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Pazopanib Effects on Bleeding in Hereditary Hemorrhagic Telangiectasia (Paz)

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ClinicalTrials.gov Identifier: NCT03850964
Recruitment Status : Not yet recruiting
First Posted : February 22, 2019
Last Update Posted : February 22, 2019
Sponsor:
Information provided by (Responsible Party):
Cure HHT

Tracking Information
First Submitted Date  ICMJE February 12, 2019
First Posted Date  ICMJE February 22, 2019
Last Update Posted Date February 22, 2019
Estimated Study Start Date  ICMJE September 2019
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
Change in epistaxis duration in minutes [ Time Frame: Cumulative duration of last 3weeks of 24week Rx period compared to last 3 weeks of 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
  • Change in average gushing frequency [ Time Frame: Cumulative number of gushing bleeds baseline 3weeks, and weeks 22-24. ]
    Patient rated intensity of each bleed, as in 0 or 1, averaged over the 3wk periods
  • Change in average bleed frequency [ Time Frame: Baseline 3 weeks, and weeks 22-24 ]
    Annotated by electronic record, number of bleeds per day, cumulative amount over 3 week periods.
  • Absolute [gm/dl] change in average serum hemoglobin levels [ Time Frame: Baseline [screening, run-in and 0 time points] and week 22 and week 24. ]
    Serum values drawn every 3wks
  • Percent change in blood transfusion frequency [ Time Frame: Baseline 6 weeks and weeks 19-24 weeks ]
    Total packed red blood cells over 6 week periods
  • Percent change in IV iron infusion frequency [ Time Frame: Baseline 6 weeks and weeks 19-24 of study ]
    IV iron infusion administration over 6 week periods.
  • Change in the averaged daily per bleed epistaxis severity [ Time Frame: Baseline 3 weeks and last 3 weeks [weeks 22-24] 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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...
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: February 20, 2019)
  • Characterize any change in Iron stores [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Pazopanib Effects on Bleeding in Hereditary Hemorrhagic Telangiectasia
Official Title  ICMJE Randomized Double Blind Study to Evaluate the Effect of Low Dose Pazopanib on Bleeding Due to Hereditary Hemorrhagic Telangiectasia
Brief Summary The investigators will study whether Pazopanib, taken daily for 6 months, will reduce the severity of nose bleeds in patients with hereditary hemorrhagic telangiectasia. Patients will either be provided drug or a placebo [sugar non-drug 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.
Detailed Description Once a single dose pk study is performed to properly establish similar exposure with the prior pilot 50mg tablet, a double blind, placebo controlled study will follow, which proposes to define primarily the value of low dose Pazopanib on nose bleed duration, in the context of assessing perceived nose bleed severity. A 3mth follow-up period will support safety and efficacy elements. Secondary endpoints will be interrogated, including ongoing blood loss, use of iron and blood products, quality of life, and drug safety.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
After at least a 3wk baseline period, patients will be assigned low dose drug or placebo. After 3mths 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 can be advanced up to double the initial dose. A strong initial trend would still permit continuance of the low dose intervention. Post-study drug discontinuance, a 3 month follow-up time period will continue assessments to define maintenance of effect, and/ or relapse. An interim to adjust total subject number, and potential futility occurs after 12 patients have completed their 24 week dosing period.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Project Manager in operation will also be masked.
Primary Purpose: Treatment
Condition  ICMJE
  • Hereditary Hemorrhagic Telangiectasia
  • Epistaxis Nosebleed
  • Anemia
Intervention  ICMJE
  • Drug: Pazopanib
    gel capsule, with 25mg-similar fills
    Other Name: Votrient
  • Drug: Placebo oral capsule
    identical gel capsule without active pharmaceutical ingredient
    Other Name: cellulose capsule
Study Arms  ICMJE
  • Active Comparator: Pazopanib
    Pazopanib 50mg oral daily dosing [two 25mg capsules]. If after 3mths primary endpoint not achieved, and safety is maintained, consideration for advance in dose to up to 100mg daily
    Intervention: Drug: Pazopanib
  • Placebo Comparator: Placebo oral capsule
    Placebo
    Intervention: Drug: Placebo oral capsule
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: February 20, 2019)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date December 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  • Epistaxis due to hereditary hemorrhagic telangiectasia at least 2x per week, for a cumulative duration of at least 25 minutes per week
  • 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).
  • 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.
  • 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.
  • QT corrected interval ≥450 msec, based on averaged QT corrected interval values of triplicate ECGs obtained over a brief recording period
  • Hemoglobin <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.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Nicole Schaefer 410-357-9932 nicole.schaefer@curehht.org
Contact: DENNIS L MD SPRECHER, MD 2678792599 sprechd1@gmail.com
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03850964
Other Study ID Numbers  ICMJE HT2
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: Over the first 1 year 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
Responsible Party Cure HHT
Study Sponsor  ICMJE Cure HHT
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: James Gossage, MD Geogia Health Sciences University
PRS Account Cure HHT
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP