A preventive study of bleeding episodes for children with severe von Willebrand disease (VWD).

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

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

Trial duration

30 Oct 2024 → ongoing

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-509877-22-00

EudraCT number

2020-003304-13

ClinicalTrials.gov

NCT05582993

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Prophylaxis, Safety, Pharmacodynamic, Pharmacokinetic, Therapy

To prospectively evaluate the efficacy of vonicog alfa (rVWF) prophylaxis in children based on the annualized bleeding rate (ABR) with intra-patient control (on-study compared to historical) for all bleeding episodes classified by the investigator as either spontaneous or traumatic while on prophylactic treatment with vonicog alfa (rVWF).

Secondary objectives 4

1. To evaluate the long-term safety of vonicog alfa (rVWF) as assessed by adverse events (AEs), including thrombogenicity, hypersensitivity, and immunogenicity, as well as by vital signs and clinical laboratory parameters
2. To evaluate additional efficacy of prophylactic treatment with vonicog alfa (rVWF)
3. To assess the efficacy of vonicog alfa (rVWF) for On Demand (OD) treatment of breakthrough bleeding episodes (spontaneous and traumatic) while on prophylactic treatment
4. To assess pharmacokinetics (PK) and pharmacodynamics (PD) of vonicog alfa (rVWF) following long-term prophylactic treatment

Conditions and MedDRA coding

severe von Willebrand Disease

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001164-PIP01-11

Plan to share IPD

Yes

IPD plan description

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. The subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of replacement therapy with VWF concentrate required to control bleeding and a diagnosis of VWD type 1, type 2 (2A, 2B, 2M, 2N), or type 3. Diagnosis is confirmed, as applicable, by genetic testing and/or by multimer analysis, which may be documented in patient's history or tested at screening.
2. The subject is <18 years of age at the time of screening.
3. Prescreening treatment requirements: a. The subject has been receiving On Demand (OD) therapy with VWF products for at least 12 months (for subjects ≥2 years of age) prior to screening, has experienced at least 1 VWF-treated bleeding event (excluding menorrhagia/heavy menstrual bleeding, as applicable) in the last 12 months, and prophylactic treatment is recommended by the investigator (Prior OD subjects); or b. The subject has been receiving prophylactic treatment with plasma derived (pd)VWF products for at least 12 months prior to screening (for subjects ≥2 years of age) and switching to prophylaxis with vonicog alfa (rVWF) is recommended by the investigator (Switch subjects), c. For subjects <2 years of age, the required duration for prior OD therapy with VWF products or for prior prophylactic treatment with pdVWF products is at least 6 months. Prior OD subjects <2 years of age should have experienced at least 1 VWF-treated bleeding event during the last 6 months based on medical records and be recommended to receive prophylactic treatment by the investigator.
4. For subjects ≥2 years of age, the subject has available records that reliably evaluate type, frequency, severity, and treatment of bleeding episodes for at least 12 months preceding enrollment. For subjects <2 years of age, the subject has available records that reliably evaluate type, frequency, severity and treatment of bleeding episodes for at least 6 months preceding enrollment.
5. If ≥12 years old at the time of screening, the subject has a body mass index (BMI) ≥15 but <40 kg/m2. If ≥2 to <12 years old at the time of screening, the subject has a BMI of ≥5th and <95th percentile (per Centers for Disease Control and Prevention [CDC] clinical charts). For younger subjects who are <2 years old, the ""weight-for-age"" clinical charts (5th to 95th percentile) provided by the CDC should be utilized to ensure the subject has a body weight of ≥5th and <95th percentiles based on gender (for clinical charts provided by CDC, refer to: https://www.cdc.gov/growthcharts/clinical_charts.htm).
6. Female subjects of childbearing potential (ie, had onset of menses/reached puberty) must have a negative blood/urine pregnancy test result at screening and agree to employ highly effective birth control measures (as defined in the protocol) for the duration of their participation in the study.
7. The subject has voluntarily provided assent (if appropriate) and the legally authorized representative(s) has provided informed consent.
8. The subject and/or legally authorized representative is willing and able to comply with the requirements of the protocol, which should also be confirmed based on a prescreening evaluation held between the investigator and the sponsor to ensure no eminent risk is present that could challenge the subject's compliance with the study requirements.

Exclusion criteria 19

1. The subject has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (eg, qualitative and quantitative platelet disorders or elevated prothrombin time/international normalized ratio less than 1.4).
2. The subject has a platelet count <100,000/mL at screening (because patients with type 2B VWD are considered eligible for this study, for patients with type 2B VWD, platelet count[s] at screening will be evaluated in consultation with the sponsor, taking into consideration historical trends in platelet counts and the investigator's medical assessment of the patient's condition).
3. The subject has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent (or assent, if appropriate).
4. The subject is pregnant or lactating at the time of enrollment.
5. The subject has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
6. The subject has participated in another clinical study involving another IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
7. The subject has not received OD or prophylactic treatment with a VWF product prior to this study.
8. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
9. The subject is unable to complete screening procedures and/or comply with the requirements of the protocol in the opinion of the investigator, based on the joint prescreening evaluation held between the investigator and the sponsor.
10. The subject has a mental condition rendering him/her unable to understand the nature, scope, and possible consequences of the study and/or evidence of an uncooperative attitude.
11. The subject has a history or presence of a VWF inhibitor at screening.
12. The subject is member of the study team or in a dependent relationship with one of the study team members, which includes close relatives (ie, children, partner/spouse, siblings, and parents) as well as employees.
13. The subject has a history or presence of an FVIII inhibitor with a titer ≥0.6 Bethesda units (BU) (by the Nijmegen-modified Bethesda assay) or ≥0.6 BU (by the Bethesda assay).
14. The subject has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
15. The subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.
16. The subject has a medical history of a thromboembolic event.
17. The subject is HIV-positive with an absolute helper T cell (CD4) count less than 200/mm3.
18. The subject has been diagnosed with significant liver disease per the investigator's medical assessment of the subject's current condition or medical history or as evidenced by, but not limited to, any of the following: serum alanine aminotransferase (ALT) greater than 5 times the upper limit of normal, hypoalbuminemia, portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices), or liver cirrhosis classified as Child-Pugh class B or C.
19. The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annualized bleeding rate (ABR) with intra-patient control (on-study compared to historical) for all (both spontaneous and traumatic) bleeding episodes classified by the investigator as either spontaneous or traumatic during prophylactic treatment with vonicog alfa (rVWF)

Secondary endpoints 21

1. Safety: a)AEs/serious AEs (SAEs): incidence, severity, causality
2. b) Occurrence of thromboembolic events
3. c) Occurrence of hypersensitivity reactions
4. d) Occurrence of infusion-related reactions (IRRs)
5. e) Immunogenicity
6. f) Development of neutralizing antibodies (inhibitors) to VWF and FVIII
7. g) Development of binding antibodies to VWF and FVIII
8. i) Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
9. Efficacy of Prophylaxis: a) Categorized ABR defined as 0, >0 to 2, >2 to 5, or >5 during vonicog alfa (rVWF) prophylaxis
10. b) ABR percent reduction success for Prior OD subjects, defined as at least 25% reduction of ABR for spontaneous bleeding episodes during vonicog alfa (rVWF) prophylaxis relative to the subject's own historical ABR during OD treatment prior to enrollment in this study
11. c) ABR preservation success for plasma-derived (pd)VWF Switch subjects, defined as achieving an ABR for spontaneous bleeding episodes during vonicog alfa (rVWF) prophylaxis that is no greater than the subject's own historical ABR during prophylactic treatment with pdVWF prior to enrollment in this study
12. d) ABR for spontaneous bleeding episodes by location of bleeding (gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia/HMB, oral and other mucosa, muscle and soft tissue) historically and while on prophylactic treatment with vonicog alfar (VWF)
13. e) ABR for bleeding episodes by cause (spontaneous, traumatic [injury related], menstrual bleeding, surgical, unknown) historically and while on prophylactic treatment with vonicog alfa (rVWF)
14. g) Total number of infusions and average number of infusions per week during prophylactic treatment with vonicog alfa (rVWF)
15. h) Total weight-adjusted consumption of vonicog alfa (rVWF) per month during prophylactic treatment
16. Efficacy of on demand (OD) Treatment of Breakthrough Bleeding Episodes: a) Overall hemostatic efficacy rating of breakthrough bleed treatment at resolution of the bleeding episode
17. b) Number of infusions of vonicog alfa (rVWF) and ADVATE utilized to treat breakthrough bleeding episodes
18. c) Weight-adjusted consumption of vonicog alfa (rVWF) and ADVATE per breakthrough bleeding episode
19. Pharmacokinetic/Pharmacodynamic Endpoints (PK/PD): a) Sparse PK/PD concentrations at scheduled time points for VWF:RCo, VWF:Ag, VWF:CB, VWFGP1bM, and FVIII:C
20. b) Incremental recovery (IR) for VWF:RCo, VWF:Ag, VWF:CB, and VWF:GP1bM
21. c) PK parameters at steady state:t1/2,area under the concentration versus time curve over a dosing interval/area under the concentration versus time curve from 0 to 96 hours,Cmax, ss, time to reach the maximum plasma concentration, volume of distribution at steady state, CLss based on VWF:RCo. The corresponding PD of vonicog alfa (rVWF) as measured in FVIII:C will be assessed using Cmax, ss, Tmax, ss, and AUCtau, ss/AUC0-96hr, ss.

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

500 Kendall Street

City

Cambridge

Postcode

02142-1108

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Jingmei Zhang

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 14

Locations

4 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

Documents 55 files

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

Application history

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