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Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

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ClinicalTrials.gov Identifier: NCT03910244
Recruitment Status : Not yet recruiting
First Posted : April 10, 2019
Last Update Posted : April 10, 2019
Sponsor:
Collaborator:
RTI International
Information provided by (Responsible Party):
Keith McCrae, 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 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.

Condition or disease Intervention/treatment Phase
Telangiectasia, Hereditary Hemorrhagic Drug: Pomalidomide Oral Product Phase 2

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 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 12 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 159 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: 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.
Drug: 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 AE criteria.
Other Name: POMALYST

Placebo Comparator: 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.
Drug: 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 AE criteria.
Other Name: POMALYST




Primary Outcome Measures :
  1. Change in Epistaxis Severity Score [ Time Frame: Baseline to 24 weeks ]
    To determine efficacy of pomalidomide compared to placebo for the change in Epistaxis Severity Score in the placebo and pomalidomide-treated group


Secondary Outcome Measures :
  1. Amount of Parenteral Iron Administration [ Time Frame: Baseline to 24 weeks ]
    Amount of parenteral iron administered (in mg) during the 24 week treatment period in the pomalidomide and placebo groups

  2. Amount of Packed red blood cell Transfusions [ Time Frame: Baseline to 24 weeks ]
    Amount of packed red blood cell transfusions (in units) during the 24 week treatment period in the pomalidomide and placebo groups

  3. Change in PROMIS Satisfaction with Social Roles and Activities [ Time Frame: Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 36 weeks ]
    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 12-week post-treatment follow-up visit in the pomalidomide and placebo groups.

  4. Change in HHT-Specific QOL [ Time Frame: Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 36 weeks ]
    Change in the HHT-specific QOL total score from baseline to weeks 12 and 24 (key timepoint), and the 12 week post-treatment follow-up visit in the pomalidomide and placebo groups

  5. Change in average weekly epistaxis duration [ Time Frame: Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 36 weeks ]
    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 weeks 8-12 post-treatment in the pomalidomide and placebo groups


Other Outcome Measures:
  1. Change in PROMIS Emotional Distress-Depression Short Form (V1.0) [ Time Frame: Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 36 weeks ]
    Change in PROMIS® Emotional Distress-Depression Short Form (V1.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 12 week post-treatment follow-up visit in the pomalidomide and placebo groups

  2. Change in PROMIS Fatigue Short Form (V1.0) [ Time Frame: Baseline to 24 weeks, Baseline to 12 weeks and Baseline to 36 weeks ]
    Change in PROMIS® Fatigue Short Form (V1.0) T-score from baseline (randomization visit) to weeks 12 and 24 (key timepoint), and the 12 week post-treatment follow-up visit in the pomalidomide and placebo groups

  3. Red Blood Cell Transfusion or Parenteral Iron Infusion [ Time Frame: Baseline to 24 weeks ]
    Proportion of patients requiring no red blood cell transfusion or parenteral iron infusion during the 24 week treatment period in the pomalidomide and placebo groups

  4. Change in the Epistaxis Severity Score [ Time Frame: Baseline to 4, 8, 12, 16, 20, 24 and 36 weeks ]
    Change in the ESS from baseline to that recorded at each individual patient assessment, including the 12 week post-treatment follow-up visit

  5. Change in the Epistaxis Severity Score [ Time Frame: Baseline to 24 weeks ]
    Change in the ESS from baseline to the average of the week 16, 20 and 24 assessments

  6. Endoscopic Interventions for management of bleeding [ Time Frame: Baseline to 24 weeks ]
    Proportion of patients requiring endoscopic interventions for management of bleeding during the 24 week treatment period in the pomalidomide and placebo groups

  7. Incidence and Severity of Adverse Events [ Time Frame: Baseline to 24 weeks ]
    Incidence and severity of adverse events in the pomalidomide and placebo groups including but not limited to a) Venous thromboembolism; b) Arterial thromboembolism; c) Thrombocytopenia; d) Leukopenia; e) Peripheral neuropathy; f) Fatigue; g) Constipation/diarrhea; h) Rash; and i) Any other AEs or SAEs of at least moderate severity that are possibly related to pomalidomide



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. WBC ≥ 2,500/µl
  5. INR ≤ 1.4 and normal activated partial thromboplastin time by local laboratory criteria (aPTT)
  6. Epistaxis severity score ≥ 3 measured over the preceding three months, measured at the screening visit
  7. A requirement for parenteral infusion of at least 250 mg of iron or transfusion of 1 unit of blood over the preceding 24 weeks
  8. 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.
  9. Ability to understand and sign informed consent
  10. 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:

  1. Women currently breast feeding
  2. Renal insufficiency, serum creatinine > 2.0 mg/dl
  3. GI bleeding thought to be related to hepatic insufficiency, bilirubin > 2.0 or transaminases > 3.0x normal
  4. Prior treatment with thalidomide or other imid drugs within previous 6 months
  5. Prior treatment with bevacizumab (systemic or nasal) within previous 8 weeks
  6. The use of octreotide or estrogens within the previous month
  7. History of prior thromboembolism confirmed by venous ultrasound or other imaging modalities
  8. Peripheral neuropathy, confirmed by neurologic consultation
  9. Known underlying hypoproliferative anemia (i.e. myelodysplasia, aplastic anemia)
  10. Currently enrolled in other interventional trials
  11. Known hypersensitivity to thalidomide or lenalidomide.
  12. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
  13. Known SMAD-4 mutation
  14. Anything that in the investigator's opinion is likely to interfere with completion of the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03910244


Contacts
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Contact: Keith McCrae, MD 216 444-6833 Mccraek@ccf.org
Contact: Sneha Natarajan, PhD 216-445-9134 nataras@ccf.org

Sponsors and Collaborators
The Cleveland Clinic
RTI International
Investigators
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Principal Investigator: Keith McCrae, MD The Cleveland Clinic

Publications:
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Responsible Party: Keith McCrae, Director, Benign Hematology, The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT03910244     History of Changes
Other Study ID Numbers: 133646
First Posted: April 10, 2019    Key Record Dates
Last Update Posted: April 10, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

The DCC will prepare de-identified data files for sharing. A final data sharing plan will be developed with NHLBI and the study Steering Committee. The data can be provided in SAS data sets and export files and documentation will be in PDF format.

The first level of data sharing will be with trial investigators. In addition, the DCC will be responsible for sharing study data with outside researchers, if approved by NHLBI and the SC.

Supporting Materials: Study Protocol
Statistical Analysis Plan (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 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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Keith McCrae, The Cleveland Clinic:
Epistaxis
pomalidomide
blood transfusion

Additional relevant MeSH terms:
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Telangiectasis
Telangiectasia, Hereditary Hemorrhagic
Vascular Diseases
Cardiovascular Diseases
Hemostatic Disorders
Hemorrhagic Disorders
Hematologic Diseases
Vascular Malformations
Cardiovascular Abnormalities
Congenital Abnormalities
Pomalidomide
Thalidomide
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents