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BT200 in Hereditary Bleeding Disorders

Primary Purpose

Von Willebrand Diseases, Hemophilia A

Status

Completed

Phase

Phase 2

Locations

Austria

Study Type

Interventional

Intervention

BT200

About this trial

This is an interventional treatment trial for Von Willebrand Diseases

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:To be eligible for this study, patients must meet all of the following inclusion criteria:

Hereditary bleeding disorder:
- Congenital hemophilia A without inhibitors with a prophylactic treatment regime
- Heterozygous carriers of hemophilia A with subnormal FVIII levels
- VWD Type 1, "Vicenza" type
- VWD Type 2b
Male or female, age ≥18-70 years old at Screening
If female, must be post-menopausal or surgically sterilized
Able to comprehend and to give informed consent
Able to cooperate with the Investigator, to comply with the requirements of the study, and to complete the full sequence of protocol-related procedures -

Exclusion Criteria: Patients meeting any of the following criteria will be excluded from the study:

Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the patient or compromise the quality of the data derived from his/her participation in this study
Medical History of spontaneous (not FVIII or FEIBA-associated) venous or arterial thromboembolic events
History of significant drug allergy or anaphylactic reactions
Substance abuse, mental illness, or any reason that makes it unlikely in the judgment of the Investigator for the patient to be able to comply fully with study procedures
Use of medication during 2 weeks before the start of the study, which in the judgment of the Investigator may adversely affect the patient's welfare or the integrity of the study's results
Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 elimination half-lives (whichever is longer) prior to treatment start -

Sites / Locations

Medical University of Vienna

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

Subcutaneous (SC) injection: BT200 dose 3 mg on Day 0, Day 4, and again on Day 7 BT200 dose titrated thereafter between 3 and 9 mg on Days 14, 21, and 28. It is anticipated that dose adjustments will be performed in 2 mg steps. The 9 mg dose will only be applied on day 28 in exceptional circumstances, if no relevant changes in pharmacodynamic and safety parameters will be observed on day 21.

Outcomes

Primary Outcome Measures

Hemophilia A

increase in FVIII activity

VWD Type 1

increase in FVIII activity

VWD Type 2b

increase in platelet count and/or FVIII activity

Secondary Outcome Measures

Pharmacokinetic (PK) Measured concentration of BT200 (and derived PK parameters)

Measured concentration of BT200

Pharmacodynamics

PFA-100

Pharmacodynamics

Multiplate electrode platelet aggregometer (ristocetin induced)

Pharmacodynamics

VWF antigen

Pharmacodynamics

VWF:ristocetin co-factor assay

Pharmacodynamics

VWF activity

Pharmacodynamics

VWF collagen bindign assay

Pharmacodynamics

ELISA for unbound VWF-A1 domain

Pharmacodynamics

VWF propeptide

Pharmacodynamics

Fibrin D-Dimer

Pharmacodynamics

Prothrombin fragement (F1.2)

Pharmacodynamics

Rotational thrombelastometry

Pharmacodynamics

Clot strength assay

Pharmacodynamics

Calibrated Thrombogram assay

Full Information

NCT ID

NCT04677803

First Posted

December 3, 2020

Last Updated

November 10, 2021

Sponsor

Medical University of Vienna

1. Study Identification

Unique Protocol Identification Number

NCT04677803

Brief Title

BT200 in Hereditary Bleeding Disorders

Official Title

A Phase 2a Multiple Dose Basket Study of the Safety, Tolerability, and Pharmacologic Activity of BT200 in Patients With Hereditary Bleeding Disorders

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Completed

Study Start Date

December 14, 2020 (Actual)

Primary Completion Date

September 10, 2021 (Actual)

Study Completion Date

September 10, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Medical University of Vienna

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

BT200 is a PEGylated aptamer that binds to the A1 domain of human von Willebrand factor (VWF). At low doses, BT200 blocks the clearance of VWF antigen (VWF Ag) from the circulation and causes an increase in concentrations of both VWF Ag and Factor VIII (FVIII), but has negligible effect on the activity of either. At higher doses, BT200 blocks clearance of VWF and also inhibits its activity, but still does not inhibit FVIII activity. Therefore, low dose BT200 could potentially be used to correct deficiency of VWF and/or FVIII in patients with hereditary bleeding disorders. This study is designed as a "basket design" pilot study to determine the relevant dose and pharmacological activity of BT200 in such patients. In this open basket study up to 25 patients with the following congenital blood-clotting disorders are to be included: Patients with hemophilia A, heterozygous carriers of hemophilia A with subnormal FVIII levels; patients with von Willebrand syndrome (VWD) type 1, "Vicenza type", and with VWD type 2b. Participants will receive BT200 subcutaneously on day 0, day 4 and day 7 in the first week and then once a week for a total of five weeks - initially in a dose of 3 mg, then in week 3 individually after response in a dose of 3 to 9 mg. Subsequently, blood samples are taken once a week for a further three weeks (wash-out phase). Patients may be enrolled in an additional pharmacokinetics sub-study. For this purpose, approximately three blood samples are taken to estimate the half-life of substituted FVIII under the influence of BT200. The primary objective of this study is to obtain clinical proof of mechanism for BT200 in one or more hereditary bleeding disorders.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Von Willebrand Diseases, Hemophilia A

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Model Description

Open-label, individual dose titration-to-response, basket trial

Masking

None (Open Label)

Allocation

N/A

Enrollment

26 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

BT200

Intervention Description

BT200 is a PEGylated synthetic RNA oligonucleotide

Primary Outcome Measure Information:

Title

Hemophilia A

Description

increase in FVIII activity

Time Frame

Baseline through 4 weeks after dosing

Title

VWD Type 1

Description

increase in FVIII activity

Time Frame

Baseline through 4 weeks after dosing

Title

VWD Type 2b

Description

increase in platelet count and/or FVIII activity

Time Frame

Baseline through 4 weeks after dosing

Secondary Outcome Measure Information:

Title

Pharmacokinetic (PK) Measured concentration of BT200 (and derived PK parameters)

Description

Measured concentration of BT200

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

PFA-100

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

Multiplate electrode platelet aggregometer (ristocetin induced)

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

VWF antigen

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

VWF:ristocetin co-factor assay

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

VWF activity

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

VWF collagen bindign assay

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

ELISA for unbound VWF-A1 domain

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

VWF propeptide

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

Fibrin D-Dimer

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

Prothrombin fragement (F1.2)

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

Rotational thrombelastometry

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

Clot strength assay

Time Frame

Baseline through 4 weeks after dosing

Title

Pharmacodynamics

Description

Calibrated Thrombogram assay

Time Frame

Baseline through 4 weeks after dosing

Other Pre-specified Outcome Measures:

Title

Overall safety and tolerability of BT200

Description

Serious, drug-related adverse events (AEs)

Time Frame

Baseline through 4 weeks after dosing

Title

Overall safety and tolerability of BT200

Description

Patterns of serious or non-serious, drug-related AEs and/or clinically relevant laboratory abnormalities, vital signs, or physical findings suggestive of one or more specific target organs for toxicity of BT200

Time Frame

Baseline through 4 weeks after dosing

Title

Overall safety and tolerability of BT200

Description

Clinically evident bleeding assessed using the International International Society on Thrombosis and Haemostasis (ISTH) Bleeding Score

Time Frame

Baseline through 4 weeks after dosing

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria:To be eligible for this study, patients must meet all of the following inclusion criteria: Hereditary bleeding disorder: Congenital hemophilia A without inhibitors with a prophylactic treatment regime Heterozygous carriers of hemophilia A with subnormal FVIII levels VWD Type 1, "Vicenza" type VWD Type 2b Male or female, age ≥18-70 years old at Screening If female, must be post-menopausal or surgically sterilized Able to comprehend and to give informed consent Able to cooperate with the Investigator, to comply with the requirements of the study, and to complete the full sequence of protocol-related procedures - Exclusion Criteria: Patients meeting any of the following criteria will be excluded from the study: Clinically significant medical history or ongoing chronic illness that would jeopardize the safety of the patient or compromise the quality of the data derived from his/her participation in this study Medical History of spontaneous (not FVIII or FEIBA-associated) venous or arterial thromboembolic events History of significant drug allergy or anaphylactic reactions Substance abuse, mental illness, or any reason that makes it unlikely in the judgment of the Investigator for the patient to be able to comply fully with study procedures Use of medication during 2 weeks before the start of the study, which in the judgment of the Investigator may adversely affect the patient's welfare or the integrity of the study's results Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days or 5 elimination half-lives (whichever is longer) prior to treatment start -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ulla Derhaschnig, MD

Organizational Affiliation

MU Vienna, Dept. of Clinical Pharmacology

Official's Role

Principal Investigator

Facility Information:

Facility Name

Medical University of Vienna

City

Vienna

ZIP/Postal Code

A-1090

Country

Austria

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

36108308

Citation

Ay C, Kovacevic KD, Kraemmer D, Schoergenhofer C, Gelbenegger G, Firbas C, Quehenberger P, Jilma-Stohlawetz P, Gilbert JC, Zhu S, Beliveau M, Koenig F, Iorio A, Jilma B, Derhaschnig U, Pabinger I. The von Willebrand factor-binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A. Blood. 2023 Mar 9;141(10):1147-1158. doi: 10.1182/blood.2022016571.

Results Reference

derived

PubMed Identifier

35772170

Citation

Ay C, Pabinger I, Kovacevic KD, Gelbenegger G, Schorgenhofer C, Quehenberger P, Jilma-Stohlawetz P, Sunder-Plassman R, Gilbert JC, Zhu S, Jilma B, Derhaschnig U. The VWF binding aptamer rondoraptivon pegol increases platelet counts and VWF/FVIII in type 2B von Willebrand disease. Blood Adv. 2022 Sep 27;6(18):5467-5476. doi: 10.1182/bloodadvances.2022007805. Erratum In: Blood Adv. 2023 Jun 13;7(11):2656.

Results Reference

derived

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BT200 in Hereditary Bleeding Disorders

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