A Single Dose Clinical Trial to Study the Safety of ART-I02 in Patients With Arthritis
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Treatment emergent (serious) adverse events
研究概览
简要总结
This study will evaluate the safety and tolerability of a single intra-articular administration of ART-I02 (AAV5.NF-kB.IFN-β), a recombinant adeno-associated virus (AAV) type 2/5 vector in subjects with Rheumatoid Arthritis (RA) or Osteoarthritis (OA) and active arthritis of the carpometacarpal (CMC), metacarpophalangeal (MCP), proximal interphalangeal (PIP), or distal interphalangeal (DIP) joints.
详细描述
Rheumatoid arthritis (RA) is a systemic, chronic, inflammatory disorder leading to accelerated joint inflammation causing pain, swelling and limited motion of joints, ultimately leading to the development of joint destruction and deformity in the majority of patients. Virtually all peripheral joints can be affected by RA, although the most commonly affected joints are those of wrists, hands, knees, and feet.
During the last decade, treatment with biologicals (e.g. TNF-inhibitors), together with improved timing and dosing of conventional therapy, has significantly improved the outcome in a significant proportion of RA patients. The advent of biologicals and implementation of more intensive treatment protocols has significantly improved the outcome in a significant proportion of RA patients and prevented disabilities. However, drug-free remissions are still rare and hence most RA patients require continued immunosuppressive treatment which predisposes them to potentially serious infections.
Also up to 50% of RA patients continue to suffer from symptomatic disease. Intra-articular glucocorticoids are often used in these patients, e.g. when single joints are inflamed. The duration of their effect is however variable. It regularly occurs in clinical practice that reasonable clinical remission in rheumatoid arthritis patients is achieved with current treatment options, but that one or more joints still display persistent signs of inflammation while the inflammation of other joints has been greatly reduced. This means that for the joint(s) still affected by active inflammation other therapies are required.
There is thus a large unmet need for additional RA therapies with good tolerability and efficacy profiles that can be used in patients who are not eligible for standard treatment, and in those who despite standard treatment suffer from inflamed joints. Local gene therapy with IFN-β could be a potential treatment to fulfil this unmet need; the selection of IFN-β as the therapeutic protein is based on the notion that IFN-β has anti-inflammatory, bone and cartilage protective effects, which have been extensively demonstrated in non-clinical studies.
Osteoarthritis (OA) is a multifactorial joint disease that involves degeneration of articular cartilage, causing pain, limited range of motion of joints and thereby disability. Although aetiology is largely unknown, important factors such as genetic pre-disposition, mechanical and biochemical stress are known to play a role in this multi factorial disease. Ligaments, menisci, and muscles can also be affected, and osteophytes may develop, causing additional pain.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients ≥18 years of age.
- •Patient have to be diagnosed with RA according to the 2010 American College of Rheumatology/ European league against rheumatism (ACR/EULAR) criteria for the classification of RA, outlined in appendix B or OA as confirmed by their treating physician/specialist.
- •Patient is scheduled for surgical intervention of the target joint.
- •Inflammation of the CMC, MCP, PIP or DIP joint as confirmed by MRI.
- •Written informed consent, able and willing to comply with the requirements of the study protocol.
- •Judged to be in general good health with, in the opinion of the investigator, no other clinically significant and relevant abnormalities of medical history, and no abnormalities at the physical examination, vital signs, electrocardiography (ECG) and laboratory safety tests, performed at the screening visit and/or prior to administration of ART-I
- •Females are not pregnant nor lactating. All patients use effective contraception in combination with barrier contraception for the first three months after administration or until three consecutive semen samples are negative.
排除标准
- •Arthrodesis or joint replacement of the target CMC, MCP, PIP or DIP joint prior to inclusion.
- •Known hypersensitivity to natural or recombinant hIFN-β, or to any excipients.
- •Contra-indication for intra-articular treatment.
- •Presence of neutralising antibody (Nab) titers against adeno-associated virus type 5 (AAV5) and/or hIFN-β.
- •Active infectious disease of any nature, including clinical active viral infections.
- •Previous treatment with an AAV-5 vector.
- •Poor functional status, defined as being bed-bound.
- •Participation in an investigational drug or device study within 90 days prior to screening or more than 4 times per year.
- •Positive for human immunodeficiency virus (HIV) infection, hepatitis C antibodies or hepatitis B surface antigen.
- •Positive for anti-double-stranded DNA antibodies (dsDNA).
- •History of liver function abnormality requiring treatment, drug induced liver injury, chronic liver disease, excessive alcohol consumption or chronic alcohol induced disease.
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 x upper limit of normal (ULN), or bilirubin > 2 x ULN. If a patient has AST or ALT > 2 x ULN but < 2.5 x ULN, re-assessment is allowed at the investigator's discretion.
- •Severely impaired renal function (estimated glomerular filtration rate ≤ 30 mL/min according to the Cockcroft-Gault formula).
- •Patient donated or lost approximately 500 ml blood within 4 months prior to the screening visit
- •Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude
- •Serious medical disease, such as severe liver or kidney disease, uncompensated congestive heart failure, myocardial infarction within six months, unstable angina, uncontrolled hypertension, severe pulmonary disease or active asthma, demyelinating neurological disease, depression or a history of depression, history of seizures or epilepsy, uncontrolled epilepsy, or history of cancer (other than cutaneous basal and squamous cell carcinoma or cervical intraepithelial neoplasia) with less than five years documentation of a disease-free state, recurrent opportunistic infections or other concurrent medical condition that, in the opinion of the investigator, would make the patient unsuitable for the study.
- •Investigator has concerns regarding the safe participation of the patient in the trial or for any other reasons: the investigator considers the patient inappropriate for participation in the trial.
研究组 & 干预措施
Cohort II
ART-I02 1.2x10e12 vg/ CMC joint, 1.2x10e13 vg/ MCP joint, 0.6x10e13 vg/ PIP joint or 0.3x10e13 vg/ DIP joint single intra-articular injection
干预措施: ART-I02 (Genetic)
Cohort I
ART-I02 1.2x10e12 vg/ CMC joint, 1.2x10e12 vg/ MCP joint, 0.6x10e12 vg/ PIP joint or 0.3x10e12 vg/ DIP joint single intra-articular injection
干预措施: ART-I02 (Genetic)
Cohort III
ART-I02 1.2x10e12 vg/ CMC joint, 1.2x10e13 vg/ MCP joint, 0.6x10e13 vg/ PIP joint or 0.3x10e13 vg/ DIP joint ART-I02 or maximum Tolerated Dose (MTD) as assessed in cohorts I and II: single intra-articular injection
干预措施: ART-I02 (Genetic)
结局指标
主要结局
Treatment emergent (serious) adverse events
时间窗: Five years
Treatment emergent (serious) adverse events
次要结局
- Change from baseline for clinical signs and symptoms of the target joint evaluated by the Composite Change Index (CCI) at week 1, week 2, week 4, week 8, week 12, week 16, week 20 and week 24 post administration of ART-I02.(Baseline, week 1, week 2 , week 4, week 8, week 12, week 16, week 20 and week 24 post administration of ART-I02)
- Induction of cellular immune responses against hIFN-β by measuring T cell responses against hIFN-β at baseline week 4, 8, 12, 16 and week 24 post administration(Baseline, week 4, 8, 12, 16 and week 24 post administration)
- Induction of humoral immune responses against AAV5 by measuring antibodies against AAV5 and neutralizing antibodies against AAV5 at baseline, week 4 and week 24 post administration(Baseline, week 4 and week 24 post administration)
- Induction of humoral immune responses against hIFN-β by measuring antibodies against IFN-β and neutralizing antibodies against hIFN-β at baseline, week 4 and week 24 post administration(Baseline, week 4 and week 24 post administration)
- Improvement of the target joint will be assessed by extension and flexion evaluation(Baseline, week 1, week 2, week 4, week 8, week 12, week 16, week 20 and week 24)
- Change from baseline on synovitis and osteitis in the injected joint (target joint) evaluated by Magnetic Resonance Imaging (MRI) 12 and 24 weeks after administration of ART-I02 using the OMERACT RA MRI scoring system (RAMRIS).(12 and 24 weeks after administration of ART-I02)
- Vector DNA in whole peripheral blood, semen, urine, feces, and saliva(Up to 24 weeks but maximally until such time that three consecutive samples have been tested negative)
- Induction of cellular immune responses against AAV5 by measuring T cell responses against AAV5 at baseline week 4, 8, 12, 16 and week 24 post administration(Baseline, week 4, 8, 12, 16 and week 24 post administration)