Clinical trial NCT03910244: Pomalidomide for the Treatment of Bleeding in HHT
Official title: Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Telangiectasia, Hereditary Hemorrhagic
Keywords: Epistaxis
pomalidomide
blood transfusion
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: RTI International
First posted: 2019-04-10
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline Epistaxis Severity Score
timeFrame: 4, 8, 12, 16, 20, and 24 Weeks and 4 weeks post treatment
Secondary outcomes:
measure: Average Total Daily Duration of Nosebleeds - Change From Baseline
timeFrame: After 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Weighted Average Total Daily Duration of Nosebleeds - Change From Baseline
timeFrame: After 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Total Iron Infused
timeFrame: Baseline through 24 Weeks
measure: Total Iron Infused
timeFrame: Baseline through 12 Weeks
measure: Total Iron Infused
timeFrame: 12 through 24 Weeks
measure: Patients With Any Packed Red Blood Cells Transfusion Through 24 Weeks
timeFrame: Baseline through 24 Weeks
measure: Patients With Any Packed Red Blood Cells Transfusion Through 12 Weeks
timeFrame: Baseline through 12 Weeks
measure: Patients With Any Packed Red Blood Cells Transfusion 12-24 Weeks
timeFrame: 12 through 24 Weeks
measure: Neuro-QoL - Satisfaction With Social Roles and Activities - T Score
timeFrame: Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Patient Reported Outcomes Measurement Information System (PROMIS) - Emotional Distress - Depression - T Score
timeFrame: Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: PROMIS - Fatigue - T Score
timeFrame: Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: HHT-Specific QOL Questionnaire - Score
timeFrame: Baseline, after 12 and 24 weeks of treatment, and 4 weeks post-treatment
Other outcomes:
measure: Average Total Daily Duration of Low Intensity Nosebleeds - Change From Baseline
timeFrame: After 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Average Total Daily Duration of Medium Intensity Nosebleeds - Change From Baseline
timeFrame: After 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Average Total Daily Duration of High Intensity Nosebleeds - Change From Baseline
timeFrame: After 12 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Total Blood Transfused
timeFrame: Baseline through 24 Weeks
measure: Total Blood Transfused
timeFrame: Baseline through 12 Weeks
measure: Total Blood Transfused
timeFrame: 12 through 24 Weeks
measure: Transferrin Saturation
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Ferritin
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Hemoglobin
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Hematocrit
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Mean Corpuscular Volume (MCV)
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Mean Corpuscular Hemoglobin Concentration (MCHC)
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
measure: Platelets
timeFrame: After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: San Diego
country: United States
facility: UCSD Hemophilia and Thrombosis Treatment Center
state: California
city: San Francisco
country: United States
facility: UCSF Outpatient Hematology Clinic
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachussets General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Health Clinical Research Unit
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania Perelman School of Medicine
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine, Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Healthcare
state: Utah
city: Milwaukee
country: United States
facility: Medical College of Wiconsin
state: Wisconsin
Study officials:
affiliation: The Cleveland Clinic
name: Keith McCrae, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.