Clinical Trials Register

Summary
EudraCT Number:	2017-000852-24
Sponsor's Protocol Code Number:	15/0552
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-05-15
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

2017-000852-24

A.3

Full title of the trial

A Phase I/II, Open label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno-associated Viral Vector (FLT180a) in Patients With Haemophilia B

A.3.1

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

A Factor IX Gene Therapy Study (FIX-GT)

A.4.1

Sponsor's protocol code number

15/0552

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	University College London (UCL)
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Freeline Therapeutics Ltd
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University College London
B.5.2	Functional name of contact point	Regulatory Manager
B.5.3	Address:
B.5.3.1	Street Address	Joint Research Office, UCL, Gower Street
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC1E 6BT
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	CTIMPS@ucl.ac.uk

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	FLT180a
D.3.2	Product code	FLT180a
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	NA
D.3.9.2	Current sponsor code	FLT180A
D.3.9.3	Other descriptive name	FLT180A
D.3.9.4	EV Substance Code	SUB187364
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2.3x10exp12 to 4.3x10exp12
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	No
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

Haemophilia B

E.1.1.1

Medical condition in easily understood language

hereditary bleeding disorder caused by a lack of blood clotting factor

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	10018939
E.1.2	Term	Haemophilia 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

Safety
To assess the safety of systemic administration of FLT180a in adults with Haemophilia B at up to
3 different dose cohorts.
Efficacy
To assess Factor IX (FIX) levels following systemic administration of FLT180a, at the terminal dose level.

E.2.2

Secondary objectives of the trial

To investigate the endogenous production of FIX following systemic administration of FLT 180a at up to 3 different dose cohorts.
To investigate the effectiveness of a single administration of FLT180a on annualized bleeding rate and exogenous FIX consumption.
To assess the immune response to the FIX transgene product following systemic administration of FLT180a.
To assess viral shedding in various body fluids after systemic administration of FLT180a.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adults males, ≥ 18 years of age;
2. Confirmed diagnosis of HB defined as one of the following: Documented severe FIX deficiency with plasma FIX activity of <1% of normal or moderately severe FIX deficiency with plasma FIX activity level between ≥1% and ≤2% and a severe bleeding phenotype defined by one of the following:
(a) On prophylaxis for a history of bleeding, or
(b) On demand therapy with a history of 4 or more bleeding episodes/year on average over the past 3 years, or
(c) Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion).
3. Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up;
4. Willing to practice barrier contraception until at least three consecutive semen samples after vector administration are negative for vector sequences;
5. Lack of neutralising anti-AAV-S3 antibodies using an in-vivo transduction inhibition assay within 4 weeks of vector administration.
6. At least 150 exposure days to FIX concentrates.

E.4

Principal exclusion criteria

1. Presence of neutralising anti-human FIX antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor;
2. Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrilation).
3. Use of investigational therapy for haemophilia within 30 days before enrolment;
4. Patients with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity, respectively, or currently on antiviral therapy for hepatitis B or C. (Negative viral assays in 2 samples, collected at least 5 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.);
5. Serological evidence of HIV-1;
6. Evidence of liver dysfunction (persistently elevated alanine aminotransferase, aspartate aminotransferase, bilirubin >1.5 x upper limit of normal).
7. Platelet count <50x109/L;
8. Uncontrolled glaucoma, diabetes mellitus, or hypertension;
9. Malignancy requiring treatment;
10. Patients with uncontrolled cardiac failure, unstable angina or myocardial infarction in the past 6 months.
11. Poor performance status (World Health Organization score >1);
12. Prior treatment with any gene transfer medicinal product;
13. Known or suspected intolerance, hypersensitivity or contrainidication to the investigational product and non-investigational medicinal products or their excipients;
14.Planned major elective surgery prior to the end of trial.
15. Current or relevant history of a physical or psychiatric illness or any medical condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments.
16. CMV IgG positive patients who are CMV PCR positive at screening.

E.5 End points

E.5.1

Primary end point(s)

Safety
Safety as assessed by the reporting of AEs according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Efficacy
The following primary endpoints will be analysed:
1. The proportion of patients achieving clinical FIX response at Week 26, at the terminal dose level. A clinical FIX response is defined as achieving FIX activity of 5% to 150%.
2. The proportion of patients also achieving normalized FIX response at Week 26, at the terminal dose level. A normalized FIX response is defined as achieving FIX activity in the normal range (50-150%)

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety
Throughout the study

Efficacy
Week 26

E.5.2

Secondary end point(s)

Safety
Safety as assessed by reporting of abnormal or change from baseline findings from safety assessments including laboratory assessments, vital signs, ECG, physical exam and liver ultrasound.
1. Endogenous FIX (hFIX) production
2. Haemostatic effectiveness
3. Immune response
4. Shedding

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Throughout study
2. Throughout study
3. Throughout study
4. Throughout study or until 3 consecutive samples test negative for vector sequences.

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

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.8.2.4

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

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

LPLV

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)

Treatment/care after study ends will be according to medical needs and local practice. Patients will be consented for a long-term follow-up trial, conducted under a separate extension 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

2017-07-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-10-20

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