A Dose-finding Phase I Study of F8IL10 Intra-articular Treatment in Rheumatoid Arthritis
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 42
- 试验地点
- 4
- 主要终点
- Incidence of injection site reactions
研究概览
简要总结
The aim of this study is to evaluate the safety of F8IL10 when administered by intra-articular injection and to determine the maximum tolerated dose (MTD) in order to establish the recommended dose (RD) in patients with Reumatoid Arthritis.
详细描述
This protocol describes an open-label, non-randomized, ascending dose, phase I study conducted in sequential cohorts of patients. The aim of the study is to assess the safety and tolerability of F8IL10 when administered via intra-articular (IA) route 3 times every 4 weeks in patients with RA.
Elegible patients of this trial are male or female, ≥ 18 and ≤ 80 years old, patients with Rheumatoid Arthritis (RA) who, despite treatment with stable doses (for at least 3 months) of DMARDs (conventional, biologic and/or targeted synthetic), present arthritis flare(s) suitable for IA injection in a knee, shoulder, ankle, wrist or elbow.
The study will take place in two stages:
- The dose escalation part of the study is designed with an accelerated phase, followed by a classical 3+3 dose escalation scheme. Patients will be sequentially assigned to the following dose levels:
- Cohort 1: 25 μg F8IL10
- Cohort 2: 50 μg F8IL10
- Cohort 3: 100 μg F8IL10
- Cohort 4: 400 μg F8IL10
- Cohort 5: 700 μg F8IL10
- Cohort 6: 1000 μg F8IL10
- Following successful identification of the RD, the study will proceed with a dose expansion part, during which 12 patients will be treated at RD (including those treated in the dose escalation part).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged ≥18 and ≤80 years.
- •Diagnosis of RA according to ACR/EULAR classification criteria (2010) with a disease duration exceeding 6 months.
- •Presence of arthritis flare(s) suitable for IA injection in a knee, ankle, shoulder, wrist or elbow, despite treatment with stable doses (for at least 3 months) of DMARDs (conventional, biologic, and targeted synthetic) background therapy.
- •No or stable regimens of NSAIDs and/or oral corticosteroid (≤ 10 mg/day; prednisone equivalent) for a period ≥2 weeks prior to screening.
- •All acute toxic effects of any prior therapy must have resolved or returned to classification "mild" (grade 1) according to CTCAE v.5.
- •Sufficient hematologic, liver and renal function defined as follows:
- •Absolute neutrophil count (ANC) ≥1.5 x 109/L, platelets ≥100 x109/L, haemoglobin (Hb) ≥10.0 g/dL.
- •Alkaline Phosphatase (AP), Alanine Aminotransferase (ALT) and or Aspartate Aminotransferase (AST) ≤3 x Upper Limit of Normal Range (ULN), and total bilirubin ≤2.0 mg/dl (34.2 μmol/L).
- •Creatinine ≤1.5 ULN or 24 h creatinine clearance ≥50 mL/min.
- •Documented negative TB test (e.g. Quantiferon or equivalent).
- •Documented negative test for HIV-HBV-HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV, HCV-RNA or HCV antibody test is required. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no ongoing infection are eligible.
- •Sexually active male or female patients of childbearing potential are eligible providing that:
- •Women of childbearing potential (WOCBP) have a negative pregnancy test performed within 4 weeks prior to treatment start.
- •WOCBP agree to use, from the screening to 6 months following the last study drug administration, effective method of birth control as applicable per local law that both results in a Pearl index <1 and considered highly effective as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the "Clinical Trial Facilitation Group" (e.g. combined estrogen and progestogen containing hormonal contraception, progestogen-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, vasectomized partner, total sexual abstinence or bilateral tubal occlusion).
- •Males agree to use two acceptable methods of contraception (e.g. condom with spermicidal gel) from the screening to 6 months following the last study drug administration. Females of childbearing potential that are partners of male study participants must observe the same birth control indications that apply to female participants.
- •Signed and dated Ethics Committee-approved informed consent form indicating that the patient, or patient's legally acceptable representative, has been informed of all pertinent aspects of the study.
- •Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures.
排除标准
- •Presence of additional RA flares or RA-related symptoms that, in the investigator's judgment, are likely to require local treatment during the study (defined as intra-articular or peri-articular injections/procedures intended to treat RA; e.g., joint, tendon-sheath, or bursal corticosteroid injections; hyaluronic acid; biologic/PRP injections; or radio synovectomy)._
- •Presence of active infections or another severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or would interfere with the study objectives or conduct.
- •Pregnancy, lactation or unwillingness to use adequate contraceptive methods.
- •Diagnosis of any other inflammatory arthritis or active autoimmune diseases other than RA.
- •Any therapy for RA apart from the allowed background therapy (i.e., stable doses of DMARDs, corticosteroids, and/or NSAIDs) within 4 weeks prior to the first IMP dosing.
- •Received intra-articular administration of corticosteroids/DMARDs within 4 weeks or 5 half-lives prior to the first IMP dosing, whichever is longer.
- •History or currently active primary or secondary immunodeficiency.
- •Concurrent malignancy or history of malignancy (except in situ melanoma and low-risk non melanoma skin cancer) from which the patient has been disease-free for less than 2 years.
- •History within the last year of acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris.
- •Treatment with warfarin or other coumarin derivatives.
- •Clinically significant cardiac arrhythmias or requiring permanent medication.
- •Abnormalities in baseline ECG analysis that are considered as clinically significant by the investigator; subjects with current or a history of QT/QTc prolongation.
- •Uncontrolled hypertension, despite optimal treatment.
- •Known arterial aneurism at high risk of rupture.
- •Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche Fontaine classification).
- •Severe diabetic retinopathy.
- •Major trauma including surgery within 4 weeks prior to administration of study treatment.
- •Known history of allergy/hypersensitivity or other intolerance to any component of F8IL10 (including excipients) or to other drugs based on human proteins/peptides/antibodies.
- •Treatment with any investigational agent within 4 weeks or 5 half-lives prior to the first dose of study drug, whichever is longer.
- •Immunization with a live/attenuated vaccine within 4 weeks prior to baseline or plan to receive vaccines during the study.
- •Non-RA related chronic pain disorders.
- •Patients requiring stable doses of corticosteroids >10 mg/day (prednisone equivalent). Limited use of corticosteroids to treat or prevent acute hypersensitivity reactions is not considered an exclusion criterion.
- •History of alcohol, drug or chemical substance abuse within the 6 months prior to screening.
- •Any condition that in the opinion of the investigator could hamper compliance with the study protocol.
研究组 & 干预措施
Treatment
The study will take place in two stages:
- In the dose escalation part, participants will be enrolled in cohorts and will be treated with different dose levels of F8IL10 in order to identify a RD. In each cohort, 1 to 6 patients will be treated until the MAD is reached.
- Following successful identification of the RD, the study will proceed with a dose expansion part, during which 12 patients will be treated at RD (including those treated in the dose escalation part).
干预措施: F8IL10 (Drug)
结局指标
主要结局
Incidence of injection site reactions
时间窗: Through study completation (up to 37 weeks)
Incidence of injection site reactions and general reactions associated with intraarticular administration
DLT
时间窗: From Day 1 to Day 28 of the treatment
Occurrence of dose limiting toxicity (DLT)
MAD, MTD and RD
时间窗: From Day 1 to Day 28 of the treatment
Definition of maximum administered dose (MAD), maximum tolerated dose (MTD) and recommended dose (RD)
AEs, SAEs and DILI
时间窗: Through study completation (up to 37 weeks)
Adverse events (AEs), serious adverse events (SAEs) and Drug-Induced Liver Injury (DILI), based on Common Terminology Criteria for Adverse Events v. 5.0 (CTCAE).
Standard laboratory parameters
时间窗: Through study completion (up to 37 weeks)
Standard laboratory (haematology, biochemistry, liver and urine analysis) parameters.
DLT
时间窗: From Day 1 to Day 28 of the treatment
Occurrence of dose limiting toxicity (DLT)
MAD, MTD and RD
时间窗: From Day 1 to Day 28 of the treatment
Definition of maximum administered dose (MAD), maximum tolerated dose (MTD) and recommended dose (RD)
AEs, SAEs and DILI
时间窗: Through study completation (up to 37 weeks)
Adverse events (AEs), serious adverse events (SAEs) and Drug-Induced Liver Injury (DILI), based on Common Terminology Criteria for Adverse Events v. 5.0 (CTCAE).
Incidence of injection site reactions
时间窗: Through study completation (up to 37 weeks)
Incidence of injection site reactions and general reactions associated with intraarticular administration
Standard laboratory parameters
时间窗: Through study completion (up to 37 weeks)
Standard laboratory (haematology, biochemistry, liver and urine analysis) parameters.
次要结局
- CCI: Composite change index(Every 4 weeks, up to week 37)
- HAFA(Every 4 weeks, up to week 17)
- SF-36(Every 4 weeks, up to week 37)
- SDAI(Every 4 weeks, up to week 37)
- Pharmacokinetic profile(Every 2 weeks, up to week 7)
- CCI: Composite change index(Every 4 weeks, up to week 37)
- SF-36(Every 4 weeks, up to week 37)
- Joint inflammation(Every 4 weeks, up to week 37)
- SDAI(Every 4 weeks, up to week 37)
- Pharmacokinetic profile(Every 2 weeks, up to week 7)
- HAFA(Every 4 weeks, up to week 17)