Pomalidomide for the Treatment of Bleeding in HHT

Study Overview
=================
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.

Official Title
-----------------
Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia

Conditions
-----------------
Telangiectasia, Hereditary Hemorrhagic

Intervention / Treatment
-----------------
* Drug: Pomalidomide Oral Product
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A clinical diagnosis of HHT as defined by the Curacao criteria Age > 18 years Platelet count ≥ 100,000/µl WBC ≥ 2,500/µl INR ≤ 1.4 and normal ± 2 sec activated partial thromboplastin time (aPTT or 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 Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing (once very two weeks) as required in the POMALYST REMS program. FCBP must a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO 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. 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 All study participants must agree to be registered into the FDA mandated POMALYST REMS program, and be willing and able to comply with the requirements of the POMALYST REMS program Exclusion Criteria: 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 imid 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-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 * Use of these treatments is not permitted during study participation.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pomalidomide<br>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<br>* 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 AE criteria.<br>* Other names: POMALYST;|
| Placebo Comparator: Placebo<br>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<br>* Matching placebo will be given.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Epistaxis Severity Score | To determine efficacy of pomalidomide compared to placebo for the change in Epistaxis Severity Score in the placebo and pomalidomide-treated group. The responses to each of the questions are converted to give a normalized ESS score which could range from a minimum of '0' (Not at all severe) to '10' (Very severe) | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amount of Parenteral Iron Administration | Amount of parenteral iron administered (in mg) during the 24 week treatment period in the pomalidomide and placebo groups | Baseline to 24 weeks | 
| Amount of Packed red blood cell Transfusions | Amount of packed red blood cell transfusions (in units) during the 24 week treatment period in the pomalidomide and placebo groups | Baseline to 24 weeks | 
| Change in PROMIS Satisfaction with Social Roles and Activities | Change in PROMIS Satisfaction with Social Roles and Activities Short Form (V2.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The response to each of the questions are summed to obtain a raw score which could range from 8 (least satisfaction) to 40 (most satisfaction). The raw-score is translated to give a T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. | Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks | 
| Change in HHT-Specific QOL | Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key timepoint), and the 4 week post-treatment follow-up visit in the pomalidomide and placebo groups. The total score for the HHT-Specific survey is obtained by summing the responses to each of the 4 questions and could range from 0 (no limitations) to 16 (severe limitations). | Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks | 
| Change in average weekly epistaxis duration | Change in average weekly epistaxis duration from the four week screening period prior to randomization to weeks 8-12 and to weeks 20-24 (key timepoint), and to the 4 weeks post-treatment in the pomalidomide and placebo groups | Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 28 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Epistaxis, pomalidomide, blood transfusion