Acquired C1-inhibitor deficiency
Conditions
Interventions
In part 1, patients will treat four consecutive angioedema attacks with three
single doses of PHA-022121 (10, 20, and 30 mg) and one single dose of placebo,
in a randomized and blinded order. In par
Sponsors
Academisch Medisch Centrum
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: In order to be eligible to participate in this study, a patient must meet all of the following criteria: • Provision of signed and dated informed consent form • Male or female, aged > 35 at enrollment • Diagnosis of AAE-C1-INH based upon all of the following: 1. Documented clinical history consistent with AAE-C1-INH (subcutaneous or mucosal, nonpruritic swelling without accompanying urticarial and C1-INH activity < 0.63mE/L) 2. At least one of the following: • Age at reported onset of first angioedema symptoms >= 40 years AND family history negative for angioedema • C1q below lower limit of normal (88 kU/L) AND absence of SERPING1 mutation • Serological confirmation of antibodies against C1-INH • Documented history of at least three angioedema attacks in the last 4 months, or at least two angioedema attacks in the last 2 months. • Reliable access and experience to use icatibant to effectively manage acute angioedema attacks • Female patients of childbearing potential must agree to be abstinent or to use highly effective forms of contraception methods from enrollment through the end of the study. This includes progestin-only oral contraceptive associated with inhibition of ovulation (oral, injectable, or implantable), intrauterine device (IUD, all types) or intrauterine hormone releasing systems (IUS). A female of childbearing potential whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception. • Male patients, including males who are surgically sterile (post vasectomy), who have a female partner of childbearing potential must agree to be sexually abstinent or use a medically acceptable form of barrier contraception for 2 weeks after each administration of study drug. In addition, they must agree to not donate sperm during study participation.
Exclusion criteria
Exclusion criteria: Patients who meet any of the following criteria will be excluded from the study: • Pregnancy or breast-feeding • Clinically significant abnormal ECG, most notably a QTcF > 470 ms (for females) or > 450 ms (for males) • Any clinically significant history of angina, myocardial infarction, syncope, stroke, left ventricular hypertrophy or cardiomyopathy, or any other cardiovascular abnormality within the previous year • Any other systemic disease (e.g., gastrointestinal, renal, respiratory, neurological) or significant disease or disorder that would interfere with the patient*s safety or ability to participate in the study • Active infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV) or hepatitis C virus (HCV) • History of abnormal hepatic function (AST > 2×ULN, ALT > 2×ULN, or total bilirubin > 1.5×ULN) • History of abnormal renal function (eGFR CKD-EPI < 60 mL/min/1.73 m2) • History of alcohol or drug abuse within the previous year, or current evidence of substance dependence or abuse (self-reported alcoholic intake > 3 drinks/day) • History of documented severe hypersensitivity to any medicinal product • Participation in any other investigational drug study currently, within the last 30 days or within 5 half-lives of study drug at enrollment (whichever was longer) • Regular use of corticosteroids, antihistamines, narcotics, and other pain relief medications for acute angioedema attack treatment • Use of concomitant medication that are moderate or potent inhibitors/inducers of CYP3A4 or are metabolized by CYP3A4 and have a narrow therapeutic range, such as clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal and grapefruit as well as phenobarbital, phenytoin, rifampicin, St. John's Wort, and glucocorticoids (not for topical use or inhalation) Patients who meet all in- and exclusion criteria but are unable to adhere to the diary and unforeseen visit requirements of part 1 as determined by the investigator, may participate in part 2 only.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The main study parameter for part 1 is the change of the 3-symptom composite visual analogue scale (VAS-3) score from pre-treatment to 4 h post-treatment. The main study parameter for part 2 is the number of investigator-confirmed angioedema attacks recorded during the treatment period expressed as the normalized number of attacks per month of exposure. | — |
Secondary
| Measure | Time frame |
|---|---|
| • Part 1: mean symptom complex severity score (MSCS) score • Part 1: treatment outcome score (TOS) • Part 1: treatment satisfaction questionnaire for medication (TSQM) score • Part 1: number of attacks requiring rescue medication • Part 1: time to rescue medication use, if applicable • Part 2: number of investigator-confirmed moderate or severe angioedema attacks during the treatment period • Part 2: number of investigator-confirmed angioedema attacks requiring acute treatment during the treatment period • Part 2: number and proportion of days with angioedema symptoms during the treatment period • Part 2: time to first investigator-confirmed attack (i.e. duration that a patient is attack-free) in the treatment period • Part 2: angioedema quality of life (AE-QoL) questionnaire • Part 2: treatment satisfaction questionnaire for medication (TSQM) score • Part 2: angioedema control test (AECT) • Part 2: angioedema activity score (AAS) | — |
Countries
Netherlands
Outcome results
None listed