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Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

Primary Purpose

Telangiectasia, Hereditary Hemorrhagic

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pomalidomide Oral Product
Placebo oral capsule
Sponsored by
The Cleveland Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Telangiectasia, Hereditary Hemorrhagic focused on measuring Epistaxis, pomalidomide, blood transfusion

Eligibility Criteria

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

Inclusion Criteria:

  1. A clinical diagnosis of HHT as defined by the Curacao criteria
  2. Age > 18 years
  3. Platelet count ≥ 100,000/µl
  4. WBC ≥ 2,500/µl
  5. INR ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or PTT per local laboratory designation) by local laboratory criteria (except for patients on a stable dose of warfarin or direct oral anticoagulants)
  6. Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the screening visit
  7. A requirement for anemia, as determined by local laboratory hemoglobin assessment and normal ranges, and/or parenteral infusion of at least 250 mg of iron or transfusion of 1 unit of blood over the 24 weeks preceding the screening visit
  8. Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing (once very two weeks) as required in the POMALYST REMS program. FCBP must a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy.
  9. Ability to understand and sign informed consent
  10. All study participants must agree to be registered into the FDA mandated POMALYST REMS program, and be willing and able to comply with the requirements of the POMALYST REMS program

Exclusion Criteria:

  1. Women currently breast feeding
  2. Renal insufficiency, serum creatinine > 2.0 mg/dl
  3. Hepatic insufficiency, bilirubin > 2.0 (or >4.0 in the setting of a prior clinical or genetic diagnosis of Gilbert's syndrome) or transaminases > 3.0x normal
  4. Prior treatment with thalidomide or other imid drugs within previous 6 months
  5. Prior treatment with bevacizumab (systemic or nasal) within previous 6 weeks*
  6. Prior treatment with pazopanib within previous 6 weeks*
  7. The use of octreotide or oral estrogens within the previous month*
  8. History of prior unprovoked thromboembolism confirmed by venous ultrasound or other imaging modalities
  9. Peripheral neuropathy, confirmed by neurologic consultation
  10. Known underlying hypoproliferative anemia (i.e. myelodysplasia, aplastic anemia)
  11. Currently enrolled in other interventional trials
  12. Known hypersensitivity to thalidomide or lenalidomide.
  13. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
  14. Known SMAD-4 mutation, unless there has been a colonoscopy with normal (negative) results, or in which the patient has had no more than 5 small (in the opinion of the gastroenterologist) colonic polyps completely removed within the preceding 18 months

  15. Anything that in the investigator's opinion is likely to interfere with completion of the study

    • * Use of these treatments is not permitted during study participation.

Sites / Locations

  • University of Alabama at Birmingham
  • UCSD Hemophilia and Thrombosis Treatment Center
  • UCSF Outpatient Hematology Clinic
  • University of Florida
  • Johns Hopkins Hospital
  • Massachussets General Hospital
  • University of Minnesota Health Clinical Research Unit
  • Mayo Clinic
  • University of North Carolina
  • Cleveland Clinic
  • University of Pennsylvania Perelman School of Medicine
  • Baylor College of Medicine, Texas Children's Hospital
  • University of Utah Healthcare
  • Medical College of Wiconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Pomalidomide

Placebo

Arm Description

Oral Pomalidomide will be provided as a capsule at 4 mg/day dose. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.

A placebo matching the study drug will be provided as a capsule. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.

Outcomes

Primary Outcome Measures

Change in Epistaxis Severity Score
To determine efficacy of pomalidomide compared to placebo for the change in Epistaxis Severity Score in the placebo and pomalidomide-treated group. The responses to each of the questions are converted to give a normalized ESS score which could range from a minimum of '0' (Not at all severe) to '10' (Very severe)

Secondary Outcome Measures

Amount of Parenteral Iron Administration
Amount of parenteral iron administered (in mg) during the 24 week treatment period in the pomalidomide and placebo groups
Amount of Packed red blood cell Transfusions
Amount of packed red blood cell transfusions (in units) during the 24 week treatment period in the pomalidomide and placebo groups
Change in PROMIS Satisfaction with Social Roles and Activities
Change in PROMIS Satisfaction with Social Roles and Activities Short Form (V2.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The response to each of the questions are summed to obtain a raw score which could range from 8 (least satisfaction) to 40 (most satisfaction). The raw-score is translated to give a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Change in HHT-Specific QOL
Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The total score for the HHT-Specific survey is obtained by summing the responses to each of the 4 questions and could range from 0 (no limitations) to 16 (severe limitations).
Change in average weekly epistaxis duration
Change in average weekly epistaxis duration from the four week screening period prior to randomization to weeks 8-12 and to weeks 20-24 (key timepoint), and to the 4 weeks post-treatment in the pomalidomide and placebo groups

Full Information

First Posted
April 8, 2019
Last Updated
August 29, 2023
Sponsor
The Cleveland Clinic
Collaborators
RTI International
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1. Study Identification

Unique Protocol Identification Number
NCT03910244
Brief Title
Pomalidomide for the Treatment of Bleeding in HHT
Acronym
PATH-HHT
Official Title
Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 17, 2019 (Actual)
Primary Completion Date
September 8, 2023 (Anticipated)
Study Completion Date
September 8, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The Cleveland Clinic
Collaborators
RTI International

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase II placebo-controlled double-blind study of pomalidomide in patients with hereditary hemorrhagic telangiectasia (HHT) with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks. Mean change from baseline to 24 weeks in the Epistaxis Severity Score (ESS) will be compared between treatment groups to determine pomalidomide efficacy.
Detailed Description
HHT is associated with substantial morbidity, leading to a reduced quality of life, decreased rate of employment and a high incidence of depression. There currently exists no medical therapy recognized as consistently efficacious in HHT. Reports of the efficacy of thalidomide in HHT, as well as interim results of a pilot trial of pomalidomide in HHT provide evidence of efficacy with minimal toxicity. The favorable efficacy:toxicity ratio of pomalidomide suggest that it may benefit patients with HHT. This study is designed as a Phase II placebo-controlled double-blind study of pomalidomide in HHT patients with moderate to severe epistaxis who have anemia and/or require parenteral iron infusions or blood transfusions. A total of 159 patients will be randomized 2:1 to treatment with oral pomalidomide or matching placebo for 24 weeks. Primary Objective: To determine efficacy of pomalidomide compared to placebo for the reduction in severity of epistaxis after 24 weeks of treatment. Secondary Objectives: To determine the safety and tolerability of pomalidomide for the treatment of HHT; to determine if pomalidomide treatment improves quality of life in HHT; to determine whether a continued response to pomalidomide is evident 4 weeks after treatment discontinuation; to develop a biorepository for future studies to define biomarkers predictive of pomalidomide response and allow investigations into the biology of HHT and mechanisms of pomalidomide.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Telangiectasia, Hereditary Hemorrhagic
Keywords
Epistaxis, pomalidomide, blood transfusion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
145 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pomalidomide
Arm Type
Experimental
Arm Description
Oral Pomalidomide will be provided as a capsule at 4 mg/day dose. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
A placebo matching the study drug will be provided as a capsule. There will be 6 treatment cycles of 28 days (4 weeks) each. Total treatment phase duration will be 24 weeks.
Intervention Type
Drug
Intervention Name(s)
Pomalidomide Oral Product
Other Intervention Name(s)
POMALYST
Intervention Description
Pomalidomide, a third generation derivative of thalidomide, given orally at a starting dose of 4 mg/day for days 1-28 of six 28-day cycles. The dose may be reduced to 3 or 2 mg/day based on specific AE criteria.
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
Matching placebo will be given.
Primary Outcome Measure Information:
Title
Change in Epistaxis Severity Score
Description
To determine efficacy of pomalidomide compared to placebo for the change in Epistaxis Severity Score in the placebo and pomalidomide-treated group. The responses to each of the questions are converted to give a normalized ESS score which could range from a minimum of '0' (Not at all severe) to '10' (Very severe)
Time Frame
Baseline to 24 weeks
Secondary Outcome Measure Information:
Title
Amount of Parenteral Iron Administration
Description
Amount of parenteral iron administered (in mg) during the 24 week treatment period in the pomalidomide and placebo groups
Time Frame
Baseline to 24 weeks
Title
Amount of Packed red blood cell Transfusions
Description
Amount of packed red blood cell transfusions (in units) during the 24 week treatment period in the pomalidomide and placebo groups
Time Frame
Baseline to 24 weeks
Title
Change in PROMIS Satisfaction with Social Roles and Activities
Description
Change in PROMIS Satisfaction with Social Roles and Activities Short Form (V2.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The response to each of the questions are summed to obtain a raw score which could range from 8 (least satisfaction) to 40 (most satisfaction). The raw-score is translated to give a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Time Frame
Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Title
Change in HHT-Specific QOL
Description
Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The total score for the HHT-Specific survey is obtained by summing the responses to each of the 4 questions and could range from 0 (no limitations) to 16 (severe limitations).
Time Frame
Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Title
Change in average weekly epistaxis duration
Description
Change in average weekly epistaxis duration from the four week screening period prior to randomization to weeks 8-12 and to weeks 20-24 (key timepoint), and to the 4 weeks post-treatment in the pomalidomide and placebo groups
Time Frame
Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Other Pre-specified Outcome Measures:
Title
Change in PROMIS Emotional Distress-Depression Short Form (V1.0)
Description
Change in PROMIS® Emotional Distress-Depression Short Form (V1.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The response to each of the questions are summed to obtain a raw score which could range from 8 (least depressed) to 40 (most depressed). The raw-score is translated to give a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Time Frame
Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Title
Change in PROMIS Fatigue Short Form (V1.0)
Description
Change in PROMIS® Fatigue Short Form (V1.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The response to each of the questions are summed to obtain a raw score which could range from 6 (least fatigue) to 30 (most fatigue). The raw-score is translated to give a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Time Frame
Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Title
Red Blood Cell Transfusion or Parenteral Iron Infusion
Description
Proportion of patients requiring no red blood cell transfusion or parenteral iron infusion during the 24 week treatment period in the pomalidomide and placebo groups
Time Frame
Baseline to 24 weeks
Title
Change in the Epistaxis Severity Score
Description
Change in the ESS from baseline to that recorded at each individual patient assessment, including the 4 week post-treatment follow-up visit. The responses to each of the questions are converted to give a normalized ESS score which could range from a minimum of '0' (Not at all severe) to '10' (Very severe).
Time Frame
Baseline to 4, 8, 12, 16, 20, 24 and 28 weeks
Title
Change in the Epistaxis Severity Score
Description
Change in the ESS from baseline to the average of the week 16, 20 and 24 assessments. The responses to each of the questions are converted to give a normalized ESS score which could range from a minimum of '0' (Not at all severe) to '10' (Very severe).
Time Frame
Baseline to 24 weeks
Title
Endoscopic Interventions for management of bleeding
Description
Proportion of patients requiring endoscopic interventions for management of bleeding during the 24 week treatment period in the pomalidomide and placebo groups
Time Frame
Baseline to 24 weeks
Title
Incidence and Severity of Adverse Events
Description
Incidence and severity of adverse events in the pomalidomide and placebo groups including but not limited to a) Venous thromboembolism; b) Arterial thromboembolism; c) Thrombocytopenia; d) Neutropenia; e) Peripheral neuropathy; f) Fatigue; g) Constipation/diarrhea; h) Rash; and i) Any other AEs or SAEs of at least moderate severity that are possibly related to pomalidomide
Time Frame
Baseline to 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: A clinical diagnosis of HHT as defined by the Curacao criteria Age > 18 years Platelet count ≥ 100,000/µl WBC ≥ 2,500/µl INR ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or PTT per local laboratory designation) by local laboratory criteria (except for patients on a stable dose of warfarin or direct oral anticoagulants) Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the screening visit A requirement for anemia, as determined by local laboratory hemoglobin assessment and normal ranges, and/or parenteral infusion of at least 250 mg of iron or transfusion of 1 unit of blood over the 24 weeks preceding the screening visit Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing (once very two weeks) as required in the POMALYST REMS program. FCBP must a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. Ability to understand and sign informed consent All study participants must agree to be registered into the FDA mandated POMALYST REMS program, and be willing and able to comply with the requirements of the POMALYST REMS program Exclusion Criteria: Women currently breast feeding Renal insufficiency, serum creatinine > 2.0 mg/dl Hepatic insufficiency, bilirubin > 2.0 (or >4.0 in the setting of a prior clinical or genetic diagnosis of Gilbert's syndrome) or transaminases > 3.0x normal Prior treatment with thalidomide or other imid drugs within previous 6 months Prior treatment with bevacizumab (systemic or nasal) within previous 6 weeks* Prior treatment with pazopanib within previous 6 weeks* The use of octreotide or oral estrogens within the previous month* History of prior unprovoked thromboembolism confirmed by venous ultrasound or other imaging modalities Peripheral neuropathy, confirmed by neurologic consultation Known underlying hypoproliferative anemia (i.e. myelodysplasia, aplastic anemia) Currently enrolled in other interventional trials Known hypersensitivity to thalidomide or lenalidomide. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. Known SMAD-4 mutation, unless there has been a colonoscopy with normal (negative) results, or in which the patient has had no more than 5 small (in the opinion of the gastroenterologist) colonic polyps completely removed within the preceding 18 months Anything that in the investigator's opinion is likely to interfere with completion of the study * Use of these treatments is not permitted during study participation.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Keith McCrae, MD
Organizational Affiliation
The Cleveland Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
UCSD Hemophilia and Thrombosis Treatment Center
City
San Diego
State/Province
California
ZIP/Postal Code
92121
Country
United States
Facility Name
UCSF Outpatient Hematology Clinic
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachussets General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Minnesota Health Clinical Research Unit
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27517
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania Perelman School of Medicine
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Baylor College of Medicine, Texas Children's Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah Healthcare
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Medical College of Wiconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The DCC will prepare de-identified data files for sharing. A final data sharing plan will be developed with NHLBI and the study Steering Committee. The data can be provided in SAS data sets and export files and documentation will be in PDF format. The first level of data sharing will be with trial investigators. In addition, the DCC will be responsible for sharing study data with outside researchers, if approved by NHLBI and the SC.
IPD Sharing Time Frame
Data will be made available to investigators 6 months after closed data sets for the trial have been prepared for final analysis or 1 month after results of the protocol are published in a peer-reviewed journal.
IPD Sharing Access Criteria
A data request form will be developed to collect information deemed necessary by the SC and NIH, including applicant name, organization, and purpose of research. Investigators will submit the request form, Data Distribution Agreement, and IRB approval to designated DCC staff. The SC or its designated Committee will review each application, and if the requestor meets established criteria for access to the data and provides the required documents, the requested data sets and associated documentation will be disseminated by a mode agreed upon by the SC in accordance with NHLBI policy.
Citations:
PubMed Identifier
25674101
Citation
McDonald J, Wooderchak-Donahue W, VanSant Webb C, Whitehead K, Stevenson DA, Bayrak-Toydemir P. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015 Jan 26;6:1. doi: 10.3389/fgene.2015.00001. eCollection 2015.
Results Reference
background
PubMed Identifier
20087969
Citation
Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010 Apr;120(4):838-43. doi: 10.1002/lary.20818. Erratum In: Laryngoscope. 2021 Dec;131(12):2834.
Results Reference
background
PubMed Identifier
28314138
Citation
Chaturvedi S, Clancy M, Schaefer N, Oluwole O, McCrae KR. Depression and post-traumatic stress disorder in individuals with hereditary hemorrhagic telangiectasia: A cross-sectional survey. Thromb Res. 2017 May;153:14-18. doi: 10.1016/j.thromres.2017.03.003. Epub 2017 Mar 9.
Results Reference
background

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Pomalidomide for the Treatment of Bleeding in HHT

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