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

Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia

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.

Study Overview

• Status: Completed
• Conditions: Telangiectasia, Hereditary Hemorrhagic
• Intervention / Treatment: Drug: Pomalidomide Oral Product; Drug: Placebo oral capsule

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.

• Study Type: Interventional
• Enrollment (Actual): 145
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • San Diego, California, United States, 92121
      • UCSD Hemophilia and Thrombosis Treatment Center
    • San Francisco, California, United States, 94143
      • UCSF Outpatient Hematology Clinic
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachussets General Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Health Clinical Research Unit
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • University of North Carolina
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Perelman School of Medicine
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine, Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Healthcare
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wiconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pomalidomide; 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.	Drug: Pomalidomide Oral Product; 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.; Other Names: POMALYST
Placebo Comparator: Placebo; 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.	Drug: Placebo oral capsule; Matching placebo will be given.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of Parenteral Iron Administration	Amount of parenteral iron administered (in mg) during the 24 week treatment period in the pomalidomide and placebo groups	Baseline to 24 weeks
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	Baseline to 24 weeks
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.	Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
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).	Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
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	Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PROMIS Emotional Distress-Depression Short Form (V1.0)	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.	Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Change in PROMIS Fatigue Short Form (V1.0)	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.	Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks
Red Blood Cell Transfusion or Parenteral Iron Infusion	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	Baseline to 24 weeks
Change in the Epistaxis Severity Score	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).	Baseline to 4, 8, 12, 16, 20, 24 and 28 weeks
Change in the Epistaxis Severity Score	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).	Baseline to 24 weeks
Endoscopic Interventions for management of bleeding	Proportion of patients requiring endoscopic interventions for management of bleeding during the 24 week treatment period in the pomalidomide and placebo groups	Baseline to 24 weeks
Incidence and Severity of Adverse Events	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	Baseline to 24 weeks

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: RTI International
• Investigators: Principal Investigator: Keith McCrae, MD, The Cleveland Clinic

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2019
• Primary Completion (Actual): September 8, 2023
• Study Completion (Actual): September 8, 2023

Study Registration Dates

• First Submitted: April 8, 2019
• First Submitted That Met QC Criteria: April 9, 2019
• First Posted (Actual): April 10, 2019

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: pomalidomide; blood transfusion; Epistaxis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Congenital Abnormalities; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Cardiovascular Abnormalities; Vascular Malformations; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Pomalidomide
• Other Study ID Numbers: 133646

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No