Evaluation of Pazopanib on Bleeding in Subjects With Hereditary Haemorrhagic Telangiectasia
Condition: Telangiectasia, Hereditary Hemorrhagic
MeSH terms: Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Hemorrhage
Intervention: Pazopanib; Placebo
Intervention description: Pazopanib is available as 50 mg and 200 mg tablets to be administered orally once daily in the morning at least one hour before or two hours after a meal for 12 weeks; Pazopanib matching placebo is available as tablets to be administered orally once daily in the morning at least one hour before or two hours after a meal for 12 weeks
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pazopanib; hereditary haemorrhagic telangiectasia; bleeding

Summary:

      This study will investigate whether pazopanib can reduce epistaxis and improve anaemia in
      subjects with hereditary haemorrhagic telangiectasia (HHT) at a dose that is well tolerated.
      The study will have 2 parts. Part A will be an open label, dose-escalation study in which up
      to 4 cohorts of approximately 6 subjects each will receive increasing doses of pazopanib for
      a maximum of 12 weeks. The dose in the first cohort will be 50mg per day and the maximum dose
      in a cohort will be 400 mg per day. Dose escalation will not occur as planned if the
      predefined safety stopping criteria are met or at least 4 subjects in a cohort have
      demonstrated efficacy (as measured by epistaxis, haemoglobin, transfusion or iron infusion
      requirements). If efficacy is demonstrated in Part A with an acceptable safety profile, Part
      B will be initiated to further define the optimal dose(s) including dose duration/schedule
      and to provide further support for the proof of mechanism. Approximately 15 subjects will
      participate and will be randomised to active or placebo in a ratio of 3:2. This part of the
      study will be double-blind.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Males/females aged between 18 and 75 years of age inclusive, at the time of signing
             the informed consent.

          -  Diagnosis of definite or possible HHT by the Curaçao criteria. According to the
             Curaçao criteria, a definite diagnosis of HHT is defined as having at least 3 of the
             following criteria while a possible diagnosis is defined as 2 criteria: a) spontaneous
             and recurrent epistaxis; b) multiple telangiectasias at characteristic sites: lips,
             oral cavity, fingers, nose; c) visceral lesions: gastrointestinal (GI) telangiectasia,
             pulmonary, hepatic, cerebral or spinal arteriovenous malformations (AVMs); d) a first
             degree relative with HHT according to these criteria.

          -  Subject meets at least one of the following criteria: a) Severe epistaxis over
             previous 4 weeks defined as an average of at least 3 nose bleeds per week AND a total
             duration of greater than 15 min per week AND requiring iron therapy (oral and/or
             intravenous); b) Moderate or severe iron deficiency anaemia (Hgb < 11gram
             [g]/deciliter [dL], at screening) despite iron infusions (at least 0.5g iron per
             month) or blood transfusions (at least 2 units per month) AND substantial compromise
             in the quality of life according to the investigator (e.g. nose bleeds, lethargic,
             cannot maintain job, listless, fatigue). Anaemia must be HHT related in the opinion of
             the investigator, ie: due to HHT-defined bleeding (epistaxis and/or bleeding from the
             GI tract [presence of telangiectatic lesions, exclusion of active ulcer disease or
             other infection, inflammation]), and lack of other known etiologies such as blood
             dyscrasias.

          -  Epistaxis (if applicable) is considered to be clinically stable during the 4 weeks
             prior to Screening in the clinical judgment of the investigator (i.e. no major changes
             in frequency or duration of epistaxis).

          -  A female subject is eligible to participate if she is of non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy
             [for this definition, "documented" refers to the outcome of the
             investigator's/designee's review of the subject's medical history for study
             eligibility, as obtained via a verbal interview with the subject or from the subject's
             medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhoea
             [in questionable cases a blood sample with simultaneous follicle stimulating hormone
             (FSH) > 40 milli-international units per milliliter (MIU/mL) and estradiol < 40
             picogram per milliliter (pg/mL) (<147 picomole per liter [pmol/L]) is confirmatory].

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form.

          -  Subject is able and willing to return for outpatient visits at the protocol specified
             intervals.

          -  Subject agrees not to undergo laser ablation of nasal telangiectasias or take any
             experimental therapies for HHT other than the study drug while participating in the
             study (over the counter medications, topical treatments, nasal hygiene and palliative
             therapies are acceptable as long as use is consistent). If subjects stop taking
             experimental therapies on entry to the study there should be a wash-out period of at
             least 5 half-lives prior to the start of the run-in).

          -  Based on averaged corrected QT either Bazett's formula (QTcB), Fridericia's formula
             (QTcF) values of triplicate ECGs obtained over a brief recording period: QTc < 450
             milliseconds (msec); or QTc < 480 msec in subjects with Bundle Branch Block.

        Exclusion Criteria:

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones; and with the
             exception of vascular abnormalities that are related to the HHT).

          -  Subject 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 vascular malformations (CVMs) (Note: magnetic
             resonance imaging [MRI] scan does not need to be repeated at Screen if CVMs were
             absent on scan after age 18 years or in the last 5 years).

          -  Currently has known pulmonary AVMs with feeding artery diameter >3 millimeter (mm).

          -  Symptomatic liver AVMs (defined as chronic right upper quadrant pain, symptomatic
             portal hypertension or heart failure).

          -  Known significant bleeding sources other than nasal or gastrointestinal.

          -  Systemic use of a vascular endothelial growth factor (VEGF) inhibitor in the past 12
             weeks or previous enrolment in this study.

          -  Current use of anticoagulants including but not limited to vitamin K antagonists
             (e.g., warfarin) at any dose; unfractionated or low molecular weight heparins at
             standard doses for treatment of venous thromboembolism (VTE) (e.g., enoxoparin);
             antiplatelets (e.g., clopidogrel), or direct factor Xa inhibitors (e.g., apixaban).
             Use of low dose aspirin <= 81mg is allowed as long as use is consistent.

          -  Active and recent onset diarrhoea.

          -  Current or recent malignancies (except non-melanoma skin cancers) Subject has: a) had
             major surgery (eg, surgical ligation of an AVM) or trauma within 28 days; b) had minor
             surgical procedures (eg, central venous access line removal) within 7 days prior to
             dosing; c) any non-healing wound, fracture or ulcer

          -  Subject has clinically significant gastrointestinal abnormalities (other than
             HHT-related vascular lesions) including, but not limited to: malabsorption syndrome,
             major resection of the stomach or small bowel that could affect the absorption of
             study drug (eg, short bowel syndrome), active peptic ulcer, known intraluminal
             metastatic lesions/s with suspected bleeding, inflammatory bowel disease, ulcerative
             colitis or other gastrointestinal conditions with increased risk of perforation,
             lifetime history of abdominal fistula, gastrointestinal perforation or intra-abdominal
             abscess

          -  Subject has a history of cerebrovascular accident (including transient ischaemic
             attacks), pulmonary embolism or untreated deep vein thrombosis (DVT) within the 6
             months prior to first dose of study drug.

          -  Subject has a history of any one or more of the following cardiovascular conditions
             within the 6 months prior to first dose of study drug: cardiac angioplasty or
             stenting, myocardial infarction, unstable angina, ischaemic stroke, symptomatic
             peripheral vascular disease

          -  Class III or IV congestive heart failure, as defined by the New York Heart Association
             (NYHA).

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening.

          -  Hgb < 7 gram per deciliter (g/dL).

          -  Platelets < 100x10^9/L, International normalized ratio (INR) > 1.2x upper limit of
             normal (ULN) and activated partial thromboplastin time (aPTT) >1.2xULN.

          -  Alanine aminotransferese (ALT) >= 2xULN or bilirubin > 1.5xULN (isolated bilirubin
             >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

        Subject has poorly controlled hypertension [defined as systolic blood pressure (SBP) >= 140
        millimeter of mercury (mmHg) or diastolic blood pressure (DBP) >= 90mmHg]. Initiation or
        adjustment of antihypertensive medication(s) is permitted prior to study entry. At
        Screening, blood pressure must be assessed three times and the mean SBP/DBP must be <140/90
        mmHg in order for a subject to be eligible for the study.

          -  Substantive renal disease (estimated glomerular filtration rate [eGFR] < 60
             mL/minute/1.73 meter^3 calculated using the Cockcroft-Gault formula)

          -  Thyroid stimulating hormone > ULN.

          -  Urine protein creatinine ratio >0.3

          -  White blood cell count< 3500/mm^3.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the start of the run-in period: 30
             days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Unable or unwilling to discontinue use of prohibited medications mentioned below for
             at least 14 days or 5 half-lives of a drug (whichever is longer) prior to the start of
             the run-in period and for the duration of the study. Medications that inhibit
             Cytochrome P450 3A4 (CYP3A4) may result in increased plasma pazopanib concentrations;
             therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED beginning 14
             days prior to the first dose of study treatment until 15 days after the last dose of
             pazopanib. Strong CYP3A4 inhibitors include (but are not limited to): Antibiotics:
             clarithromycin, telithromycin, troleandomycin; human immunodeficiency virus (HIV):
             protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir,
             lopinavir); Antifungals: itraconzaole, ketoconazole, voriconazole, fluconazole;
             Antidepressants: nefazodone, Miscellaneous: grapefruit, grapefruit juice or other
             grapefruit product. statins, anticoagulants and tamoxifen use is prohibited.