Baricitinib in CPPD - the BAPTIST Study

Official title

Baricitinib in Calcium PyrophosphAte DePosiTion DIseaSe Trial - a Proof of Concept Phase II Clinical Trial

Overview

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.

Detailed description

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.

Therefore, the study could open the way for phase II and III trials, giving hope to all patients with CPPD for a treatment option, as there is no drug with a specific indication for CPPD.

In the early years of JAK inhibitors (JAKi) in clinical practice, concerns arose about cardiovascular and thromboembolic events, particularly with tofacitinib, prompting a comprehensive evaluation of the entire drug class. However, real-world data have been reassuring. A recent editorial reviewing pre- and post-marketing studies for tofacitinib, baricitinib, and upadacitinib in rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis highlights that the actual risk of major cardiovascular events (MACE) in patients with inflammatory diseases remains unclear. Post-marketing studies have shown no significant increase in MACE incidence and, in some cases, a lower incidence in RA patients treated with baricitinib.

The incidence of adverse events (AEs) does not appear to correlate with JAKi dosage but may be linked to high disease activity, as persistent inflammation is a known risk factor for MACE. The analysis suggests that major risk factors for MACE during baricitinib treatment include a history of MACE and advanced age (though no specific threshold is provided). In this study, patients with recent MACE (\<6 months) will be excluded. Those with a more distant history of MACE will undergo a thorough cardiovascular risk assessment and may be enrolled based on the clinician\'s judgment, considering that persistent joint inflammation is a risk factor for MACE and should be treated. Finally, an important aspect to keep in mind are the recent findings that suggest that acute CPPD arthritis is also a risk factor for MACE.

Therefore, taking under consideration all the above mentioned issues, the increase of cardiovascular risk in patients with uncontrolled inflammation and the possible adverse events in patients with specific risk factors, only patients that have a clearly favourable benefit/risk profile will fulfil both the inclusion and exclusion criteria and could be enrolled in the study.

The primary aim of this proof-of-concept study is to evaluate the effect of baricitinib on inflammation of the synovial membrane in CPPD. The outcome for the primary objective is the changes in the synovial tissue CD68 scoring at 12 weeks, an objective outcome measure.

The secondary objectives of the study are:

* To assess changes in Krenn synovitis score and cytokines at the synovial level; * To evaluate the improvement of patient-reported outcomes (PROs) and pain; * To determine changes at ultrasound examination in terms of calcium crystal deposition, synovitis and degenerative changes; * To identify subsets of the disease that could have a better response to the treatment; * To evaluate the effect of baricitinib on serum cytokine levels at a plasmatic level.

Finally, exploratory objectives of the study are:

* To explore the possible baricitinib-induced impact on whole-body metabolism; * To explore differences in biochemical and immunohistological markers between patients with the acute and the chronic form of CPPD.

The result of baricitinib will be tested against the standard of care for CPPD arthropathy as defined by the 2011 recommendations for managing CPPD.

This is a single-centre, National, prospective, monocentric, randomized, controlled, phase II pharmacological trial. Consecutive patients reaching the outpatient clinic of the IRCCS Ospedale Galeazzi - Sant'Ambrogio in an 18-month period satisfying the 2023 American College of Rheumatology (ACR)/EULAR classification criteri for CPPD disease, belonging in any of the clinical subsets of CPPD described below, will be enrolled and randomized in two groups. One group will receive baricitinib at the dose of 4mg/daily, while the second group will receive the standard of care, for a total number of 32 patients, 16 for each group. Randomization and drug administration will be carried out by one operator, while clinical, laboratory and ultrasound assessments and histological examinations will be carried out by different operators blind to patients' treatment arms.

The study include tree different phases:

1. Screening/Enrolment: phase for patients selection and consent collection. Screening and Enrolment may coincide 2. Treatment: phase of drugs administration (Baricitinib or comparator); the treatment period consists of 24 weeks of drug administration, so it coincides with the study visits. 3. Study Visits: 24 weeks of therapy control punctuated by visits at week 4, 12 and 24.

The total expected duration for the clinical study is 28 months, of which:

* From month 0 to month 18 for enrolment * From month 1 to month 24 for Study Visits The unblinded clinician will provide all drugs at each visit in adequate quantity to reach the next study visit.

Number of tablets of each medication delivered to the patients and the effective number of consumed tablets will be registered at each visit.

All drugs listed in the protocol will be stored, labelled and dispensed to the doctor by the Institute Pharmacy located in the Hospital itself. Any residual medicine will be destroyed at the end of the study by the Pharmacy according to institute procedures. The Pharmacy, certified with adequate quality certification, will follow the internal procedures approved by the Institution for the management of experimental drugs.

The unblinded clinicians and the Pharmacy (see below) will keep a cumulative inventory and dispensing records and will maintain all supplies under adequate security conditions. Adequate record of receipt and use or loss of drug will be retained. This inventory record must be available for inspection by at any time.

For each patient enrolled, complete demographic (age, sex, type of occupational activity, smoking habit) and anthropometric data (height and weight) will be recorded. Furthermore, complete anamnestic data will be collected. Notably, they will include information about previous or current therapies (both continue and on-demand, including steroids, NSAIDs, DMARDs, and biological DMARDs), the date of the symptom onset, the disease duration and the main comorbidities.

All the patients will undergo a physical examination to assess the presence of tender and swollen joints according to the 44 swollen joint counts and Ritchie articular index.

A co-investigator, blind to treatment allocation, ultrasound and laboratory findings, will carry out the clinical examination. The blinding of this investigator will be ensured with patient training and information compartmentalization. Patients will be worn to avoid telling the doctor the drug that he/she is taking. Furthermore, all the personnel involved in the study will be instructed not to reveal to the blinded investigator patients' therapies. This investigator will not have access to the clinical and/or experimental material in which the therapeutic indication is reported and will perform only the clinical examination. Finally, the primary outcome of the study is an objective, quantitative measure and the

Interventions

• Drug Baricitinib 4 MG Oral Tablet
  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. 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 mor
• Drug Methylprednisolone (Corticosteroid)
  The initial dosage of methylprednisolone may vary depending on the entity of inflammation and the patient's comorbidities. Usually in CPPD a short-term administration of methylprednisolone starts with 16 mg per day after breakfast decreasing the initial dosage in small decrements at appropriate time intervals until discontinuation, in about 2 weeks. Methylprednisolone will be given in combination with gastroprotective agents such as proton pump inhibitors.
• Drug Colchicine 1 MG Oral Tablet
  1 or ½ tablet (depending on individual tolerance) daily after breakfast
• Drug Hydroxychloroquine 200 mg
  1 tablet daily after lunch
• Combination product Methotrexate + Folic Acid
  MTX 2.5 mg tablets, from 2 to 4 tablets (5-10mg), depending on disease severity, to be administered once weekly after dinner, always in the same day of the week. One tablet of folic acid (folina 5 mg) will be administered the day after MTX administration, after breakfast, to reduce and prevent the common side effects of MTX.

Primary outcome measures

• The evaluation the effect of baricitinib on inflammation of the synovial membrane in CPPD [Time frame: The outcome for the primary objective is the changes in the synovial tissue CD68 scoring at 12 weeks, an objective outcome measure.]

Secondary outcome measures (12)

• To assess the changes in Krenn synovitis score at the synovial level [Time frame: 12 weeks]
• To assess the changes in cytochin levels at the synovial membrane [Time frame: 12 weeks]
• To determine changes at ultrasound examination in terms of calcium crystal deposition [Time frame: 4, 12 and 24 weeks]
• To determine changes at ultrasound examination in terms of synovitis [Time frame: 4, 12 and 24 weeks]
• To determine changes at ultrasound examination in terms of bone changes [Time frame: 4, 12 and 24 weeks]
• To evaluate the effect of baricitinib on serum cytokine levels at a plasmatic level. [Time frame: 12 and 24 weeks]
• Change from baseline in joint pain [Time frame: 4, 12 and 24 weeks]
• Change from baseline in DAS score [Time frame: 4, 12 and 24 weeks]
• Change from baseline in HAQ score [Time frame: 4, 12 and 24 weeks]
• Change from baseline in WOMAC index [Time frame: 4, 12 and 24 weeks]
• Change from baseline in CD3, CD8, CD20 at synovial level [Time frame: 12 weeks]
• To identify subsets of the disease that could have a better response to the treatment [Time frame: baseline - 24 weeks]

Eligibility criteria

Inclusion criteria

• 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.

Exclusion criteria

• 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

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

Italy · 1 center

• IRCCS Galeazzi - Sant Ambrogio Hospital — Milan

Publications

• Krenn V, Morawietz L, Burmester GR, Kinne RW, Mueller-Ladner U, Muller B, Haupl T. Synovitis score: discrimination between chronic low-grade and high-grade synovitis. Histopathology. 2006 Oct;49(4):358-64. doi: 10.1111/j.1365-2559.2006.02508.x. PMID 16978198
• Krenn V, Morawietz L, Haupl T, Neidel J, Petersen I, Konig A. Grading of chronic synovitis--a histopathological grading system for molecular and diagnostic pathology. Pathol Res Pract. 2002;198(5):317-25. doi: 10.1078/0344-0338-5710261. PMID 12092767
• Kelly S, Humby F, Filer A, Ng N, Di Cicco M, Hands RE, Rocher V, Bombardieri M, D'Agostino MA, McInnes IB, Buckley CD, Taylor PC, Pitzalis C. Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients. Ann Rheum Dis. 2015 Mar;74(3):611-7. doi: 10.1136/annrheumdis-2013-20460 PMID 24336336
• Sirotti S, Terslev L, Filippucci E, Iagnocco A, Moller I, Naredo E, Vreju FA, Adinolfi A, Becce F, Hammer HB, Cazenave T, Cipolletta E, Christiansen SN, Delle Sedie A, Diaz M, Figus F, Mandl P, MacCarter D, Mortada MA, Mouterde G, Porta F, Reginato AM, Schmidt WA, Serban T, Wakefield RJ, Zufferey P, Sarzi-Puttini P, Zanetti A, Damiani A, Pineda C, Keen HI, D'Agostino MA, Filippou G; OMERACT Ultras PMID 38251579
• Terslev L, Naredo E, Aegerter P, Wakefield RJ, Backhaus M, Balint P, Bruyn GAW, Iagnocco A, Jousse-Joulin S, Schmidt WA, Szkudlarek M, Conaghan PG, Filippucci E, D'Agostino MA. Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR-OMERACT ultrasound taskforce-Part 2: reliability and application to multiple joints of a standardised consensus-based scoring system. RMD Open. 2017 Jul 11;3(1): PMID 28948984
• Uson J, Rodriguez-Garcia SC, Castellanos-Moreira R, O'Neill TW, Doherty M, Boesen M, Pandit H, Moller Parera I, Vardanyan V, Terslev L, Kampen WU, D'Agostino MA, Berenbaum F, Nikiphorou E, Pitsillidou IA, de la Torre-Aboki J, Carmona L, Naredo E. EULAR recommendations for intra-articular therapies. Ann Rheum Dis. 2021 Oct;80(10):1299-1305. doi: 10.1136/annrheumdis-2021-220266. Epub 2021 May 25. PMID 34035002
• Genovese MC, Smolen JS, Takeuchi T, Burmester G, Brinker D, Rooney TP, Zhong J, Daojun M, Saifan C, Cardoso A, Issa M, Wu WS, Winthrop KL. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020 Jun;2(6):e347-e357. doi: 10.1016/S2665-9913(20)30032-1. PMID 38273598
• Caporali R, Taylor PC, Aletaha D, Sanmarti R, Takeuchi T, Mo D, Haladyj E, Bello N, Zaremba-Pechmann L, Fang Y, Dougados M. Efficacy of baricitinib in patients with moderate-to-severe rheumatoid arthritis up to 6.5 years of treatment: results of a long-term study. Rheumatology (Oxford). 2024 Oct 1;63(10):2799-2809. doi: 10.1093/rheumatology/keae012. PMID 38258434

Identifiers

NCT: NCT06768294 · Baptist (L4194)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗