A phase III trial investigating a gene therapy (AAV-hFIXco-Padua, AMT061), in adult patients with severe or moderately severe haemophilia B, to firstly evaluate if it's effective, and secondly further describe it's safety profile.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

CSL Behring LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

3 Dec 2018 → 20 Mar 2025

Decision date (initial)

2024-08-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

CSL Behring LLC

External identifiers

EU CT number

2024-510738-42-00

EudraCT number

2017-004305-40

ClinicalTrials.gov

NCT03569891

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Demonstrate the non-inferiority of CSL222 (formerly AMT-061 [2 x 10^13 gc/kg]) during the 52 weeks following establishment of stable factor IX expression (months 6 to 18) post-treatment (CSL222) followup compared to standard of care continuous routine factor IX prophylaxis during the lead-in phase, as measured by the annualized bleeding rate (ABR).

Secondary objectives 1

1. The secondary objective is to demonstrate additional efficacy and safety aspects of systemic administration of CSL222 (formerly AMT,061) on: Endogenous factor IX activity 6 months, 12 months, and 18 months, Bleeding prevention, Trough FIX activity, Discontinuation of previous continuous routine prophylaxis, Consumption of FIX replacement therapy, Occurrence & resolution of target joints, Estimated ABR during the 52 weeks following stable factor IX expression, Correlation of pre,IMP anti,AAV5 antibody titers, Exploratory efficacy objectives. The secondary safety objective include: monitoring of AEs, changes in abdominal ultrasound, formation of anti,AAV5 antibodies (total IgM & IgG neutralizing antibodies), AAV5 capsid,specific T cell response, anti,FIX antibodies, FIX inhibitors and recovery, hematology & serum chemistry, shedding of vector DNA (blood & semen), inflammatory markers, AST/ALT increase and alpha,fetoprotein (AFP)

Conditions and MedDRA coding

Haemophilia B

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male
2. Age ≥18 years
3. Subjects with congenital hemophilia B with known severe or moderately severe factor IX deficiency (≤2% of normal circulating factor IX ) for which the subject is on continuous routine factor IX prophylaxis (continuous routine prophylaxis is defined as the intent of treating with an a priori defined frequency of infusions [e.g., twice weekly, once every two weeks, etc.] as documented in the medical records).
4. >150 previous exposure days of treatment with factor IX protein
5. Have been on stable prophylaxis for at least 2 months prior to screening
6. Have demonstrated capability to independently, accurately and in a timely manner complete the diary during the lead-in phase as judged by the investigator
7. Acceptance to use a condom during sexual intercourse in the period from IMP administration until AAV5 has been cleared from semen, as evidenced by the central laboratory from negative analysis results for at least 3 consecutively collected semen samples (this criterion is applicable also for subjects who are surgically sterilized)
8. Able to provide informed consent following receipt of verbal and written information about the trial.

Exclusion criteria 16

1. History of factor IX inhibitors
2. Positive factor IX inhibitor test at screening and Visit L-Final (based on local laboratory results)
3. Screening and Visit L-Final laboratory values (based on central laboratory results): a) ALT >2 times upper normal limit b) Aspartate aminotransferase (AST) >2 times upper normal limit c) Total bilirubin >2 times upper normal limit (except if this is caused by Gilbert disease) d) Alkaline phosphatase (ALP) >2 times upper normal limit e) Creatinine >2 times upper normal limit
4. Positive human immunodeficiency virus (HIV) serological test at E7 screening and Visit LFinal, not controlled with anti-viral therapy asshown by CD4+ counts ≤ 200/μL (based on central laboratory results)
5. Hepatitis B or C infection with the following criteria present at screening: i. Currently receiving antiviral therapy for this/these infection(s) and/or ii. Positive for any of the following (based on central laboratory results): • Hepatitis B surface antigen (HBsAg), except if in the opinion of the investigator this is due to a previous Hepatitis B vaccination rather thanactive Hepatitis B infection • Hepatitis B virus deoxyribonucleic acid (HBV DNA) • Hepatitis C virus ribonucleic acid (HCV RNA)
6. Known coagulation disorder other than hemophilia B
7. Thrombocytopenia, defined as a platelet count below 50 × 10^9/L, at screening and Visit L-Final (based on central laboratory results)
8. Known severe infection or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, alcoholism, drug dependency or any other psychological disorder valuated by the investigator to interfere with adherence to the protocol procedures or with the degree of tolerance to the IMP
9. Known significant medical condition that may significantly impact the intended transduction of the vector and/or expression and activity of the protein, including but not limited to: • Disseminated intravascular coagulation • Accelerated fibrinolysis • Advanced liver fibrosis (suggestive of or equal to METAVIR Stage 3 disease; e.g. a FibroScan™ score of ≥9 kPa is considered equivalent)
10. Known history of an allergic reaction or anaphylaxis to factor IX products
11. Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients
12. Known history of allergy to corticosteroids
13. Known medical condition that would require chronic administration of steroids
14. Previous gene therapy treatment
15. Receipt of an experimental agent within 60 days prior to screening
16. Current participation or anticipated participation within one year after IMP administration in this trial in any other interventional clinical trial involving drugs or devices.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ABR comparison between CSL222 (formerly: AMT-061) and prophylaxis for non-inferiority between the lead-in phase and the 52 weeks following stable factor IX expression (months 6-18 post treatment)

Secondary endpoints 17

1. Endogenous factor IX activity at 6 months after CSL222 dosing
2. Endogenous factor IX activity at 12 months after CSL222 dosing
3. Endogenous factor IX activity at 18 months after CSL222 dosing
4. Annualized consumption of factor IX replacement therapy during the 52 weeks following stable factor IX expression (months 6-18 post-treatment), excluding factor IX replacement for invasive procedures, compared to the lead-in phase
5. Annualized infusion rate of factor IX replacement therapy during the 52 weeks following stable factor IX expression (months 6-18 posttreatment), excluding factor IX replacement for invasive procedures, compared to the lead-in phase
6. Proportion of subjects remaining free of previous continuous routine prophylaxis during the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
7. Comparison of the percentage of subjects with trough factor IX activity <12% of normal between the lead in phase and after treatment with CSL222 over the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
8. ABR comparison between CSL222 and prophylaxis for superiority between the lead-in phase and the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
9. Rate of spontaneous bleeding events during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) compared to the lead in phase
10. Rate of joint bleeding events during the 52 weeks following stable factor IX expression (months 6-18 post treatment) compared to the lead-in phase
11. Estimated ABR – during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) – as a function of pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay (as a "correlation" analysis)
12. Correlation of factor IX activity levels during the 52 weeks following stable factor IX expression (months 6-18 post-treatment) with pre-IMP anti-AAV5 antibody titers using the luciferase based NAB assay
13. Occurrence of (and resolution of) new target joints during the 52 weeks following stable factor IX expression (months 6-18 posttreatment) and resolution of pre-existing target joints following CSL222 dosing
14. Proportion of subjects with zero bleeds during the 52 weeks following stable factor IX expression (months 6-18 post-treatment)
15. PRO questionnaire scores from the international Physical Activity Questionnaire (iPAQ; total physical activity score) during the 12 months following CSL222 dosing compared with the lead-in phase
16. PRO questionnaire scores from the EuroQol-5 dimensions-5 levels (EQ 5D 5L) visual analogue scale (VAS) score during the 12 months followingCSL222 dosing compared with the lead-in phase
17. Secondary safety endpoints - Adverse events - Changes in abdominal ultrasound - Anti-AAV5 antibodies (total [IgM and IgG], neutralizing antibodies) - AAV5 capsid-specific T cells - Anti-factor IX antibodies - Factor IX inhibitors and recovery - Hematology and serum chemistry parameters - ALT/AST levels, and corticosteroid use for ALT/AST increases - Vector DNA in blood and semen - Inflammatory markers: IL-1β, IL-2, IL-6, IFNγ, MCP-1 - Alpha-fetoprotein (AFP)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

CSL Behring LLC

Sponsor organisation

CSL Behring LLC

Address

1020 1st Avenue

City

King Of Prussia

Postcode

19406-1310

Country

United States

Scientific contact point

Organisation

CSL Behring LLC

Contact name

Trial Registration Coordinator

Public contact point

Organisation

CSL Behring LLC

Contact name

Trial Registration Coordinator

Third parties 13

Locations

6 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 64 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications