Efficacy and Safety of RPH-104 for Resolution and Prevention of Recurring Attacks in Adult Subjects With Familial Mediterranean Fever With Resistance to or Intolerance of Colchicine

Sponsor

R-Pharm International, LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05092776

Collaborator

Data Management 365 (Industry), Atlant Clinical LLC (Other), R-Pharm (Industry), Center of Pharmaceutical Analytics LLC (Other), Unimed Laboratories CJSC (Other)

Enrollment

Locations

Arms

22.8

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary purpose of this study is to assess the efficacy and safety profiles of investigational product RPH-104 (R-Pharm Overseas, Inc., USA) for treatment of Familial Mediterranean Fever (FMF) in adult patients resistant/intolerant to colchicine (crFMF). Pharmacokinetic and pharmacodynamic parameters of RPH-104 single or multiple doses in this patient population will be assessed as well.

Condition or Disease	Intervention/Treatment	Phase
Familial Mediterranean Fever FMF	Biological: RPH-104 Drug: Placebo	Phase 2

Detailed Description

The study is supposed to enroll (randomize) 60 subjects with familial Mediterranean fever (FMF) with colchicine inefficacy or intolerance. Given potential withdrawal at the screening, the number of screened subjects (signed informed consent) will be approximately 84.

The study will consists of three following periods:

Screening period (up to 12 weeks); Throughout the screening the subjects will be monitored to identify "marker" attacks and verify the subject eligibility. The subjects having an attack during screening period and meeting inclusion/exclusion criteria will be enrolled into treatment period.
Double-blind randomized placebo-controlled treatment period (16 weeks);

The subjects enrolled will be randomized to one of the treatment groups in 1:1 ratio:

Test product group receiving RPH-104 at 80 mg as subcutaneous (s.c.) injections or
Placebo group receiving the equivalent placebo dose also as s.c. injections every 2 weeks.

Further the efficacy assessments will be performed at Visit 2 (Day 7) then at Visit 3 (Day 14) and subsequently every 2 weeks: the subjects will be monitored for resolution of "marker" attacks and development of new attacks based on which the decision on further treatment approach will be made (dose escalation to 160 mg for the test product group or switch from placebo to the study product RPH-104 80 mg for placebo group).

Based on the results of efficacy assessment throughout the treatment period the subjects may undergo blinded dose escalation or be switched from placebo to active therapy with preserved randomization group: subjects may receive additional therapy with the study product RPH-104 at 80 mg without the randomization group unblinding. Such blinded dose escalation may only be made once for each subject throughout the whole treatment period both in placebo group and in RPH-104 group. After the first dose escalation based on the results of efficacy evaluation the subjects may undergo the second or unblinded dose escalation. The second dose escalation is only allowed in the group of the subjects receiving placebo + RPH-104 80 mg. Further dose escalation is forbidden for the subjects receiving RPH-104 at 160 mg. These two dose escalation steps are possible within the period from study Visit 2 to Visit 10 (Days 7-112) for all the subjects from placebo group and the first step

for the subjects receiving RPH-104 at 80 mg. After reaching the total dose of RPH-104 of 160 mg once in 2 weeks no dose escalation will be performed. Subjects already receiving the maximum 160mg dose may continue therapy with RPH-104 at 160 mg only at the investigator's discretion. No dose reduction is made throughout the study. In case of a recurrent attack the subject should make a visit to the study center within 48 hours. Maximum treatment period is 16 weeks.

Subjects receiving both blinded and unblinded therapy will undergo regular evaluation of efficacy and safety; the visits will be performed every 2 weeks for this purpose.

Follow-up period (8 weeks).

On the first follow-up visit the subjects with therapeutic response to RPH-104 will be invited to proceed in an open-label long-term safety study of RPH-104. In case of lacking relevant clinical response and if the subjects do not wish to participate in the open-label study, they should complete all safety follow-up visits.

Overall expected study period is approximately 37 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

International, Multicenter, Double Blind, Placebo-controlled, Randomized Clinical Study of Efficacy and Safety of RPH-104 for Resolution and Prevention of Recurring Attacks in Adult Subjects With Familial Mediterranean Fever With Resistance to or Intolerance of Colchicine

Actual Study Start Date :

Apr 29, 2021

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Mar 23, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RPH-104 Test product group receiving RPH-104 at 80 mg as 1 subcutaneous (s.c.) injection every 2 weeks. In case the "marker" attack does not resolve at Visit 2 or in case of a new attack on further days of treatment period until Visit 10 inclusive the subject will receive RPH-104 as s.c. injections at 160 mg (80 mg will be administered in a blinded manner, additional 80 mg - unblinded) once in 2 weeks. In case of a new attack in a subject who has previously received step 1 additional therapy (RPH-104 80 mg), the treatment group will be unblinded. Further dose escalation is forbidden.	Biological: RPH-104 solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial
Placebo Comparator: Placebo Placebo group receiving the equivalent placebo dose also as s.c. injections every 2 weeks. In case the "marker" attack does not resolve at Visit 2 or in case of a new attack on further days of treatment period until Visit 10 inclusive the subject will receive blinded injections of placebo in addition to unblinded doses of RPH-104 as s.c. injections at 80 mg once in 2 weeks In case of a new attack in a subject who has previously received step 1 additional therapy (RPH-104 80 mg), the treatment group will be unblinded and the subject will receive RPH-104 in form of s.c. injections at dose of 160 mg once in 2 weeks. Further dose escalation is forbidden.	Drug: Placebo Normal Saline (0.9% Sodium Chloride solution for subcutaneous Injection), 2 mL in the 4 mL-glass vial. The placebo will contain no active pharmaceutical ingredients.

Arm

Intervention/Treatment

Experimental: RPH-104

Test product group receiving RPH-104 at 80 mg as 1 subcutaneous (s.c.) injection every 2 weeks. In case the "marker" attack does not resolve at Visit 2 or in case of a new attack on further days of treatment period until Visit 10 inclusive the subject will receive RPH-104 as s.c. injections at 160 mg (80 mg will be administered in a blinded manner, additional 80 mg - unblinded) once in 2 weeks. In case of a new attack in a subject who has previously received step 1 additional therapy (RPH-104 80 mg), the treatment group will be unblinded. Further dose escalation is forbidden.

Biological: RPH-104

solution for subcutaneous administration 40 mg/mL, 2 mL in the 4-mL glass vial

Placebo Comparator: Placebo

Placebo group receiving the equivalent placebo dose also as s.c. injections every 2 weeks. In case the "marker" attack does not resolve at Visit 2 or in case of a new attack on further days of treatment period until Visit 10 inclusive the subject will receive blinded injections of placebo in addition to unblinded doses of RPH-104 as s.c. injections at 80 mg once in 2 weeks In case of a new attack in a subject who has previously received step 1 additional therapy (RPH-104 80 mg), the treatment group will be unblinded and the subject will receive RPH-104 in form of s.c. injections at dose of 160 mg once in 2 weeks. Further dose escalation is forbidden.

Drug: Placebo

Normal Saline (0.9% Sodium Chloride solution for subcutaneous Injection), 2 mL in the 4 mL-glass vial. The placebo will contain no active pharmaceutical ingredients.

Outcome Measures

Primary Outcome Measures

Proportion of subjects with complete response during 16 week therapy with RPH-104 vs. placebo in FMF subjects with colchicine inefficacy or intolerance. [Up to 16 weeks]
Proportion of subjects with complete response during 16 week therapy with RPH-104 vs. placebo in FMF subjects with colchicine inefficacy or intolerance as compared between RPH-104 and placebo groups. Complete response defined as resolution of "marker" attack by Day 7(the subject's state matching to two conditions at Visit 2 (Day 7): Evaluation (score) by Physician Global Assessment (PGA) <2 (i.e. minimum or complete lack of clinical signs and symptoms); CRP ≤ 10 mg/L or CRP reduction by ≥ 70% compared to baseline at Visit 1 (Day 0)) and lack of recurring (new) attacks up to Day 112 (subject's state matching to both criteria : Evaluation (score) by Physician Global Assessment (PGA) <2 (i.e. minimum or complete lack of clinical signs and symptoms); CRP ≤ 10 mg/L) PGA is a 5-point scale: from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.

Secondary Outcome Measures

Proportion of subjects with Physician Global Assessment (PGA) score < 2 during the study [Up to 16 weeks]
(PGA) score < 2 during the treatment period with RPH-104 compared to placebo in FMF subjects with colchicine inefficacy or intolerance. PGA is a 5-point scale from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.
Proportion of subjects with serological remission [Up to 16 weeks]
Proportion of subjects with serological remission (CRP ≤ 10 mg/L) throughout the study.
Proportion of subjects with normalized Serum Amyloid A (SAA) level [Up to 16 weeks]
Proportion of subjects with normalized serum amyloid A level (SAA < 10 mg/L) throughout the study
Proportion of subjects receiving additional symptomatic therapy with Nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol or glucocorticoids due to FMF [Up to 16 weeks]
Proportion of subjects receiving additional symptomatic therapy with NSAIDs, paracetamol or glucocorticoids due to FMF
Change in inflammation parameters vs. baseline [From baseline (Day 0) up to 16 weeks]
Change in inflammation parameters vs. baseline (Day 0) - CRP and SAA
PGA score change compared to baseline [From baseline (Day 0) up to 16 weeks]
PGA score change compared to baseline (Day 0) during the study. PGA is a 5-point scale from 0 = no disease-related clinical signs and symptoms to 4 = severe clinical signs and symptoms of the disease.
Change in evaluation of severity of the main disease symptoms compared to baseline [From baseline (Day 0) up to 16 weeks]
Change in evaluation of severity of the main disease symptoms (chest pain, abdominal pain, joint pain/arthritis, skin rash) by physician compared to baseline (Day 0). Fever (body temperature ≥38ºC) will be evaluated as part of vital signs assessment.
Frequency of recurring fever attacks [Up to 16 weeks]
Frequency of recurring fever attacks throughout the study
Renal function and proteinuria dynamics in subjects with renal impairment and proteinuria at baseline [Up to 16 weeks]
Renal function and proteinuria dynamics in subjects with renal impairment (ClCr < 90 mL/min calculated using Cockcroft-Gault formula) and proteinuria at baseline (Day 0)
Changes in patients' quality of life during the treatment period with RPH-104 [Baseline (Day 0) and Day 28, Day 56, Day 84 and Day 112]
Change in quality of life vs. baseline (Day 0) based on SF-12® questionnaire throughout the study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Presence of voluntarily signed and dated Informed consent form to participate in this study. Informed consent implies ability of the subject, according to the investigator reasonable opinion, to understand and make voluntary decision concerning signing Informed consent form;
Verified diagnosis of familial Mediterranean fever (FMF) based on Tel HaShomer diagnostic criteria (Pras M., 1998);
Analysis for confirmation of presence of at least one mutation in Mediterranean fever gene (MEFV) exon 10 (results of the study performed earlier at any time may be provided);
Presence (at screening onset) of data on history of at least one disease attack monthly throughout the last 6 months (Ozen et al., 2016);
Presence of at least one of the below-mentioned (at screening onset) documented data confirming:
inefficacy of colchicine at the dose of 1.5-3 mg daily confirmed by at least one monthly attack despite the therapy specified within at least 6 last months. Colchicine administration will be continued at stable dose if it is not associated with unacceptable adverse effects;
intolerance of therapeutic or subtherapeutic doses of colchicine (unacceptable adverse effects).

Colchicine dose should be stable for at least 5 days before patient enrollment into the study (prior to screening period start);

Ability and willingness of the subject, according to the reasonable investigator's judgment, to attend the study site at all scheduled visits, undergo the study procedures and follow the protocol requirements including subcutaneous injections by qualified site personnel;
Consent of female subjects with childbearing potential defined as all females with physiological potential to conceive (except for those with absolute termination of menses to be determined retrospectively after 12 months of natural amenorrhea, i.e. amenorrhea with relevant clinical status, e.g. appropriate age) to use highly effective contraception throughout the study starting from the screening (signed Informed consent form) and for at least 8 weeks after discontinuation of the study therapy; and negative pregnancy test (serum test for chorionic gonadotropin). OR Consent of the sexually active men participating in the clinical trial to use highly effective contraception throughout the study starting from the screening (signed Informed consent form) and for at least 8 weeks after discontinuation of the study therapy. A highly effective method of contraception is defined as follows:
complete abstinence: if it corresponds to the preferred and conventional lifestyle of the female subject. [Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation method) and interrupted coitus are not considered acceptable contraceptive methods];
surgical intervention for female sterilization: bilateral ovariectomy (with/without hysterectomy) or tubal ligation at least 6 weeks prior to the study therapy initiation. In case of ovariectomy only the female reproductive status should be verified by further hormonal test;
sterilization of male partner (with documented absence of sperm in ejaculate post vasectomy] at least 6 months for screening [Vasectomized male partner should be the only partner of the participating female subject];
combination of two of the following methods (a+b or a+c or b+c):

а) oral, injection or implanted hormonal contraceptives; in case of oral contraceptives the female subjects should administer the same product for at least 3 months prior to the study therapy;

intrauterine device or contraceptive system;

с) barrier methods: condom or occlusive cap (diaphragm or cervical cap / vaginal fornix cap) with spermicidal foam/gel/film/cream/vaginal suppository.

Presence of active FMF attack at Visit 1 (Day 0) lasting for not more than 2 days before Visit 1 defined as simultaneous development of clinical and serological signs of the attack including:
Physician Global Assessment (PGA) score ≥ 2 supposing mild, moderate or severe activity of the disease (i.e. clinical signs), and
CRP level > 10 mg/L (i.e. serological signs).

Exclusion criteria:

Hypersensitivity to the study product (RPH-104) and/or its components/excipients and/or the products of the same chemical class.
Systemic therapy with glucocorticosteroids at high doses (> 0.2 mg/kg/day of prednisolone equivalent) (the dose of glucocorticoids should be stable for at least 4 weeks prior to screening) or intravenous glucocorticosteroids therapy for less than 1 week prior to the screening period, or necessity in such therapies starting from the screening onset. Intramuscular, intra-articular or periarticular glucocorticosteroids administration for less than 4 weeks prior to the screening period.
Administration of live (attenuated) vaccines less than 3 months prior to Day 0 (treatment initiation) and/or necessity to use such vaccine within 3 months after the study product discontinuation. Live attenuated vaccines include viral vaccines against: measles, rubella, parotitis, varicella, rotavirus, influenza (as nasal spray), yellow fever, poliomyelitis (oral polio-vaccine); tuberculosis vaccine (BCG), typhoid (oral typhoid fever vaccine) and camp fever (epidemic typhoid vaccine). Immunocompetent family members should refuse to use oral polio-vaccine throughout the subject's participation in the study.
Conditions or signs which, according to the investigator, evidence impaired (reduced) immune response and/or significantly increase the risk of immunomodulating therapy including (but not limited to):
active bacterial, fungal, viral or protozoal infection at screening onset;
opportunistic infections and/or Kaposi's sarcoma at the screening period onset;
chronic bacterial, fungal or viral infection requiring systemic therapy with parenteral products at the main screening period onset;
HIV, hepatitis B or C;
listeriosis including in the history
Active tuberculosis (TB) in the history or risk factors or signs evidencing active or latent infection with M. Tuberculosis including (not limited to) the following:
living in specific conditions increasing the risk of contact with tuberculosis such as detention facilities, in crowded areas of person of no fixed abode, etc. within the last year before the main therapy period;
working in a medical institution with unprotected contact with subjects under high risk of tuberculosis or subjects with tuberculosis within the last year until the main therapy period;
close contact, i.e. confinement to a place (home or another confined area) for a long period of time (several days or weeks, not minutes or hours) with a subject with active pulmonary tuberculosis within the last year until the main therapy period;
results of examinations indicating active or latent infection with M. Tuberculosis: positive QuantiFERON-TB / T-SPOT.TB test at screening; chest X-ray findings confirming pulmonary tuberculosis during screening.
Any other relevant concomitant diseases (cardiovascular, nervous, endocrine, urinary, gastrointestinal, hepatic disorders, coagulation disorders, thyroid diseases and other autoimmune diseases, etc.) or conditions which, according to the investigator's judgment, may affect the subject's participation or well-being in the study and/or distort assessment of the study results.
History of organ transplantation or necessity in transplantation at the screening onset.
Any malignancies during the screening period or for 5 years before screening except for non-metastatic basal cell and squamous cell skin cancer after total resection or in situ carcinoma of any type after total resection.
Pregnancy or breastfeeding.
History of alcohol or psychoactive substance abuse according to the investigator's evaluation.
Severe renal failure: creatinine clearance (ClCr) calculated using Cockcroft-Gault formula < 30 mL/min.
Administration of anakinra (Kineret®) less than 72 hours prior to Day 0 (at the treatment period initiation).
Administration of any other biological products less than 5 half-life periods before Day 0 (treatment initiation).
Administration of immunosuppressant products (e.g. cyclosporin, methotrexate, dapsone, etc.) less than 4 weeks or 5 half-life periods (whichever is longer) before Day 0 (treatment initiation). In case of leflunomide administration complete elimination course using cholestyramine should be documented.
Any of the deviations in the laboratory tests below:
absolute neutrophil count < 1.5 x 10^{9/L (1500 /mm}3),
White blood cell (WBC) count < 3 x 10^{9/L L (<3000/mm}3),
platelet count < 10 ^{9/L (<100000/mm}3 or <100000×10^6/L),
alanine aminotransferase (ALT) and/or aspartate transaminase (AST) ≥ 2.0 x upper limits of normal (ULN) if at the screening ALT, AST ≥ 2 x ULN but < 3 ULN, the test may be repeated,
bilirubin > 1.5 x ULN
Concomitant participation in other clinical studies at the screening onset or administration of any unauthorized (investigational) products less than 4 weeks or 5 half-life periods (whichever is longer) before Day 0 (treatment initiation).
Previous participation in this clinical study, in case of passing the randomization procedure.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Center of Medical Genetics and Primary Health Care	Yerevan	Armenia	0001
2	Mikaelyan Institute Of Surgery CJSC	Yerevan	Armenia	0052
3	LLC Tbilisi State Medical University and Ingorokva High Medical Technology University Clinic	Tbilisi	Georgia	0144
4	Inova LLC	Tbilisi	Georgia	0179
5	Medical Technologies Ltd	Saint Petersburg	Russian Federation	191025