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: Placebo oral capsule; Drug: Pomalidomide Oral Product

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. White Blood Count (WBC) ≥ 2,500/µl
5. International Normalized Ratio (INR) ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or partial thromboplastin time (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. All study participants must agree to be registered into the FDA mandated POMALYST Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program
9. Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in the POMALYST REMS program. FCBP must have a negative pregnancy test with a sensitivity of at least 50 milli-international units per milliliter (mIU/mL) within 10 - 14 days prior to and again within 24 hours prior to prescribing pomalidomide and must either commit to continued abstinence from heterosexual intercourse or use two (2) 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, during therapy and for at least 4 weeks following discontinuation of therapy. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy.
10. Ability to understand and sign informed consent

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 Immunomodulatory imide 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 Family Member 4 (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 adverse event (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 From Baseline Epistaxis Severity Score	The primary outcome measure is the change from baseline in Epistaxis Severity Score (ESS) after 6 months of treatment administration to compare the outcomes of Pomalidomide versus Placebo. The ESS ranges from 0-10 with higher scores indicating worse condition in the prior 4 weeks. The minimal important difference is 0.71	4, 8, 12, 16, 20, and 24 Weeks and 4 weeks post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Total Daily Duration of Nosebleeds - Change From Baseline	The daily epistaxis duration is calculated as the total duration of all reported nose bleeding events in a day, averaged across all days reported in a 4-week smartphone diary. The outcome is the change between the baseline diary on the specified timepoint	After 12 and 24 weeks of treatment, and 4 weeks post-treatment
Weighted Average Total Daily Duration of Nosebleeds - Change From Baseline	The daily epistaxis duration is calculated as the total duration of all reported nose bleeding events in a day, averaged across all days reported in a 4-week smartphone diary, weighted by the intensity, with 90%% winsorization. The outcome is the change between the baseline diary on the specified timepoint	After 12 and 24 weeks of treatment, and 4 weeks post-treatment
Total Iron Infused	Total iron infused (mg) is calculated as the total in 4 weeks, averaged across all visits reported through the 24-week treatment period. Patients with no infusions have a value of zero.	Baseline through 24 Weeks
Total Iron Infused	Total iron infused (mg) is calculated as the total in 4 weeks, averaged across all visits reported through the first 12 weeks of the treatment period. Patients with no infusions have a value of zero.	Baseline through 12 Weeks
Total Iron Infused	Total iron infused (mg) is calculated as the total in 4 weeks, averaged across all visits reported through the second 12 weeks of the treatment period. Patients with no infusions have a value of zero.	12 through 24 Weeks
Patients With Any Packed Red Blood Cells Transfusion Through 24 Weeks	Patients with any packed red blood cells transfusion through the 24-week treatment period	Baseline through 24 Weeks
Patients With Any Packed Red Blood Cells Transfusion Through 12 Weeks	Patients with any packed red blood cells transfusion through the first 12 weeks of the treatment period	Baseline through 12 Weeks
Patients With Any Packed Red Blood Cells Transfusion 12-24 Weeks	Patients with any packed red blood cells transfusion through the second 12 weeks of the treatment period	12 through 24 Weeks
Neuro-QoL - Satisfaction With Social Roles and Activities - T Score	The outcome measure is the Neuro-QoL Satisfaction with Social Roles and Activities T-Score to compare the outcomes of Pomalidomide versus Placebo. The Neuro-QoL Satisfaction with Social Roles and Activities Short Form (V1.1) T-score has a value of 50 representing the average general US population, with a standard deviation of 10, and with higher scores indicating more satisfaction. The minimal detectable change is 3.7 T score points	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
Patient Reported Outcomes Measurement Information System (PROMIS) - Emotional Distress - Depression - T Score	The outcome measure is the PROMIS Emotional Distress - Depression T-Score to compare the outcomes of Pomalidomide versus Placebo. The PROMIS Emotional Distress-Depression Short Form (V1.0) T-score has a value of 50 representing the average general US population, with a standard deviation of 10, and with higher scores indicating more depression	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
PROMIS - Fatigue - T Score	The outcome measure is the PROMIS Fatigue T-Score to compare the outcomes of Pomalidomide versus Placebo. The PROMIS® Fatigue Short Form (V1.0) T-score has a value of 50 representing the average general US population, with a standard deviation of 10, and with higher scores indicating more fatigue	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
HHT-Specific QOL Questionnaire - Score	The outcome measure is the HHT-Specific QOL Questionnaire - Score to compare the outcomes of Pomalidomide versus Placebo. The HHT-specific QOL score ranges from 0 to 16 with higher scores indicating more limitations due to HHT in the prior 4 weeks	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Total Daily Duration of Low Intensity Nosebleeds - Change From Baseline	The daily of low intensity epistaxis duration is calculated as the total duration of "spotting" or "dripping" nose bleeding events in a day, averaged across all days reported in a 4-week smartphone diary. The outcome is the change between the baseline diary on the specified timepoint	After 12 and 24 weeks of treatment, and 4 weeks post-treatment
Average Total Daily Duration of Medium Intensity Nosebleeds - Change From Baseline	The daily of medium intensity epistaxis duration is calculated as the total duration of "dripping quickly" or "steady stream" nose bleeding events in a day, averaged across all days reported in a 4-week smartphone diary. The outcome is the change between the baseline diary on the specified timepoint	After 12 and 24 weeks of treatment, and 4 weeks post-treatment
Average Total Daily Duration of High Intensity Nosebleeds - Change From Baseline	The daily of high intensity epistaxis duration is calculated as the total duration of "gushing" or "pouring" nose bleeding events in a day, averaged across all days reported in a 4-week smartphone diary. The outcome is the change between the baseline diary on the specified timepoint	After 12 and 24 weeks of treatment, and 4 weeks post-treatment
Total Blood Transfused	Total blood transfused (units of blood) is calculated as the total in 4 weeks, averaged across all visits reported through the 24-week treatment period. Patients with no transfusions have a value of zero.	Baseline through 24 Weeks
Total Blood Transfused	Total blood transfused (units of blood) is calculated as the total in 4 weeks, averaged across all visits reported through the first 12 weeks of the treatment period. Patients with no transfusions have a value of zero.	Baseline through 12 Weeks
Total Blood Transfused	Total blood transfused (units of blood) is calculated as the total in 4 weeks, averaged across all visits reported through the second 12 weeks of the treatment period. Patients with no transfusions have a value of zero.	12 through 24 Weeks
Transferrin Saturation	Change from baseline transferrin saturation collected from blood iron studies	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Ferritin	Change from baseline ferritin level collected from blood iron studies	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Hemoglobin	Change from baseline Hemoglobin level taken from complete blood counts	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Hematocrit	Change from baseline Hematocrit level taken from complete blood counts	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Mean Corpuscular Volume (MCV)	Change from baseline MCV level taken from complete blood counts	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Mean Corpuscular Hemoglobin Concentration (MCHC)	Change from baseline MCHC level taken from complete blood counts	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Platelets	Change from baseline platelets taken from complete blood counts	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment

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

• 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.
• 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. doi: 10.1002/lary.29919.

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): October 23, 2024
• Last Update Submitted That Met QC Criteria: September 30, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: pomalidomide; blood transfusion; Epistaxis
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hematologic Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Hemostatic Disorders; Hemorrhagic Disorders; Vascular Malformations; Telangiectasis; Telangiectasia, Hereditary Hemorrhagic; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; 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 Data Coordinating Center (DCC) will prepare de-identified data files for sharing. A final data sharing plan will be developed with NHLBI and the study Steering Committee (SC). The data can be provided in Statistical Analysis System (SAS) data sets and export files and documentation will be in portable document format (PDF).

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 Institutional Review Board (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