Evaluation of Upadacitinib on Axial Symptoms and Inflammation in Patients with Active Psoriatic Arthritis and Axial Spondyloarthritis

Trial ID: 2023-510242-24-00
Protocol: B24-033
Sponsor: Care Arthritis Ltd.

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Diseases & Conditions

Axial spondyloarthritis Psoriatic arthropathy

Objectives

The primary objective of this study is to evaluate the **efficacy** of upadacitinib 15mg once daily in reducing axial signs and symptoms, as well as inflammation in the sacroiliac joints (SIJ) and spine, as observed on MRI in patients with psoriatic arthritis. These patients meet the CASPAR criteria and present with active axial symptoms, including chronic back pain lasting at least three months, a BASDAI score of 4 or higher, and a total back pain score of 4 or higher on a numerical rating scale. Additionally, the study focuses on patients with definite active inflammation on MRI of the SIJ and/or spine, as defined by the ASAS criteria, with at least four SIJ quadrants or discovertebral units showing bone marrow edema (BME), excluding those with degenerative disc disease at the affected units. This objective is clinically relevant as it aims to address the significant burden of axial symptoms in psoriatic arthritis, which can severely impact patient quality of life and functional ability.

Secondary objectives include: - Evaluating the efficacy of upadacitinib 15mg once daily on concomitant peripheral clinical efficacy parameters and pain. - Assessing the effect of upadacitinib on MRI structural lesions in the SIJ. - Evaluating the safety and tolerability of upadacitinib in adult subjects with active axial psoriatic arthritis. - Assessing the efficacy of upadacitinib in placebo patients switching to active therapy. - Evaluating the efficacy of upadacitinib over a 24-week period.

Participants

The clinical trial involves a total of **35 participants** diagnosed with **Psoriatic Arthritis** and **Axial Spondyloarthritis**. The study population includes both male and female subjects, aged between 18 and 64 years, who are in general good health but present with active axial symptoms. Participants were selected based on specific criteria, including a history of chronic back pain and active inflammation as confirmed by MRI. The trial does not include vulnerable populations. Lifestyle considerations such as the use of NSAIDs, analgesics, and corticosteroids are accounted for, with participants required to maintain stable dosages prior to the baseline visit. The selection process ensures that participants have a history of inadequate response or intolerance to previous treatments, including DMARDs and NSAIDs. The trial population is not restricted by gender, and both males and females are included, provided they meet the specified inclusion criteria.

Plans and Procedures

The clinical trial is designed as a **randomized**, **placebo-controlled**, multicenter study to evaluate the efficacy of **upadacitinib** in patients with active **psoriatic arthritis** and **axial spondyloarthritis**. The trial will assess the impact of upadacitinib on spondyloarthritis outcomes, specifically targeting axial signs and symptoms and inflammation in the sacroiliac joints (SIJ) and spine. The study will involve a double-blind methodology, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to commence recruitment in March 2025 and conclude by October 2027, with a total duration of approximately 24 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on predefined criteria, including age, medical history, and current treatment regimens. The screening visit will also involve a comprehensive assessment of the participant's condition, including imaging studies to confirm active inflammation. Following the baseline visit, participants will be randomly assigned to receive either upadacitinib or a matching placebo, administered orally in a modified-release tablet form. The maximum daily dose of upadacitinib is set at 15 mg, with a total treatment period of 24 weeks.

Subsequent follow-up visits will occur at regular intervals to monitor the participants' response to treatment, assess any adverse events, and ensure adherence to the study protocol. The primary endpoint will be evaluated at 12 weeks, focusing on the change from baseline in the Total Spondyloarthritis Research Consortium of Canada (SPARCC) MRI inflammation score for the SIJ and spine. Secondary endpoints include changes in the Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 12.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to evaluate the overall efficacy and safety of the treatment. Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination, such as significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide valuable insights into the therapeutic potential of upadacitinib for individuals with psoriatic arthritis and axial spondyloarthritis, contributing to the advancement of treatment options for these conditions.

Treatment

The clinical trial involves the administration of **Upadacitinib**, a **modified-release tablet** formulated for oral administration. Upadacitinib is a chemical substance with the active ingredient identified as UPADACITINIB. The pharmaceutical form is designed to release the active substance in a controlled manner over time. The maximum daily dose is 15 mg, with a total maximum dose of 2520 mg over the treatment period. The treatment duration is set for a maximum of 24 weeks. Participants are required to take the medication once daily (QD). Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The sponsor of the product is ABBVIE DEUTSCHLAND GMBH & CO. KG, and the product is identified by the sponsor product code ABT-494.

The study also includes a **matching placebo** that contains no active ingredients. The placebo is administered in the same pharmaceutical form and route as Upadacitinib, ensuring blinding of the study. The placebo is also given orally, with a maximum daily dose equivalent to that of the active treatment, ensuring consistency in administration. The placebo is used to evaluate the efficacy of Upadacitinib by providing a comparator for assessing the treatment's impact on spondyloarthritis outcomes in patients with active psoriatic arthritis. The placebo administration follows the same dosing schedule and treatment period as the active medication, with compliance monitoring in place to maintain the integrity of the study results.

Efficacy

The efficacy of upadacitinib in patients with active psoriatic arthritis will be assessed through a randomized, placebo-controlled, multicenter study. The primary endpoint for evaluating efficacy is the change from baseline in the Total Spondyloarthritis Research Consortium of Canada (SPARCC) MRI inflammation score for the sacroiliac joints (SIJ) and spine at 12 weeks of therapy. This score combines the 23-DVU SPARCC spine (range 0-414) and the SPARCC SIJ (range 0-72) scores. Secondary endpoints include changes from baseline in the Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) at Week 12. These assessments will be conducted in both the DMARD-IR (conventional and/or biologic) subgroup and the overall population, which includes NSAID-IR, c-DMARD-IR, and bio-DMARD-IR groups.

The efficacy parameters will be measured at baseline and at Week 12 using validated scales and MRI imaging. The SPARCC MRI inflammation score will be used to quantify inflammation in the SIJ and spine, while the ASDAS-CRP and BASDAI will assess disease activity and symptom severity. These tools are widely recognized in clinical research for their reliability and validity in measuring outcomes related to spondyloarthritis and psoriatic arthritis. The analysis will compare the changes in these scores between the upadacitinib and placebo groups to determine the drug's efficacy in reducing axial signs and symptoms and inflammation in patients with psoriatic arthritis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject ≥18 years of age at the screening visit.
Subject must be able to understand and willing to adhere to all protocol requirements and voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or study-specific procedures.
Diagnosis of PsA by their treating rheumatologist.
Classification of PsA according to the CASPAR criteria19: Inflammatory articular disease (joint, spine, or entheseal) AND at least 3 points of the following categories: a) Evidence of psoriasis: (Score for one of the following) i) Current psoriasis – 2 points (Psoriatic skin or scalp disease present today as judged by a dermatologist or rheumatologist) ii) Personal history of psoriasis – 1 point (A history of psoriasis that may be obtained from the subject, family physician, dermatologist, rheumatologist, or other qualified health care provider) iii) Family history of psoriasis – 1 point (A history of psoriasis in a first- or second-degree relative according to subject report) b) Psoriatic nail dystrophy – 1 point i) Typical psoriatic nail dystrophy, including onycholysis, pitting, and hyperkeratosis, observed on current physical examination c) A negative test for rheumatoid factor – 1 point i) By any method except latex, but preferably by enzyme-linked immunosorbent assay (ELISA) or nephelometry, according to the local laboratory reference range d) Dactylitis: (Score for 1 of the following) i) Current dactylitis – 1 point (Swelling of an entire digit) ii) History of dactylitis – 1 point (A history of dactylitis recorded by a rheumatologist) e) Radiologic evidence of juxta-articular new bone formation – 1 point i) Ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot.
Evidence of axial involvement (e.g., active inflammation, structural changes) that has been demonstrated by previous imaging techniques (e.g., radiography, MRI, CT), is considered indicative of axial disease by central reader assessment (2 readers and adjudicator).
Screening/baseline MRI demonstrates definite active inflammation on MRI of SIJ and/or spine (ASAS definition of positive MRI and ≥4 SIJ quadrants with BME and/or ≥4 vertebral units with BME (in the absence of degenerative disc disease at those discovertebral units with BME)) as determined by central readers
Presence of chronic back pain in the 3 months prior to screening.
Active disease as defined by a BASDAI value of ≥4 and TBP score of ≥4 (on a 0-10 NRS scale) at screening and baseline.
History of an inadequate response to at least two different NSAIDs over a period of 4 weeks in total at the maximum recommended or tolerated doses, or intolerance/contraindication (e.g., allergic reaction, gastrointestinal symptoms or signs, severe arterial hypertension, etc.) for NSAIDs.
Subjects will be a mixed population of DMARD-naïve and DMARD experienced (including inadequate responders (IR) and DMARD intolerant). The requirements for prior DMARD treatment follow the local product labels for PsA: a) Subjects recruited in Europe: Subjects must have previously been treated with one or more DMARD (csDMARD as defined in inclusion criterion 16, and/or bDMARD) and deemed to be inadequate responders and/or intolerant. b) Subjects recruited in the US: Subjects must be TNFi-IR or TNFi intolerant. c) Subjects recruited in Canada: Subjects must have previously been treated with one or more DMARD (csDMARD as defined in inclusion criterion 16, and/or bDMARD) and deemed to be inadequate responders and/or intolerant. All subjects deemed DMARD-IR must have been treated for ≥ 3 consecutive months prior to the study entry with DMARD therapy (including csDMARD and/or bDMARD) but continue to exhibit active SpA. Subjects deemed DMARD intolerant will have discontinued previous DMARD treatment due to intolerability or toxicity, irrespective of treatment duration. Up to 20 patients presenting with purely axial disease and current psoriasis (at the time of screening) may be included in the study. These patients may have had a past history of joint involvement, but do not currently require csDMARD therapy, in accordance with the local product label for nr-axSpA/AS. In order to be deemed eligible, these patients must meet both the 2009 ASAS Classification Criteria for axSpA, the CASPAR criteria, as well as all other inclusion/exclusion criteria, including inadequate response to 2 NSAIDs (all countries, inclusion criterion #9), bDMARD-IR/intolerant (Canada), and TNFi-IR/intolerant (US). The 2009 ASAS Classification Criteria for axSpA are provided in Appendix A. Subjects recruited under the nr-axSpA label must also present with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or positive magnetic resonance imaging (MRI).
For all females of child-bearing potential: must not have a positive serum pregnancy test at the Screening Visit and must have a negative urine pregnancy test at Baseline prior to the first dose of study drug (local practices may require serum pregnancy testing at Baseline). Subjects with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of pregnancy or other pathological causes of borderline results and a serum pregnancy test ≥3 days later to document continued lack of a positive result (unless prohibited by local requirements). a) Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control that is effective from Study Day 1 through at least 30 days after the last dose of study drug (local practices may require 2 methods of birth control). Female subjects of non-childbearing potential do not need to use birth control. b) Females must not be pregnant, breastfeeding, or considering becoming pregnant during the study and for approximately 30 days after the last dose of study drug. Females must commit to one of the following methods of highly effective birth control: o Combined (estrogen- and progestogen-containing) hormonal birth control (oral, intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at least 30 days prior to study baseline. o Progestogen-only hormonal birth control (oral, injectable, implantable) associated with inhibition of ovulation initiated at least 30 days prior to study baseline. o Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a hysterosalpingogram confirms success of the procedure) (For Japan: only bilateral tubal ligation). o Intrauterine device (IUD). o Intrauterine hormone-releasing system (IUS). o Vasectomized sexual partner (the partner has received medical confirmation of the surgical success of the vasectomy and is the sole sexual partner of the trial subject). o Practice true abstinence (unless not acceptable per local practices), defined as: refraining from heterosexual intercourse 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).
If required per local practices, females of childbearing potential must commit to using 2 methods of contraception (either 2 highly effective methods or 1 highly effective method combined with 1 effective method). Effective methods of birth control are the following: • Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action, initiated at least 30 days prior to baseline. • Male or female condom with or without spermicide. • Cap, diaphragm, or sponge with spermicide. • A combination of male condom with a cap, diaphragm, or sponge with spermicide (double barrier method). • In questionable cases of menopausal status, a blood sample with simultaneous levels of follicle stimulating hormone (FSH) above 40 U/l and estradiol below 30 pg/ml is confirmatory.
Subjects who are regularly taking NSAIDs or analgesics (including mild opioids) as part of their PsA therapy are required to be on a stable dose/dose regimen for at least 14 days prior to the baseline visit. If entering the study on concomitant tramadol, combination of acetaminophen/paracetamol and codeine or combination of acetaminophen/paracetamol and hydrocodone, and/or non-opioid analgesics, subject must be on stable dose(s) for at least 14 days prior to the baseline Visit. However, subject must not have used opioid analgesics (except for combination of acetaminophen/paracetamol and codeine or combination of acetaminophen/paracetamol and hydrocodone which are allowed) within 14 days prior to the BL Visit.
Subjects taking oral corticosteroids must be on an average daily and stable dose of ≤10mg/day prednisone or equivalent for at least 14 days prior to the baseline visit.
Subjects taking topical therapies (e.g., topical JAKi, salicylic acid preparations, corticosteroids, retinoids) are allowed, but must be on a stable dose at least 4 weeks prior to the BL visit.
Subjects entering the study on the following concomitant csDMARDs must be on a stable dose as indicated below for at least 28 days prior to the baseline Visit (in case of Leflunomide washout must be either 8 weeks or 4 weeks with a standard cholestyramine wash-out). A combination of up to 2 background csDMARDs is allowed EXCEPT the combination of methotrexate (MTX) and leflunomide. • MTX (≤ 25 mg/week); or • Sulfasalazine (SSZ) (≤ 3 g/day); or • Hydroxychloroquine (≤ 400 mg/day); or • Chloroquine (≤ 250 mg/day); or • Leflunomide (≤ 20 mg/day); or • Apremilast (≤ 60 mg/day)
If subjects are currently taking bDMARD therapy, a wash-out period prior to the screening MRI may be appropriate, based on local investigator standard of care practice. Prior exposure to a bDMARD is allowed for no more than 75 subjects.

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Exclusion Criteria

Active infection(s) requiring treatment with parenteral anti-infectives within 30 days, or oral anti-infectives within 14 days prior to the baseline Visit; Chronic recurring infection and/or active viral infection that based on the investigator's clinical assessment makes the subject an unsuitable candidate for the study.
Female subjects who are breastfeeding, pregnant, or plan to become pregnant during the study or within 4 weeks following the last dose of study drug.
Subjects with chronic inflammatory articular disease (other than PsO or PsA or SpA), or systemic autoimmune diseases, e.g., systemic lupus erythematosus, Sjögren´s syndrome, RA, unequivocal chronic fatigue syndrome, or unequivocal fibromyalgia. Subjects with a diagnosis of Crohn’s disease or ulcerative colitis are allowed as long as they have no active symptomatic disease within 4 weeks prior to BL
Concomitant treatment with strong inductors or inhibitors of cytochrome P450 3A. Examples of commonly used inhibitors and inducers are provided below. Information regarding potential drug interactions with upadacitinib is located in the upadacitinib Investigator's Brochure, FDA Label, Product Monograph, or Summary of Product Characteristics.
Prior treatment with upadacitinib or another JAK-inhibitor or TYK2-inhibitor.
History of hypersensitivity to any component of upadacitinib tablets.
Treatment with intravenous, intramuscular or intraarticular/periarticular, or intrarectal steroids within 4 weeks prior to baseline Visit; treatment with oral steroids in a dose of >10 mg prednisolone equivalent per day.
Subject must not have been treated with any investigational drug of chemical or biologic nature within a minimum of 30 days or five half-lives (whichever is longer) prior to the first dose of study drug or is currently enrolled in another interventional clinical study.
History of an infected joint prosthesis at any time, with the prosthesis still in situ.
Actual malignancies or history of malignancies with curative treatment within 5 years prior to screening, except successfully treated non-metastatic squamous cell or basal cell carcinoma of the cutis or carcinoma in situ of the cervix.
A subject with any condition possibly affecting oral drug absorption, e.g., total gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass. Procedures such as a sleeve gastrectomy or gastric banding, that simply divides the stomach into separate chambers, are NOT exclusionary.
Confirmed COVID-19: the baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, defined as resolution of fever without use of antipyretics and improvement in symptoms;
Significant trauma or surgery procedure within 4 weeks prior to baseline or any preplanned elective surgery during the study period.
Evidence of other severe uncontrolled gastrointestinal, hepatic (serum albumin <25 mg/l or Child-Pugh-Score >10), renal, pulmonary, cardiovascular, nervous or endocrine disorders.
Any history of prior cardiovascular event, including but not limited to cerebrovascular accident, myocardial infarction, coronary stenting, and aorto-coronary bypass surgery.
History of thrombosis and/or hematological disorder increasing the propensity to thrombosis.
Any subject who has been vaccinated with live or attenuated vaccines within the 4 weeks prior to the first dose of study medication or is to be vaccinated with these vaccines at any time during treatment or within 4 weeks after the last dose of study drug. Examples of live vaccines include, but are not limited to, the following: Monovalent live influenza A (H1N1) (intranasal); Seasonal trivalent live influenza (intranasal); Zostavax (herpes zoster, live attenuated); Rotavirus; Varicella (chicken pox); Measles-mumps-rubella or measles-mumps-rubella-varicella; Oral polio vaccine; Smallpox; Yellow fever; Bacille Calmette-Guérin; Typhoid (oral). Administration of inactivated (non-replicating) vaccines is permitted prior to or during the study according to local practice guidelines. Examples of common vaccines that are inactivated, toxoid or biosynthetic include, but are not limited to, injectable influenza vaccine, pneumococcal, Shingrix (zoster vaccine, recombinant, adjuvanted), pertussis (Tdap) vaccines, monkey pox vaccine and SARS-CoV-2 (inactivated, mRNA, RNA). Whenever possible, subjects should not have received a COVID-19 vaccination in the 7 days prior to randomization or plan to receive a COVID-19 vaccination within the first 7 days after initiation of study drug.
Any of the following lab abnormalities detected at screening: Hemoglobin <8 g/dl; Absolute neutrophil count <1.0 x 109/L (<1000/mm3) Absolute lymphocyte count <0.50 x 109/L (<750/mm3) Platelet count <100 x 109/L (<100,000/mm3).
Patients with contraindications for the MRI including but not limited to claustrophobia, seizure disorders, presence of an implanted electronic device (e.g. heart pacemaker, insulin pump, etc.) or metal implants not known to be MRI safe and metal foreign bodies in the patient’s body suspected to be ferromagnetic, tattoos performed with metal-containing paints or tattoos of large skin areas.
Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high-risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure;
History of recurrent (more than one episode) herpes zoster or disseminated/multi-dermatomal (a single episode) herpes zoster or disseminated (a single episode) herpes simplex.
Primary or secondary immunodeficiency.
Current clinical signs and symptoms suggestive for tuberculosis.
Positive Tuberculosis Interferon Gamma Release Assay (IGRA) serum test and abnormal chest x-ray (positive x-ray) suggestive of past or present tuberculosis (both at screening, may be accepted if performed within 180 days prior to screening). If the IGRA test is indeterminate the test should be repeated. If it remains indeterminate the patient should be considered positive. Patients with a positive Tuberculosis IGRA serum test but negative chest x-ray and without clinical symptoms suggestive for tuberculosis may participate in the study after initiation of standard prophylactic anti-tuberculous treatment according to the current local treatment guidelines. At least 2 weeks prophylactic treatment is considered necessary prior to study participation. Patients should not take rifampin concurrently with Upadacitinib.
Chronic infection with hepatitis B virus. At screening HBsAg and anti-HBc will be tested. Patients who are HBsAg positive will be excluded. In case of HBsAg negativity, but anti-HBc positivity, participation in the study is possible if HBV-DNA testing is negative and liver function tests are normal.
Chronic infection with hepatitis C (HCV) (HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab), or Human Immunodeficiency Virus (HIV) infection confirmed by positive anti-HIV antibody test.
History or current clinically significant medical conditions or any other reason that in the opinion of the Investigator or Sponsor would interfere with the subject’s participation in this study, would place the subject at risk by participating in the study, or would make the subject an unsuitable candidate to receive study drug, also with regard to the European Commission Decision as of 10 March 2023 on measures to minimize risk of serious side effects with JAK inhibitors (EMA/142279/2023, see Supplement 1.0)