Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz) (Paz)
Hereditary Hemorrhagic Telangiectasia, Epistaxis, Anemia
About this trial
This is an interventional treatment trial for Hereditary Hemorrhagic Telangiectasia focused on measuring Osler-Weber-Rendu, Hereditary Hemorrhagic Telangiectasia, Patient Reported Outcome, HHT, Anemia, Nosebleed, Epistaxis
Eligibility Criteria
Part B
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.
- Stable IV iron use and/or blood transfusions stable for 12 weeks prior to test product initiation.
- Must agree not to undergo cautery of nasal telangiectasias or to start new therapies for HHT while on study.
- Women of childbearing potential must agree to abstinence or to use double method contraception until 4 weeks after drug termination.
- Capable of giving signed informed consent.
- Able and willing to return for outpatient visits at the protocol specified intervals.
- Able and willing to complete blood pressure monitoring at home.
- Able and willing to complete daily patient reported outcome measurements at home.
Must meet all of the inclusion criteria for either:
Severe Cohort:
- Anemia mainly due to HHT (in the judgment of the PI).
- Infusion of at least 250 mg of elemental iron in the last 12 weeks, or 1 units of blood in the last 24 weeks.
- Epistaxis averaging at least 20 minutes per week over the six-week baseline.
Moderate Cohort:
- Anemia mainly due to HHT (in the judgment of the PI).
- Epistaxis due to HHT for a cumulative duration of at least 20 minutes per week over the 6 week baseline.
- Epistaxis is clinically stable during the 12 weeks prior to Screening.
Part B
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 incompletely 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 4 weeks, or systemic use of bevacizumab in the 6 weeks prior to enrollment due to its longer half-life.
- 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.
- Presence of intrinsic heart disease as evidenced by any of the following: Echo derived left ventricular ejection fraction < 45%; Unstable obstructive CAD; history of MI, or CABG, or PCI in the last 6 months; Infiltrative and/or restrictive cardiomyopathies; Significant pericardial disease; or clinical heart failure with more than moderate mitral valve or aortic valve disease.
- Unable or unwilling to discontinue use of prohibited medications list in Section 6.5.2 for at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the randomization and for the duration of the study.
- The participant has participated in a clinical trial and has received an investigational product within the following time period prior to the start of randomization: 4 weeks, 4 half-lives or the duration of the biological effect of the investigational product (whichever is longer).
QT corrected interval ≥450 msec, based on averaged QT corrected interval values of triplicate ECGs obtained over a brief recording period.
- History of familial prolonged QT.
- Any concomitant medication which is known to prolong QT.
- Average baseline hemoglobin <6 g/dL.
- Platelets < 100x10^9 /L.
- International normalized ratio (INR) >1.5 x upper limit of normal and activated partial thromboplastin time (aPTT) >1.5 x upper limit of normal.
- Alanine Transaminase (ALT) >2 x 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 < 45%.
- Thyroid stimulating hormone (TSH) > 1.5 x upper limit of normal.
- Urine protein to creatinine ratio > 0.3.
- Neutrophil count <1000 /mm^3.
Part C Eligibility
All patients who completed Part B and who received placebo will be eligible for Part C.
For those patients who received active drug during Part B, the final decision to enter Part C will be based primarily on discussion with the PI based on safety.
Patients must be able and willing to sign the Extension ICF.
Sites / Locations
- Yale UniversityRecruiting
- Augusta UniversityRecruiting
- John Hopkins UniversityRecruiting
- Washington UniversityRecruiting
- Oregon Health & Science UniversityRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Active Comparator
Placebo Comparator
Active Comparator
Placebo Comparator
Experimental
Part B (Moderate Cohort) Pazopanib - 150 mg
Part B (Moderate Cohort) Placebo
Part B (Severe Cohort) Pazopanib - 150 mg
Part B (Severe Cohort) Placebo
Part C Pazopanib - 150 mg
150 mg pazopanib oral capsules (six 25 mg placebo capsules daily).
Placebo oral capsules (six 25 mg placebo capsules daily).
Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).
Placebo oral capsules (six 25 mg placebo capsules daily).
Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).