C1 Esterase Inhibitor Deficiency, C1 Inhibitor Deficiency, Hereditary Angioedema, Hereditary Angioedema Attack, Hereditary Angioedema - Type 1, Hereditary Angioedema - Type 2, Hereditary Angioedema Type I, Hereditary Angioedema Type II, Hereditary Angioedema Types I and II, Hereditary Angioedema With C1 Esterase Inhibitor Deficiency
Conditions
Keywords
HAE, HAE Type I, HAE Type II, Oral Treatment, Bradykinin B2 Receptor Antagonist, PHVS416, PHA121, Prophylaxis, Deucrictibant
Brief summary
This study evaluates the safety and efficacy of PHA-022121 administered orally for prophylaxis against angioedema attacks in patients with hereditary angioedema (HAE). The study consists of 2 parts, with patients completing participation in Part 1 prior to initiation of treatment in Part 2. Part 1 of the study has 3 parallel arms and approximately 30 patients will be equally randomized to one of two dose regimens of PHA-022121 or matching placebo. Patients will continue to the single open-label arm in Part 2 of the study after completion of Part 1. The screening period is up to 8 weeks and the treatment periods are 12 weeks (Part 1) and 30 months (Part 2) in duration.
Interventions
DRUGDeucrictibant low dose
Deucrictibant softgel capsules for oral use (PHVS416)
DRUGDeucrictibant high dose
Deucrictibant softgel capsules for oral use (PHVS416)
DRUGPlacebo
Matching placebo capsules for oral use
Sponsors
Pharvaris Netherlands B.V.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Signed and dated informed consent form * Diagnosis of HAE type I or II * Documented history of at least 3 HAE attacks within the last 3 consecutive months prior to screening, or a minimum of 2 HAE attacks during the screening period * Reliable access and experience to use standard of care acute attack medications
Exclusion criteria
* Pregnancy or breast-feeding * Clinically significant abnormal electrocardiogram * Any other systemic disease or significant disease or disorder that would interfere with the patient's safety or ability to participate in the study * Use of C1-esterase inhibitor, oral kallikrein inhibitors, attenuated androgens, anti-fibrinolytics, or monoclonal HAE therapy within a defined period prior to enrolment * Abnormal hepatic function * Abnormal renal function * History of alcohol or drug abuse within defined period, or current evidence of substance dependence or abuse * Participation in any other investigational drug study within defined period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Investigator-confirmed Hereditary Angioedema (HAE) Attacks (Expressed as the Normalized Number of Attacks Per Month [4 Weeks] of Exposure) During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily electronic patient-reported outcome (ePRO) diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days, multiplied by 28. Mean rate ratio, confidence interval (CI), and p-value were estimated using a generalized linear model with Poisson distribution, with baseline attack rate included as a factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Investigator-confirmed Moderate or Severe HAE Attacks During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days×28. Moderate HAE attack defined as which limits/interferes with the participant's ability to attend work/school or participate in family life and social/recreational activities whereas Severe HAE attack significantly limits the participant's ability. |
| Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days, multiplied by 28. |
| Number of Participants Achieving ≥50%, ≥70% and ≥90% Reduction in Attack Rate Relative to Baseline During the Treatment Period in Part 1 | Up to Day 84 | Baseline attack rate was defined as each participant's normalized HAE attack rate (attacks per 4 weeks) prior to randomization, based on documented history or confirmed during screening. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days, multiplied by 28. Percent reduction from baseline was calculated for each participant by comparing the normalized treatment-period attack rate to the baseline attack rate. Participants were classified as responders if they achieved ≥50%, ≥70%, or ≥90% reduction in attack rate relative to baseline during Part 1. |
| Number of Participants Who Were Investigator-confirmed Attack-free During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Participants reporting no confirmed attacks over the treatment period were considered attack-free. |
| Number of Days With Investigator-confirmed HAE Symptoms During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). HAE symptom days were identified from daily participant entries in the ePRO diary and were confirmed by the investigator. |
| Proportion of Days With Investigator-confirmed HAE Symptoms During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). HAE symptom days were identified from daily participant entries in the ePRO diary and were confirmed by the investigator. |
| Time to First Investigator-confirmed HAE Attack in the Treatment Period in Part 1 | Up to Day 84 | Time to first investigator-confirmed HAE attack was defined as days from date of first administration of study drug until the onset date of first Investigator-confirmed HAE attack. Participants without an Investigator-confirmed HAE attack during the treatment period in Part 1 were censored at the date of the last dose of study drug +1 in Part 1 or last day of the study, whichever came sooner. |
| Number of Investigator-confirmed HAE Attacks Resulting in a Visit to the Emergency Department or an Admission to Hospital During the Treatment Period in Part 1 | Up to Day 84 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days, multiplied by 28. Only Investigator-confirmed attacks resulting in emergency department visits or hospital admissions were included. |
| Number of Investigator-confirmed HAE Attacks During the Treatment Period in Part 2 | Day 84 to Day 938 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days, multiplied by 28. An attack will be counted as in Part 2 if it occurs after the first IMP administration in Part 2 and within 24 hours after last IMP administration in Part 2. |
| Number of Investigator-confirmed Moderate or Severe HAE Attacks During the Treatment Period in Part 2 | Day 84 to Day 938 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days×28. Moderate HAE attack defined as which limits/interferes with the participant's ability to attend work/school or participate in family life and social/recreational activities whereas Severe HAE attack significantly limits the participant's ability. LSM and SE were estimated using a generalized linear model with Poisson distribution. |
| Number of Investigator-confirmed HAE Attacks Requiring Acute Treatment During the Treatment Period in Part 2 | Day 84 to Day 938 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). A new attack was counted if symptoms occurred ≥24 hours after complete resolution of a prior attack. Attacks were recorded via daily ePRO diaries and confirmed by the investigator. Monthly attack rate was calculated as number of attacks during treatment divided by treatment days, multiplied by 28. LSM and SE were estimated using a generalized linear model with Poisson distribution. |
| Number of Days With Investigator-confirmed HAE Symptoms During the Treatment Period in Part 2 | Day 84 to Day 938 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). HAE symptom days were identified from daily participant entries in the ePRO diary and were confirmed by the investigator. |
| Proportion of Days With Investigator-confirmed HAE Symptoms During the Treatment Period in Part 2 | Day 84 to Day 938 | HAE attack was defined as signs or symptoms in ≥1 location: peripheral angioedema (cutaneous swelling involving an extremity, face, neck, torso, and/or genitourinary region), abdominal angioedema (abdominal pain with or without abdominal distension, nausea, vomiting, or diarrhea), or upper airway angioedema (lump sensation, difficulty swallowing, throat tightening, difficulty speaking, hoarseness, stridor, dyspnea, or swelling of tongue, palate, uvula, or larynx). HAE symptom days were identified from daily participant entries in the ePRO diary and were confirmed by the investigator. |
Countries
Austria, Bulgaria, Canada, Germany, Ireland, Italy, Poland, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORMarc Riedl, MD
UC San Diego, La Jolla, California, United States
PRINCIPAL_INVESTIGATOREmel Aygören-Pürsün, MD
University Hospital Frankfurt - Goethe University, Frankfurt, Germany
Participant flow
Recruitment details
A total of 34 participants were enrolled and randomized to receive placebo, deucrictibant 10 mg BID, or deucrictibant 20 mg BID in Part 1 (Double-blind Treatment Period). Participants who completed Part 1 were eligible to continue in Part 2 (Open-label Treatment Period) and were assigned to receive to receive deucrictibant 20 mg BID.
Pre-assignment details
Out of 30 completed participants from Part 1, 21 participants in Part 2 were rolled over to study PHA022121-C307 (NCT06679881).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 40.2 years STANDARD_DEVIATION 15.24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 12 | 0 / 30 |
| other Total, other adverse events | 7 / 11 | 6 / 11 | 7 / 12 | 24 / 30 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 12 | 2 / 30 |
Outcome results
None listed