Clinical Trials Register

Summary
EudraCT Number:	2018-004024-11
Sponsor's Protocol Code Number:	SHP648-101
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-08-02
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2018-004024-11

A.3

Full title of the trial

An Open-Label, Multinational, Phase 1/2 Study of the Safety and Dose Escalation of SHP648, an Adeno-Associated Virus Serotype 8 (AAV8) Vector Expressing FIX Padua in Hemophilia B Subjects

Nyílt, nemzetközi, I/II. fázisú vizsgálat az SHP648, Padua IX-es faktort expresszáló 8-as szerotípusú adeno-asszociált vírus (AAV8) vektor biztonságosságának és dóziseszkalációjának értékelésére B hemofíliában szenvedő betegek esetében

A.3.1

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

A Phase 1/2 study of SHP648, an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia B Subjects

A.4.1

Sponsor's protocol code number

SHP648-101

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	Baxalta Innovations GmbH
B.1.3.4	Country	Austria
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	Baxalta Innovations GmbH
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Baxalta Innovations GmbH
B.5.2	Functional name of contact point	Judit Koranyi
B.5.3	Address:
B.5.3.1	Street Address	Industriestrasse 67
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	A-1221
B.5.3.4	Country	Austria
B.5.4	Telephone number	+431201002473301
B.5.5	Fax number	+43120100-2475990
B.5.6	E-mail	judit.koranyi@takeda.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	SHP648 (TAK748)
D.3.4	Pharmaceutical form	Solution for injection
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 applicable
D.3.9.2	Current sponsor code	SHP648
D.3.9.3	Other descriptive name	TAK-748
D.3.9.4	EV Substance Code	SUB199254
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4.1E12
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	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	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

Hemophilia B is a X-linked recessive bleeding disorder caused by mutations in the gene encoding clotting factor IX (FIX) that result in disruption of the normal clotting pathway. Hemophilia B affects 1 in 25,000 male births. Disease severity correlates directly with the concentration of functional FIX protein in the plasma. Severe disease is characterized as having <1% of normal plasma levels of FIX (100% = 1 IU activity/mL or approximately 5000 ng protein/mL).

E.1.1.1

Medical condition in easily understood language

Hemophilia B is an inherited bleeding disorder caused by a lack of the
blood clotting factor IX (9) in your blood. Without enough factor
IX, the blood cannot clot properly to stop bleeding.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10060614
E.1.2	Term	Hemophilia B (Factor IX)
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

The primary objective of the study is to assess the safety of single, escalating, IV doses of SHP648.

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are as follows:
• Evaluate plasma FIX levels before and after SHP648 infusion and study the relationship
between change in FIX activity and SHP648 dose.
• Evaluate bleeding episodes post SHP648 administration.
• Assess humoral and cellular immune responses to FIX and the viral capsid.
• Determine the duration of SHP648 genomes present in bodily fluids.
• Compare the consumption of exogenous FIX before and after gene transfer

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The subject will not be considered eligible for the study without meeting all of the criteria below.
1. Male, aged 18 to 75 years at the time of screening.
2. Established severe or moderately severe hemophilia B (plasma FIX activity
≤ 2% measured following ≥ 5 half-lives of most recent exposure to exogenous FIX)
and either ≥ 3 hemorrhages per year requiring treatment with exogenous FIX or use
of prophylactic therapy.
3. History of > 50 exposure days to exogenously administered FIX concentrates or
cryoprecipitates.
4. Sexually active men must agree to use barrier contraception (combination of a condom and spermicide) or limit sexual intercourse to post-menopausal, surgically sterilized, or contraception-practicing partners for a minimum of 6 months after administration of SHP648, or until SHP648 genomes are no longer detected in the semen (whichever is sooner).
5. Signed informed consent.

E.4

Principal exclusion criteria

The subject will be excluded from the study if any of the following exclusion criteria are met.
1. Bleeding disorder(s) other than hemophilia B.
2. Documented laboratory evidence of having developed inhibitors (≥ 0.6 BU on any single test) to FIX proteins at any time.
3. Documented prior allergic reaction to any FIX product.
4. Anti-AAV8 neutralizing antibody titer ≥ 1:5.
5. Known hypersensitivity to prednisolone or prednisone, or to any of the excipients.
6. Having a disease in which treatment with prednisolone or prednisone is not tolerated
(including, but not limited to osteoporosis with vertebral fractures, severe labile
hypertension, and brittle diabetes).
7. Evidence of markers of potential underlying risk for autoimmune mediated hepatic disease:
a. Anti-smooth muscle antibody (ASMA) titer ≥ 1:40. Values of 1:31 to 1:39 will be
flagged as possibly abnormal and the Investigator and Medical Monitor will evaluate the subject for eligibility.
b. Elevated anti-liver-kidney microsomal antibody type 1 (LKM1) titers.
c. Total IgG > 1.5x ULN.
d. Antinuclear antibody (ANA) titer > 1:320 OR ANA titer > 1:80 if demonstrated
concurrently with ALT that is > ULN.
8. Active Hepatitis C: As indicated by detectable HCV RNA by PCR.
9. Hepatitis B: If surface HBV antigen is positive.
10. Receiving chronic systemic antiviral and/or interferon therapy within 4 weeks prior to enrollment.
11. Clinically significant infections (e.g., systemic fungal infections) requiring systemic treatment.
12. Known immune disorder (including myeloma and lymphoma).
13. Concurrent chemotherapy or biological therapy for treatment of neoplastic disease or other disorders.
14. An absolute neutrophil count < 1000 cells/mm3.
15. Markers of hepatic inflammation or cirrhosis as evidenced by 1 or more of the following:
a. Platelet count < 150,000/μL.
b. Albumin ≤ 3.5 g/dL.
c. Total bilirubin > 1.5x ULN and direct bilirubin ≥ 0.5 mg/dL.
d. ALT or AST > 1.0x ULN.
e. Alkaline phosphatase > 2.0x ULN.
f. History of liver biopsy or imaging indicating moderate or severe fibrosis
(Metavir staging of F2 or greater).
g. History of ascites, varices, variceal hemorrhage, or hepatic encephalopathy.
h. FibroSURE Score ≥ 0.4.
i. Prothrombin time INR ≥ 1.4.
16. Serum creatinine > 1.5 mg/dL.
17. HIV if CD4+ cell count ≤200 mm3 and/or viral load >20 copies/mL.
18. Urine protein > 30 mg/dL.
19. Body mass index > 38.
20. Orthopedic or other major surgery planned within 6 months after enrollment.
21. Acute or chronic disease that, in the opinion of the Investigator, would adversely affect subject safety or compliance or interpretation of study results.
22. Received an AAV vector previously or any other gene transfer agent in the previous 12 months prior to Study Day 0.
23. Significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, congestive heart failure, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or significant pulmonary disease (including obstructive pulmonary disease).
24. History of arterial or venous thrombosis / thromboembolism, or a known pro-thrombotic condition.
25. Recent history of psychiatric illness or cognitive dysfunction (including drug or alcohol abuse) that, in the opinion of the Investigator, is likely to impair subject’s ability to comply with protocol mandated procedures.
26. Participation in another study involved with an investigational agent.
27. Subject is family member or employee of the Investigator

E.5 End points

E.5.1

Primary end point(s)

Incidence of AEs (serious or non-serious) related to IP
that include development of FIX inhibitory antibodies,
ECG findings, and clinically significant changes in
standard laboratory parameters and in vital signs

E.5.1.1

Timepoint(s) of evaluation of this end point

Subjects will be monitored for 1 year after dosing. Every effort will be made to enroll subjects to an extension study and follow them for approximately 4 additional years until a 5 year total post-gene transfer period is attained.

E.5.2

Secondary end point(s)

•Circulating plasma FIX activity and antigen levels
•ABR in comparison to before gene transfer
•Neutralizing and Binding antibody titers to AAV8
• T-cell response to AAV8 and FIX transgene products
•Presence of SHP648 genome by type of bodily fluid
•Percentage of change in consumption of exogenous FIX before and after gene transfer

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.7.1

Other trial design description

Dose Escalation

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.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

France

Germany

Hungary

Italy

Spain

Turkey

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

The end of the trial is defined by 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

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

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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)

No aftercare is planned for this study. Subjects completing the current Phase 1/2 Study
(SHP648-101) will be highly encouraged to enroll seamlessly into a follow-up interventional
study (Extension Study), in which they will be observed for an additional 4 years.

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

2019-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2021-05-03

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