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Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz) (Paz)

Primary Purpose

Hereditary Hemorrhagic Telangiectasia, Epistaxis, Anemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pazopanib
Placebo oral capsule
Sponsored by
Cure HHT
About
Eligibility
Locations
Arms
Outcomes
Full info

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

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Experimental

Arm Label

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

Arm Description

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).

Outcomes

Primary Outcome Measures

Change in epistaxis duration in minutes
>=50% decrease in the duration of epistaxis in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)
Hemoglobin Response rate increase in hemoglobin
Increase in hemoglobin by ≥ 2 g/dl in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)

Secondary Outcome Measures

Achievement of meaningful improvement in epistaxis for HHT patients
Compare patients reported being bothered by epistaxis at baseline and report not bothered at week 24
Percent change in blood transfusion rate in the Severe Cohort
Reduction in RBC transfusion rate by at least one unit
Assess the safety of up to 24 and 48 weeks of treatment of pazopanib
AEs; absolute values and changes over time of hematology, clinical chemistry, urinalysis, blood pressure, and heart rate. Physical exam, leg and abdominal evaluations, and CNS symptoms. ECG parameters (PR, QRS, QT, QTc intervals) in addition to cardiac echocardiogram to evaluate LV function from pre-dose values in at-risk patients (baseline EF <50)
Assess pharmacokinetics and pharmacodynamics (PK/PD) of treatment
Cτ, data permitting Graphical exploration of PK/PD relationships between pazopanib and selected PD endpoints
Establish comparability of endpoint outcomes for each hemoglobin stratification
Trends for primary endpoint in severe (hemoglobin (<9.5 g/dl) and moderate (9.5-10.9 g/dl) groups.

Full Information

First Posted
February 12, 2019
Last Updated
September 28, 2023
Sponsor
Cure HHT
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1. Study Identification

Unique Protocol Identification Number
NCT03850964
Brief Title
Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz)
Acronym
Paz
Official Title
A Phase II/III Randomized, Placebo Controlled, Double Blind Study to Evaluate the Effects of up to 24 Weeks of Low Dose Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 8, 2023 (Actual)
Primary Completion Date
July 31, 2025 (Anticipated)
Study Completion Date
March 31, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cure HHT

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
During the Efficacy Study (Part B), the investigators will study whether Pazopanib, taken daily for 24 weeks, will reduce the severity of nose bleeds in patients with hereditary hemorrhagic telangiectasia (HHT). Patients will either be provided active drug or a placebo [sugar - inactive 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. This study is funded by the US Department of Defense USAMRAA and FDA/OOPD.
Detailed Description
Now that a single dose pharmacokinetics (PK) study (Part A) has been completed to properly establish similar exposure with the prior pilot 50mg tablet, a double blind, placebo controlled study will follow (Part B), which proposes to define primarily the value of low dose (150 mg) Pazopanib on nose bleed duration, in the context of assessing perceived nose bleed severity. After a patient completes Part B of the study, the patient will be invited to take part in an Extension Study (Part C) in which the patient will be provided with active drug equal to the dose they were assigned in Part B. All patients in Part C will receive active drug for 24 weeks. Part C will further assess the effects of Pazopanib on the severity of nose bleeds in patients with HHT and also support safety and efficacy elements. After the patient completes their treatment period (either Part B or Parts B and C), a 12 week follow-up period will follow to support safety and efficacy elements. Secondary endpoints will be assessed, including ongoing blood loss, use of iron and blood products, quality of life, and drug safety.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hereditary Hemorrhagic Telangiectasia, Epistaxis, Anemia, Nosebleed, HHT
Keywords
Osler-Weber-Rendu, Hereditary Hemorrhagic Telangiectasia, Patient Reported Outcome, HHT, Anemia, Nosebleed, Epistaxis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Model Description
After at least a 6-week baseline period, participants will be assigned low dose pazopanib (150 mg) or placebo. At the termination of the 24-week Efficacy study participants will be provided the option to advance into an open label extension program including 24 weeks of treatment, followed by a 12-week non-drug follow up period. The extension would be on active drug, but otherwise blinded to the dose provided in the primary trial. This decision to continue into the extension will be based on a physician-participant discussion of any efficacy and safety concerns at week 24. A decision would be reached whether to proceed into the extension study and whether to consider a dose modification. A top dose of 150 mg will be maintained. After the extension, a 12 week follow-up time period will continue assessments to define maintenance of effect, and/ or relapse.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Project Manager in operation will also be masked.
Allocation
Randomized
Enrollment
70 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Part B (Moderate Cohort) Pazopanib - 150 mg
Arm Type
Active Comparator
Arm Description
150 mg pazopanib oral capsules (six 25 mg placebo capsules daily).
Arm Title
Part B (Moderate Cohort) Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo oral capsules (six 25 mg placebo capsules daily).
Arm Title
Part B (Severe Cohort) Pazopanib - 150 mg
Arm Type
Active Comparator
Arm Description
Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).
Arm Title
Part B (Severe Cohort) Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo oral capsules (six 25 mg placebo capsules daily).
Arm Title
Part C Pazopanib - 150 mg
Arm Type
Experimental
Arm Description
Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).
Intervention Type
Drug
Intervention Name(s)
Pazopanib
Other Intervention Name(s)
Votrient
Intervention Description
gel capsule, with 25mg-similar fills
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Other Intervention Name(s)
cellulose capsule
Intervention Description
identical gel capsule without active pharmaceutical ingredient
Primary Outcome Measure Information:
Title
Change in epistaxis duration in minutes
Description
>=50% decrease in the duration of epistaxis in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)
Time Frame
Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline.
Title
Hemoglobin Response rate increase in hemoglobin
Description
Increase in hemoglobin by ≥ 2 g/dl in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)
Time Frame
Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline.
Secondary Outcome Measure Information:
Title
Achievement of meaningful improvement in epistaxis for HHT patients
Description
Compare patients reported being bothered by epistaxis at baseline and report not bothered at week 24
Time Frame
Baseline [screening, run-in and 0 time points] and week 24.
Title
Percent change in blood transfusion rate in the Severe Cohort
Description
Reduction in RBC transfusion rate by at least one unit
Time Frame
Baseline, and weeks 13-24
Title
Assess the safety of up to 24 and 48 weeks of treatment of pazopanib
Description
AEs; absolute values and changes over time of hematology, clinical chemistry, urinalysis, blood pressure, and heart rate. Physical exam, leg and abdominal evaluations, and CNS symptoms. ECG parameters (PR, QRS, QT, QTc intervals) in addition to cardiac echocardiogram to evaluate LV function from pre-dose values in at-risk patients (baseline EF <50)
Time Frame
1st dose of intervention until Weeks 24 and 48
Title
Assess pharmacokinetics and pharmacodynamics (PK/PD) of treatment
Description
Cτ, data permitting Graphical exploration of PK/PD relationships between pazopanib and selected PD endpoints
Time Frame
Weeks 12, 24, 36 and 48
Title
Establish comparability of endpoint outcomes for each hemoglobin stratification
Description
Trends for primary endpoint in severe (hemoglobin (<9.5 g/dl) and moderate (9.5-10.9 g/dl) groups.
Time Frame
Baseline, Weeks 19-24, Week 48
Other Pre-specified Outcome Measures:
Title
Assess effects of up to 24 weeks of pazopanib treatment on epistaxis duration
Description
Decrease in Epistaxis duration by ≥50% averaged over weeks 19-24 versus baseline
Time Frame
Baseline and weeks 19-24 of study.
Title
Assess the effects of up to 24 weeks of pazopanib treatment on hemoglobin levels
Description
Increase in hemoglobin over the 24 weeks by 2g/dL of greater average over weeks 19-24 versus baseline (overall and stratified by hemoglobin)
Time Frame
Baseline and weeks 19-24 of study
Title
Assess the effects of up to 24 weeks of pazopanib treatment on frequency of nose bleeds and speed of flow
Description
Establish percentage decrease in frequency of nose bleeds and speed of flow category improvement averaged over weeks 19-24 versus baseline
Time Frame
Baseline and weeks 19-24 of study
Title
Change with pazopanib treatment for epistaxis frequency and speed of flow, and fatigue
Description
Meaningful change quantities will be determined using domain-specific, patient-reported anchors focusing on importance and severity of change. Focus will be on change from baseline to 12, 24, and 48 weeks
Time Frame
Baseline, 12, 24, and 48 weeks
Title
Assess effects of up to 24 weeks of pazopanib treatment on epistaxis symptom elements
Description
Change in epistaxis: frequency, speed of flow, and epistaxis duration
Time Frame
Baseline, 3-week dosing intervals over study
Title
Assess effect of up to 24 and 48 weeks of pazopanib treatment on level of epistaxis severity
Description
Change in level of epistaxis severity by at least one unit Change in ESS by time
Time Frame
Epistaxis severity - average of last 6 weeks of study compared to baseline 6 weeks; Change in ESS at 12, 24 and 48 weeks (versus baseline)
Title
Change or reduction in iron supplementation for up to 48 weeks of treatment
Description
IV and oral iron use (together and separately)
Time Frame
Baseline, Week 19-24, Weeks 43-48
Title
Effects of up to 48 weeks of pazopanib treatment on serum ferritin for all patients
Description
Serum ferritin levels
Time Frame
Weeks 0, 12, 24, 36, and 48
Title
Effects of up to 48 weeks of pazopanib treatment on quality of life
Description
Changes in social and physical activity PROMIS self-reported questionnaire
Time Frame
Part B: Baseline, every 6 weeks; Part C: Baseline, every 12 weeks
Title
Perceived benefits of up to 48 weeks of pazopanib treatment for reducing symptoms, specifically satisfaction
Description
Response to an exit interview at the last visit
Time Frame
Week 24, 48 or early study termination visit
Title
Effects of up to 48 weeks of pazopanib treatment on cardiac function
Description
BNP protein levels in all patients Echo, 6 min walk, and diuretic usage record in patients with clinical heart failure due to liver AVM
Time Frame
Baseline, weeks 24 and 48
Title
Examine the drug mechanism of pazopanib treatment
Description
Measure VEGFR2 serum values
Time Frame
Baseline, Weeks 24 and 48
Title
Examine the role of genotype on response to pazopanib treatment
Description
Epistaxis and hemoglobin outcomes stratified by genotype (Alk1, Endoglin, SMAD)
Time Frame
Weeks 24 and 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Part B Inclusion Criteria (all of the following are necessary): A definite or probable diagnosis of hereditary hemorrhagic telangiectasia (HHT): Definite clinical HHT 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 HHT according to these criteria. OR a definite diagnosis of HHT based on a pathogenic genetic mutation for HHT. OR probable HHT based on having 2 of the above criteria with high clinical suspicion of HHT. 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 an acceptable double method contraception until 4 weeks after drug termination. Pregnancy testing will be done throughout the trial. 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) with average Hgb <9.5g/dl. Infusion of at least 250mg of elemental iron or 1 unit of blood in the last 12 weeks Epistaxis averaging at least 20 minutes per week over the six-week baseline and is generally stable in the clinical judgement of the investigator. Moderate Cohort: Anemia mainly due to HHT (in the judgment of the PI) with average Hgb 9.5 g/dl to 10.9 g/dl. Epistaxis averaging at least 20 minutes per week over the six-week baseline and is generally stable in the clinical judgement of the investigator. 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 treated cerebral arterio-venous malformations (AVMs) or cerebral arteriovenous fistulas (AVFs) that are symptomatic or have high-risk features detected on either MRI/MRA or digital subtraction angiography. High-risk features include: microhemorrhage seen on MRI; feeding artery aneurysm, nidus aneurysm or venous outflow stenosis seen on MRA, CTA, or catheter angiography. Non-shunting vascular brain lesions such as capillary vascular malformations, telangiectasias, and cavernous malformations are not an exclusion criterion. (Note: MRI scan does not need to be repeated at screening if AVMs and AVFs 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 potent VEGF inhibitor (e.g., direct inhibitors of VEGF-receptor signaling such as sunitinib) in the 4 weeks prior to enrollment. 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 periods of active treatment and 6 weeks of follow up; case by case evaluation if PI desires inclusion with medical monitor agreement. 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, 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. In the absence of clinical heart failure, EKG abnormalities, or known cardiac functional disease (e.g., MI or cardiomyopathy), a previous echo during adulthood is adequate. If there is history for coronary disease or cardiomyopathy, an echo in the past 5 years will be adequate for screening. If the patient has current clinical heart failure, a recent cardiac event in last 5 yrs, or a cardiac event since the most recent echo, an echo in the past 6 months will be necessary for screening. Clinical heart failure due to liver AVM or anemia, and not associated with the above findings (with an EF >=45%) will be eligible for enrollment. 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) > 1.5x ULN or activated partial thromboplastin time (aPTT) > 1.5x ULN (unless due to known concurrent medications, e.g. warfarin). 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]. If BP is poorly controlled at screen visit, initiation or adjustment of antihypertensive medication(s) is permitted during the run-in period prior to randomization. Prior to randomization, blood pressure must be assessed three times and the mean SBP/DBP must be < 140/90 mmHg in order for a patient to be randomized. 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 will be eligible for Part C unless significant safety concerns have been raised. Participants must be able and willing to sign the Extension ICF. Neither the Study Doctor or the participant will be informed of which drug (active or placebo) received during Part B.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Cassi Friday, PhD
Phone
410-357-9932
Email
cassi.friday@curehht.org
First Name & Middle Initial & Last Name or Official Title & Degree
Dennis Sprecher, MD
Phone
410-357-9932
Email
dennis.sprecher@curehht.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James Gossage, MD
Organizational Affiliation
Augusta University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06519
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Katharine Henderson, RN
Phone
203-737-1427
Email
katharine.henderson@yale.edu
First Name & Middle Initial & Last Name & Degree
Jeffrey Pollak, MD
Facility Name
Augusta University
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melissa E James, RN
Phone
706-721-5599
Email
mejames@augusta.edu
First Name & Middle Initial & Last Name & Degree
James R Gossage, MD
Facility Name
John Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Eugene Bosworth
Phone
443-974-8071
Email
eboswor1@jhmi.edu
First Name & Middle Initial & Last Name & Degree
Hannatu Bwayili
Phone
443-929-9641
Email
hbwayil1@jh.edu
First Name & Middle Initial & Last Name & Degree
Clifford Weiss, MD
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ellen Newton-Lovato, SC
Phone
314-454-8717
Email
elovato@wustl.edu
First Name & Middle Initial & Last Name & Degree
Kristine Kempf, SC
Phone
314-273-8131
Email
kempf@wustl.edu
First Name & Middle Initial & Last Name & Degree
Murali Chakinala, MD
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lori Russel, RN
Phone
503-494-7226
Email
watsonlo@ohsu.edu
First Name & Middle Initial & Last Name & Degree
Eleanor Lottsfeldt
Phone
(503) 494-3199
First Name & Middle Initial & Last Name & Degree
Mark Chesnutt, MD

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Over the first 18 months post study, the participating sites and PI's will produce primary and adjunct reports. After this period, study data will be posted on an available internet site for others to interrogate
Citations:
PubMed Identifier
30599027
Citation
Clark M, Berry P, Martin S, Harris N, Sprecher D, Olitsky S, Hoag JB. Nosebleeds in hereditary hemorrhagic telangiectasia: Development of a patient-completed daily eDiary. Laryngoscope Investig Otolaryngol. 2018 Nov 14;3(6):439-445. doi: 10.1002/lio2.211. eCollection 2018 Dec.
Results Reference
background
PubMed Identifier
34292451
Citation
Parambil JG, Gossage JR, McCrae KR, Woodard TD, Menon KVN, Timmerman KL, Pederson DP, Sprecher DL, Al-Samkari H. Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia. Angiogenesis. 2022 Feb;25(1):87-97. doi: 10.1007/s10456-021-09807-4. Epub 2021 Jul 22.
Results Reference
background
PubMed Identifier
30191360
Citation
Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW, McWilliams JP, Parambil JG, Vozoris N, Donaldson J, Paul G, Berry P, Sprecher DL. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis. 2019 Feb;22(1):145-155. doi: 10.1007/s10456-018-9646-1. Epub 2018 Sep 6.
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Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz)

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