BT200 in Hereditary Bleeding Disorders

• ClinicalTrials.gov Identifier: NCT04677803
• Recruitment Status: Completed
• First Posted: December 21, 2020
• Last Update Posted: November 11, 2021
• Sponsor: Medical University of Vienna
• Information provided by (Responsible Party): Ulla Derhaschnig, MD, Medical University of Vienna

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.

Condition or disease	Intervention/treatment	Phase
Von Willebrand Diseases; Hemophilia A	Drug: BT200	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open-label, individual dose titration-to-response, basket trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2a Multiple Dose Basket Study of the Safety, Tolerability, and Pharmacologic Activity of BT200 in Patients With Hereditary Bleeding Disorders
• Actual Study Start Date: December 14, 2020
• Actual Primary Completion Date: September 10, 2021
• Actual Study Completion Date: September 10, 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment; 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.

Drug: BT200; BT200 is a PEGylated synthetic RNA oligonucleotide

Outcome Measures

Primary Outcome Measures :

1. Hemophilia A [ Time Frame: Baseline through 4 weeks after dosing ]
   increase in FVIII activity
2. VWD Type 1 [ Time Frame: Baseline through 4 weeks after dosing ]
   increase in FVIII activity
3. VWD Type 2b [ Time Frame: Baseline through 4 weeks after dosing ]
   increase in platelet count and/or FVIII activity

Secondary Outcome Measures :

1. Pharmacokinetic (PK) Measured concentration of BT200 (and derived PK parameters) [ Time Frame: Baseline through 4 weeks after dosing ]
   Measured concentration of BT200
2. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   PFA-100
3. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   Multiplate electrode platelet aggregometer (ristocetin induced)
4. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   VWF antigen
5. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   VWF:ristocetin co-factor assay
6. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   VWF activity
7. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   VWF collagen bindign assay
8. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   ELISA for unbound VWF-A1 domain
9. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
   VWF propeptide
10. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
    Fibrin D-Dimer
11. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
    Prothrombin fragement (F1.2)
12. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
    Rotational thrombelastometry
13. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
    Clot strength assay
14. Pharmacodynamics [ Time Frame: Baseline through 4 weeks after dosing ]
    Calibrated Thrombogram assay

Other Outcome Measures:

1. Overall safety and tolerability of BT200 [ Time Frame: Baseline through 4 weeks after dosing ]
   Serious, drug-related adverse events (AEs)
2. Overall safety and tolerability of BT200 [ Time Frame: Baseline through 4 weeks after dosing ]
   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
3. Overall safety and tolerability of BT200 [ Time Frame: Baseline through 4 weeks after dosing ]
   Clinically evident bleeding assessed using the International International Society on Thrombosis and Haemostasis (ISTH) Bleeding Score

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

1. 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
2. Male or female, age ≥18-70 years old at Screening
3. If female, must be post-menopausal or surgically sterilized
4. Able to comprehend and to give informed consent
5. 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:

1. 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
2. Medical History of spontaneous (not FVIII or FEIBA-associated) venous or arterial thromboembolic events
3. History of significant drug allergy or anaphylactic reactions
4. 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
5. 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
6. 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 -

Contacts and Locations

Locations

Austria

Medical University of Vienna

Vienna, Austria, A-1090

Sponsors and Collaborators

Medical University of Vienna

Investigators

• Principal Investigator: Ulla Derhaschnig, MD; MU Vienna, Dept. of Clinical Pharmacology

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ay C, Kovacevic KD, Kraemmer D, Schoergenhofer C, Gelbenegger G, Firbas CU, Quehenberger P, Jilma-Stohlawetz P, Gilbert JC, Zhu S, Beliveau M, Koenig F, Iorio A, Jilma B, Derhaschnig U, Pabinger I. von Willebrand Factor-binding aptamer rondoraptivon pegol as treatment for severe and non-severe hemophilia A. Blood. 2022 Sep 15:blood.2022016571. doi: 10.1182/blood.2022016571. Online ahead of print.

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.

• Responsible Party: Ulla Derhaschnig, MD, Associate Professor, Medical University of Vienna
• ClinicalTrials.gov Identifier: NCT04677803
• Other Study ID Numbers: BT200-02
• First Posted: December 21, 2020
• Last Update Posted: November 11, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hemostatic Disorders; Hemophilia A; Blood Coagulation Disorders; Von Willebrand Diseases; Blood Coagulation Disorders, Inherited; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Vascular Diseases; Cardiovascular Diseases; Blood Platelet Disorders