Study of the Efficacy and Safety of Goflikicept and Olokizumab as the Second-line Therapy in Patients With Still's Disease

Official title

International Multicenter, Double-blind, Randomized, Placebo-controlled Clinical Study of the Efficacy and Safety of Goflikicept and Olokizumab as the Second-line Therapy in Patients With Still's Disease

Overview

The primary objective of the study is to evaluate the efficacy and safety of goflikicept (GFC) and olokizumab (OKZ) in patients with Still's disease

Detailed description

This is an international, multicenter, double-blind, randomized, placebo-controlled, Phase III clinical trial to evaluate the efficacy and safety of goflikicept (GFC) administered over 16-36 weeks

Additionally, the study evaluates the pharmacokinetics/pharmacodynamics (PK/PD), immunogenicity, efficacy, and safety of GFC and olokizumab (OKZ) as the second-line therapy

The study includes the following periods:

1. Screening period: up to 4 weeks 2. Treatment Period

Eligible patients should be randomized to one of two treatment arms (in a 1:1 ratio): * Active Treatment Arm taking GFC * Placebo arm

At the Day 7 assessment: * Responders to therapy are defined as patients who achieve or maintain low disease activity or achieve remission compared to baseline according to DAVID criteria, with the exception of arthritis * Non-responders in the placebo arm switch to GFC (Day 0 procedures of GFC therapy). Seven days after the first GFC dose (Day 7 procedures of GFC therapy), the investigator performs a response assessment. Patients who respond to the new therapy continue GFC therapy throughout the treatment period * Non-responders on GFC therapy (either after randomization or after switching from placebo to GFC) switch to Olokizumab (OKZ) (at a visit with procedures identical to Day 0). Seven days after the first dose of the second-line therapy (Day 7 procedures), the investigator performs a response assessment. Patients who respond to the new therapy continue OKZ therapy throughout the treatment period

At the Day 28 assessment, response to therapy is defined as: * absence of fever * absence of typical skin rash * C-reactive protein (CRP) ≤ 10 mg/L * PtGA \< 5 cm * absence of arthritis

Starting from Day 28, patients who have responded have a gradual reduction of the glucocorticosteroid (GCS) dose, with the goal of achieving inactive disease without GCS by the end of the study. In this case, the duration of participation is determined by the baseline GCS dose

The final visit for patients completing the maximum treatment period is the Week 36 visit 3. Safety Follow-up Period (Weeks 8 / 22)

During the safety follow-up period, patients are required to visit the clinical center for assessments at 4 and 8 weeks after the last dose of study treatment (for patients who received at least one dose of OKZ - at 4, 8, and 22 weeks), after which their participation in the study will be considered complete

The maximum possible duration of study participation for each patient is 70 weeks

Interventions

• Drug Placebo
  0.9% Sodium Chloride solution for Injection
• Biological Goflikicept
  solution for subcutaneous injection and intravenous infusion, 40 mg/mL
• Biological Olokizumab
  solution for subcutaneous injection and intravenous infusion, 160 mg/mL

Primary outcome measures

• Proportion of patients who achieved and maintained low disease activity or remission according to DAVID criteria at Day 7 (excluding the arthritis criterion) and achieved DAVID remission criteria at Day 28 [Time frame: Day 7 (low disease activity or remission) and Day 28 (remission)]

Secondary outcome measures (12)

• Proportion of patients who developed a flare of Still's disease within 24 weeks after randomization [Time frame: at screening, Day 28 (week 4), and every 4 weeks up to Day 168 (week 24)]
• Proportion of patients with resolution of fever on Day 3 and Day 7 [Time frame: Day 3 and Day 7]
• Proportion of patients who achieved inactive disease while on low-dose glucocorticosteroids (0.1 mg/kg/day) during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Proportion of patients who achieved inactive disease without glucocorticosteroids during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Proportion of patients with Disease Activity Score-28 (DAS28) <2.6 during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Proportion of patients with absence of typical skin rash during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Proportion of patients with PtGA < 5 during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Proportion of patients with absence of sore throat during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Change in C-reactive protein concentration during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Change in erythrocyte sedimentation rate (ESR) during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Change in white blood cell (WBC) count during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]
• Change in ferritin level during the study [Time frame: at screening, on Day 7 (week 1), Day 14 (week 2), Day 28 (week 4), and every 4 weeks up to Day 252 (week 36)]

Eligibility criteria

Inclusion criteria

• Voluntarily signed and dated Informed Consent Form (ICF) of the patient agreed to take part in this Study
• Confirmed diagnosis of Adult-Onset Still's Disease (AOSD) based on the Yamaguchi M. diagnostic criteria
• Patient with active disease or low disease activity per DAVID criteria
• In case of current corticosteroid (CS) use, doses must be stable for at least 2 weeks prior to Day 0. The maximum allowed dose of CS is 1 mg/kg/day, up to 60 mg/day (prednisolone equivalent)
• In case of current nonsteroidal anti-inflammatory drugs (NSAID) use, dose of NSAIDs must be stable for at least 2 weeks prior to Day 0
• In case of current methotrexate (MTX) use, the dose of MTX must be stable for at least 4 weeks prior to Day 0. The maximum allowed dose is 30 mg/week. In case of prior MTX discontinuation, it must be performed at least 4 weeks before Day 0
• Patient's ability and willingness, in the reasonable opinion of the investigator, to attend the clinical center for all scheduled visits, perform study procedures, and comply with protocol requirements, including consent to receive subcutaneous injections by qualified personnel
• Women of childbearing potential, defined as all women physiologically capable of becoming pregnant (excluding women who are post-menopausal, defined retrospectively as 12 months of natural amenorrhea with appropriate clinical status, e.g., age-appropriate), must agree to use highly effective methods of contraception throughout the study, starting from the signing of the ICF until at least 8 weeks after the last dose of study treatment; and must have a negative pregnancy test (serum human chorionic gonadotropin, hCG)
• Sexually active male participants must agree to use highly effective methods of contraception throughout the study, starting from the signing of the ICF until at least 8 weeks after the last dose of study treatment

Exclusion criteria

• Hypersensitivity to the active and/or inactive ingredients of the investigational product
• Prior use of the following medications:

• Rilonacept - less than 6 weeks prior to Day 0
• Canakinumab - less than 20 weeks prior to Day 0
• Anakinra - less than 1 week prior to Day 0
• TNF-alpha inhibitors: etanercept less than 2 weeks, adalimumab, certolizumab, or golimumab less than 10 weeks prior to Day 0
• IL-6 inhibitors: olokizumab - less than 20 weeks, tocilizumab - less than 16 weeks, or sarilumab less than 8 weeks prior to Day 0
• Janus kinase (JAK) inhibitors - less than 1 week prior to Day 0
• Immunosuppressants (azathioprine less than 3 days, cyclosporine less than 1 week, mycophenolate mofetil less than 1 week, tacrolimus less than 10 days, mercaptopurine less than 2 days, etc., except for methotrexate) - less than 5 half-lives prior to Day 0
• Leflunomide - less than 10 weeks prior to Day 0
• Corticosteroid pulse therapy (e.g., intravenous methylprednisolone 250-1000 mg/day or equivalent dose of dexamethasone for 3 days) - less than 4 weeks (from the completion of pulse therapy) prior to Day 0
• Intravenous immunoglobulin (IVIG) - less than 4 weeks prior to Day 0
• Other biologic drug with immunosuppressive effects - less than 5 half-lives prior to Day 0
• Use of live-attenuated vaccines within less than 3 months prior to Day 0 (start of the treatment period in the study) and/or anticipated need for such vaccination within 3 months after completion of the investigational therapy. Live-attenuated vaccines include vaccines against measles, rubella, mumps, varicella, rotavirus, influenza (intranasal), yellow fever, poliomyelitis (oral polio vaccine), as well as vaccines against tuberculosis (BCG), typhoid (oral typhoid vaccine), and epidemic typhus. Immunocompetent household members of the patient must refrain from receiving oral polio vaccine during the patient's participation in the study
• Presence of conditions or signs that, in the investigator's opinion, indicate impaired immune response and/or significantly increase the risk associated with immunomodulatory therapy, including but not limited to:

• Active bacterial, fungal, viral, or protozoal infection at the start of the screening period
• Opportunistic infections and/or Kaposi's sarcoma at the start of screening
• Chronic bacterial, fungal, or viral infection requiring systemic parenteral therapy at the start of screening
• HIV infection, viral hepatitis B or C, or syphilis (patients with hepatitis B and/or C who have received antiviral therapy and have had undetectable viral load for at least 6 months may be eligible, subject to confirmation by an appropriate specialist)
• History of active tuberculosis (TB); suspected or confirmed active tuberculosis at present; or signs of active tuberculosis, including chest computed tomography (CT) or chest X-ray findings consistent with pulmonary tuberculosis during screening; or presence of risk factors for tuberculosis, including but not limited to:

• Living conditions associated with increased risk of exposure (e.g., correctional facilities, homeless shelters) within 1 year prior to randomization
• Healthcare workers with unprotected exposure to patients at high risk of TB or with TB within 1 year prior to randomization
• Close contact (i.e., prolonged cohabitation for days or weeks, not minutes or hours) with a person with active tuberculosis within 1 year prior to randomization
• History of latent TB without adequate treatment, regardless of screening QuantiFERON-TB/T-SPOT.TB results, or a positive QuantiFERON-TB/T-SPOT.TB result at screening. Such patients may be re-screened and enrolled if all of the following are met:

• Active TB is ruled out by a certified TB specialist
• The patient has completed at least 30 days of prophylactic anti-TB therapy for LTBI prior to screening, using country-recommended regimens
• The patient agrees to complete the full course of LTBI treatment
• Any other significant comorbidities (cardiovascular, neurological, endocrine, renal, gastrointestinal, hepatic, coagulation disorders, other systemic rheumatic diseases, psychiatric disorders, etc.) that, in the investigator's judgment, may adversely affect participation, patient safety, or study results
• History of organ transplantation or need for transplantation at screening
• Malignancy during screening or within 5 years prior, except adequately treated non-metastatic basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of any type after complete resection
• Pregnancy or breastfeeding
• Alcohol or substance abuse, in the investigator's opinion
• Severe renal impairment: creatinine clearance (Cockcroft-Gault) < 30 mL/min
• Laboratory abnormalities:

• Absolute neutrophil count < 1.5 × 10\^9/L
• Leukocytes < 3.5 × 10\^9/L
• Platelets < 100 × 10\^9/L
• Hemoglobin ≤ 80 g/L
• HbA1c ≥ 8%
• ALT and/or AST > 8 × ULN
• AST and/or ALT > 3 × ULN with bilirubin > 1.5 × ULN
• Total bilirubin > 2 × ULN (except confirmed Gilbert's syndrome)
• Participation in another clinical trial at screening or use of any investigational drug within 4 weeks or 5 half-lives (whichever is longer) prior to Visit 1 (start of treatment period)
• Presence or suspicion of macrophage activation syndrome (MAS) at screening. MAS criteria includes persistent fever, splenomegaly, elevated or rising serum ferritin levels, cytopenia, abnormal liver function tests, intravascular activation of coagulation, and elevated or rising serum triglyceride levels
• Diagnosis of MAS within 2 months prior to Day 0
• Prior participation in this clinical study, provided the patient received at least one dose of the investigational product

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Russia · 25 centers

• Republic Clinical and Diagnostic Center of the Ministry of Health of the Udmurt Republic — Izhevsk
• "Vashe Zdorovie" Research Medical Complex, LLC — Kazan'
• Family Clinic No. 4, LLC — Korolyov
• Limited Liability Company "OLLA-MED" — Moscow
• State Budgetary Healthcare Institution "A.S. Loginov Moscow Clinical Scientific Center of — Moscow
• V.A. Nasonova Research Institute of Rheumatology (Federal State Budgetary Scientific Insti — Moscow
• Limited Liability Company "Firm ORIS" — Moscow
• State Budgetary Healthcare Institution of the City of Moscow "N.I. Pirogov City Clinical H — Moscow
• … and 17 more centers

Identifiers

NCT: NCT07625384 · CL04018375

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗