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

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Brief Title

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

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

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.
    

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:

        1. 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.

        2. 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.

        3. 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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of subjects with complete response during 16 week therapy with RPH-104 vs. placebo in FMF subjects with colchicine inefficacy or intolerance.

Secondary Outcome

 Proportion of subjects with Physician Global Assessment (PGA) score < 2 during the study

Condition

Familial Mediterranean Fever

Intervention

RPH-104

Study Arms / Comparison Groups

 RPH-104
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

60

Start Date

April 29, 2021

Completion Date

March 23, 2023

Primary Completion Date

January 2023

Eligibility Criteria

        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;

                  b) 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.
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Mikhail Samsonov, , 

Location Countries

Armenia

Location Countries

Armenia

Administrative Informations


NCT ID

NCT05092776

Organization ID

CL04018065


Responsible Party

Sponsor

Study Sponsor

R-Pharm International, LLC

Collaborators

 Data Management 365 LLC

Study Sponsor

Mikhail Samsonov, Study Director, R-Pharm International, LLC


Verification Date

October 2021