Randomized Trial for Pazopanib in HHT-Related Bleeding

Sponsor

Cure HHT (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT03850964

Collaborator

United States Department of Defense (U.S. Fed)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

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.

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

Once a single dose pharmacokinetics (PK) study is performed 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 (50 mg or 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 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 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

Anticipated Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

After at least a 6 week baseline period, patients will be assigned low dose pazopanib (50 mg or 150 mg) or placebo. After 24 weeks of therapy, if epistaxis duration endpoint has been reached, the drug dose will remain the same. However, if this end point is not reached, and no safety signals have been observed, the dose may be advanced by 50 mg up to a maximum dose of 150 mg (patients already receiving 150 mg of active drug will not be eligible to have a dose increase). A strong initial trend would still permit continuance of the low dose intervention. Post-study drug discontinuance, a 12 week follow-up time period will continue assessments to define maintenance of effect, and/ or relapse.After at least a 6 week baseline period, patients will be assigned low dose pazopanib (50 mg or 150 mg) or placebo. After 24 weeks of therapy, if epistaxis duration endpoint has been reached, the drug dose will remain the same. However, if this end point is not reached, and no safety signals have been observed, the dose may be advanced by 50 mg up to a maximum dose of 150 mg (patients already receiving 150 mg of active drug will not be eligible to have a dose increase). A strong initial trend would still permit continuance of the low dose intervention. Post-study drug discontinuance, 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

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Sep 30, 2024

Anticipated Study Completion Date :

Jun 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: (Moderate Cohort) Pazopanib - 50 mg Pazopanib 50 mg oral daily dosing [two 25 mg Pazopanib capsules, and four 25 mg placebo capsules]. If after 12 weeks the primary endpoint is not achieved, and safety is maintained, the PI will consider an advance in dose up to 100 mg daily (four 25 mg Pazopanib capsules, and two 25 mg placebo capsules).	Drug: Pazopanib gel capsule, with 25mg-similar fills Other Names: Votrient Drug: Placebo oral capsule identical gel capsule without active pharmaceutical ingredient Other Names: cellulose capsule
Placebo Comparator: (Moderate Cohort) Placebo Placebo oral capsules (six 25 mg placebo capsules daily).	Drug: Placebo oral capsule identical gel capsule without active pharmaceutical ingredient Other Names: cellulose capsule
Active Comparator: (Moderate Cohort) Pazopanib - 150 mg Pazopanib 150 mg oral daily dosing [six 25 mg Pazopanib capsules].	Drug: Pazopanib gel capsule, with 25mg-similar fills Other Names: Votrient
Active Comparator: (Severe Cohort) Pazopanib - 150 mg Pazopanib 150 mg oral daily dosing [six 25 mg Pazopanib capsules].	Drug: Pazopanib gel capsule, with 25mg-similar fills Other Names: Votrient
Placebo Comparator: Severe Cohort) Placebo Placebo oral capsules (six 25 mg placebo capsules daily).	Drug: Placebo oral capsule identical gel capsule without active pharmaceutical ingredient Other Names: cellulose capsule

Outcome Measures

Primary Outcome Measures

Change in epistaxis duration in minutes [Cumulative duration of weeks 19 - 24 week Pazopanib treatment period compared to baseline.]
A daily electronic recording of each bleed, with start and end times to define per-bleed duration, over the drug dosing period of the study.
Hemoglobin Response rate increase in hemoglobin [Baseline and weeks 19 - 24.]
Increase in hemoglobin by ≥ 2 g/dl averaged over weeks 19 - 24 versus baseline in the Moderate Cohort over weeks 19 - 24 versus baseline in the 50 mg dosing arm and in the 150 mg dosing arm.

Secondary Outcome Measures

Change in average gushing frequency [Cumulative number of gushing bleeds baseline, and weeks 19 - 24.]
Patient rated intensity of each bleed, as in 0 or 1, averaged over the 3-week intervals.
Change in average bleed frequency [Baseline, and weeks 19 - 24]
Annotated by electronic record, number of bleeds per day, cumulative amount over the 3-week intervals.
Absolute [gm/dl] change in average plasma hemoglobin levels [Baseline [screening, run-in and 0 time points] and week 24.]
Plasma values drawn every 3 weeks
Percent change in blood transfusion frequency [Baseline and weeks 19-24 weeks]
Total packed red blood cells over 6 week periods.
Percent change in IV iron infusion frequency [Baseline and weeks 19-24 of study.]
IV iron infusion administration over 6 week periods.
Change in the averaged daily per bleed epistaxis severity [Baseline and 3 week intervals of the study.]
A specific query on "severity" [0-10] will be asked daily or for each bleed within the current patient reported outcome and averaged over 3 week periods.
Establish the presence of an Active/ safe serum trough drug concentration [baseline, 3, 6, 12, and 24 weeks.]
Samples will be sent for Pazopanib concentrations during the trial, steady state achieved within 3 weeks of time.
Change in composite mental quality of life score [baseline, 12 and 24 weeks]
Short Form Health Survey 36 [range 0-100; with increase suggesting improvement in self-reported perception of mental health [change of 7 points considered clinically relevant]
Increase/ improvement in composite physical quality of life score [baseline, 12 and 24 weeks]
Short Form Health Survey 36 [range 0-100, with higher values representing improvement in self-reported perception of physical health; 7 point change considered clinically significant]
Monitor for a rise in Systolic blood pressure [Daily during the on-drug portion of the study; 24 weeks]
Daily electronic measurements, mm mercury, will be evaluated to assess upward trends as part of a safety monitoring, with triggers at 20mm mercury rise, or surpassing bp 140 mm mercury.
Monitor for a rise in Diastolic blood pressure [Daily during the on-drug portion of the study; 24 weeks]
Daily electronic measurements, mm mercury, will be evaluated to assess upward trends as part of safety monitoring, with triggers at 10mm mercury rise, or surpassing bp 90mm mercury.
Monitor for a fold rise in alanine aminotransferase [liver function test] elevation [baseline and every 3 weeks for the 24 weeks of the on-drug portion of the trial]
This value will be apprised to monitor for safety, triggered to mandate a drug agent pause once the values reaches a 2 fold elevation
Identify percent change in left ventricular ejection fraction [echo] in at risk patients [baseline and 24 weeks.]
An evaluation of the ejection fraction of the left ventricle will be compared at baseline, and those below 50% will also have one done at 24 weeks to identify reductions of 15% or greater...

Other Outcome Measures

Characterize any change in Iron stores [baseline and 24 weeks.]
Ferritin [normal serum values of 12 ug/ ml to 150 ug/ ml in females, 300 ug/ ml in males]. However, values in below 30 ug/ ml can limit erythropoiesis.
Elucidate changes in Left ventricular stress [baseline and 24 weeks.]
NTproBNP serum assay which serves as a surrogate for left ventricular stress. Values <125 pg/ml is considered normal, with values above 300 pg/ml considered high/ consistent with elements of heart failure.
Change in fatigue composite score [Baseline and 24 weeks.]
Patient Reported Outcome Measurement Information System-fatigue queries [0-100 range; targets level of fatigue and impact on physical functioning; 5 point change considered clinically significant.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts 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.
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 500 mg of elemental iron in the last 12 weeks, or 2 units of blood in the last 24 weeks.
Epistaxis averaging at least 5 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 at least 2 times per week, for a cumulative duration of at least 25 minutes per week.
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 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 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, in the last 6 months; or PCI (performed during ACS) in the last 12 months (patients with known coronary vascular disease who do not fit the above exclusions should be discussed with the medical monitor prior to inclusion in the study); Infiltrative and/or restrictive cardiomyopathies; Significant pericardial disease; or clinical heart failure with more than moderate mitral valve or aortic valve disease.
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.