A study to determine the effectiveness, safety, and tolerability of the Recombinant Von Willebrand Factor administered with or without Advate for children diagnosed with Severe von Willebrand Disease who experience bleeding episodes and/or will undergo major, minor or oral surgery procedures.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Baxalta Innovations GmbH

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

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

Trial duration

15 Mar 2017 → 17 Apr 2026

Decision date (initial)

2024-05-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Baxalta Innovations GmbH, Austria

External identifiers

EU CT number

2023-509769-18-00

EudraCT number

2016-001477-33

ClinicalTrials.gov

NCT02932618

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Others, Safety, Efficacy

To evaluate the hemostatic efficacy and safety of vonicog alfa, with or without ADVATE, in the treatment and control of nonsurgical bleeding events in pediatric subjects (<18 years of age) diagnosed with severe, hereditary VWD.

Secondary objectives 3

1. Elective or emergency surgery:to evaluate the hemostatic efficacy after the last perioperative vonicog alfa infusion.
2. To evaluate the safety of vonicog alfa.
3. To evaluate the PK of vonicog alfa.

Conditions and MedDRA coding

Hereditary severe von Willebrand Disease in children

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. Diagnosis of severe VWD (defined as VWF:RCo <20%): a. Type 1 (VWF:RCo <20 IU/dL); or b. Type 2A (VWF:RCo <20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C <10% and historically documented genetics), Type 2M; or c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Age 0 to <18 years at the time of screening.
3. The subject has provided assent (if appropriate) and legally authorized representative(s) has provided informed consent.
4. If female of childbearing potential, subject presents with a negative serum pregnancy test.
5. If applicable, subject agrees to employ adequate birth control measures for the duration of the study.
6. Subject and/or the legally authorized representative are 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.
7. Additional inclusion criteria for previously treated subjects as well as for subjects undergoing surgery: 1. Unable to tolerate, inadequately responsive to not a good candidate for 1-deamino-8-D-arginine vasopressin (DDAVP). Examples of subjects who are not good candidates for DDAVP include subjects with type 2B or type 3 VWD. 2. The subject has had a minimum of 1 documented bleed requiring VWF coagulation factor replacement therapy (ie, treatment with a VWF product) during the previous 12 months prior to enrollment and overall historically 3 or more exposure days (EDs) to VWF replacement therapy.
8. Additional inclusion criterion for previously untreated subjects: The subject has not received prior VWF coagulation factor replacement therapy.

Exclusion criteria 15

1. Diagnosis of pseudo-VWD or another hereditary or acquired coagulation disorder (eg, qualitative and quantitative platelet disorders or elevated prothrombin time/international normalized ratio >1.4)
2. History or presence of a VWF inhibitor at Screening.
3. History or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by Nijmegen assay) or ≥0.6 BU (by Bethesda assay.)
4. Documented history of a VWF:RCo half-life <6 hours.
5. Known hypersensitivity to any of the components of the study drug, such as mouse or hamster proteins.
6. Medical history of immunological disorders, excluding seasonal allergic rhinitis/ conjunctivitis/ asthma, food allergies, or animal allergies
7. Medical history of a thromboembolic event.
8. Human immunodeficiency virus positive, with an absolute CD4 count <200/mm3.
9. In the judgment of the Investigator, the subject has another clinically significant concomitant disease (eg, uncontrolled hypertension, cancer) that may pose additional risks for the subject.
10. Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following: serum alanine aminotransferase 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 B or C.
11. Diagnosis of renal disease, with a serum creatinine level ≥2.5 mg/dL.
12. Immunomodulatory drug treatment other than anti-retroviral chemotherapy (eg, α-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day (excluding topical treatment [eg, ointments, nasal sprays]), within 30 days prior to signing the informed consent (or assent, if appropriate).
13. If female, subject is pregnant or lactating at the time informed consent (or assent, if appropriate) is obtained.
14. Subject has participated in another clinical study involving an IP, other than vonicog alfa with or without ADVATE, or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP other than vonicog alfa or investigational device during the course of this study.
15. Subject's legal representative is a family member or employee of the Investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary outcome measure is hemostatic efficacy, defined as the number of pediatric subjects with treatment success for vonicog alfa-treated nonsurgical bleeding episodes (using a 4-point scale). Bleeding episode treatment success is defined as a mean efficacy rating score of <2.5.

Secondary endpoints 13

1. Efficacy: 1. Number of treated nonsurgical bleeding episodes with an efficacy rating of 'excellent' or 'good'.
2. 2. Number of infusions, vonicog alfa units, and ADVATE units (if needed), per bleeding episode.
3. 3. For elective or emergency surgery: an overall assessment of hemostatic efficacy 24 hours after the last perioperative infusion of vonicog alfa, or on Day 14, whichever is earlier, assessed by the Investigator (hematologist) on a 4-point scale.
4. Safety: 1. Incidence and severity of adverse events (AEs) by system organ class (SOC) and preferred term.
5. 2. Incidence of thromboembolic events.
6. 3. Incidence of severe hypersensitivity reactions.
7. 4. Development of neutralizing antibodies to VWF and Factor VIII (FVIII).
8. 5. Development of total binding antibodies to VWF.
9. 6. Development of antibodies to CHO proteins, murine IgG, and rFurin.
10. PK/PD: 1. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion (AUC0-96h), area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞),
11. Mean residence time (MRT), maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), clearance (CL), incremental recovery (IR), in-vivo recovery (IVR), elimination phase half-life (T1/2), and volume of distribution at steady state (Vss) for VWF:RCo., VWF:Ag and VWF:CB using non-compartmental analysis (NCA) methodology.
12. 2. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion (AUC0-96h) for VWF:Ag and VWF:CB. Point estimates per age cohort will be presented.
13. 3. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion (AUC0-96h) for FVIII activity. Point estimates per age cohort will be presented.

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Baxalta Innovations GmbH

Sponsor organisation

Baxalta Innovations GmbH

Address

Industriestrasse 67, Donaustadt Donaustadt

City

Vienna

Postcode

1221

Country

Austria

Scientific contact point

Organisation

Baxalta Innovations GmbH

Contact name

Jingmei Zhang

Public contact point

Organisation

Baxalta Innovations GmbH

Contact name

Takeda

Third parties 10

Locations

5 EU/EEA countries · 11 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 112 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