Pomalidomide for the Treatment of Bleeding in HHT

Pomalidomide for the Treatment of Bleeding in Hereditary Hemorrhagic Telangiectasia

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03910244

Acronym

PATH-HHT

Enrollment

145

Registered

2019-04-10

Start date

2019-10-17

Completion date

2023-09-08

Last updated

2024-10-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Telangiectasia, Hereditary Hemorrhagic

Keywords

Epistaxis, pomalidomide, blood transfusion

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.

Interventions

DRUGPomalidomide 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 adverse event (AE) criteria.

DRUGPlacebo oral capsule

Matching placebo will be given.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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	Baseline through 24 Weeks	Total iron infused (mg) is calculated as the total in 4 weeks, averaged across all visits reported through the 24-week 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

Other

Measure	Time frame	Description
Average Total Daily Duration of Low Intensity Nosebleeds - Change From Baseline	After 12 and 24 weeks of treatment, and 4 weeks post-treatment	The daily of low intensity epistaxis duration is calculated as the total duration of spotting or dripping 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
Average Total Daily Duration of Medium Intensity Nosebleeds - Change From Baseline	After 12 and 24 weeks of treatment, and 4 weeks post-treatment	The daily of medium intensity epistaxis duration is calculated as the total duration of dripping quickly or steady stream 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
Average Total Daily Duration of High Intensity Nosebleeds - Change From Baseline	After 12 and 24 weeks of treatment, and 4 weeks post-treatment	The daily of high intensity epistaxis duration is calculated as the total duration of gushing or pouring 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
Total Blood Transfused	Baseline through 24 Weeks	Total blood transfused (units of blood) is calculated as the total in 4 weeks, averaged across all visits reported through the 24-week treatment period. Patients with no transfusions have a value of zero.
Transferrin Saturation	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline transferrin saturation collected from blood iron studies
Ferritin	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline ferritin level collected from blood iron studies
Hemoglobin	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline Hemoglobin level taken from complete blood counts
Hematocrit	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline Hematocrit level taken from complete blood counts
Mean Corpuscular Volume (MCV)	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline MCV level taken from complete blood counts
Mean Corpuscular Hemoglobin Concentration (MCHC)	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline MCHC level taken from complete blood counts
Platelets	After 4, 8, 12, 16, 20 and 24 weeks of treatment, and 4 weeks post-treatment	Change from baseline platelets taken from complete blood counts

Countries

United States

Participant flow

Participants by arm

Arm	Count
Placebo Daily dose of placebo for 24 weeks	49
Pomalidomide Daily dose of 4, 3, or 2 mg of Pomalidomide for 24 weeks	95
Total	144

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	14	0
Overall Study	Death	1	0
Overall Study	Joint withdrawal decision	1	0
Overall Study	Lost to Follow-up	0	2
Overall Study	Physician Decision	1	0
Overall Study	Protocol Violation	1	0
Overall Study	Study Terminated by Sponsor	7	4
Overall Study	Withdrawal by Subject	7	2

Baseline characteristics

Characteristic	Placebo	Pomalidomide	Total
Activin A Receptor Like Type 1 Gene (ACVRL1) Mutation Known Pathogenic Mutation	25 Participants	34 Participants	59 Participants
Activin A Receptor Like Type 1 Gene (ACVRL1) Mutation No Mutation	5 Participants	8 Participants	13 Participants
Activin A Receptor Like Type 1 Gene (ACVRL1) Mutation Not done	3 Participants	10 Participants	13 Participants
Activin A Receptor Like Type 1 Gene (ACVRL1) Mutation Unknown	8 Participants	30 Participants	38 Participants
Activin A Receptor Like Type 1 Gene (ACVRL1) Mutation Variant, Likely Pathogenic	6 Participants	4 Participants	10 Participants
Activin A Receptor Like Type 1 Gene (ACVRL1) Mutation Variant of Unknown Significanc	2 Participants	9 Participants	11 Participants
Age, Continuous	58.7 years STANDARD_DEVIATION 11	58.8 years STANDARD_DEVIATION 13	58.8 years STANDARD_DEVIATION 12
Education Associate degree	5 Participants	8 Participants	13 Participants
Education Bachelor�s degree	12 Participants	15 Participants	27 Participants
Education Doctoral degree	1 Participants	5 Participants	6 Participants
Education Don�t Know	18 Participants	36 Participants	54 Participants
Education grade (specify)	0 Participants	1 Participants	1 Participants
Education High School Grad	4 Participants	9 Participants	13 Participants
Education Master�s degree	4 Participants	9 Participants	13 Participants
Education Refused	1 Participants	3 Participants	4 Participants
Education Years of college no degree (specify)	4 Participants	9 Participants	13 Participants
Emergency room for epistaxis in the previous 3 months No	40 Participants	79 Participants	119 Participants
Emergency room for epistaxis in the previous 3 months Yes	9 Participants	16 Participants	25 Participants
Employment status Disabled permanently or temporary	3 Participants	2 Participants	5 Participants
Employment status Looking for work unemployed	0 Participants	1 Participants	1 Participants
Employment status Other (specify)	9 Participants	16 Participants	25 Participants
Employment status Retired	12 Participants	28 Participants	40 Participants
Employment status Working Now	25 Participants	48 Participants	73 Participants
Endoglin Gene (ENG) Mutation Known Pathogenic Mutation	13 Participants	35 Participants	48 Participants
Endoglin Gene (ENG) Mutation No Mutation	8 Participants	16 Participants	24 Participants
Endoglin Gene (ENG) Mutation Not done	4 Participants	8 Participants	12 Participants
Endoglin Gene (ENG) Mutation Unknown	23 Participants	33 Participants	56 Participants
Endoglin Gene (ENG) Mutation Variant, Likely Pathogenic	0 Participants	2 Participants	2 Participants
Endoglin Gene (ENG) Mutation Variant of Unknown Significanc	1 Participants	1 Participants	2 Participants
EPHB4 Mutation No Mutation	10 Participants	12 Participants	22 Participants
EPHB4 Mutation Not done	6 Participants	21 Participants	27 Participants
EPHB4 Mutation Unknown	33 Participants	62 Participants	95 Participants
Growth Differentiation Factor 2 (GDF2) Mutation No Mutation	10 Participants	16 Participants	26 Participants
Growth Differentiation Factor 2 (GDF2) Mutation Not done	6 Participants	17 Participants	23 Participants
Growth Differentiation Factor 2 (GDF2) Mutation Unknown	33 Participants	62 Participants	95 Participants
HHT Diagnosis Genetically Confirmed No	3 Participants	7 Participants	10 Participants
HHT Diagnosis Genetically Confirmed Yes	46 Participants	88 Participants	134 Participants
HHT involvement of the brain No	39 Participants	77 Participants	116 Participants
HHT involvement of the brain Unknown	4 Participants	9 Participants	13 Participants
HHT involvement of the brain Yes	6 Participants	9 Participants	15 Participants
HHT involvement of the liver No	28 Participants	47 Participants	75 Participants
HHT involvement of the liver Unknown	11 Participants	23 Participants	34 Participants
HHT involvement of the liver Yes	10 Participants	25 Participants	35 Participants
HHT involvement of the lungs No	25 Participants	45 Participants	70 Participants
HHT involvement of the lungs Unknown	8 Participants	8 Participants	16 Participants
HHT involvement of the lungs Yes	16 Participants	42 Participants	58 Participants
History of or current GI bleeding No	30 Participants	61 Participants	91 Participants
History of or current GI bleeding Yes	19 Participants	34 Participants	53 Participants
Marital status Divorced	3 Participants	10 Participants	13 Participants
Marital status Domestic Partner	0 Participants	2 Participants	2 Participants
Marital status Married	33 Participants	64 Participants	97 Participants
Marital status Never Been Married	9 Participants	15 Participants	24 Participants
Marital status Separated	2 Participants	1 Participants	3 Participants
Marital status Unknown	0 Participants	1 Participants	1 Participants
Marital status Widowed	2 Participants	2 Participants	4 Participants
Pre-menopausal No	17 Participants	33 Participants	50 Participants
Pre-menopausal Not Applicable	25 Participants	50 Participants	75 Participants
Pre-menopausal Yes	7 Participants	12 Participants	19 Participants
Race/Ethnicity, Customized Asian	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Black/African American	5 Participants	6 Participants	11 Participants
Race/Ethnicity, Customized Hispanic/Latino	3 Participants	2 Participants	5 Participants
Race/Ethnicity, Customized Not Hispanic/Latino	44 Participants	90 Participants	134 Participants
Race/Ethnicity, Customized Other	0 Participants	3 Participants	3 Participants
Race/Ethnicity, Customized Unknown	2 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Unknown/Not Reported	2 Participants	3 Participants	5 Participants
Race/Ethnicity, Customized White	41 Participants	85 Participants	126 Participants
RAS p21 Protein Activator (RASA1) Mutation No Mutation	10 Participants	16 Participants	26 Participants
RAS p21 Protein Activator (RASA1) Mutation Not done	6 Participants	17 Participants	23 Participants
RAS p21 Protein Activator (RASA1) Mutation Unknown	33 Participants	61 Participants	94 Participants
RAS p21 Protein Activator (RASA1) Mutation Variant of Unknown Significanc	0 Participants	1 Participants	1 Participants
Sex/Gender, Customized Female	24 Participants	45 Participants	69 Participants
Sex/Gender, Customized Male	25 Participants	50 Participants	75 Participants
SMAD4 Mutation Known Pathogenic Mutation	0 Participants	1 Participants	1 Participants
SMAD4 Mutation No Mutation	10 Participants	20 Participants	30 Participants
SMAD4 Mutation Not done	6 Participants	13 Participants	19 Participants
SMAD4 Mutation Unknown	33 Participants	61 Participants	94 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 49	1 / 95
other Total, other adverse events	43 / 49	90 / 95
serious Total, serious adverse events	8 / 49	22 / 95

Outcome results

Primary

Change From Baseline Epistaxis Severity Score

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

Time frame: 4, 8, 12, 16, 20, and 24 Weeks and 4 weeks post treatment