Clinical Trials Register

Summary
EudraCT Number:	2020-004184-12
Sponsor's Protocol Code Number:	DTX401-CL301
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-09-20
Trial 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2020-004184-12

A.3

Full title of the trial

A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Adeno-associated Virus Serotype 8-mediated Gene Transfer of Glucose-6-phosphatase in Patients With Glycogen Storage Disease Type Ia.

EMA Decision number on PIP: EMA/PDCO/154270/2021

A.3.1

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

An Phase 3 clinical study comparing a vector transferring the gene for Glucose-6-Phosphatase with placebo in adults with Glycogen Storage Disease Type Ia.

A.4.1

Sponsor's protocol code number

DTX401-CL301

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/278/2021

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	Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	60 Leveroni Court
B.5.3.2	Town/ city	Novato
B.5.3.3	Post code	CA 94949
B.5.3.4	Country	United States
B.5.4	Telephone number	+4161 563 1167
B.5.6	E-mail	MPhan@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/3/16/1771
D.3 Description of the IMP
D.3.1	Product name	DTX401
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 available.
D.3.9.2	Current sponsor code	DTX401
D.3.9.4	EV Substance Code	SUB192511
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.8 × 10^13 GC/mL
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/506999/2016.
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Glycogen Storage Disease Type Ia (GSDIa).

E.1.1.1

Medical condition in easily understood language

Inherited disorder causing decrease of glucose.

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10056911
E.1.2	Term	Glycogen storage disease type IA
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 evaluate the efficacy of DTX401 to reduce or eliminate dependence on
exogenous glucose replacement therapy needed to maintain glucose
control.

E.2.2

Secondary objectives of the trial

subject to multiplicity:
•To evaluate the effect of DTX401 on reducing the frequency of exogenous glucose replacement therapy
•To evaluate the effect of DTX401 on glucose control
•To evaluate the effect of DTX401 on subject experience of disease
not subject to multiplicity:
•To evaluate the effect of DTX401 on glucose control
•To evaluate the safety of DTX401

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female patients ≥ 8 years of age at time of informed consent or assent.
2. Subject has a diagnosis of GSDIa confirmed by deficient enzymatic activity (on liver biopsy), or by molecular testing of G6PC gene revealing 2 pathogenic mutations. In the case where only a single pathogenic mutation is identified, clinical diagnosis is compatible with GSDIa and absence of characteristic features of GSDIb (ie, chronic neutropenia, inflammatory bowel disease).
3. Subject is currently receiving a therapeutic regimen of cornstarch (or equivalent),following international guidance/recommendations
(Appendix 1) with stable nutrition, glycemic, and clinical status as evidenced by:
a. no more than a 10% variation in weekly average daily cornstarch (or equivalent) intake over the last 4 weeks.
b. no more than a 25% variation in weekly average daily non-cornstarch carbohydrate over the last 4 weeks.
c. No more than 15% variation in weekly percentage of values in the target blood glucose range (60-120 mg/dL) over the last 4 weeks as
measured by CGM and corroborated by SMBG. If adequate corroboration is not observed, this assessment should be made by SMBG.
d. No hospitalization for hypoglycemia and no severe hypoglycemic event (SHE) during the 4-week period preceding randomization and dosing (see Section 10.4.2 for more detail on SHE), notwithstanding events of hypoglycemia due to unavoidable and unforeseeable events (eg, infection, trauma) that transiently prevent the subject from tolerating enteral intake or acutely change the subject's metabolic demands, provided that the subject quickly returns to their prior physiologic state.
4. Subject is willing and able to comply with study procedures, requirements and study medication, including periodic inpatient hospitalization or admission in a research facility; CFC studies; frequent blood collection; wearing a CGM device for the duration of the study (and excluding the use of any non-study CGM or flash glucose device); performing capillary glucose measurements according to the protocol using a study-approved glucometer (and excluding the use of any other glucometer); completing an eDiary to track daily cornstarch, diet intake, and reasons for doing SMBG routinely throughout the study as required by the protocol; and completing patient-reported questionnaires. Subject must strictly comply with prednisolone/placebo prednisolone prescription including changes in prescription that may be implemented during the study by the Investigator, if needed. (See Section 9.2, Prednisolone Taper.) If < 18 years (or as required by region), has a parent or legal guardian willing and able to assist with study requirements.
5. From the period following informed consent through the duration of participation in the study, female subjects of childbearing potential and fertile male subjects must consent to use highly effective contraception as defined by the Food and Drug Administration (FDA) and Clinical Trial Facilitation Group Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials (Version 1.1 dated 21 Sep 2020). Female subjects must agree not to become pregnant and male subjects must agree not father a child or donate sperm for at least 48 weeks after the last dose of IP if they decide to withdraw early from the study.
6. Subject is willing and able to provide written informed consent after the study has been explained and before any study-related procedures are performed. If < 18 years (or as required by region), willing and able to provide written assent and have a parent or legal guardian willing and able to provide written informed consent after the study has been explained and before any study-related procedures are performed.

E.4

Principal exclusion criteria

1. Detectable pre-existing antibodies to the AAV8 capsid during screening.
2. History of liver transplant, including hepatocyte cell therapy/transplant.
3. History of of severe hepatic fibrosis or cirrhosis as evidenced by any of the following: portal hypertension, ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy with evidence of stage III fibrosis.
4. Presence of liver adenoma > 5 cm in size or presence of liver adenoma > 3 cm and ≤ 5 cm in size with a documented annual growth rate of ≥ 0.5 cm per year.
5. Significant hepatic injury or dysfunction as evidenced by imaging or any of the following laboratory abnormalities:from 2 consecutive
samples(collected at least 4 weeks apart). Liver function tests may be repeated during Screening at the Investigator's discretion; those with initially
abnormal values may be retested and the subject will qualify for this criterion if the most recent results during Screening are within the
allowed range:
− ALT or aspartate aminotransferase > 2.5 × the ULN
− Total bilirubin > ULN (unless the subject has Gilbert’s syndrome)
− Alkaline phosphatase > ULN, with gamma-glutamyl transferase > ULN
6.Presence or history of hepatitis B virus infection, hepatitis C virus
infection, or both.
7.Non-fasting triglycerides ≥ 1000 mg/dL. For the purposes of this study, non-fasting refers to the longest fasting period that each individual subject is able to tolerate. Depending on the meal and cornstarch schedule, the blood draw could occur in the morning before breakfast or before the first dose of cornstarch.
8. Human immunodeficiency virus infection AND any of the following: CD4+ cell count < 350 cells/mm3, change in antiretroviral therapy regimen within 6 months before baseline, or plasma viral load > 200 copies/mL on 2 separate occasions as measured by polymerase chain reaction.
9. Presence or history of any disease or condition that, in the Investigator’s opinion, would interfere with the subject’s safety or ability to participate in the study or would significantly affect interpretation of study results. This includes any intercurrent febrile or nonfebrile illness including common viral infections, epidemic influenza, and other viral Illness, and coronavirus disease 2019 (COVID-19) until full clinical recovery.
10. Female subjects of childbearing potential who have a positive pregnancy test, who are unwilling to use contraception, or are unwilling to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have not experienced menarche, are postmenopausal (defined as having no menses for at least 12 months without an alternative medical cause), or are permanently sterile due to having total hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.
11. Pregnant, breastfeeding, or planning to become pregnant (self or partner) at any time during the study.
12. Presence or history of any hypersensitivity to the excipients of DTX401 or placebo or to prednisolone, or inability to swallow capsules that, in the judgment of the Investigator, places the subject at increased risk for adverse effects.
13. Current or previous participation in another gene transfer study.
14. Use of any IP or investigational medical device within 3 months preceding screening or planning to use at any time during the study.
15. History of illicit drug use within 60 days prior to screening or positive results from a 9-panel urine drug screen prior to dosing and completed at 2 time points at least 4 weeks apart. Positive results that are due to a prescribed medication may be allowed if not impacting glycemic control and liver function and after agreement with the Sponsor. For the purposes of this protocol, the use of recreational cannabis products is not allowed, even if legal in the region where the patient lives.

E.5 End points

E.5.1

Primary end point(s)

1. Percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 Group compared with the Placebo Group.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Baseline, week 12, week 24, week 30, week 36, week 42, week 48.

E.5.2

Secondary end point(s)

1. Change from Baseline to Week 48 in number of total daily doses of cornstarch.
2. Change from Baseline to Week 48 in the percentage of glucose values in hypoglycemic range (<70 mg/dL [3.9 mmol/L]), assessed for non
inferiority; if non-inferiority is established, the endpoint will be tested for superiority.
3. PGIC assessment score at Week 48.
4. Change from Baseline to Week 48 in time to hypoglycemia (<54mg/dL [3.0 mmol/L]) during the CFC.
5. Change from Baseline to Week 48 in percentage of glucose values in the range of 70-120 mg/dL [3.9-6.7 mmol/L], assessed for non inferiority;
if non-inferiority is established, the endpoint will be tested for superiority.
6. Incidence, severity, and relationship to investigational product of TEAEs, TEAEs of special interest, serious TEAEs, related TEAEs, discontinuations from study or investigational product due to AEs, and fatal AEs.

E.5.2.1

Timepoint(s) of evaluation of this end point

1 to 5 Baseline, week 12, week 24, week 30, week 36, week 42, week 48.

6. From the time the subject signs the informed Consent Form(ICF) and up to 30 days after the End of Study Visit or Early Withdrawal/Termination Visit.

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

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

E.8.1.6

Cross over

Yes

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

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

Brazil

Canada

Japan

United States

Denmark

France

Germany

Italy

Netherlands

Portugal

Spain

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 date of the Week 96 Visit (or Early Withdrawal Visit, if applicable) for the last participant enrolled in the study.

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

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)

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)

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. Upon completion of this study, all subjects who receive DTX401 are expected to enroll in a long-term follow-up study to evaluate safety and effectiveness of DTX401 via the DMP for at least 10 years after DTX401 administration. The DMP for GSDIa will be conducted under a separate protocol.

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

2021-11-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-17

P. End of Trial
P.	End of Trial Status	Trial now transitioned

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials