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Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia

Primary Purpose

Hereditary Hemorrhagic Telangiectasia, Epistaxis

Status

Not yet recruiting

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

Pazopanib

About this trial

This is an interventional treatment trial for Hereditary Hemorrhagic Telangiectasia focused on measuring osler-weber-rendu, nose bleeds, open label, HHT, Pazopanib

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

a definite diagnosis of hereditary hemorrhagic telangiectasia 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 gene sequencing diagnosis of hereditary hemorrhagic telangiectasia
  2. Epistaxis due to hereditary hemorrhagic telangiectasia at least 2x per week, for a cumulative duration of at least 25 minutes per week
  3. 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).
  4. 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.
  5. 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.
QTc ≥450 msec, based on averaged QTc values of triplicate ECGs obtained over a brief recording period [The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. The same QT correction formula must be used for each individual participant to determine eligibility for and withdrawal from the study.]
Hgb <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. Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry [between screen and baseline]. At Screening, blood pressure must be assessed three times and the mean SBP/DBP must be <140/90 mmHg in order for a participant to be eligible for the study.]
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.

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Pazopanib

Arm Description

Pazopanib, initiated after a baseline period at 25mg oral dosing daily, for this one treatment arm, to be compared to the patient's baseline. If endpoint not achieved and safety demonstrated in 2-3mths, an advance of dose to 50mg daily for the ensuing 3mths of study will be considered.

Outcomes

Primary Outcome Measures

Percent change in epistaxis duration in minutes

A daily electronic record of each bleed, with start and end time, provides the daily epistaxis duration, compounded over each 3 weeks of study time

Secondary Outcome Measures

Percent change in average gushing frequency

Patient rated intensity of each bleed, as in 0 or 1, averaged over 3 wk periods.

Percent change in average bleed frequency

Annotated number of bleeds per day, and summed over 3 week periods

Absolute [gm/dl] change in serum hemoglobin

Serum values drawn every 3 weeks

Change in the frequency of blood transfusions

Use of packed red blood cells over 6 week time periods.

Change in the frequency of IV iron infusions

Number of interval IV iron infusions in 6 week periods

Percent change in the per bleed average epistaxis severity

Epistaxis severity score [0-10] housed in the current patient reported outcome instrument will be averaged

Daily monitoring for change in systolic blood pressure [mm mercury] using daily recordings

Patients rising above 140 mm mercury, or those who increase by 20 or more mm mercury will trigger protocol defined treatments.

Daily monitoring for change in diastolic blood pressure [mm mercury]

Patients rising above 90 mm mercury, or those who increase by 10 mm mercury or more will trigger protocol defined treatments.

Number of participants with changes in alanine aminotransferase [liver function test]

measurement every 3 weeks to evaluate fold increase with use of drug

Monitor for active and safe trough serum drug concentrations

Assays to be analyzed to evaluate the exposures done to remain within safe and effective range [1ug/ ml to 10ug/ml].....

Evaluate for change in composite mental quality of life scores

short form health survey 36 [range 1-100, higher number representing better self-reported mental health]

Evaluate for change in composite physical quality of life scores

short form health survey 36 [range 1-100, higher number representing better self-reported physical health]

Evaluate for change in fatigue composite scores

Patient-report outcome measurement information system-fatigue; [0-100 scale; lower number representing less fatigue]. Queries the degree of fatigue and the implications on physical functioning. Reduction of 5 or more in the composite score represents clinically relevant reductions in fatigue.

Full Information

NCT ID

NCT03850730

First Posted

February 12, 2019

Last Updated

September 7, 2022

Sponsor

Cure HHT

Collaborators

University of North Carolina

1. Study Identification

Unique Protocol Identification Number

NCT03850730

Brief Title

Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia

Official Title

An Open-label, Non-randomized Study of the Efficacy of Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Not yet recruiting

Study Start Date

July 1, 2023 (Anticipated)

Primary Completion Date

June 30, 2025 (Anticipated)

Study Completion Date

December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Cure HHT

Collaborators

University of North Carolina

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Investigators will test the value of very low dose Pazopanib administered to patients with hereditary hemorrhagic telangiectasia for the reduction in the severity of nose bleeds in those with frequent and long duration bleeding episodes.

Detailed Description

Based on frequency and nose bleed duration, a non-randomized, single arm, open label study of 30 hereditary hemorrhagic telangiectasia patients will be treated with very low dose Pazopanib [25mg-similar] for between 16 and 24 weeks.. The primary endpoint is a reduction in bleeding duration of 50% or more, along with multiple secondary related endpoints, including bleed frequency, blood counts and quality of life; as compared to 6-12 weeks of baseline characteristics. If after the first 8 weeks of therapy benefit is suboptimal, dose advance to 50mg-similar daily can be considered.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hereditary Hemorrhagic Telangiectasia, Epistaxis

Keywords

osler-weber-rendu, nose bleeds, open label, HHT, Pazopanib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

After at least a 6 week baseline, patients will be placed on very low dose Pazopanib [25mg-similar], for 8 weeks.. If the primary bleeding duration endpoint is achieved, than the patient will continue for another 8wks, or a total of 16 weeks on the same dose. Lack of any response will result in a dose advance to 50mg for another 3mths. If a moderate change has occurred, than the 25mg dose will be continued for another 4 weeks, and if primary endpoint achieved, continue for another 12 weeks... Lack of endpoint achievement, will augment dose to 50mg and extend study for 12 weeks, or a total of 24 weeks.

Masking

None (Open Label)

Masking Description

This is an open label study and thus all personnel and patients will be aware of the assignment.

Allocation

N/A

Enrollment

30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Pazopanib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Pazopanib

Other Intervention Name(s)

Pazopanib capsule

Intervention Description

Active pharmaceutical ingredient plus excipients filled into a capsule for the lower dosing necessary in this study

Primary Outcome Measure Information:

Title

Percent change in epistaxis duration in minutes

Description

A daily electronic record of each bleed, with start and end time, provides the daily epistaxis duration, compounded over each 3 weeks of study time

Time Frame

Summed minutes of bleeding at baseline 3 weeks and the last 3 weeks of dosing, over16-24 weeks of dosing

Secondary Outcome Measure Information:

Title

Percent change in average gushing frequency

Description

Patient rated intensity of each bleed, as in 0 or 1, averaged over 3 wk periods.

Time Frame

Last 3 weeks of drug period vs baseline 3 weeks; over 16-24 weeks of dosing

Title

Percent change in average bleed frequency

Description

Annotated number of bleeds per day, and summed over 3 week periods

Time Frame

Last 3 weeks compared to the baseline 3 weeks; over 16-24 weeks of dosing

Title

Absolute [gm/dl] change in serum hemoglobin

Description

Serum values drawn every 3 weeks

Time Frame

comparing last 6 weeks to baseline 3-6 weeks; over 16-24 weeks of drug dosing

Title

Change in the frequency of blood transfusions

Description

Use of packed red blood cells over 6 week time periods.

Time Frame

Final 6 weeks of study, compared to baseline 3-6 weeks; over 16- 24 weeks of dosing

Title

Change in the frequency of IV iron infusions

Description

Number of interval IV iron infusions in 6 week periods

Time Frame

Last 6 weeks of dosing to first 6 weeks; over 16-24 weeks of drug administration

Title

Percent change in the per bleed average epistaxis severity

Description

Epistaxis severity score [0-10] housed in the current patient reported outcome instrument will be averaged

Time Frame

The final 3 weeks to the baseline 3 weeks of the study; for a16-24 week duration study

Title

Daily monitoring for change in systolic blood pressure [mm mercury] using daily recordings

Description

Patients rising above 140 mm mercury, or those who increase by 20 or more mm mercury will trigger protocol defined treatments.

Time Frame

Daily from baseline through up to 24 weeks till on-drug study completion.

Title

Daily monitoring for change in diastolic blood pressure [mm mercury]

Description

Patients rising above 90 mm mercury, or those who increase by 10 mm mercury or more will trigger protocol defined treatments.

Time Frame

Daily from baseline through up to 24 weeks till on-drug study completion

Title

Number of participants with changes in alanine aminotransferase [liver function test]

Description

measurement every 3 weeks to evaluate fold increase with use of drug

Time Frame

Baseline and throughout the 16-24 week dosing period

Title

Monitor for active and safe trough serum drug concentrations

Description

Assays to be analyzed to evaluate the exposures done to remain within safe and effective range [1ug/ ml to 10ug/ml].....

Time Frame

Over 16-24 week duration of study; once at steady state for each administered dose

Title

Evaluate for change in composite mental quality of life scores

Description

short form health survey 36 [range 1-100, higher number representing better self-reported mental health]

Time Frame

baseline, week 12 and at study drug-dosing end; 16, 20 or 24weeks

Title

Evaluate for change in composite physical quality of life scores

Description

short form health survey 36 [range 1-100, higher number representing better self-reported physical health]

Time Frame

baseline, week 12 and at study drug-dosing end; up to 24 weeks.

Title

Evaluate for change in fatigue composite scores

Description

Time Frame

baseline and study end; up to 24 weeks

Other Pre-specified Outcome Measures:

Title

Interrogate levels of Iron stores

Description

Ferritin serum levels [normal range 12 ug/ ml to 150ug/ml female, 300ug/ ml male]. However, above 30ug/ ml valued as relevant for proper erythropoiesis]

Time Frame

baseline and at on-drug study end; 16, 20 or 24 weeks depending on study duration

Title

Characterize change in left ventricular stress

Description

NTproBNP serum values represent a surrogate for left ventricular stress [<125pg/ml normal, while above 350pg/ml high and potentially consistent with heart failure]

Time Frame

baseline and on-drug study end; 16, 20 or 24 weeks depending on study duration]

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: a definite diagnosis of hereditary hemorrhagic telangiectasia 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 gene sequencing diagnosis of hereditary hemorrhagic telangiectasia 2. Epistaxis due to hereditary hemorrhagic telangiectasia at least 2x per week, for a cumulative duration of at least 25 minutes per week 3. 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). 4. 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. 5. 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. QTc ≥450 msec, based on averaged QTc values of triplicate ECGs obtained over a brief recording period [The QTc is the QT interval corrected for heart rate according to either Bazett's formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual overread. The same QT correction formula must be used for each individual participant to determine eligibility for and withdrawal from the study.] Hgb <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. Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry [between screen and baseline]. At Screening, blood pressure must be assessed three times and the mean SBP/DBP must be <140/90 mmHg in order for a participant to be eligible for the study.] 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Nicole Schaefer

Phone

410-357-9932

nicole.schaefer@curehht.org

First Name & Middle Initial & Last Name or Official Title & Degree

Dennis L Sprecher, MD

Phone

410-357-9932

dennis.sprecher@curehht.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Raj Kasthuri, MD

Organizational Affiliation

University of North Carolina

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

After the PI and associates produce the primary and adjunct reports, these data can be posted on data files for public access

Learn more about this trial

Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia

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