Baricitinib in Calcium PyrophosphAte DePosiTion DIseaSe Trial - a Proof of Concept Phase II Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- The evaluation the effect of baricitinib on inflammation of the synovial membrane in CPPD
研究概览
简要总结
The aim of this clinical trial is to determine if baricitinib is effective in treating calcium pyrophosphate deposition disease (CPPD) in adults. The primary objective is to assess its impact on joint inflammation. The key questions the study seeks to answer are:
- Can baricitinib reduce inflammation in affected joints?
- Will baricitinib lead to changes in ultrasound findings, such as calcium crystal deposition and synovitis?
Researchers will compare baricitinib to other treatments, including methylprednisolone, colchicine, hydroxychloroquine, and methotrexate with folic acid, for managing CPPD.
详细描述
Calcium Pyrophosphate Deposition disease (CPPD) is a frequent arthropathy in the elderly (over 55 years old), varying from 7% to over 45% depending on the diagnostic method used (X-rays, ultrasonography, synovial fluid analysis, or microscopic analysis of tissues) and the age of the sample group. No data are available on the incidence of the disease. Osteoarthritis (OA) and CPPD are usually associated (aging is a common risk factor for both diseases), but their relationship is not clear even if CPPD is believed to be a primary factor that causes joint damage and worsens the clinical outcome of OA. Recent evidence highlights substantial differences between the two diseases with OA and concomitant CPPD presenting a higher degree of inflammation in both the monoarticular and polyarticular phenotype, resembling more a seronegative arthritis than a prevalent degenerative disease alone. Increasing interest in CPPD is underlined by the recent proposal for a creation of a specific Outcome Measures in Rheumatology (OMERACT) group aimed at establishing the core domains of the disease and the proper instruments for disease diagnosis and assessment over time. Currently, no specific treatment for this disease has been identified. The first line of treatment is designed to reduce pain and inflammation using symptomatic drugs (steroids, non-steroidal anti-inflammatory drugs [NSAIDs], colchicine) that demonstrate some efficacy but are unsuitable for long-term use. Other drugs have been tested in spontaneous observational studies (methotrexate [MTX], interleukin-1 [IL-1] inhibitors), though data on their efficacy is controversial. Similarly, anti-tumor necrosis factor (TNF)α drugs also seem to have limited effect on the inflammation in CPPD disease.
The Janus kinase (JAK) family of non-receptor tyrosine kinases transduce signals from multiple cytokines, including IL-6, and growth factors. Baricitinib is a JAK1/JAK2 inhibitor approved for use in Rheumatoid Arthritis. It is under investigation for use in several inflammatory diseases, including Psoriasis and Psoriatic Arthritis, Atopic Dermatitis, Inflammatory Bowel Disease and Systemic Lupus Erythematosus, with encouraging results[4]. As IL-6 plays a central role in CPPD inflammatory process, a broad spectrum of interleukins and other proinflammatory proteins (including interferons) could be involved. A drug that acts by blocking more than one proinflammatory cytokine could be a promising treatment for a multifaceted disease such as CPPD.
At the moment there are no drugs with precise indication for use in CPPD. Published recommendations of the task force of the European League Against Rheumatisms (EULAR), based on the mechanism of action of the drugs used in chronic arthritis, on the scarn literature and on expert's opinion, suggest the use of non-steroidal anti-inflammatory drugs (NSAIDs) and local or systemic steroids for acute attacks combined if necessary with colchicine and the use of hydroxychloroquine or methotrexate for the use in chronic arthritis. Colchicine may also be used for prophylaxis in case of frequent acute attacks of arthritis. A recent European retrospective study on the treatment of CPPD demonstrated that colchicine and methotrexate were the most frequently used first line drugs for chronic CPPD and demonstrated to be efficient (significant improvement) in 41.9% of patients for colchicine and 58.3% for MTX. The 24 months retention rate was 29.1% for colchicine and 44.4% for MTX. Hydroxychloroquine also demonstrated a good efficacy (improvement in 87.5% of patients) but only a small number of patients were in treatment with such drug .
In summary, many features of CPPD are still unclear and need to be investigated. Basic and clinical research is necessary to understand the disease's pathogenetic mechanisms and possibly amplify the efficacy of available treatments. The failure or partial efficacy of drugs that block only one proinflammatory protein indicates that the pathogenesis of the disease involves more than one pathway. We are therefore interested in testing Baricitinib as a potential treatment in CPPD by synovial, clinical, ultrasound and biochemical Study in a pilot study.
All participants will benefit a tight study visit of the disease and their symptoms during the study with accurate monitoring and will be granted the most up-to-date treatment modalities for this disease. The interventional drug, already in commerce and used for patients with Rheumatoid arthritis and other inflammatory conditions (Juvenile inflammatory arthritis, atopic dermatitis) ), has been highly effective in reducing inflammation and joint pain. Further, baricitinib blocks one of the most expressed proinflammatory cytokines in CPPD, IL-6, raising the possibility of improved outcomes in this disease.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed Informed Consent;
- •Male and female patients aged ≥55 years;
- •Patients that according to the investigator's judgement will benefit from the proposed treatments (favourable benefit/risk profile)
- •Menopause for women;(no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a high follicle stimulating single measurement is insufficient.);
- •Male patients must avoid having a child during the trial and must use one of the highly effective methods of contraception or sexual abstinence or have a menopause partner (no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a high follicle stimulating single measurement is insufficient). Contraception methods include:
- •Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
- •Sterilization of the female partner (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks before the partner enrollment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment
- •Male sterilization (vasectomy) at least 6 months prior to screening
- •Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).
- •The female partner use oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
- •Patients fulfilling the 2023 ACR/EULAR classification criteria for CPPD disease;
- •Patients with feasibility of synovial biopsy at the knee or wrist joint;
- •Patients with CPPD clinical presentation that may be:
- •Subset 1: patients with prevalent polyarticular involvement of the small joints and tendons of hands and wrists (rheumatoid-like subset). Patients that present with prevalent inflammatory involvement of the hands and wrists (joints and/or tendons), with or without acute attacks of arthritis of the large joints, will be included in this group. Inclusion criteria will be joint effusion and/or synovitis of the II and/or III metacarpal phalangeal (MCP) joint of at least one hand, tenosynovitis of at least 1 tendon of one hand or wrist, hyperostosis of the II and/or III MCP head;
- •Subset 2: patients with prevalent involvement of the large joints (oligoarthritis). Patients with recurrent/persistent effusion in one or more large joints (independently of the presence and grade of OA), not responsive to a single injection of steroid and white cell count in joint synovial fluid that is more than 2000 cells/mm3 and/or patients with acute monoarticular arthritis, with more than 3 attacks in one joint in the last 12 months, will be included in this group.
排除标准
- •Patients positive at anticitrullinated positive antibodies (ACPA), any titre;
- •Patients affected by seronegative arthritis or other conditions that may be responsible of arthritis (i.e. gout, rheumatic polymyalgia, etc);
- •Patients that refuse synovial biopsy or present contraindications, according to investigator's judgement, including (but not limited to) increased risk for bleeding (platelet count <100000 or use of anticoagulants), allergy to local anesthetics, suspicion of septic arthritis;
- •Patients with history of malignancy or lymphoproliferative disease; or have signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or have active primary or recurrent malignant disease; or have been in remission from clinically significant malignancy for < 5 years;
- •Patients with cervical carcinoma in situ, basal cell carcinoma or squamous cell carcinomas who have had active disease within 3 years of screening for this study;
- •Patients with active, untreated, acute or chronic infection (such as untreated tuberculosis), or immunocompromised to an extent that such that participation in the study would pose an unacceptable risk to the subject. Patients with treated infections such as latent tuberculosis after completion of the appropriate therapy are not excluded;
- •Patients with clinically serious infection or that have received intravenous antibiotics for an infection, within 4 weeks of randomization;
- •Patients with active viral infection that, based on the investigator's clinical assessment, makes the patient an unsuitable candidate for the study;
- •Patients with serology suggestive for active or chronic hepatitis B or hepatitis C infection; anti-HCV, anti-HBs, anti-HBc antibodies and HBcAg, HBsAg will be tested. Patients that will result positive for anti-HCV and/or HBcAg and/or HBsAg and/or anti-HBc antibodies will be excluded from the study. Patients who are positive for both anti-HBc and antiHBs, but negative for HBcAg and HBsAb could be enrolled.
- •Patients with symptomatic herpes zoster infection within 12 weeks of screening or recurrent or disseminated (even a single episode) herpes zoster;
- •Patients with a history of disseminated opportunistic infections (e.g., listeriosis and histoplasmosis);
- •Patients with a history of venous thromboembolism (VTE), or are considered at high risk for VTE as deemed by the investigator
- •Patients who are currently on immunosuppressive therapies or have not discontinued them for at least 4 weeks;
- •Patients with clinically significant (per investigator's judgement) drug or alcohol abuse within the last 6 months preceding the baseline visit;
- •Patients with any major surgery within 8 weeks prior to baseline or requiring major surgery during the study, which in the opinion of the investigator would pose an unacceptable risk to the patient;
- •Patients with recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting and uncontrolled hypertension (confirmed systolic blood pressure >160 mmHg or diastolic blood pressure >100 mm Hg); patients with less recent major cardiovascular events (> 6 months) will be thoroughly assessed for cardiovascular risk taking under consideration all possible risk factors and the disease phenotype and activity and will be included only in case of favourable benefit/risk ratio according to the principal investigators judgement.
- •Patients with presence of significant uncontrolled respiratory, hepatic, renal, endocrine, hematologic, neurologic, or neuropsychiatric disorders, or abnormal laboratory screening values that, in the opinion of the investigator, pose an unacceptable risk to the patient if participating in the study or of interfering with the interpretation of the data;
- •Patients with clinical laboratory test results at screening that are outside the normal reference range of the population and are considered clinically significant, or have any of the following specific abnormalities: neutrophil count <1500 cells/µL, lymphocyte count <500 cells/µL, platelet count <100,000 cells/µL, aspartate transaminase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of normal, haemoglobin <10 g/dL for male and female subjects, eGFR < 30 mL/min;
- •Patients with any other condition that precludes him/her from following and completing the protocol, in the opinion of the investigator;
- •Patients currently enrolled in or discontinued from a clinical trial involving an investigational product or non-approved use of a drug or device within the last 4 weeks or a period of at least 5 half-lives of the last administration of the drug, whichever is longer, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
- •Hypersensitivity to the active substance or to any of the excipients
研究组 & 干预措施
One group will receive baricitinib at the dose of 4mg/daily
干预措施: Baricitinib 4 MG Oral Tablet (Drug)
standard of care (to be decided according to the guidelines)
Methylprednisolone tablets, Colchicine 1 mg tablets, Hydroxychloroquine 200 mg tablets, MTX + folic acid (to be decided according to the guidelines)
干预措施: Methylprednisolone (Corticosteroid) (Drug)
standard of care (to be decided according to the guidelines)
Methylprednisolone tablets, Colchicine 1 mg tablets, Hydroxychloroquine 200 mg tablets, MTX + folic acid (to be decided according to the guidelines)
干预措施: Colchicine 1 MG Oral Tablet (Drug)
standard of care (to be decided according to the guidelines)
Methylprednisolone tablets, Colchicine 1 mg tablets, Hydroxychloroquine 200 mg tablets, MTX + folic acid (to be decided according to the guidelines)
干预措施: Hydroxychloroquine 200 mg (Drug)
standard of care (to be decided according to the guidelines)
Methylprednisolone tablets, Colchicine 1 mg tablets, Hydroxychloroquine 200 mg tablets, MTX + folic acid (to be decided according to the guidelines)
干预措施: Methotrexate + Folic Acid (Combination Product)
结局指标
主要结局
The evaluation the effect of baricitinib on inflammation of the synovial membrane in CPPD
时间窗: The outcome for the primary objective is the changes in the synovial tissue CD68 scoring at 12 weeks, an objective outcome measure.
CD68 score will be used as outcome measure for the primary objective. CD68 score will be calculated from an analysis of 6 images from each biopsy section and expressed as the mean area of tissue occupied by positively stained cells.
次要结局
- To assess the changes in Krenn synovitis score at the synovial level(12 weeks)
- To assess the changes in cytochin levels at the synovial membrane(12 weeks)
- To determine changes at ultrasound examination in terms of calcium crystal deposition(4, 12 and 24 weeks)
- To determine changes at ultrasound examination in terms of synovitis(4, 12 and 24 weeks)
- To determine changes at ultrasound examination in terms of bone changes(4, 12 and 24 weeks)
- To evaluate the effect of baricitinib on serum cytokine levels at a plasmatic level.(12 and 24 weeks)
- Change from baseline in joint pain(4, 12 and 24 weeks)
- Change from baseline in DAS score(4, 12 and 24 weeks)
- Change from baseline in HAQ score(4, 12 and 24 weeks)
- Change from baseline in WOMAC index(4, 12 and 24 weeks)
- Change from baseline in CD3, CD8, CD20 at synovial level(12 weeks)
- To identify subsets of the disease that could have a better response to the treatment(baseline - 24 weeks)
- To determine changes at ultrasound examination in terms of inflammation and degenerative changes(4, 12 and 24 weeks)