Pomalidomide for the Treatment of Bleeding in HHT

Phase 2

Completed

• Conditions: Telangiectasia, Hereditary Hemorrhagic
• Interventions: Drug: Pomalidomide Oral Product; Drug: Placebo oral capsule

• Registration Number: NCT03910244
• Lead Sponsor: The Cleveland Clinic

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.

Study Timeline

• Study First Submitted: 2019-04-08
• Study First Submitted QC: 2019-04-09
• Study First Posted: 2019-04-10
• Study Start: 2019-10-17
• Primary Completion: 2023-09-08
• Study Completion: 2023-09-08
• Status Verified: 2024-09
• Results First Submitted: 2024-09-05
• Results First Submitted QC: 2024-09-30
• Last Update Submitted: 2024-09-30
• Results First Posted: 2024-10-23
• Last Update Posted: 2024-10-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 145

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pomalidomide	Pomalidomide Oral Product	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.
Placebo	Placebo oral capsule	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline Epistaxis Severity Score	4, 8, 12, 16, 20, and 24 Weeks and 4 weeks post treatment	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

Secondary Outcome Measures

Name	Time	Method
Average Total Daily Duration of Nosebleeds - Change From Baseline	After 12 and 24 weeks of treatment, and 4 weeks post-treatment	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
Weighted Average Total Daily Duration of Nosebleeds - Change From Baseline	After 12 and 24 weeks of treatment, and 4 weeks post-treatment	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
Total Iron Infused	12 through 24 Weeks	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.
Patients With Any Packed Red Blood Cells Transfusion Through 24 Weeks	Baseline through 24 Weeks	Patients with any packed red blood cells transfusion through the 24-week treatment period
Patients With Any Packed Red Blood Cells Transfusion Through 12 Weeks	Baseline through 12 Weeks	Patients with any packed red blood cells transfusion through the first 12 weeks of the treatment period
Patients With Any Packed Red Blood Cells Transfusion 12-24 Weeks	12 through 24 Weeks	Patients with any packed red blood cells transfusion through the second 12 weeks of the treatment period
Neuro-QoL - Satisfaction With Social Roles and Activities - T Score	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment	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
Patient Reported Outcomes Measurement Information System (PROMIS) - Emotional Distress - Depression - T Score	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment	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
PROMIS - Fatigue - T Score	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment	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
HHT-Specific QOL Questionnaire - Score	Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment	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

Trial Locations

Locations (14)

UCSD Hemophilia and Thrombosis Treatment Center; 🇺🇸 San Diego, California, United States

University of Minnesota Health Clinical Research Unit; 🇺🇸 Minneapolis, Minnesota, 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

UCSF Outpatient Hematology Clinic; 🇺🇸 San Francisco, California, United States

University of Utah Healthcare; 🇺🇸 Salt Lake City, Utah, United States

Massachussets General Hospital; 🇺🇸 Boston, Massachusetts, United States

University of Alabama at Birmingham; 🇺🇸 Birmingham, Alabama, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Medical College of Wiconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States