Evaluation of Baricitinib on Synovial Inflammation in Calcium Pyrophosphate Deposition Disease: A Phase II Proof-of-Concept Study
- Trial ID
- 2024-511864-95-00
- Protocol
- BAPTIST (L4194)
- Sponsor
- Ospedale Galeazzi S.p.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **Baricitinib** on the inflammation of the synovial membrane in patients with calcium pyrophosphate deposition disease (CPPD). This is clinically relevant as it aims to measure changes in the synovial tissue CD68 scoring at 12 weeks, providing an objective outcome measure for assessing the therapeutic impact of Baricitinib on synovial inflammation.
Secondary objectives include:
- Assessing changes in the Krenn synovitis score and cytokines at the synovial level.
- Evaluating the improvement of patient-reported outcomes (PROs) and pain.
- Determining changes at ultrasound examination in terms of calcium crystal deposition, synovitis, and degenerative changes.
- Identifying subsets of the disease that could have a better response to the treatment.
- Evaluating the effect of Baricitinib on serum cytokine levels at a plasmatic level.
- Exploring the possible Baricitinib-induced impact on whole-body metabolism.
- Exploring differences in biochemical and immunohistological markers between patients with the acute and the chronic form of CPPD.
Participants
The clinical trial focuses on evaluating the effect of Baricitinib on inflammation of the synovial membrane in patients with **calcium pyrophosphate deposition disease** (CPPD). The study population includes both male and female participants aged 55 years and older. Participants are required to be in general good health, with specific inclusion criteria such as fulfilling the 2023 ACR/EULAR classification criteria for CPPD disease and having the feasibility of synovial biopsy at the knee or wrist joint. The trial does not involve a vulnerable population. Lifestyle considerations include the requirement for male participants to avoid fathering a child during the trial, using highly effective contraception methods or maintaining sexual abstinence. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **Baricitinib** on inflammation of the synovial membrane in patients with calcium pyrophosphate deposition disease (CPPD). This is a randomized, double-blind, controlled trial with a primary objective to assess changes in synovial tissue CD68 scoring at 12 weeks. The trial is expected to last until October 2026, with recruitment starting in November 2024. Participants will be involved for a maximum of 24 weeks, with the possibility of early termination if they do not adhere to the study protocol or if adverse events occur that compromise their safety.
Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, gender, and specific disease characteristics. Follow-up visits will occur at 4, 12, and 24 weeks to monitor changes in synovial inflammation, as well as secondary endpoints like Krenn synovitis score, DAS, HAQ score, WOMAC, and serum cytokine levels. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary post-trial care is arranged.
Participants will be randomly assigned to receive either the investigational product or a comparator, with all medications administered orally. The trial will include several medicinal products, such as **Methotrexate Sodium**, **Colchicine**, **Calcium Folinate**, **Hydroxychloroquine Sulfate**, and **Lidocaine Hydrochloride Monohydrate**, each with specific roles and dosage limits. The trial's design ensures that neither the participants nor the investigators know which treatment is being administered, maintaining the double-blind nature of the study.
Inclusion criteria require participants to be 55 years or older, with a confirmed diagnosis of CPPD and the feasibility of synovial biopsy. Exclusion criteria are not explicitly detailed but would typically include conditions that could interfere with the study's objectives or participant safety. The trial's methodology and design are structured to provide robust data on the efficacy and safety of Baricitinib in treating CPPD, contributing valuable insights into potential therapeutic options for this condition.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **Baricitinib**, marketed as Olumiant, which is provided in the form of 4 mg film-coated tablets. The maximum daily dose is 4 mg, with a total maximum dose of 672 mg over a 24-week period. Baricitinib is administered orally and functions as an immunosuppressant. The medication is used to evaluate its effect on inflammation of the synovial membrane in patients with calcium pyrophosphate dihydrate deposition disease (CPPD).
**Methotrexate Sodium** is included as a comparator treatment. It is administered orally in a pharmaceutical form identified as PHF00231MIG. The maximum daily dose is 10 mg, with a total maximum dose of 240 mg over the 24-week treatment period. Methotrexate Sodium acts as an antineoplastic antimetabolite.
Another comparator treatment is **Colchicine**, combined with Tiemonium Methylsulphate, provided in the pharmaceutical form PHF00082MIG. The maximum daily dose for Colchicine is 1 mg, with a total maximum dose of 168 mg over the 24-week period. This combination is administered orally and serves as an anti-inflammatory agent.
**Calcium Folinate**, also known as Leucovorin Calcium, is administered orally in the form PHF00169MIG. The maximum daily dose is 5 mg, with a total maximum dose of 120 mg over the 24-week period. Calcium Folinate functions as an antianemic agent and is used as a comparator treatment.
**Hydroxychloroquine Sulfate** is another comparator treatment, administered orally in the form PHF00082MIG. The maximum daily dose is 200 mg, with a total maximum dose of 33,600 mg over the 24-week period. Hydroxychloroquine Sulfate is classified as an antimalarial.
Lastly, **Lidocaine Hydrochloride Monohydrate** is included as a comparator treatment, administered orally in the form PHF00243MIG. The maximum daily dose is 16 mg, with a total maximum dose of 2,688 mg over the 24-week period. Lidocaine Hydrochloride Monohydrate is categorized under corticosteroids.
All medications are administered orally, and participant compliance is monitored throughout the trial. The trial aims to assess the efficacy and safety of Baricitinib in comparison to these established treatments in managing inflammation associated with CPPD.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in **CD68** scoring at 12 weeks, which serves as an objective measure of the effect of Baricitinib on inflammation of the synovial membrane in Calcium Pyrophosphate Dihydrate Deposition Disease (CPPD). Secondary endpoints include changes from baseline in the Krenn synovitis score, CD3, CD8, and CD20 at the synovial level at 12 weeks. Additionally, changes in Disease Activity Score (DAS), Health Assessment Questionnaire (HAQ) score, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) will be evaluated at 4, 12, and 24 weeks.
Further secondary endpoints involve the assessment of changes from baseline in Musculoskeletal Ultrasound (MSUS) EULAR-OMERACT synovitis score, CPP deposition extent according to the OMERACT CPPD scoring system, and degenerative changes at 4, 12, and 24 weeks. Serum cytokine levels, including IL-1, IL-6, IL-8, anti-TNFα, Interferon α and γ, and TGF-β, will be measured at 12 and 24 weeks. The visual analog scale (VAS) for pain will also be assessed at 4, 12, and 24 weeks. These efficacy parameters will be collected and analyzed at specified timepoints to determine the therapeutic impact of the investigational product.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Informed Consent
- Male and female patients aged ≥55 years
- 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 accordingly to the Contraception Guidance Version_1.2_March_2024). HMA/03-Working_Groups/CTCG/2024_HMA_CTCG_Contraception_guidance_Version_1.2March_2024.
- 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.
- Patients that according to the investigator’s judgement will benefit from the proposed treatments (favourable benefit/risk profile)
Exclusion Criteria
- Patients positive at anticitrullinated positive antibodies (ACPA), any titre
- 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 affected by seronegative arthritis or other conditions that may be responsible of arthritis (i.e. gout, rheumatic polymyalgia, etc)
- 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
- 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 symptomatic herpes zoster infection within 12 weeks of screening or recurrent or disseminated (even a single episode) herpes zoster
- 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 anti-HBs, but negative for HBcAg and HBsAb could be enrolled.
- Hypersensitivity to the active substance or to any of the excipients
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 15 Nov 2024 | 32 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
METHOTREXATE | Comparator | PHF00231MIG | ORAL | 10 | 24 | SCP10339494 |
Olumiant 4 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 4 | 24 | PRD4765061 |
FOLIC ACID | Comparator | PHF00169MIG | ORAL | 5 | 24 | SCP128175 |
COLCHICINE | Comparator | PHF00082MIG | ORAL | 1 | 24 | SCP129899 |
METHYLPREDNISOLONE | Comparator | PHF00243MIG | ORAL | 16 | 24 | SCP101878658 |
HYDROXYCHLOROQUINE | Comparator | PHF00082MIG | ORAL | 200 | 24 | SCP134762 |