Clinical Trials Register

Summary
EudraCT Number:	2016-000925-38
Sponsor's Protocol Code Number:	UCL13/0076
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:	2016-12-23
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

UK - MHRA

A.2

EudraCT number

2016-000925-38

A.3

Full title of the trial

GO-8: Gene therapy for haemophilia A using a novel serotype 8 capsid pseudotyped adeno-associated viral vector encoding Factor VIII-V3

A.3.1

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

Gene Therapy for Haemophilia A

A.3.2

Name or abbreviated title of the trial where available

Gene therapy for Haemophilia A; version 1

A.4.1

Sponsor's protocol code number

UCL13/0076

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	MRC
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Biomarin
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Hemophilia of Georgia
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	Alison Evans
B.5.2	Functional name of contact point	Regulatory Manager Advanced Therapy
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.5.4	Telephone number	020 7679 6595
B.5.5	Fax number	020 3108 2312
B.5.6	E-mail	a.j.evans@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	AAV2/8-HLP-FVIII-V3
D.3.4	Pharmaceutical form	Solution for injection/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	AAV2/8-HLP-FVIII-V3
D.3.9.3	Other descriptive name	AAV8-HLP-codop-hFVIII-V3
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2.38x10^12 vg/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	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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Severe Haemophilia A

E.1.1.1

Medical condition in easily understood language

An X-linked inherited bleeding disorder

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	10060612
E.1.2	Term	Hemophilia A
E.1.2	System Organ Class	100000004850

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	10060613
E.1.2	Term	Hemophilia A (Factor VIII)
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 is to assess the safety of systemic administration of our novel AAV2/8-HLP-FVIII-V3 vector in adults with severe haemophilia A over five dose levels: 6x10^11,2x10^12, 4x10^12, 6x10^12 and 8x10^12vg/kg. Safety will be assessed according to the schedule of study investigations which are designed to enable early detection of signals of adverse reactions, to prevent clinical consequences of such reactions and to ensure timely treatment, whilst gaining information on the acute and long-term safety and efficacy of systemic administration of AAV2/8-HLP-FVIII-V3. Toxicity is not expected to be substantial in the dose range to be evaluated for AAV2/8-HLP-FVIII-V3. Therefore, the identification of the highest dose that can be given with acceptable toxicity, though desirable, may not be feasible due to limitations in the amount of vector that is available for further dose escalation. The key objective, therefore, will be to determine the range of optimally effective and safe

E.2.2

Secondary objectives of the trial

The secondary objectives are:
(1) To establish the doses of AAV2/8-HLP-FVIII-V3 that mediates stable expression of hFVIII above 5% of normal (>5u/dl). Based on our dose finding study in mice we predict that a dose of 2x10^12vg/kg will result in circulating levels of FVIII at ~5% of normal and that a dose of 4x10^12vg/kg will result in hFVIII expression at levels ~15% of normal.
(2) To describe the kinetics and duration of AAV-mediated hFVIII expression. As with the haemophilia B gene therapy trial (AGT4HB) we predict that hFVIII expression will be detectable within two weeks and that expression will remain stable over 6 month after a single administration of AAV2/8-HLP-FVIII-V3.
(3) To describe the immunologic responses to AAV8 capsid proteins following peripheral vein administration of AAV2/8-HLP-FVIII-V3. The specific hypothesis to be tested is that: As in our haemophilia B gene therapy trial (AGT4HB) there may be a subclinical rise in liver enzymes that occurs between 6-10 weeks

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

i. Adult males, aged 18 years or over, with a confirmed diagnosis of severe Haemophilia A defined as baseline plasma FVIII levels of <1% of normal as assessed by a validated one-stage clotting assay or a chromogenic assay, resulting from for example intron 22 inversions, intron 1 inversions, splice-site mutations, small deletions/insertions, duplications and missense mutations.
ii. A severe bleeding phenotype as defined by at least one of the following:
a) On prophylaxis for a history of bleeding, or
b) On demand therapy with a current or past history of 4 or more bleeding episodes/year, or
c) Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion);
iii. Received treatment with human FVIII concentrates with at least > 50 exposure days;
iv. Able to give full informed consent and able to comply with all requirements of the trial including 5-year long-term follow-up;
v. Willing to practice barrier contraception after vector administration until at least three consecutive semen samples are below the sensitivity of the assay for vector sequences (may be for 2-3 months);

E.4

Principal exclusion criteria

I. Presence of neutralising anti-hFVIII antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of hFVIII inhibitor;
II. Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations of the F8 gene.
III. Use of investigational therapy for haemophilia within 30 days before enrolment;
IV. Subjects 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 two samples, collected at least six months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible).
V. Serological evidence of HIV.
VI. Evidence of liver dysfunction (persistently elevated ALT >1.5X upper limit of normal);
VII. Uncontrolled glaucoma, diabetes mellitus, or hypertension;
VIII. Any disease or condition (including cancer) at the physician's discretion that would prevent the patient from fully complying with the requirements of the study;
IX. Suspicious Lung lesions on CT scan that raise the possibility of cancer or premalignant pathology (based on chest CT scan done at screening or within 6 months prior to the screening visit);
X. Presence of liver abnormality that is suspicious of malignancy on screening liver ultrasound
XI. Patients with uncontrolled cardiac failure or unstable angina;
XII. Detectable neutralising anti-AAV8 antibodies
XIII. Received an AAV vector, or any other gene transfer agent in the previous 6 months
XIV. History of active tuberculosis, fungal disease or other chronic infection
XV. Subjects who are unwilling to provide the required semen samples
XVI. Poor performance status (WHO score >1)
XVII. Previous history or family history of venous or arterial thromboembolism
XXIII. Patients with a CHA2DS2-VASc score of 2 and above

E.5 End points

E.5.1

Primary end point(s)

Primary end point is safety.
Monitoring for primary outcome measures will include:
1. Monitoring of haematology, chemistry, and other standard blood tests
2. Immune response to hFVIII transgene
• Neutralising antibodies (NAB) response to hFVIII
• IFNγ ELIspot assay to hFVIII peptides including regions at the junction of A2-V3 and A3-V3, which represent potential neoantigenic sites

3. Hepatic monitoring
• Monitoring of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and bilirubin levels, and
• Annual ultrasound assessments
4. Cardiac function: Troponin I or T, electrocardiograms [ECGs], echocardiography [ECHO]
5. Pulmonary monitoring via High resolution chest CT scan

Toxicity will be assessed according to CTCAE, version 4.03 and by regular monitoring for neutralising hFVIII antibodies.

E.5.1.1

Timepoint(s) of evaluation of this end point

Data will be collected and monitored continuously for trend. Formal analysis will be performed 12 months after last patient is dosed at the terminal dose level and then at approximately 5 years post infusion of the last patient dosed, in the absence of stopping rules being met in the interim

E.5.2

Secondary end point(s)

1. Assessments of plasma hFVIII activity using a validated chromogenic assay.
2. Assessment of bleeding frequency using participant diaries before and after gene transfer.
3. Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer.
4. Viral shedding (blood, urine, saliva, faeces, semen).
5. Immune response to the AAV8 capsid.
Efficacy is a secondary endpoint and will be defined as persistence of biologically active hFVIII at ≥ 5% of normal levels. Efficacy of gene transfer will be assessed by a chromogenic assay that specifically evaluates biological activity of hFVIII. This assay will be performed at least weekly after vector administration but only after a minimum of 72 hrs have elapsed since the last administration of hFVIII protein concentrates. It is anticipated that endogenously synthesised hFVIII transgene will be detectable within 1 week of gene transfer and reach steady state level by 21 days. Subjects’ treatment diaries that document bleeding episodes and infusion of hFVIII protein concentrates will also be reviewed at regular intervals to establish any benefit, although this is recognised as a crude and subjective marker of efficacy.
Immune response to the AAV8 capsid will be assessed by measurement of the AAV8 antibody titre (humoral response) in plasma samples collected at various time points after gene transfer. Cellular immune response to AAV capsid will be determined using gamma interferon (IFNγ) ELIspot assay to AAV8 capsid.

Exploratory Endpoint:
Health Related Quality of life change from baseline will be assessed using the Haem-A-QOL score at 6 months and during long term follow up visits.

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

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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

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

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

Participants will be followed up for 5 years as per regulatory requirement/guidelines to determine longer term safety and efficacy. The end of trial is the date of the last trial visit of the last participant. The trial will then be declared ended to the regulatory authorities and ethics committees/institutional review boards.

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