Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia

NCT03850730 | Unknown Phase 1 FDA Drug

• 1 other identifier: HT3
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

Investigators will test the value of very low dose Pazopanib administered to patients with hereditary hemorrhagic telangiectasia for the reduction in the severity of nose bleeds in those with frequent and long duration bleeding episodes.

Conditions

Hereditary Hemorrhagic Telangiectasia; Epistaxis

Keywords

osler-weber-rendu; nose bleeds; open label; HHT; Pazopanib

Outcome Measures

Primary Outcomes (1)

• Percent change in epistaxis duration in minutes

  A daily electronic record of each bleed, with start and end time, provides the daily epistaxis duration, compounded over each 3 weeks of study time

  Summed minutes of bleeding at baseline 3 weeks and the last 3 weeks of dosing, over16-24 weeks of dosing

Secondary Outcomes (13)

• Percent change in average gushing frequency

  Last 3 weeks of drug period vs baseline 3 weeks; over 16-24 weeks of dosing

• Percent change in average bleed frequency

  Last 3 weeks compared to the baseline 3 weeks; over 16-24 weeks of dosing

• Absolute [gm/dl] change in serum hemoglobin

  comparing last 6 weeks to baseline 3-6 weeks; over 16-24 weeks of drug dosing

• Change in the frequency of blood transfusions

  Final 6 weeks of study, compared to baseline 3-6 weeks; over 16- 24 weeks of dosing

• Change in the frequency of IV iron infusions

  Last 6 weeks of dosing to first 6 weeks; over 16-24 weeks of drug administration

Other Outcomes (2)

• Interrogate levels of Iron stores

  baseline and at on-drug study end; 16, 20 or 24 weeks depending on study duration

• Characterize change in left ventricular stress

  baseline and on-drug study end; 16, 20 or 24 weeks depending on study duration]

Study Arms (1)

Pazopanib

EXPERIMENTAL

Pazopanib, initiated after a baseline period at 25mg oral dosing daily, for this one treatment arm, to be compared to the patient's baseline. If endpoint not achieved and safety demonstrated in 2-3mths, an advance of dose to 50mg daily for the ensuing 3mths of study will be considered.

Drug: Pazopanib

Interventions

Pazopanib DRUG

Active pharmaceutical ingredient plus excipients filled into a capsule for the lower dosing necessary in this study

Also known as: Pazopanib capsule

Pazopanib

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• a definite diagnosis of hereditary hemorrhagic telangiectasia defined as having at least 3 of the following criteria:
• Spontaneous and recurrent epistaxis.
• Multiple telangiectasias at characteristic sites: lips, oral cavity, fingers, nose.
• Visceral lesions: GI telangiectasia, pulmonary, hepatic, cerebral or spinal AVMs.
• A first degree relative with hereditary hemorrhagic telangiectasia according to these criteria.
• OR a gene sequencing diagnosis of hereditary hemorrhagic telangiectasia
• \. Epistaxis due to hereditary hemorrhagic telangiectasia at least 2x per week, for a cumulative duration of at least 25 minutes per week
• \. Epistaxis is clinically stable during the 12 weeks prior to screening in the clinical judgment of the investigator (i.e. no major changes in frequency or duration of epistaxis).
• \. Participant agrees not to undergo cautery of nasal telangiectasias or take any experimental therapies for hereditary hemorrhagic telangiectasia other than the study drug while participating in the study.
• \. Male or female \[non-child bearing potential\]

You may not qualify if:

• Participant has known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib that in the opinion of the investigator contradicts their participation.
• Currently has untreated cerebral arterio-venous malformations (AVMs), cerebral arteriovenous fistulae, or cerebral cavernous malformations (CCMs) (Note: MRI scan does not need to be repeated at screening if AVMs, arterio-venous fistulas and CCMs were absent on a scan at age ≥18 years).
• Currently has perfused pulmonary AVMs with feeding artery diameter \>3mm.
• Known significant bleeding sources other than nasal or gastrointestinal.
• Systemic use of a vascular endothelial growth factor inhibitor in the past 3 months or previous enrollment in this study.
• Active and recent onset of clinically significant diarrhea.
• Current or recent (in the last 5 years) malignancies (except non-melanoma skin cancers)
• Participant has had major surgery (e.g. surgical ligation of an AVM) or trauma within 28 days or had minor surgical procedures (e.g. central venous access line removal) within 7 days prior to dosing, the latter representing a recent wound, fracture or ulcer
• Participant has a planned surgery during the period to include active treatment and 6 weeks of follow up.
• Participant has clinically significant gastrointestinal abnormalities (other than hereditary hemorrhagic telangiectasia related vascular lesions)
• Participant during the 6 months prior to first dose of study drug has a history of cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, untreated deep vein thrombosis (DVT), myocardial infarction, or any other thrombotic event.
• QTc ≥450 msec, based on averaged QTc values of triplicate ECGs obtained over a brief recording period \[The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. The same QT correction formula must be used for each individual participant to determine eligibility for and withdrawal from the study.\]
• Hgb \<6 g/dL.
• Platelets \< 100x109/L.
• International normalized ratio (INR) \>1.2x upper limit of normal and activated partial thromboplastin time (aPTT)\>1.2x upper limit of normal.

Sponsors & Collaborators

• Cure HHT: lead
• University of North Carolina: collaborator

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Epistaxis

Interventions

pazopanib

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Study Officials

• Raj Kasthuri, MD

  University of North Carolina

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nicole Schaefer

CONTACT

410-357-9932; nicole.schaefer@curehht.org

Dennis L Sprecher, MD

CONTACT

410-357-9932; dennis.sprecher@curehht.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: This is an open label study and thus all personnel and patients will be aware of the assignment.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: After at least a 6 week baseline, patients will be placed on very low dose Pazopanib \[25mg-similar\], for 8 weeks.. If the primary bleeding duration endpoint is achieved, than the patient will continue for another 8wks, or a total of 16 weeks on the same dose. Lack of any response will result in a dose advance to 50mg for another 3mths. If a moderate change has occurred, than the 25mg dose will be continued for another 4 weeks, and if primary endpoint achieved, continue for another 12 weeks... Lack of endpoint achievement, will augment dose to 50mg and extend study for 12 weeks, or a total of 24 weeks.

Study Record Dates

• First Submitted: February 12, 2019
• First Posted: February 22, 2019
• Study Start: July 1, 2023
• Primary Completion: June 30, 2025
• Study Completion: December 31, 2025
• Last Updated: September 8, 2022

Record last verified: 2022-09