential are defined as all females physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for the duration of the study. Females are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to enrollment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.

E.4

Principal exclusion criteria

1. At Screening or Baseline (Day 0), plasma ammonia level =100 µmol/L for patients who historically maintain normal ammonia levels; OR plasma ammonia level = 200 µmol/L for patients who historically are not able to fully control ammonia levels with baseline management; OR signs and
symptoms of hyperammonemia, with documented elevated ammonia level, during the 4-week period preceding Day 0. If ammonia level is inconsistent with the subject's clinical status, the ammonia level may be repeated to ensure accurate results.
2. Liver transplant, including hepatocyte cell therapy/transplant.
3. History of liver disease as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage 3 fibrosis.
4. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the following laboratory abnormalities: alanine aminotransferase or aspartate aminotransferase >2.0 × upper limit of normal (ULN), total bilirubin >1.5 × ULN, alkaline phosphatase >2.5 × ULN.
5. Serum creatinine >2.0 mg/dL.
6. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, documented by current use of antiviral therapy for HBV or HCV or by hepatitis B surface antigen (HBsAg) or HCV RNA positivity.
NOTE: Subjects with a history of HCV infection must have documentation of 2 negative viral assays by polymerase chain reaction (PCR), collected at least 6 months apart, to be considered negative for HCV. Subjects with a history of HCV infection who test positive for HCV RNA at Screening can be rescreened once, after they have been treated and have documentation of at least 2 negative samples collected at least 6 months apart.
7. History of human immunodeficiency virus (HIV) infection AND any of the following: CD4+ cell count <350 cells/mm3, change in antiretroviral therapy regimen within 6 months prior to Day 0, or plasma viral load >200 copies/mL, documented on 2 separate occasions, as measured by PCR.
8. Active infection (viral or bacterial).
9. Anti-AAV8 neutralizing antibody titer >1:5.
10. Participation (current or previous) in another gene transfer study.
11. Participation in another investigational medicine study within 3 months of Screening.
12. History of a malignancy for which the subject has received treatment in the past 2 years except for prostate cancer treated with watchful waiting or surgically removed non-melanoma skin cancer.
13. Has a positive serum pregnancy test at screening (females of childbearing potential only), a positive urine pregnancy test at Baseline (Day 0; females of childbearing potential only), or is nursing.
14. Has any other significant medical condition that the investigator feels would be a risk to the subject or would impede the study.

E.5 End points

E.5.1

Primary end point(s)

The incidence of adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) for each dosing cohort, assessed by severity and relationship to study product.

E.5.1.1

Timepoint(s) of evaluation of this end point

From the time the subject signs the Informed Consent Form through the end of study/early withdrawal visit.

E.5.2

Secondary end point(s)

- The change from baseline in the rate of ureagenesis (as measured by the generation of [13C]urea over 4 hours) as determined by gas chromatography mass spectrometry over time to 52 weeks after the IV
administration of DTX301.
- The change from baseline (Day 0) in plasma ammonia area under the curve from time zero to 24 hours (AUC 0-24) over time to 52 weeks after IV administration of DTX301 in the setting of tapering or discontinuing ammonia scavenger medications.

E.5.2.1

Timepoint(s) of evaluation of this end point

Ureagenesis: at Screening, Day 1 prior to DTX301 infusion, Week 6, Week 12, Week 20, Week 24, Week 52

Serum ammonia: Day 0, Week 6, Week 12, Week 24, Week 52

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.1.1

First administration to humans

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

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

Canada

Spain

United Kingdom

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

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)

Yes

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

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)

After patients have ended their participation in the trial, they will be treated according to the normal standard of care. After completion of this study, subjects will be asked to enroll in a 4-year extension study to evaluate the long-term (a total of 5 years) safety and efficacy of DTX301.

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

2017-03-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-14

P. End of Trial
P.	End of Trial Status	GB - no longer in EU/EEA

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