Lanadelumab in FXII-associated Cold Autoinflammatory Syndrome (FACAS) (LANA-FXII)

Factor XII-associated Cold Autoinflammatory Syndrome (FACAS) Linked to Kallikrein-kinin Pathology: Proof of Concept Treatment With Lanadelumab (DX-2930)

This is a Phase 2, exploratory, proof-of-concept, single-center, open-label pilot study to assess the effects and safety of Lanadelumab in patients with FXII-associated cold autoinflammatory syndrome (FACAS).

Study Overview

• Status: Active, not recruiting
• Conditions: Hereditary Autoinflammatory Disease
• Intervention / Treatment: Drug: Lanadelumab

Detailed Description

Factor XII is a serine protease with diverse functions that participates in coagulation, fibrinolysis, complement and contact system activation. So far, mutations in the factor XII gene were linked to the rare coagulation disorder Hagemann factor deficiency and hereditary angioedema (FXII-HAE).

The investigators recently identified a novel FXII mutation in a 4-generation family with profound contact system activation and an autoinflammatory clinical phenotype.

Lanadelumab is a specific kallikrein Inhibitor that is known to prevent clinical symptoms and contact system activation in hereditary angioedema.

This study aims at assessing the clinical effects and safety of Lanadelumab in patients with FXII-associated cold autoinflammatory syndrome (FACAS).

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Karoline Krause, Prof.; Phone Number: +4930450518336; Email: karoline.krause@charite.de

Study Locations

• Germany
  • Berlin, Germany, 12203
    • Charite University, Berlin, Germany

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adolescents (12 - 17 years) and adults (18 years or older)
• Documented FXII-associated autoinflammatory disorder (FACAS) by positive genetic analysis result
• Clinical symptoms of cold-associated wheals, arthralgia, headache, fatigue (FACAS)
• Able to read, understand and willing to sign the informed consent form and abide with study procedures
• Males and females who are fertile and sexually active must adhere to contraception requirements for the duration of the study as follows:
• Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from the screening period through 30 days after the final study visit: progestin-only oral contraceptive, condom with or without spermicidal jelly, diaphragm or cervical cap with spermicidal jelly, or intra-uterine device (IUD, all types). Female participants whose male partner has had a vasectomy must agree to use one additional form of medically acceptable contraception.
• Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
• Males, including males who are surgically sterile (post vasectomy), with female partners of childbearing potential must agree to be abstinent or else use a medically acceptable form of contraception from the screening period through 60 days after the last IMP injection.

Exclusion Criteria:

• 1. Any other forms of urticaria or angioedema not related to genetic mutations within the FXII gene 2. Concurrent/ongoing treatment with biologics or recent treatment (less than 5 half-lives) 3. Concurrent/ongoing treatment with anakinra within 7 days prior to screening, with canakinumab within 100 days prior to screening 4. Concurrent/ongoing treatment with oral/parenteral corticosteroids greater than 10 mg/d within 2 weeks prior to screening 5. Concurrent/ongoing treatment with other immunosuppressives within 4 weeks or 5 half-lives prior to screening, whichever is longer 6. Treatment with a live (attenuated) virus vaccine within 4 weeks prior to Baseline visit 7. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.

  8. Use of prophylactic therapy with C1-INH, attenuated androgens, or antifibrinolytics within 2 weeks prior to the start of the treatment period (Day 0).

  9. Any of the following liver function test abnormalities:

  • alanine aminotransferase (ALT) > 3x upper limit of normal, or
  • aspartate aminotransferase (AST) > 3x upper limit of normal, or

  • total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of Gilbert's Syndrome).

    10. Pregnancy or breastfeeding. 11. Subject has any condition that, in the opinion of the Investigator or Sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (e.g., history of substance abuse or dependence, a significant pre-existing illness or other major comorbidity that the Investigator considers may confound the interpretation of study results).

    12. Significant medical condition rendering the patient immunocompromised or not suitable for a clinical trial.

    13. Enrollment in another investigational treatment or device study or use of an investigational agent, or less than 4 weeks or 5 half-lives, whichever is longer, since end of another investigational device or drug trial.

    14. Patients with known hypersensitivity to any constituent of the products of lanadelumab.

    15. Dementia, altered mental status, or any psychiatric condition, or stay in an institution further to an official or court order that would prohibit the understanding or rendering of informed consent or participation in the study.

    16. Subjects who are study site employees, or immediate family members of a study site or sponsor employee.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lanadelumab	Drug: Lanadelumab; 300mg Lanadelumab s.c. administration every 2 weeks; Other Names: DX-2930

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab treatment	Patient-reported total disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF) grading the severity of 5 key symptoms of FACAS: urticarial rash, fatigue, chills/fever, arthralgia and headache (scale 0=no symptoms to 50=max. of symptoms).	weeks 9 to 12 compared to weeks -4 to -1 (baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urticarial rash disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab treatment	Patient-reported urticarial rash disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF; scale 0=no symptoms to 10=max. of symptoms)	weeks 9 to 12 and weeks 24 to 28, each compared to weeks -4 to -1 (baseline)
Change in fatigue disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab treatment	Patient-reported fatigue disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF; scale 0=no symptoms to 10=max. of symptoms)	weeks 9 to 12 and weeks 24 to 28, each compared to weeks -4 to -1 (baseline)
Change in chills/fever disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab treatment	Patient-reported chills/fever disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF;scale 0=no symptoms to 10=max. of symptoms)	weeks 9 to 12 and weeks 24 to 28, each compared to weeks -4 to -1 (baseline)
Change in arthralgia disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab treatment	Patient-reported arthralgia disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF; scale 0=no symptoms to 10=max. of symptoms)	weeks 9 to 12 and weeks 24 to 28, each compared to weeks -4 to -1 (baseline)
Change in headache disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab treatment	Patient-reported headache disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF; scale 0=no symptoms to 10=max. of symptoms)	weeks 9 to 12 and weeks 24 to 28, each compared to weeks -4 to -1 (baseline)
Change in total disease activity score as assessed by daily health assessment form (DHAF) questionnaire following lanadelumab Treatment over Long-term use	Patient-reported total disease activity is assessed by a disease-specific daily health assessment form (FXII-associated Cold autoinflammatory Syndrome daily Health assessment form; FACAS-DHAF; scale 0=no symptoms to 50=max. of symptoms	weeks 24 to 28 compared to weeks -4 to -1 (baseline)
Change in inflammation markers following lanadelumab Treatment	Assessment of CRP levels	from Baseline to week 12 and week 28
Change in inflammation markers following lanadelumab Treatment	Assessment of ESR levels	from Baseline to week 12 and week 28
Change in inflammation markers following lanadelumab Treatment	Assessment of SAA levels	from Baseline to week 12 and week 28
Change in inflammation markers following lanadelumab Treatment	Assessment of S100 A8/9 levels	from Baseline to week 12 and week 28
Change in dermatology-specific quality-of-life following lanadelumab Treatment	assessed by Dermatology Life Quality Index (DLQI); scale 0=no impairment to 30=max. impairment	from Baseline to week 12 and week 28
Changes in generic Health-related quality-of-life	assessed by 36-Item Short Form Health Survey (SF-36); scale 0=max. impairment to 100=no impairment (best Quality of life)	from Baseline to week 12 and week 28
Incidence of of Treatment-emergent adverse Events, abnormal physical examination, abnormal Routine safety laboratory assessments, abnormal vital signs (safety and tolerability)	Safety of lanadelumab Treatment is assessed by physical examination, routine safety laboratory assessments, vital signs, and adverse Event reporting.	from Baseline to end of study (week 36 follow-up)
Change in physician global assessment following lanadelumab Treatment as assessed by verbal rating scale	Verbal Rating scale assesses overall Symptoms from 0-10 (0=no symptoms; 10=very severe symptoms)	from Baseline to week 12 and week 28
Changes of plasma levels of potential biomarkers following Lanadelumab treatment	Potential biomarkers include Plasma FXII Levels	from Baseline to week 28
Changes of plasma levels of potential biomarkers following Lanadelumab treatment	Potential biomarkers include Plasma prekallikrein Levels	from Baseline to week 28
Changes of plasma levels of potential biomarkers following Lanadelumab treatment	Potential biomarkers include Plasma cHMWK Levels	from Baseline to week 28
Changes of plasma levels of potential biomarkers following Lanadelumab treatment	Potential biomarkers include IL-1ß release from donor PBMCs	from Baseline to week 28

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Shire International GmbH
• Investigators: Principal Investigator: Karoline Krause, Prof., Charite University, Berlin, Germany

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2020
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 13, 2020
• First Submitted That Met QC Criteria: February 19, 2020
• First Posted (Actual): February 20, 2020

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: FXII-associated cold autoinflammatory syndrome (FACAS)
• Additional Relevant MeSH Terms: Skin Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Familial Mediterranean Fever; Hereditary Autoinflammatory Diseases
• Other Study ID Numbers: DEALSZ-2019-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No