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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03910244
Recruitment Status : Active, not recruiting
First Posted : April 10, 2019
Last Update Posted : July 15, 2020
Sponsor:
Collaborator:
RTI International
Information provided by (Responsible Party):
Keith McCrae, The Cleveland Clinic

Tracking Information
First Submitted Date  ICMJE April 8, 2019
First Posted Date  ICMJE April 10, 2019
Last Update Posted Date July 15, 2020
Actual Study Start Date  ICMJE October 17, 2019
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
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. 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)
Original Primary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 22, 2019)
  • 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
  • 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
  • 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. 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.
  • 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. 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).
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
  • 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
  • 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
  • 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.
  • 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
  • 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
Current Other Pre-specified Outcome Measures
 (submitted: July 22, 2019)
  • 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. The response to each of the questions are summed to obtain a raw score which could range from 8 (least depressed) to 40 (most depressed). 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.
  • 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. The response to each of the questions are summed to obtain a raw score which could range from 6 (least fatigue) to 30 (most fatigue). 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.
  • 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
  • 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. 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).
  • 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. 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).
  • 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
  • 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
Original Other Pre-specified Outcome Measures
 (submitted: April 9, 2019)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
 
Descriptive Information
Brief Title  ICMJE Pomalidomide for the Treatment of Bleeding in HHT
Official Title  ICMJE Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Telangiectasia, Hereditary Hemorrhagic
Intervention  ICMJE
  • 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
  • Drug: Placebo oral capsule
    Matching placebo will be given.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Pomalidomide Oral Product
  • 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.
    Intervention: Drug: Placebo oral capsule
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 13, 2020)
2
Original Estimated Enrollment  ICMJE
 (submitted: April 9, 2019)
159
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date March 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03910244
Other Study ID Numbers  ICMJE 133646
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: 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.
Responsible Party Keith McCrae, The Cleveland Clinic
Study Sponsor  ICMJE The Cleveland Clinic
Collaborators  ICMJE RTI International
Investigators  ICMJE
Principal Investigator: Keith McCrae, MD The Cleveland Clinic
PRS Account The Cleveland Clinic
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP