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

• ClinicalTrials.gov Identifier: NCT03850964
• Recruitment Status: Recruiting
• First Posted: February 22, 2019
• Last Update Posted: April 30, 2024
• Sponsor: Cure HHT
• Information provided by (Responsible Party): Cure HHT

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.

Condition or disease	Intervention/treatment	Phase
Hereditary Hemorrhagic Telangiectasia; Epistaxis; Anemia; Nosebleed; HHT	Drug: Pazopanib; Drug: Placebo oral capsule	Phase 2; Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Project Manager in operation will also be masked.
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 8, 2023
• Estimated Primary Completion Date: July 31, 2025
• Estimated Study Completion Date: March 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Part B (Severe Anemia) Pazopanib - 150 mg; 150 mg pazopanib oral capsules (six 25 mg placebo capsules daily).	Drug: Pazopanib; gel capsule, with 25mg-similar fills; Other Name: Votrient
Placebo Comparator: Part B (Severe Anemia) Placebo; Placebo oral capsules (six 25 mg placebo capsules daily).	Drug: Placebo oral capsule; identical gel capsule without active pharmaceutical ingredient; Other Name: cellulose capsule
Active Comparator: Part B (Severe Epistaxis) Pazopanib - 150 mg; Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).	Drug: Pazopanib; gel capsule, with 25mg-similar fills; Other Name: Votrient
Placebo Comparator: Part B (Severe Expistaxis) Placebo; Placebo oral capsules (six 25 mg placebo capsules daily).	Drug: Placebo oral capsule; identical gel capsule without active pharmaceutical ingredient; Other Name: cellulose capsule
Experimental: Part C Pazopanib - 150 mg; Pazopanib 150 mg oral daily dosing (six 25 mg Pazopanib capsules).	Drug: Pazopanib; gel capsule, with 25mg-similar fills; Other Name: Votrient

Outcome Measures

Primary Outcome Measures :

1. Change in epistaxis duration in minutes [ Time Frame: Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline. ]
   >=50% decrease in the duration of epistaxis in the 150 mg pazopanib arm versus the placebo arm (moderate and severe cohorts combined)
2. Hemoglobin Response rate increase in hemoglobin [ Time Frame: Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline. ]
   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 :

1. Achievement of meaningful improvement in epistaxis for HHT patients [ Time Frame: Baseline [screening, run-in and 0 time points] and week 24. ]
   Compare patients reported being bothered by epistaxis at baseline and report not bothered at week 24
2. Percent change in blood transfusion rate in the Severe Cohort [ Time Frame: Baseline, and weeks 13-24 ]
   Reduction in RBC transfusion rate by at least one unit
3. Assess the safety of up to 24 and 48 weeks of treatment of pazopanib [ Time Frame: 1st dose of intervention until Weeks 24 and 48 ]
   • 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)
4. Assess pharmacokinetics and pharmacodynamics (PK/PD) of treatment [ Time Frame: Weeks 12, 24, 36 and 48 ]
   • Cτ, data permitting
   • Graphical exploration of PK/PD relationships between pazopanib and selected PD endpoints
5. Establish comparability of endpoint outcomes for each hemoglobin stratification [ Time Frame: Baseline, Weeks 19-24, Week 48 ]
   Trends for primary endpoint in severe (hemoglobin (<9.5 g/dl) and moderate (9.5-10.9 g/dl) groups.

Other Outcome Measures:

1. Assess effects of up to 24 weeks of pazopanib treatment on epistaxis duration [ Time Frame: Baseline and weeks 19-24 of study. ]
   Decrease in Epistaxis duration by ≥50% averaged over weeks 19-24 versus baseline
2. Assess the effects of up to 24 weeks of pazopanib treatment on hemoglobin levels [ Time Frame: Baseline and weeks 19-24 of study ]
   Increase in hemoglobin over the 24 weeks by 2g/dL of greater average over weeks 19-24 versus baseline (overall and stratified by hemoglobin)
3. Assess the effects of up to 24 weeks of pazopanib treatment on frequency of nose bleeds and speed of flow [ Time Frame: Baseline and weeks 19-24 of study ]
   Establish percentage decrease in frequency of nose bleeds and speed of flow category improvement averaged over weeks 19-24 versus baseline
4. Change with pazopanib treatment for epistaxis frequency and speed of flow, and fatigue [ Time Frame: Baseline, 12, 24, and 48 weeks ]
   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
5. Assess effects of up to 24 weeks of pazopanib treatment on epistaxis symptom elements [ Time Frame: Baseline, 3-week dosing intervals over study ]
   Change in epistaxis: frequency, speed of flow, and epistaxis duration
6. Assess effect of up to 24 and 48 weeks of pazopanib treatment on level of epistaxis severity [ 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) ]
   • Change in level of epistaxis severity by at least one unit
   • Change in ESS by time
7. Change or reduction in iron supplementation for up to 48 weeks of treatment [ Time Frame: Baseline, Week 19-24, Weeks 43-48 ]
   IV and oral iron use (together and separately)
8. Effects of up to 48 weeks of pazopanib treatment on serum ferritin for all patients [ Time Frame: Weeks 0, 12, 24, 36, and 48 ]
   Serum ferritin levels
9. Effects of up to 48 weeks of pazopanib treatment on quality of life [ Time Frame: Part B: Baseline, every 6 weeks; Part C: Baseline, every 12 weeks ]
   Changes in social and physical activity PROMIS self-reported questionnaire
10. Perceived benefits of up to 48 weeks of pazopanib treatment for reducing symptoms, specifically satisfaction [ Time Frame: Week 24, 48 or early study termination visit ]
    Response to an exit interview at the last visit
11. Effects of up to 48 weeks of pazopanib treatment on cardiac function [ Time Frame: Baseline, weeks 24 and 48 ]
    • BNP protein levels in all patients
    • Echo, 6 min walk, and diuretic usage record in patients with clinical heart failure due to liver AVM
12. Examine the drug mechanism of pazopanib treatment [ Time Frame: Baseline, Weeks 24 and 48 ]
    Measure VEGFR2 serum values
13. Examine the role of genotype on response to pazopanib treatment [ Time Frame: Weeks 24 and 48 ]
    Epistaxis and hemoglobin outcomes stratified by genotype (Alk1, Endoglin, SMAD)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Part B

Inclusion Criteria (all of the following are necessary):

• A definite or probable diagnosis of hereditary hemorrhagic telangiectasia (HHT):

  1. 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.
  2. OR a definite diagnosis of HHT based on a pathogenic genetic mutation for HHT.
  3. 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.
• Men are mandated to use condoms.
• 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 Anemia Cohort:

i. Anemia mainly due to HHT (in the judgment of the PI) with average Hgb <10 g/dL regardless of gender (average of at least three measures during screening and run in).

ii. Epistaxis averaging at least 5 min/week over the six-week baseline and is generally stable in the clinical judgement of the investigator.

Severe Epistaxis Cohort:

i. Anemia mainly due to HHT (in the judgment of the PI) with Hgb <12 g/dL in women or <13 g/dL in men (average of at least three measures during screening and run in).

ii. Epistaxis averaging at least 20 min/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 for men or >460 msec for women, 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 < 75x10^9 /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 > 0.4.
• 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.

Contacts and Locations

Contacts

Contact: Cassi Friday, PhD; 410-357-9932; cassi.friday@curehht.org

Contact: Dennis Sprecher, MD; 410-357-9932; dennis.sprecher@curehht.org

Locations

United States, California

University of California - Los Angeles; Recruiting

Los Angeles, California, United States, 90095

Contact: Victoria Rueda 310-562-9694 vrueda@mednet.ucla.edu

Principal Investigator: Justin McWilliams, MD

United States, Colorado

University of Colorado; Recruiting

Denver, Colorado, United States, 80045

Contact: Johan Allingmon johan.allingmon@cuanschutz.edu

Principal Investigator: Peter Hountras, MD

United States, Connecticut

Yale University; Recruiting

New Haven, Connecticut, United States, 06519

Contact: Katharine Henderson, RN 203-737-1427 katharine.henderson@yale.edu

Principal Investigator: Jeffrey Pollak, MD

United States, Georgia

Augusta University; Recruiting

Augusta, Georgia, United States, 30912

Contact: Melissa E James, RN 706-721-5599 mejames@augusta.edu

Principal Investigator: James R Gossage, MD

United States, Maryland

John Hopkins University; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Eugene Bosworth 443-974-8071 eboswor1@jhmi.edu

Contact: Hannatu Bwayili 443-929-9641 hbwayil1@jh.edu

Principal Investigator: Clifford Weiss, MD

United States, Minnesota

Mayo Clinic; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Sue Ann Donlinger 507-284-9259 donlinger.sueann@mayo.edu

Principal Investigator: Vivek Iyer, MD

United States, Missouri

Washington University; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Ellen Newton-Lovato, SC 314-454-8717 elovato@wustl.edu

Contact: Kristine Kempf, SC 314-273-8131 kempf@wustl.edu

Principal Investigator: Murali Chakinala, MD

United States, North Carolina

University of North Carolina; Recruiting

Chapel Hill, North Carolina, United States, 27514

Contact: Mason Donaldson, MSPH 919-843-3801 masdonal@email.unc.edu

Principal Investigator: Raj Kasthuri, MD

United States, Ohio

Cleveland Clinic; Recruiting

Cleveland, Ohio, United States, 44195

Contact: Joanne Baran-Smiley 216-444-5023 baranj2@ccf.org

Principal Investigator: Jospeh Parambil, MD

United States, Oregon

Oregon Health & Science University; Recruiting

Portland, Oregon, United States, 97239

Contact: Lori Russel, RN 503-494-7226 watsonlo@ohsu.edu

Contact: Eleanor Lottsfeldt (503) 494-3199

Principal Investigator: Mark Chesnutt, MD

United States, Utah

University of Utah Medical Center; Recruiting

Salt Lake City, Utah, United States, 84132

Contact: Mac McPherson 801-585-7295 Jamil.McPherson@hsc.utah.edu

Principal Investigator: Kevin Whitehead, MD

Sponsors and Collaborators

Cure HHT

Investigators

• Principal Investigator: James Gossage, MD; Augusta University

More Information

Publications of Results:

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.

Other Publications:

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.

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.

• Responsible Party: Cure HHT
• ClinicalTrials.gov Identifier: NCT03850964
• Other Study ID Numbers: HT2; CDMRP-PR203473 ( Other Grant/Funding Number: US Department of Defense USAMRAA ); 1R01FD006840-01A1 ( U.S. FDA Grant/Contract )
• First Posted: February 22, 2019
• Last Update Posted: April 30, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• 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

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

Keywords provided by Cure HHT:

Osler-Weber-Rendu; Hereditary Hemorrhagic Telangiectasia; Patient Reported Outcome; HHT; Anemia; Nosebleed; Epistaxis

Additional relevant MeSH terms:

Epistaxis; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Anemia; Hematologic Diseases; Vascular Diseases; Cardiovascular Diseases; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Signs and Symptoms, Respiratory; Hemostatic Disorders; Hemorrhagic Disorders; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities