Clinical trial NCT04898309: Efficacy and Safety of GNR-038 vs Berinert® in Patients With Hereditary Angioedema
Official title: A Placebo-controlled Randomized Trial to Evaluate the Efficacy and Safety of GNR-038 in Comparison With Berinert® for Acute Attacks Relief in Patients With Hereditary Angioedema
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
PHASE3
Conditions: Hereditary Angioedema
Keywords: Hereditary angioedema
Swelling
GNR-038
C1-inhibitor
Mutation
SERPING1 gene
HAE
Genetic disease
C1-INH deficiency
Hypersensitivity
Immune System Diseases
Genetic Diseases, Inborn
Immunologic Factors
Physiological Effects of Drugs
Complement Inactivating Agents
Immunosuppressive Agents
Angioedema
Angioedemas, Hereditary
Complement C1 Inhibitor Protein
Complement C1 Inactivator Proteins
Lead sponsor: AO GENERIUM
Sponsor class: INDUSTRY
First posted: 2021-05-24
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Two-stage study. In the first stage - 4 groups are presented. At the second stage - 2 study groups 200 HAE attacks to be randomized in 50 patients
Primary purpose: TREATMENT

Brief summary: It is a placebo-controlled randomized trial to evaluate the efficacy and safety of GNR-038 in comparison with Berinert® in patients with hereditary angioedema

Detailed description: Hereditary angioedema is a rare, potentially life-threatening genetically determined disease associated with a deficiency or impairment of the functional activity of the C1-esterase inhibitor (C1-inhibitor). The main clinical manifestation of hereditary angioedema is recurrent subcutaneous or submucosal swelling of various localization. Most often, the development of the disease is based on a mutation in the SERPING1 gene. The prevalence of the disease in the world ranges from 1:10 000 to 1:150 000. GNR-038 is a recombinant C1 inhibitor (rhC1INH), which is a complete structural and functional analog of the plasma C1 inhibitor. Phase I study results showed convincing safety and tolerability evidence of GNR-038.

Eligibility criteria: Inclusion Criteria

1. Men and women 18 years and older at the time of signing the Informed Consent Form.
2. Availability of written informed consent signed by the patient prior to the start of any procedures related to the study.
3. Confirmed diagnosis of HAE:

   * C4 level \<50% of the lower limit of the range of normal laboratory values and one of the points below:
   * the C1INH level \<50% of the lower limit of the range of normal laboratory values, OR
   * the level of C1INH within normal values, while the level of functional activity of C1INH is below 50% of the lower limit of the range of normal values.
4. Localization of the edema in the abdominal cavity, in the face area (lips, eyelids, subcutaneous tissue), limbs, trunk or in the area of the external genitals in the anamnesis.
5. ≥4 HAE attacks requiring treatment or causing significant functional impairment for 2 consecutive months in the 3-month period prior to Screening, properly documented in the medical records.
6. Patient's consent to adhere to reliable methods of contraception.

Exclusion Criteria

1. Deviation of the C1q level below the normal limit.
2. B-cell lymphoproliferative diseases in the anamnesis or at the time of inclusion in clinical trial.
3. The presence of anti-C1INH autoantibodies.
4. Allergic reactions to the components of C1INH drugs or other blood components.
5. Glomerular filtration rate ≤59 ml/min/1.73 m2, calculated by the formula CKD-EPI Creatinine Equation (2009) (see Appendix).
6. The concentration of peripheral blood leukocytes \>20\*109/L.
7. Drug addiction, solvent abuse, alcoholism in the anamnesis or at the time of inclusion.
8. Participation in clinical trials of C1-esterase inhibitor drugs, blood transfusion and its components during the last 90 days prior to screening.
9. Participation in clinical trials of any other investigational drugs within the last 30 (thirty) days prior to screening.
10. Positive laboratory results for HIV and hepatitis B and C.
11. Pregnancy and lactation.
12. Diseases and conditions associated with thrombosis (myocardial infarction, transient ischemic attacks, deep and superficial vein thrombosis, and pulmonary embolism) less than 6 months before the start of the screening period, as well as an increased risk of arterial or venous thrombosis according to the study doctor's opinion.
13. Concomitant diseases and conditions that according to the study doctor's opinion put the patient's safety at risk when participating in the study, or that will affect the analysis of safety data if this disease/condition worsens during the study, including:

    * Mental illness;
    * Diseases of the immune and endocrine system that are not controlled by drug therapy (including decompensated diabetes mellitus and thyroid diseases);
    * Hematological diseases requiring chemotherapy;
    * Cancer or cancer in the past medical history, with the exception of cured basal cell carcinoma;
    * Decompensated liver diseases.

Primary outcomes:
measure: Time to symptoms relief onset of acute HAE attack within 24 hours after the end of the drug administration.
timeFrame: 24 hours
Secondary outcomes:
measure: Time to complete resolution of the symptoms of an acute HAE attack within 24 hours after the end of the study drug administration.
timeFrame: 24 hours
measure: Time to minimum manifestation onset of acute HAE attack symptoms after the completion of study drug administration.
timeFrame: 24 hours
measure: The proportion of HAE exacerbation episodes that achieved symptom relief after 1 hour and 4 (four) hours after the end of study drug administration.
timeFrame: 1 hour; 4 hours.
measure: The rate of attacks with HAE current localization relapse or with the occurrence of a new acute attack of a different localization within 24 (twenty-four) hours after the study drug administration.
timeFrame: 24 hours
measure: The rate of attacks that required additional administration of emergency drugs (human C1-esterase inhibitor or icatibant).
timeFrame: 24 hours
measure: The rate of attacks that did not respond therapeutically to the study drug administration
timeFrame: 4 hours; 24 hours
measure: The intensity of acute HAE attack symptoms within 24 (twenty-four) hours after study drug administration.
timeFrame: 24 hours
measure: Frequency of adverse events.
timeFrame: 14 days
measure: Frequency of anti-drug antibody formation.
timeFrame: 7 and 14 days
measure: The level of anti-drug antibodies neutralizing activity.
timeFrame: 7 and 14 days
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: National Research Center - Institute of Immunology Federal Medical-Biological Agency of Russia
city: Moscow
country: Russian Federation
facility: Moscow City Clinical Hospital 52
city: Moscow
country: Russian Federation
facility: Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology
city: Rostov-on-Don
country: Russian Federation
facility: Rostov State Medical University
city: Stavropol'
country: Russian Federation
facility: LLC "Scientific Medical Center of General Therapy and Pharmacology"
Study officials:
affiliation: AO GENERIUM
name: Oksana A. Markova, MD
role: STUDY_CHAIR
References: