Ziclumeran (mRNA); Lonvoguran (single guide RNA) for Hereditary angioedema (C1 esterase inhibitor deficiency; Type 1 or 2)

Inclusion criteria

• {"criterion_text":"- 1. Participants must be ≥ 16 years of age.\n- 10. Female participants must agree to not undergo oocyte retrieval for in vitro fertilization from the date of randomization through 7 months after the second administration of blinded study intervention.\n- 11. Participants ≥ 18 years of age, emancipated minors, and legal guardians of participants 16 to < 18 years of age must be capable of providing signed informed consent. Participants 16 to < 18 years of age, whose legal guardian provides informed consent, must be willing and able to read, understand, and sign an assent form.\n- 12. Participants must agree not to participate in another interventional study for the duration of this study.\n- 2. Clinical history consistent with HAE (recurrent episodes of subcutaneous or mucosal swelling without accompanying urticaria) and all of the following characteristics consistent with HAE-C1INH (Type 1 or 2): a. Symptom onset before age 40 OR documented normal C1q levels to rule out acquired angioedema. b. Functional C1-INH level < 40% of normal OR between 40% and 50% of normal with C4 level below the lower limit of the reference range. Laboratory testing (C1-INH, C4, and C1q) during SCR-2, at either the central or an accredited local laboratory, or previously documented results from an accredited local laboratory may be used to confirm eligibility. If frequent use of C1-INH for the prevention or treatment of HAE attacks would confound interpretation of C1-INH testing, local genetic testing for known variants in the SERPING1 gene may be used to confirm eligibility upon consultation with the Sponsor.\n- 3. Participants must have at least 2 Investigator-confirmed and documented HAE attacks during the 8-week Run-in Period. a. Participants experiencing ≥ 2 attacks meeting the above criteria within the first 28 days of the Run-in Period may be randomized at any time after Day 28 of the Run-in Period provided that all eligibility criteria have been met. b. Participants who do not have at least 2 attacks in the first 28 days of the Run-in Period must remain in the Run-inPeriod for the full duration of 8 weeks (56 days).\n- 4. Participants must agree to refrain from the use of long-term prophylactic therapies from within 5 half-lives prior to the start of the Run-in Period through the end of the 28-week Primary Observation Period, and the Investigator must confirm that this does not place the participant at undue safety risk. Short-term prophylaxis prior to dental or medical procedures is allowed.\n- 5. Participants must have access to, and the ability to use, on-demand medication(s) to treat angioedema attacks.\n- 6. Participants must meet the following laboratory criteria: a. AST, ALT, and total bilirubin (see exception for Gilbert’s Syndrome below) ≤ 1.5 × ULN. b. For participants with a history of Gilbert’s Syndrome, total bilirubin ≤ 3 × ULN. c. eGFR is > 30 mL/min/1.73 m2 as measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. d. Platelet count ≥ 100,000 cells/mm3 and ≤ 400,000 cells/mm3. e. INR ≥ 0.8 and ≤ 1.5. f. Within reference range or Principal Investigator-determined clinically nonsignificant aPTT.\n- 7. Male participants with partners of childbearing potential must agree to using a condom from the date of randomization through 4 months after the second administration of blinded study intervention.\n- 8. Male participants must agree not to donate sperm from the date of randomization through 4 months after the second administration of blinded study intervention. The time frame may be extended beyond the 4 months if sperm donation is contraindicated based on country-specific guidelines.\n- 9. Female participants of childbearing potential must agree to use a protocol-specified highly effective method of contraception from completion of the informed consent/assent process through 7 months after the second administration of blinded study intervention. This is not required of female participants who are either: a. Postmenopausal (defined as no menses for 12 months without an alternative medical cause) prior to SCR-2. In addition, at least 2 FSH measurements in the postmenopausal range may be used to confirm a postmenopausal state in women with less than 12 months of amenorrhea and not using hormonal contraception or hormonal replacement therapy; OR b. Surgically sterile (ie, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) at least 1 month prior to SCR-2."}

Exclusion criteria

• {"criterion_text":"- 1. HAE with normal C1-INH or concurrent diagnosis of any other type of recurrent angioedema, including acquired or idiopathic angioedema.\n- 10. Exposure to ACE inhibitors or any estrogen-containing medications with systemic absorption within 90 days prior to study intervention.\n- 11. Antithrombotic therapy (eg, warfarin, dabigatran, apixaban) other than low-dose aspirin (< 100 mg) within 14 days of study intervention.\n- 12. Prior liver, heart, or other solid organ transplant; bone marrow transplant; or anticipated transplant within 1 year of SCR-2. Note: Prior history of or planned corneal transplant is not exclusionary.\n- 13. Previous treatment with gene therapy for HAE.\n- 14. Known or suspected intolerance or contraindication to the IMP, auxiliary products, or ingredients of either, including placebo solution.\n- 15. Unable or unwilling to take the required pretreatment medication regimen.\n- 16. Female participants of childbearing potential are excluded from the study if they: a. Are breastfeeding or plan to breastfeed from the date of randomization through 3 months after the second administration of blinded study intervention. b. Are pregnant or have a positive pregnancy test at SCR-2 and/or Day -1.\n- 17. Any condition, laboratory abnormality, or other reason that, in the Investigator’s opinion, could adversely affect the safety of the participant, impair the assessment of study results, or preclude adherence to the study protocol.\n- 18. Unwilling to comply with study procedures including follow-up as specified by the protocol or unwilling to cooperate fully with the Investigator.\n- 2. History of cirrhosis.\n- 3. History of venous thromboembolism.\n- 4. History of hemophilia or other bleeding diathesis.\n- 5. Active or chronic hepatitis B or C infection or positive HBsAg or HCV Ab test.\n- 6. History of positive HIV status.\n- 7. Known or suspected systemic viral, parasitic, or fungal infection, or received antibiotics for bacterial infection or vaccines within 14 days prior to study intervention (30 days for live vaccines)\n- 8. History of active malignancy within 3 years prior to SCR-2 or during the Run-in Period, except: a. Basal cell carcinoma of skin. b. Curatively resected squamous cell carcinoma of the skin. c. Cervical carcinoma in situ curatively treated. d. Nonmetastatic prostate adenocarcinoma stably managed on hormonal therapy by a medical oncologist or for which appropriate management is observation alone.\n- 9. History of alcohol or drug abuse within 3 years prior to SCR-2."}

Primary endpoints

• {"endpoint_text":"- Time-normalized number of Investigator-confirmed HAE attacks from Week 5 through Week 28","definition_or_measurement_approach":"Measured as the time-normalized (per time at risk) count of Investigator-confirmed hereditary angioedema (HAE) attacks occurring from Week 5 through Week 28."}

Secondary endpoints

• {"endpoint_text":"- Time-normalized number of Investigator- confirmed HAE attacks requiring on-demand treatment from Week 5 through Week 28\n- Time-normalized number of moderate or severe Investigator-confirmed HAE attacks from Week 5 through Week 28\n- Investigator-confirmed HAE attack-free status from Week 5 through Week 28\n- Change from baseline to Week 28 in AE-QoL Questionnaire total score","definition_or_measurement_approach":"Secondary endpoints are measured over Weeks 5–28: time-normalized counts of Investigator-confirmed HAE attacks requiring on-demand treatment; time-normalized counts of moderate or severe Investigator-confirmed HAE attacks; proportion of participants who are Investigator-confirmed attack-free; change from baseline to Week 28 in Angioedema Quality of Life (AE-QoL) questionnaire total score."}

Methods

• K1_Recruitment Arrangements documents (country-specific) — Netherlands, Germany, France (document titles indicate tailored recruitment arrangements per country).
• K2 Recruitment materials: Brochure (patient brochure) — available (country-specific versions).
• K2 Recruitment material_ICF Flipchart — flipchart used for informed consent discussion.
• K2 Recruitment material_Website package / 2024-515741-42_SITE WEB — website recruitment materials/site web package.
• K2 Recruitment material_Storyboard and 2024-515741-42_Storyboard — storyboard/video materials for recruitment.
• 2024-515741-42_RECRUTEMENT_Presentation Etude — recruitment presentation materials (France).
• Patient-facing materials (patient contact card, patient folder, welcome letter, payment/account FAQ) included in document list (titles indicate use for participant engagement).

Netherlands

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

11-07-2025

Processing Time Days

176

Number Of Sites

1

Number Of Participants

10

Germany

Earliest CTIS Part Ii Submission Date

13-12-2024

Latest Decision Or Authorization Date

08-07-2025

Processing Time Days

207

Number Of Sites

3

Number Of Participants

11

France

Earliest CTIS Part Ii Submission Date

07-01-2025

Latest Decision Or Authorization Date

08-07-2025

Processing Time Days

182

Number Of Sites

4

Number Of Participants

8

Primary sponsor

Full Name

Intellia Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Medpace Finland Oy

Responsibilities

Sponsor duties codes: 1,12,2,4,5,8 (as listed in CTIS thirdParty sponsorDuties)

Third parties

• {"country":"Finland","full_name":"Medpace Finland Oy","duties_or_roles":"1,12,2,4,5,8","organisation_type":"Pharmaceutical company"}