Extension Study of Oral PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema

Study Overview
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Brief Summary
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This study evaluates the safety and efficacy of long-term on-demand treatment with orally administered deucrictibant for acute hereditary angioedema (HAE) attacks, including laryngeal attacks, in patients with HAE due to C1-esterase inhibitor (C1-INH) deficiency (type I/II). The study will enroll patients from Study PHA022121-C201 (NCT04618211) who elect to participate in this extension study and meet the eligibility requirements.

Detailed Description
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In Part A of the study, the double-blind treatment assignment from Study PHA022121-C201 will be maintained. The treatment in Part A will consist of 3 soft capsules per administered dose as in Study PHA022121-C201. In Part B of the study, the selected dose and formulation of deucrictibant will be administered. The to-be-marketed deucrictibant formulation will be one single soft capsule at the strength proposed for marketing, based on the unblinding and evaluation of clinical data from Study PHA022121-C201. The duration of the treatment period (Part A plus Part B) is dependent upon the time of patient enrollment. The study is planned to continue until the availability of commercial supply, or another means of continued treatment can be provided.

Official Title
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A Phase II/III, Extension Study of Orally Administered PHA-022121 for Acute Treatment of Angioedema Attacks in Patients With Hereditary Angioedema Due to C1-Inhibitor Deficiency (Type I or Type II)

Conditions
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Hereditary Angioedema, Hereditary Angioedema Type I, Hereditary Angioedema Type II, Hereditary Angioedema Types I and II, Hereditary Angioedema Attack, Hereditary Angioedema With C1 Esterase Inhibitor Deficiency, Hereditary Angioedema - Type 1, Hereditary Angioedema - Type 2, C1 Esterase Inhibitor [C1-INH] Deficiency, C1 Esterase Inhibitor Deficiency, C1 Esterase Inhibitor, Deficiency of, C1 Inhibitor Deficiency

Intervention / Treatment
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* Drug: deucrictibant low dose
* Drug: deucrictibant medium dose
* Drug: deucrictibant high dose
* Drug: deucrictibant selected dose


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed and dated informed consent form Diagnosis of HAE type I or II must have received at least 1 dose of study drug (including the non-attack visit) in Study PHA022121-C201. Key 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 History of alcohol or drug abuse within defined period, or current evidence of substance dependence or abuse Discontinued from Study PHA022121-C201 after enrollment for any study drug-related safety reason. Use of concomitant medications that are potent CYP3A4 inhibitors (e.g., clarithromycin, erythromycin, itraconazole, ketoconazole, ritonavir, grapefruit) or potent CYP3A4 inducers (e.g., phenytoin, rifampicin, St. John's Wort). Participation in any other investigational drug study within defined period

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Low dose<br>Single low dose of deucrictibant | Drug: deucrictibant low dose<br>* deucrictibant soft capsules for oral use<br>* Other names: PHA-022121;|
| Experimental: Part A: Medium dose<br>Single medium dose of deucrictibant | Drug: deucrictibant medium dose<br>* deucrictibant soft capsules for oral use<br>* Other names: PHA-022121;|
| Experimental: Part A: High dose<br>Single high dose of deucrictibant | Drug: deucrictibant high dose<br>* deucrictibant soft capsules for oral use<br>* Other names: PHA-022121;|
| Experimental: Part B: Selected dose<br>Single dose of deucrictibant | Drug: deucrictibant selected dose<br>* deucrictibant soft capsule for oral use<br>* Other names: PHA-022121;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent Adverse Events (TEAEs), treatment-related TEAEs, treatment-emergent serious adverse events (TESAEs), and treatment-related TESAEs |  | From enrollment through study completion, up to 40 months (dependent on time of enrollment). | 
| Heart Rate | Descriptive in nature, no formal statistical hypothesis testing will be performed. | From enrollment through study completion, up to 40 months (dependent on time of enrollment). | 
| Blood pressure | Systolic and diastolic blood pressure will be measured. Descriptive in nature, no formal statistical hypothesis testing will be performed. | From enrollment through study completion, up to 40 months (dependent on time of enrollment). | 
| Body temperature | Descriptive in nature, no formal statistical hypothesis testing will be performed. | From enrollment through study completion, up to 40 months (dependent on time of enrollment). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to onset of symptom relief (TOSR) assessed by the 3- or 5-symptom visual analog scale score (VAS-3 or VAS-5) | VAS-3 (non-laryngeal attacks) and VAS-5 (laryngeal attacks) scores range between 0 and 100. Symptom relief is defined as a 50% or higher reduction of the VAS-3 or VAS-5 score from the pre-treatment value. | Assessed from pre-treatment to 48 hours post-treatment | 
| Time to almost complete or complete symptom relief (TACSR and TCSR) assessed by VAS-3 or VAS-5 | VAS scores range between 0 and 100. Almost complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 or VAS-5 having a value < 10. Complete symptom relief is defined as all 3 individual VAS scores of the VAS-3 or VAS-5 having a value of 0. | Assessed from pre-treatment to 48 hours post-treatment | 
| Time to symptom improvement based on patient global impression of severity (PGI-S) | PGI-S evaluates the severity of attack symptoms with a 5-point response scale. | Assessed from pre-treatment to 48 hours post-treatment | 
| Time to symptom improvement based on patient global impression of change (PGI-C) | PGI-C evaluates the change in the attack symptoms over time with a 7-point response scale. | Assessed from pre-treatment to 48 hours post-treatment | 
| Change of VAS-3 score and individual VAS score from pre-treatment to 4 h post-treatment for non-laryngeal attacks | VAS-3 scores range between 0 and 100. A larger reduction means a better outcome. | Pre-treatment and 4 hours post-treatment | 
| Change in Mean symptom complex severity (MSCS) score | MSCS scores range between 0 and 3. A higher score means a worse outcome. | Assessed from pre-treatment to 48 hours post-treatment | 
| Treatment outcome score (TOS) | TOS scores range between -100 and 100. A positive score indicates improvement, a score of 0 indicates no change, and a negative score indicates worsening compared to pre-treatment. | Assessed from pre-treatment to 4 hours post-treatment | 
| Proportion of PHA-022121-treated attacks requiring a second dose of PHA-022121 |  | From enrollment through study completion, up to 40 months (dependent on time of enrollment). | 
| Treatment satisfaction questionnaire for medication (TSQM) scores | TSQM scores range from 0 to 100. A higher score means a better outcome. | 48 hours post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HAE, HAE Type I, HAE Type II, Oral Treatment, Bradykinin B2 Receptor Antagonists, On-Demand, PHA121, PHVS416, PHA-022121, Deucrictibant