Pazopanib Effects on Bleeding in Hereditary Hemorrhagic Telangiectasia

• Status: Unknown status
• Trial end date: 2021-03-01
• Target enrollment: 0
• Participant gender: All

Summary

The investigators will study whether Pazopanib, taken daily for 6 months, will reduce the severity of nose bleeds in patients with hereditary hemorrhagic telangiectasia. Patients will either be provided drug or a placebo [sugar non-drug pill], and be tested for nose bleed severity throughout the trial, including particularly nose bleed duration. Investigators will also test for blood loss, as well as for safety.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Cure HHT

Criteria

Inclusion Criteria:

• A definite diagnosis of hereditary hemorrhagic telangiectasia is 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 definite diagnosis of hereditary hemorrhagic telangiectasia is defined as having 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]

Exclusion Criteria:

• 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.

• QT corrected interval ≥450 msec, based on averaged QT corrected interval values of triplicate ECGs obtained over a brief recording period

• Hemoglobin <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.

• Alanine Transaminase >2x upper limit of normal.

• Bilirubin >1.5x upper limit of normal (isolated bilirubin >1.5x upper limit of normal is acceptable if bilirubin is fractionated and direct bilirubin <35%).

• Participant has poorly controlled hypertension [defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg.

• Substantive renal disease (eGFR <30 mL/min/1.73m2calculated using the Cockcroft-Gault formula)

• Echo derived left ventricular ejection fraction <30%.

• Thyroid stimulating hormone > upper limit of normal.

• Urine protein to creatinine ratio >0.3.

• Neutrophil count <1500/mm3.