A Trial to Evaluate the Efficacy and Safety of Different Doses of KVD824 for Prophylactic Treatment of HAE Type I or II

Study Overview
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Brief Summary
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A study to assess whether different doses of KVD824 are effective in preventing attacks of Hereditary Angiodedema Type I or Type II.

Official Title
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Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial to Evaluate the Efficacy and Safety of 3 Dose Levels of KVD824, an Oral Plasma Kallikrein Inhibitor, for Long-Term Prophylactic Treatment of Hereditary Angioedema Type I or II

Conditions
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Angioedema, Hereditary, Types I and II

Intervention / Treatment
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* Drug: KVD824
* Drug: Placebo to KVD824


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 years of age and older. Confirmed diagnosis of HAE type I or II at any time in the medical history: Documented clinical history consistent with HAE (subcutaneous or mucosal, nonpruritic swelling episodes without accompanying urticaria) AND EITHER Diagnostic testing results obtained prior to randomization that confirm HAE Type I or II: C1-INH functional level <40% of the normal level. Subjects with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range. Testing may be obtained from central or local laboratories or obtained from documented historical testing results. Subjects may be restested at anytime prior to randomization if results are incongruent with clinical history or believed by the Investigator to be confounded by recent prophylactic or therapeutic C1 INH use, OR Documented genetic results that confirm known mutations for HAE Type I or II. Subject has access to and ability to use conventional treatment for HAE attacks. Subject is willing to cease any current medications being taken for HAE prophylaxis and Investigator determines that doing so would not place the subject at any undue safety risk. Subject's last dose of attenuated androgens was at least 28 days prior to first dose of IMP. During the Run-in Period subject meets one of the following criteria: Two Investigator-confirmed attacks in the first 4-week period. Three Investigator-confirmed attacks in ≤8 weeks. Subjects who are fertile and heterosexually active must adhere to contraception requirements throughout the trial as follows: a) Female subjects must agree to use at least one highly effective contraception method from the Screening Visit until the end of the trial. Highly effective methods of contraception include: i) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral/injectable/implantable (hormonal contraception that contains estrogen including ethinylestradiol is excluded per Exclusion 4). ii) Intrauterine device (IUD). iii) Intrauterine hormone-releasing system (IUS). iv) Bilateral tubal occlusion. v) Vasectomized partner (provided that the partner is the sole sexual partner of the female subject of childbearing potential and that the vasectomized partner has received medical assessment of surgical success). b) Male subjects with a female partner of childbearing potential must agree to use condoms for the entire Treatment Period AND for 90 days following the final dose of investigational medicinal product (IMP). Female partners are encouraged to use contraception as outlined in Inclusion 7a) from the Screening Visit until the end of the trial. Hormonal contraception that contains estrogen including ethinylestradiol is acceptable for the female partner. Subjects who are not fertile or not sexually active, as defined below, do not require contraception. Subjects who refrain from heterosexual intercourse during the trial if the reliability of the heterosexual abstinence has been evaluated in relation to the duration of the clinical trial and is the preferred and usual lifestyle of the subject. Male subjects who are surgically sterile (e.g. vasectomized with medical assessment of surgical success). Female subjects who are surgically sterile (e.g. status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post menopausal for at least 12 months. Subjects must be able to swallow trial tablets whole. Subjects assessed by the Investigator must be able to appropriately receive and store IMP, and be able to read, understand, and complete the eDiary. Investigator believes that the subject is willing and able to adhere to all protocol requirements. Subject provides signed informed consent and is willing and capable of complying with trial requirements and procedures. Exclusion Criteria Any concomitant diagnosis of another form of chronic angioedema, such as acquired C1 inhibitor deficiency, HAE with normal C1-INH (previously known as HAE type III), idiopathic angioedema, or angioedema associated with urticaria. A clinically significant history of poor response to C1-INH therapy or plasma kallikrein inhibitor therapy for the management of HAE, in the opinion of the Investigator. Use of angiotensin converting enzyme (ACE) inhibitors after the Screening Visit or within 7 days prior to randomization. Any estrogen containing medications with systemic absorption (such as oral contraceptives including ethinylestradiol or hormonal replacement therapy) after the Screening Visit or within 7 days prior to randomization. Use of narrow therapeutic index drugs metabolized by CYP3A4 or CYP2C9 or transported by OAT1, OCT2, and OATP1B1, starting at screening, as determined by the Investigator. Use of strong CYP3A4 inhibitors and inducers during participation in the trial, starting at the Screening Visit. Note: These medications include but are not limited to the following: Inhibitors: boceprevir, clarithromycin, cobicistat, dasabuvir, denoprevir, elvitegravir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, and voriconazole. Inducers: apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's Wort. Inadequate organ function, including but not limited to; Alanine aminotransferase (ALT) > 2x Upper limit of Normal (ULN). Aspartate aminotransferase (AST) > 2x ULN. Bilirubin direct > 1.25x ULN. International normalized ratio (INR) > 1.2. Clinically significant hepatic impairment defined as a Child-Pugh B or C. Estimated glomerular filtration rate (eGFR) <60 mL/min. Any clinically significant comorbidity or systemic dysfunction that in the opinion of the Investigator would jeopardize the safety of the subject by participating in the trial. History of substance abuse or dependence that would interfere with the completion of the trial, as determined by the Investigator. Known hypersensitivity to KVD824 or placebo or to any of the excipients. Any prior use of any gene therapy treatment for HAE. Participation in any interventional investigational clinical trial, including an investigational COVID-19 vaccine trial, within 4 weeks of the last dosing of investigational drug prior to screening. Any pregnant or breastfeeding subject.

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 300 mg KVD824<br>300 mg KVD824 twice a day for 12 weeks | Drug: KVD824<br>* KVD824 300 mg Modified-Release Tablets<br>|
| Experimental: 600 mg KVD824<br>Two 300 mg KVD824 tablets twice a day for 12 weeks | Drug: KVD824<br>* KVD824 300 mg Modified-Release Tablets<br>|
| Experimental: 900 mg KVD824<br>Three 300 mg KVD824 tablets twice a day for 12 weeks | Drug: KVD824<br>* KVD824 300 mg Modified-Release Tablets<br>|
| Placebo Comparator: Placebo to KVD824<br>One, two or three placebo tablets to be taken twice a day for 12 weeks | Drug: Placebo to KVD824<br>* Placebo to KVD824 300 mg Modified-Release Tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate of Investigator-confirmed HAE attacks during the Treatment Period | To examine the number of investigator-confirmed attacks whilst on treatment compared to placebo | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects without Investigator-confirmed HAE attacks during the Treatment Period. |  | 12 weeks | 
| Rate of Investigator-confirmed HAE attacks that require conventional treatment during the Treatment Period. |  | 12 weeks | 
| Angioedema Quality of Life Questionnaire (AE-QoL) total score and domain scores during the Treatment Period. | AE-QoL is a quality of life questionnaire with a range of 0 (minimum) to 100 (maximum). A total score of 100 indicates worst possible impairment. | 12 weeks | 
| Angioedema Control Test (AECT) score and domain scores during the Treatment Period. | AECT is a 4-item patient-reported outcome measure. The total score is from 0 (minimum) to 16 (maximum). A higher score indicates a higher level of angioedema control. | 12 weeks | 
| Proportion of subjects with an AECT score ≥12 at the end of the Treatment Period. | AECT is a 4-item patient-reported outcome measure. The total score is from 0 (minimum) to 16 (maximum). A higher score indicates a higher level of angioedema control. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KVD824, KOMPLETE