Pomalidomide for the Treatment of Bleeding in HHT

NCT03910244 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 133646
• Study Type: interventional
• Target: 145
• Locations: 1 country
• Sites: 14

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.

Conditions

Telangiectasia, Hereditary Hemorrhagic

Keywords

Epistaxis; pomalidomide; blood transfusion

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• Average Total Daily Duration of Nosebleeds - Change From Baseline

  After 12 and 24 weeks of treatment, and 4 weeks post-treatment

• Weighted Average Total Daily Duration of Nosebleeds - Change From Baseline

  After 12 and 24 weeks of treatment, and 4 weeks post-treatment

• Total Iron Infused

  Baseline through 24 Weeks

• Total Iron Infused

  Baseline through 12 Weeks

• Total Iron Infused

  12 through 24 Weeks

Other Outcomes (13)

• Average Total Daily Duration of Low Intensity Nosebleeds - Change From Baseline

  After 12 and 24 weeks of treatment, and 4 weeks post-treatment

• Average Total Daily Duration of Medium Intensity Nosebleeds - Change From Baseline

  After 12 and 24 weeks of treatment, and 4 weeks post-treatment

• Average Total Daily Duration of High Intensity Nosebleeds - Change From Baseline

  After 12 and 24 weeks of treatment, and 4 weeks post-treatment

Study Arms (2)

Pomalidomide

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Pomalidomide Oral Product DRUG

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.

Also known as: POMALYST

Pomalidomide

Placebo oral capsule DRUG

Matching placebo will be given.

Placebo

Eligibility Criteria

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

You may qualify if:

• A clinical diagnosis of HHT as defined by the Curacao criteria
• Age ≥ 18 years
• Platelet count ≥ 100,000/µl
• White Blood Count (WBC) ≥ 2,500/µl
• 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)
• 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
• 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
• 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.
• Ability to understand and sign informed consent

You may not qualify if:

• 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 Immunomodulatory imide 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 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
• Anything that in the investigator's opinion is likely to interfere with completion of the study

Sponsors & Collaborators

• The Cleveland Clinic: lead
• RTI International: collaborator

Study Sites (14)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

UCSD Hemophilia and Thrombosis Treatment Center

San Diego, California, 92121, United States

Location

UCSF Outpatient Hematology Clinic

San Francisco, California, 94143, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

Massachussets General Hospital

Boston, Massachusetts, 02114, United States

Location

University of Minnesota Health Clinical Research Unit

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27517, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania Perelman School of Medicine

Philadelphia, Pennsylvania, 19104, United States

Location

Baylor College of Medicine, Texas Children's Hospital

Houston, Texas, 77030, United States

Location

University of Utah Healthcare

Salt Lake City, Utah, 84132, United States

Location

Medical College of Wiconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (4)

• 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.

  PMID: 25674101 BACKGROUND

• 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.

  PMID: 20087969 BACKGROUND

• 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.

  PMID: 28314138 BACKGROUND

• Al-Samkari H, Kasthuri RS, Iyer VN, Pishko AM, Decker JE, Weiss CR, Whitehead KJ, Conrad MB, Zumberg MS, Zhou JY, Parambil J, Marsh D, Clancy M, Bradley L, Wisniewski L, Carper BA, Thomas SM, McCrae KR. Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia. N Engl J Med. 2024 Sep 19;391(11):1015-1027. doi: 10.1056/NEJMoa2312749.

  PMID: 39292928 DERIVED

MeSH Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic; Epistaxis

Interventions

pomalidomide

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; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms, Respiratory; Signs and Symptoms

Results Point of Contact

• Title: Keith McCrae, MD
• Organization: Cleveland Clinic

mccraek@ccf.org

216-445-7809

Study Officials

• Keith McCrae, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Benign Hematology

Study Record Dates

• First Submitted: April 8, 2019
• First Posted: April 10, 2019
• Study Start: October 17, 2019
• Primary Completion: September 8, 2023
• Study Completion: September 8, 2023
• Last Updated: October 23, 2024
• Results First Posted: October 23, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• 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.

Locations

US (14)