E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is an X-linked congenital bleeding disorder causing frequent bleedings and recurrent spontaneous bleeds into the soft tissue and joints, leading to joint damage and severe disability. |
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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 | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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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 |
Investigate the safety and tolerability of single ascending intravenous (IV) doses of BAY 2599023 (DTX2ß1) in adult patients with severe hemophilia A, who have been previously treated with FVIII product |
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E.2.2 | Secondary objectives of the trial |
Identify a dose of BAY 2599023 (DTX201) that will achieve expression of vector-derived B-domain deleted human factor VIII above 5% at 6 months and 12 months following an IV administration |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Males ≥ 18 years of age
• Subjects with severe hemophilia A (baseline FVIII activity FVIII:C <1%) determined by measurement at the time of Screening (unless there is genetic testing compatible with severe deficiency)
• Previously treated with FVIII concentrate(s) (plasma derived or recombinant) or cryoprecipates for a minimum of 150 exposure days (ED)
• Are on one of the following therapies: Prophylaxis, and is willing to stop prophylactic treatment at specified time points throughout the study or On-demand: have had > 4 bleeding events in the last 52 weeks
• Subjects must agree to use double barrier and effective contraception methods. Vasectomized subjects must agree to use condoms. This is applicable from the time of the study drug administration until notified by the investigator. Time until discontinuation of contraception will be at a minimum 6 months, and will progressively increase with increasing
dose.Recommendation to investigators is to continue the contraception until three consecutive blood and semen samples BLOD of shed virus have been obtained.
Acceptable methods of contraception include, but are not limited to, (i) condoms with a spermicidal agent (ii) diaphragm or cervical cap with spermicide; if an intra-uterine device or hormone-based contraception is used by the patient’s partner, an additional barrier method must be used.
• Male subjects must agree not to donate cells, semen, blood, tissue or organs from the time of study drug administration |
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E.4 | Principal exclusion criteria |
• Current evidence of inhibitor to FVIII with a titer ≥ 0.6 BU/mL
• History of inhibitor to FVIII with a titer ≥ 0.6 BU, or clinical history requiring modification of treatment, suggestive of inhibitor. Family history of inhibitors will not exclude the subject.
• Have significant underlying liver disease as evidenced by any of the following: portal hypertension, splenomegaly, ascites, esophageal varices, hepatic encephalopathy, reduction below normal limits of serum albumin or a liver biopsy with evidence of stage 3 fibrosis
• Any of the following: Hemoglobin <11 g/dL; Platelets <100,000 cells/μL; Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × ULN; Alkaline phosphatase (AP) >2.5 × ULN; Total bilirubin >1.5 × ULN; Prothrombin time (PT) or international normalized ratio (INR) >1.0 × ULN; Serum creatinine >1.5 mg/dL
• Have active hepatitis B or C infection, as reflected by HBsAg or HCV-RNA viral load positivity
• Currently on antiviral therapy for hepatitis B or C.
• Serological evidence of active HIV-1 or HIV-2 as measured by CD4+ cell count <200 cells/mm3 and a viral load >50 gc/mL
• Anti-AAVhu37 neutralizing antibody titer ≥1:5
• Any major and/or orthopedic surgery within screening period prior to trial product administration, and at least 6 months thereafter
• History of a malignancy for which the subject has received treatment in the past 2 years except for prostate cancer being monitored without medical intervention, or surgically removed non-melanoma skin cancer
• Known or suspected autoimmune diseases
• Known prior history of hypersensitivity or anaphylaxis associated with any FVIII or immunoglobulin administration.
• Known or suspected hypersensitivity or allergic reaction to trial product(s) or related FVIII products or any component of BAY 2599023(DTX201), or a contraindication to prednisolone (as of amendment 6)
• Known or suspected hypersensitivity or allergic reaction to trial product(s) or related FVIII products or any component of BAY 2599023 (DTX201)
• Live vaccines and COVID-19 vaccines within the last 30 days prior to the study drug administration; live vaccines may be re-introduced after viral shedding has been cleared
• Subjects on treatment with immunomodulatory agents within the last 3 months prior to study entry or during the study
• Any individual who requires any pre-medication to tolerate FVIII treatment (e.g., antihistamines)
• Prior use of emicizumab within 3 months before dosing
• Clinically relevant findings in the physical examination considered critical by the treating physician, including obesity with BMI > 35 kg/m2 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of adverse events, treatment-emergent adverse events, serious adverse events and Adverse events/serious adverse events of special interest |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End points will be assessed over the course of part A and Part B of the study. |
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E.5.2 | Secondary end point(s) |
1. Expression pattern of FVIII activity.
2. Proportion of patients in the respective dose step, that reached an
expression of FVIII above 5% at 6 months and 12 months following the
IV administration of BAY2599023 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at 6 months & 12 months following an IV administration |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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 | No |
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 |
Bulgaria |
France |
Germany |
Netherlands |
United Kingdom |
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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
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LVLS (primary completion event for this study will be reached after the
last subject completes his last visit). |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |