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

• Register: ClinicalTrials.gov
• Last refreshed on: 6 May 2024
• Main ID: NCT03850964
• Date of registration: 12/02/2019
• Prospective Registration: Yes
• Primary sponsor: Cure HHT
• Public title: Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz) Paz
• Scientific 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
• Date of first enrolment: May 8, 2023
• Target sample size: 70
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03850964
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2/Phase 3

Countries of recruitment

United States

Contacts

• Name: James Gossage, MD
• Affiliation: Augusta University

• Name: Cassi Friday, PhD

Key inclusion & exclusion 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


Age minimum: 18 Years
Age maximum: 85 Years
Gender: All

Health Condition(s) or Problem(s) studied

HHT

Hereditary Hemorrhagic Telangiectasia

Anemia

Nosebleed

Epistaxis

Intervention(s)

Drug: Pazopanib

Drug: Placebo oral capsule

Primary Outcome(s)

Hemoglobin Response rate increase in hemoglobin [Time Frame: Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline.]

Change in epistaxis duration in minutes [Time Frame: Average duration in weeks 19-24 (last 6 weeks of blinded phase) versus baseline.]

Secondary Outcome(s)

Assess pharmacokinetics and pharmacodynamics (PK/PD) of treatment [Time Frame: Weeks 12, 24, 36 and 48]

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]

Establish comparability of endpoint outcomes for each hemoglobin stratification [Time Frame: Baseline, Weeks 19-24, Week 48]

Percent change in blood transfusion rate in the Severe Cohort [Time Frame: Baseline, and weeks 13-24]

Achievement of meaningful improvement in epistaxis for HHT patients [Time Frame: Baseline [screening, run-in and 0 time points] and week 24.]

Secondary ID(s)

1R01FD006840-01A1

HT2

CDMRP-PR203473

Source(s) of Monetary Support

Please refer to primary and secondary sponsors