Evaluation of Pazopanib on Bleeding in Subjects With Hereditary Haemorrhagic Telangiectasia

NCT02204371 | Terminated Phase 2 Results

• 1 other identifier: 201128
• Study Type: interventional
• Target: 7
• Locations: 2 countries
• Sites: 6

Brief 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.

Conditions

Telangiectasia, Hereditary Hemorrhagic

Keywords

Pazopanib; hereditary haemorrhagic telangiectasia; bleeding

Outcome Measures

Primary Outcomes (9)

• Change From Baseline in Epistaxis Severity Score at the Indicated Time Points

  The Epistaxis (nose bleeding) severity score (ESS) is a 6-item par-reported outcome measure designed to be a uniform epistaxis severity scoring system to assess the effectiveness of specific treatments on HHT-related epistaxis. Four questions document epistaxis frequency, duration, intensity and need for treatment, whereas two additional questions detail the presence of anemia and if a par has required a blood transfusion as a consequence of their epistaxis. Questions are variably weighted and results are tabulated on a 0-10 scale (0=no disease, 10 = severe disease). The minimum important difference is 0.71. Baseline is the Day1 pre-dose assessment value. Change from Baseline is calculated as the Post dose value at the indicated visit minus the Baseline value. Par were evaluated at Baseline, Treatment period (Weeks 6 and 12) and Follow-up period (Weeks 16, 20, 24 and 28). Only those par available at the indicated timepoints were analysed (specified by n=X in the category titles).

  Baseline, Week 6, Week 12, Week 16, Week 20, Week 24 and Week 28

• Change From Baseline in the Average of the Last 3 Hemoglobin Measures in the Dosing Period (Week 9, Week 10.5 and Week 12)

  For post-Baseline hemoglobin assessments, average of the last 3 measurements of the dosing period (Weeks 9, 10.5 and 12) was computed. Only pre-transfusion hemoglobin values have been included in the analyses. Baseline hemoglobin value is the average of the last two measurements during the run-in period. . Average of the last two measurements during the run-in period was calculated as sum of the last 2 measured values of hemoglobin divided by 2. Change from Baseline was calculated as the average of the last 3 measured values of hemoglobin minus the Baseline value. Average of the last 3 measurements was calculated as sum of the last 3 measured values of hemoglobin divided by 3. If measurements were missing at one or two of the 3 visits at Weeks 9, 10.5 and 12, then the average was based on the available measurements.

  Baseline, Week 9, Week 10.5 and Week 12

• Change From Baseline in Hemoglobin at the Indicated Time Points

  Only pre-transfusion hemoglobin values have been included in the analyses. All hemoglobin values that fall within 5 days of packed red blood cells (PRBC) transfusion are considered as post-transfusion values. Baseline hemoglobin value is defined as the average of the last two measurements during the run-in period. Average of the last two measurements during the run-in period was calculated as sum of the last 2 measured values of hemoglobin divided by 2. Change from Baseline was calculated as the Post dose value at the indicated visit minus the Baseline value. Par. were evaluated at Treatment period (Weeks 1.5, 3, 4.5, 6, 7.5, 9, 10.5 and 12) and Follow-up period (Weeks 16, 20, 24 and 28).

  Baseline, Week 1.5, Week 3, Week 4.5, Week 6, Week 7.5, Week 9, Week 10.5, Week 12, Week 16, Week 20, Week 24 and Week 28

• Duration of Epistaxis Over the Last 2 Weeks of the Dosing Period and by Time Over the Entire Dosing and Follow-up Period by 2 Week Interval (From Daily Diaries)

  Duration of epistaxis based on daily diaries has been reported over Baseline, On-Therapy (OT) to Follow-up (F). Individual participant data from the daily diaries has been reported.

  Over last 2 weeks of the run-in phase and then 2 week intervals throughout treatment period and follow-up period (from daily diaries)

• Frequency of Epistaxis Over the Last 2 Weeks of the Dosing Period and by Time Over the Entire Dosing and Follow-up Period by 2 Week Interval (From Daily Diaries)

  Frequency of epistaxis based on daily diaries has been reported over Baseline, On-Therapy (OT) to Follow-up (F). Individual participant data from the daily diaries has been reported.

  Over last 2 weeks of the run-in phase and then 2 week intervals throughout treatment period and follow-up period (from daily diaries)

• Intensity of Epistaxis Over the Last 2 Weeks of the Dosing Period and by Time Over the Entire Dosing and Follow-up Period by 2 Week Interval (From Daily Diaries)

  Intensity of epistaxis based on daily diaries has been reported as total gushing and total non gushing from Baseline, On-Therapy (OT) to Follow-up (F). Individual participant data from the daily diaries has been reported.

  Over last 2 weeks of the run-in phase and then 2 week intervals throughout treatment period and follow-up period (from daily diaries)

• Total Iron Intake Over the Last 4 Weeks of the Dosing Period

  Total iron intake at Baseline is defined as the sum total of iron intake (oral + intravenous infusion) during the last 4 weeks of run-in period (i.e., Day -28 to Day -1). Total iron intake over the last 4 weeks of run-in and during last 4 weeks of dosing period was listed. Individual participant data has been reported.

  Last 4 weeks of run-in and during last 4 weeks of dosing period

• Total Iron Intake Over the Entire Dosing and Follow-up Period by 4 Week Interval

  Total iron intake at Baseline is defined as the sum total of iron intake (oral + intravenous infusion) during the last 4 weeks of run-in period (i.e., Day -28 to Day -1). Total iron intake over the entire dosing and follow-up period was listed by 4 week interval. Individual participant data has been reported.

  Last 4 weeks of run-in and during last 4 weeks of dosing period

• Total Units of Packed Red Blood Cells (PRBCs) Transfused During the Entire Dosing and Follow-up Period by 4 Week Interval

  Baseline PRBC transfused is defined as the number of units of PRBC transfused during the last 4 weeks of run-in period (i.e., Day -28 to Day -1). Total units of PRBCs transfused during the entire dosing and follow-up period was listed by 4 week interval. Individual participant data been reported.

  Over the last 4 weeks of run-in and at 4 week intervals during dosing and follow-up

Secondary Outcomes (11)

• Change From Baseline in the Average of the Last 3 Ferritin Measures in the Dosing Period (Week 9, Week 10.5 and Week 12)

  Baseline, Week 9, Week 10.5 and Week 12

• Change From Baseline in Ferritin at the Indicated Time Points

  Baseline, Week 1.5, Week 3, Week 4.5, Week 6, Week 7.5, Week 9, Week 10.5, Week 12, Week 16, Week 20, Week 24 and Week 28

• Overall Health-related (HR) Quality of Life (QOL) Score Measured Using SF-36v2 at Day 1, Week 6 and Week 12

  Day (D) 1, Week (W) 6 and Week 12

• Number of Participants With the Indicated Clinical Chemistry Values of Potential Clinical Concern

  Up to Week 16

• Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern

  Up to Week 16

Study Arms (2)

Part A- Dose Escalation phase

EXPERIMENTAL

Part A will be an open label, dose-escalation study in which 4 cohorts of approximately 6 subjects 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 if the predefined safety stopping criteria are met or at least 4 subjects in a cohort have demonstrated efficacy. Cohort 4 receiving 400 mg dosing schedule may involve cycles of up to 3 weeks of active treatment, followed by up to 3 weeks wash-out (instead of 12 weeks continuous dosing). Decision will be based on safety data obtained from lower doses

Drug: Pazopanib

Part B-Dose Optimization phase

EXPERIMENTAL

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

Drug: Pazopanib; Drug: Placebo

Interventions

Pazopanib DRUG

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

Part A- Dose Escalation phase; Part B-Dose Optimization phase

Placebo DRUG

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

Part B-Dose Optimization phase

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (6)

GSK Investigational Site

Los Angeles, California, 90095, United States

Location

GSK Investigational Site

Augusta, Georgia, 30912-3135, United States

Location

GSK Investigational Site

St Louis, Missouri, 63110, United States

Location

GSK Investigational Site

Cleveland, Ohio, 44195, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84132, United States

Location

GSK Investigational Site

Toronto, Ontario, M5B 1W8, Canada

Location

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Hemorrhage

Interventions

pazopanib

Condition Hierarchy (Ancestors)

Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Telangiectasis; Hemorrhagic Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Vascular Malformations; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 28, 2014
• First Posted: July 30, 2014
• Study Start: February 25, 2015
• Primary Completion: February 10, 2016
• Study Completion: February 10, 2016
• Last Updated: July 6, 2017
• Results First Posted: July 6, 2017

Record last verified: 2017-04

Locations

CA (1); US (5)