Pomalidomide for the Treatment of Bleeding in HHT

NCT ID: NCT03910244

Last Updated: 2024-10-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 145 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-17
• Study Completion Date: 2023-09-08

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.

Conditions

Telangiectasia, Hereditary Hemorrhagic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Pomalidomide Oral Product

Intervention Type: 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.

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.

Group Type: PLACEBO_COMPARATOR

Placebo oral capsule

Intervention Type: DRUG

Matching placebo will be given.

Interventions

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.

Intervention Type: DRUG

Placebo oral capsule

Matching placebo will be given.

Intervention Type: DRUG

Other Intervention Names

POMALYST

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

RTI International

OTHER

Sponsor Role: collaborator

The Cleveland Clinic

OTHER

Sponsor Role: lead

Responsible Party

Keith McCrae

Director, Benign Hematology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Keith McCrae, MD

Role: PRINCIPAL_INVESTIGATOR

The Cleveland Clinic

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

UCSD Hemophilia and Thrombosis Treatment Center

San Diego, California, United States

UCSF Outpatient Hematology Clinic

San Francisco, California, United States

University of Florida

Gainesville, Florida, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Massachussets General Hospital

Boston, Massachusetts, United States

University of Minnesota Health Clinical Research Unit

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Cleveland Clinic

Cleveland, Ohio, United States

University of Pennsylvania Perelman School of Medicine

Philadelphia, Pennsylvania, United States

Baylor College of Medicine, Texas Children's Hospital

Houston, Texas, United States

University of Utah Healthcare

Salt Lake City, Utah, United States

Medical College of Wiconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 25674101 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20087969 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28314138 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 39292928 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form: Part 1 Master Consent

View Document

Document Type: Informed Consent Form: Part 2 Local Site Information Consent

View Document

Other Identifiers

133646

Identifier Type: -

Identifier Source: org_study_id