Safety and Efficacy of RPH-104 Used to Prevent Recurrent Fever Attacks in Adult Patients With Colchicine Resistant or Colchicine Intolerant Familial Mediterranean Fever

Study Overview
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Brief Summary
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The primary purpose of this study is to assess the safety of the long-term treatment with RPH-104 at doses 80 mg or 160 mg once every 2 weeks in a population of patients with colchicine resistant or colchicine intolerant familial Mediterranean fever (FMF) who completed the core study, during which they received at least one dose of RPH-104. Long-term efficacy of RPH-104, the immunogenicity of the RPH-104, the pharmacokinetics of the RPH-104 and quality of life change in the population of patients receiving long-term treatment with RPH-104 will be assessed as well.

Detailed Description
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This long-term open-label study is an extension of the core double blind, randomized, placebo-controlled study, CL04018065. It is planned that this study will include no more than 60 patients who completed the core study, where they received blinded therapy. This study will have the following periods: Screening period - within one day, Day 0, which is also the day of Visit 11 of the main study. This period envisages unblinding of the treatment groups determined in the main study (for not-unblinded patients) and determination of the eligibility for this study. Patients who do not meet the inclusion/exclusion criteria will not receive treatment with the study drug, such patients should attend a safety follow-up visit 6 weeks after the screening period (i.e. 8 weeks after the last injection of the study drug or placebo during the core study) with all procedures performed in accordance with the last planned visit of the safety follow-up (Visit 17), after which their participation in the study will be considered completed. Treatment period - all patients included in this period will receive open-label treatment with RPH-104 for 54 weeks. The possible drug dose will be: 80 mg once every 2 weeks subcutaneously; 160 mg once every 2 weeks subcutaneously. An injection of the study drug to patients is performed by qualified medical personnel every 2 weeks when the patient visits the study site; it is also possible for the patients to self-administer the drug at home (for which patients will be appropriately trained and provided with the necessary quantity of the drug, materials for the injection (including special containers for their disposal) and proper drug transportation). Safety and efficacy assessments are performed at Visit 1, Visit 2 (after 2 weeks) and then every 4 weeks according to the visits schedule. Safety and efficacy assessments are performed at Visit 1, Visit 2 (after 2 weeks) and then every 4 weeks according to the visits schedule.If FMF attack is confirmed in a patient, then patient's therapy can be adjusted based on the informed decision of an investigator: for patients who receive RPH-104 at a dose of 80 mg q2w, a dose can be increased to 160 mg q2w; for patients who already receive the maximum dose of RPH-104 that is 160 mg q2w, the dose will be not increased; these patients will be able to continue therapy with the study drug at a dose of 160 mg at the justified investigator's discretion. Reduction of the study drug dose is not planned in this study. Safety follow-up period - 8 weeks. After patients receive the last dose of the study drug at Week 54 of the study, the treatment period will be considered completed and an 8 weeks period of safety follow-up will start. During this period patients will have to visit the study site twice at Week 4 and Week 8 after the last dose of the study drug for safety assessments. Patients who have discontinued open-label therapy with the study drug early for any reason, should perform two safety follow-up visits at Week 4 and Week 8 after the last dose of the study drug.

Official Title
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An International Multicenter Open-label Clinical Study of the Safety and Efficacy of RPH-104 for Prevention of Recurring Attacks in Adult Subjects With Familial Mediterranean Fever With Resistance to or Intolerance of Colchicine

Conditions
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FMF, Familial Mediterranean Fever

Intervention / Treatment
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* Biological: RPH-104


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient who completed the last visit of the treatment period in the core study, according to the protocol, during which he/she received at least one dose of RPH-104. Voluntarily signed and dated Patient Informed Consent Form for participation in this study. The patient's ability and desire, according to the investigator, to follow the schedule of visits, follow the study procedures and follow the protocol requirements, i.e they agree to: come to the study site every 2 weeks for the investigational product administration by qualified site staff. OR learn the subcutaneous injection technique and self-administer the investigational product at home as per protocol of this study. Exclusion Criteria: Any medically important event that was observed in a patient during his/her participation in the core study, and, in the opinion of the investigator, is a reason for not including this patient in the present study, and any other medical (including psychiatric) conditions or laboratory abnormalities, which may increase the potential risk associated with participation in the study and receiving the investigational product, or may affect the interpretation of the results of the study, and which, in the Investigator's reasonable opinion, result in the patient's non-compliance with the inclusion criteria Pregnant and/or lactating women or women planning pregnancy during the study or within 2 months after the last dose of the study drug. Women of childbearing potential, i.e. all women with the physiological ability to become pregnant (except for women with a final cessation of menstruation, which should be determined retrospectively after 12 months of natural amenorrhea, i.e. amenorrhea with an appropriate clinical status, for example, an appropriate age), who DO NOT agree to use highly effective contraception for of the entire study period, starting from the beginning of the screening phase (signing informed consent) and for a minimum of 8 weeks after the last dose of the study drug. OR Men who are sexually active and do NOT agree to use highly effective contraceptives throughout the study, starting from the beginning of the screening phase and for at least 8 weeks after the last dose of the study drug. Highly effective contraception methods include: sterilization in women: surgical bilateral removal of the ovaries (with or without removal of the uterus) or ligation of the fallopian tubes at least 6 weeks before the start of the study therapy. In the case of removal of only the ovaries, the reproductive status of a woman should be confirmed by a subsequent assessment of hormone level; sterilization in men, at least 6 months before the start of the study therapy with proper documentation of the absence of sperm in the ejaculate after vasectomy. For the women participating in the study, the sexual partner after a vasectomy should be the only partner; using a combination of any two of the following methods (a+b or a+c or b+c): the use of oral, injectable or implanted hormonal contraceptives; in the case of the use of oral contraceptives, women should constantly use the same drug for at least 3 months before the start of the study therapy; the installation of an intrauterine device or contraceptive system; barrier methods of contraception: condom or occlusive cap (diaphragm or cervical cap/contraceptive vaginal ring) with spermicidal foam/gel/film/cream/vaginal suppository. The need for systemic glucocorticoid therapy at doses > 0.2 mg/kg/day of prednisolone (0.16 mg/kg/day of methylprednisolone or an equivalent dose of another glucocorticoid) orally from the moment of signing the Informed Consent Form to the end of the period of therapy with the study drug. The need to use a live (attenuated) vaccine during the study or within 3 months after the last dose of the study drug. Live attenuated vaccines include vaccines against viruses: measles, rubella, mumps, chickenpox, rotavirus, flu (as a nasal spray), yellow fever, polio (oral polio vaccine); vaccines against tuberculosis (BCG), typhoid fever (oral typhoid vaccine) and typhus (typhus vaccine). Immunocompetent family members of the patient should not be vaccinated with the oral polio vaccine during the patient's participation in the study. Positive results of tuberculosis screening performed at Visit 10 of the core study (QuantiFERON-TB/T-SPOT.TB test, chest x-ray).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RPH-104 80 mg q2w (160 mg q2w) depending on the dose in the core CL04018065 study<br>RPH-104 80 mg once every 2 weeks subcutaneously or RPH-104 160 mg once every 2 weeks subcutaneously (In case of FMF attack development, patients who receive 80 mg of the drug may be switched to the increased maximum drug dose 160 mg based at the discretion of the investigator. A dose of 160 mg should be administered by two subcutaneous injections in two different quadrants.) | Biological: RPH-104<br>* solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (AEs), by System Organ Class and Preferred Term |  | Up to 62 weeks | 
| Incidence of Treatment-Emergent Serious Adverse Events (SAEs), by System Organ Class and Preferred Term |  | Up to 62 weeks | 
| Incidence of Treatment-Emergent Adverse Events of Special Interest (AESI), by System Organ Class and Preferred Term |  | Up to 62 weeks | 
| Incidence rate for serious adverse events (SAEs) | Incidence rate, expressed as the number of events per 100 patient-years of follow-up, for SAEs | Up to 62 weeks | 
| Incidence rate for adverse events of special Interest (AESI) | Incidence rate, expressed as the number of events per 100 patient-years of follow-up, for AESI | Up to 62 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physician global assessment of disease activity scale (PGA) | Percentage of patients with physician global assessment of disease activity scale (PGA) <2. PGA of disease activity involves a 5-point system: from 0 = no clinical signs and symptoms associated with the disease to 4 = severe clinical signs and symptoms associated with the disease. | Up to 62 weeks | 
| Percentage of patients with serological remission | Percentage of patients with serological remission (i.e., C-reactive protein (CRP) level ≤10 mg/L). | Up to 62 weeks | 
| Percentage of patients whose Serum amyloid A (SAA) levels returned to normal values | Percentage of patients whose SAA levels returned to normal values (i.e. SAA <10 mg/L) | Up to 62 weeks | 
| Percentage of patients who have experienced ≥ 1 attacks per month (since Day 0) | Percentage of patients who have experienced ≥ 1 attacks per month (since Day 0). Criteria for the diagnosis of an attack are defined as the simultaneous development of clinical and serological signs of an attack, including: the score on the scale of global physician's assessment of disease activity (PGA) ≥ 2, suggesting mild, moderate or severe activity of the disease (i.e., clinical signs), AND CRP level ≥ 30 mg/L (i.e. serological signs) | Up to 54 weeks | 
| Percentage of patients who have not had a single attack | Percentage of patients who have not had a single attack. Criteria for the diagnosis of an attack are defined as the simultaneous development of clinical and serological signs of an attack, including: the score on the scale of global physician's assessment of disease activity (PGA) ≥ 2, suggesting mild, moderate or severe activity of the disease (i.e., clinical signs), AND CRP level ≥ 30 mg/L (i.e. serological signs) | Up to 54 weeks | 
| Increase in the dose of the study drug | Percentage of patients who required an increase in the dose of the study drug to 160 mg twice weekly. | Up to 54 weeks | 
| Additional symptomatic FMF therapy | Percentage of patients who have received additional symptomatic FMF therapy with NSAIDs, paracetamol or glucocorticoids. | Up to 62 weeks | 
| Changes in the inflammatory markers over time | Changes in the inflammatory markers over time - CRP | Up to 62 weeks | 
| Changes in the inflammatory markers over time | Changes in the inflammatory markers over time - SAA. | Up to 62 weeks | 
| Changes in the PGA score over time | Changes in the PGA score over time. PGA of disease activity involves a 5-point system: from 0 = no clinical signs and symptoms associated with the disease to 4 = severe clinical signs and symptoms associated with the disease. | Up to 54 weeks | 
| Changes in the severity of the main disease symptoms score | Changes in the severity of the main disease symptoms score. An assessment of severity of the main symptoms of the disease will also be based on a 5-point scale for the following symptoms: chest pain, abdominal pain, arthralgia/arthritis, skin rash. The severity of each symptom should be evaluated as follows: 0 = no symptom, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe. | Up to 54 weeks | 
| Changes in the renal function in patients with impaired renal function at the screening | Changes in the renal function in patients with impaired renal function (ClCr <90 ml/min [calculated using the Cockcroft-Gault formula] at the screening) | Up to 62 weeks | 
| Changes in urinary protein levels in patients with proteinuria at the screening | Median changes from baseline (timepoint week 0) to timepoint week 62. | Up to 62 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RPH-104, colchicine inefficacy, colchicine intolerance, colchicine resistance, subcutaneous