Multicentre, 26-week, open-label phase 2 trial of the JAK inhibitor filgotinib in Behçet’s disease, idiopathic inflammatory myopathies and IgG4-related disease: DRIMID study protocol

Abstract

Introduction

Research into novel therapies for rare, immune-mediated inflammatory diseases (IMIDs) faces significant challenges, including small patient populations, complex clinical trial design and difficulties in patient recruitment. Patients with Behçet’s disease (BD), idiopathic inflammatory myopathies (IIM) and IgG4-related disease (IgG4-RD) typically undergo treatment involving prolonged administration of high-dose glucocorticoids and immunosuppressants. Both are associated with an increased risk of infection. Additionally, glucocorticoids carry long-term toxicity risks. Thus, there is an urgent need to develop more targeted and effective anti-inflammatory treatments. Given the activation of the type 1 interferon pathway in BD, IIM and IgG4-RD, inhibition of the Janus kinase (JAK) STAT pathway emerges as a promising therapeutic strategy. The Drug Rediscovery in IMIDs (DRIMID) consortium aims to conduct a prospective pilot basket trial to investigate the effects of filgotinib, a JAK1 preferential inhibitor approved for ulcerative colitis and rheumatoid arthritis, on disease activity, quality of life and safety in patients with refractory BD, IIM and IgG4-RD.

Methods and analysis

In this investigator-initiated, multicentre, open-label phase 2 study, up to 60 patients with rare IMIDs will be enrolled for a 26-week treatment period with filgotinib 200 mg once daily. The trial consists of two stages, each involving a consecutively treated cohort of up to 20 patients per disease. An interim analysis is conducted between these stages, where the trial will proceed only in diseases showing potential effectiveness. Baseline, 3-month and 6-month assessments will include data on quality of life, disease activity, corticosteroid toxicity and biomarkers. The coprimary endpoints are disease activity and quality of life across and within each disease.

Ethics and dissemination

The study received approval from the Medical Research Ethics Committee in Utrecht, Netherlands. A Data Safety Monitoring Board has been established to monitor the trial’s safety and progress.

Trial registration number

NCT06285539.

Strengths and limitations of this study.

• The multicentre design across six hospitals ensures diverse patient recruitment, enhancing the generalisability of the findings.

• The two-stage trial design minimises patient exposure to ineffective treatment while determining potential efficacy.

• The open-label design, without a control group, increases the risk of bias and limits the ability to differentiate drug effects from placebo.

• The small cohort sizes, necessitated by the rarity of the diseases, may reduce the statistical power and the precision of the effect estimates.

Introduction

Immune-mediated inflammatory diseases (IMIDs) such as Behҫet’s disease (BD), idiopathic inflammatory myopathies (IIMs) and IgG4-related disease (IgG4-RD) are rare, chronic conditions driven by dysregulated immune responses that lead to inflammation and tissue damage.¹,³ Despite their distinct clinical manifestations, these diseases share common underlying immune pathways, particularly activating proinflammatory cytokines, making them suitable for investigation in a combined therapeutic trial to target these shared mechanisms.⁴,⁶

Study diseases

BD, IIM and IgG4-RD represent distinct but related IMIDs. BD is an autoinflammatory vasculitis of unknown aetiology, primarily presenting with recurrent oral ulcers, inflammatory skin changes and uveitis, often accompanied by systemic complications, such as arthritis, thrombosis, neurological involvement and colitis.⁷ Histologically, BD is characterised by vaso-occlusive vasculitis with T cell and neutrophil infiltration.¹ IIM, the denominator for different subtypes of myositis, constitutes a group of IMIDs marked by muscle inflammation, skin lesions and interstitial lung disease. The most prevalent subtypes include dermatomyositis (DM) and antisynthetase syndrome (ASS).⁸ If untreated, these conditions can lead to irreversible damage, such as muscle degeneration and lung fibrosis, contributing to fatigue, pain and reduction in quality of life.⁹ IgG4-RD is characterised by chronic fibroinflammatory lesions that can affect multiple organs, including the pancreas, bile ducts, kidneys and salivary glands.¹⁰ Clinical symptoms are the result of tumour-like swelling of involved organs, leading to organ compression or obstruction.¹¹

Rationale for study

The therapeutic goal for patients with these IMIDs is to reduce inflammation, induce disease remission and improve health-related quality of life. Initial treatment involves high-dose glucocorticoids, frequently in combination with immunosuppressants, such as methotrexate, mycophenolate mofetil, azathioprine or ciclosporin. In more refractory cases, treatments like rituximab, cyclophosphamide, TNF-alpha inhibitors and intravenous immunoglobulin are used.¹² However, large clinical trials for these diseases are limited due to their rarity, leaving many patients with chronic illness and the long-term side effects of steroid use.^{5 13 14} This underscores the need for more effective therapies in BD, IIM and IgG-RD.^{6 15}

These three diseases share common inflammatory pathways, particularly involving the Janus kinase (JAK) STAT signalling pathway.^{4 5} Studies have identified upregulation of type 1 interferon (IFN) inducible genes in IIM,² as well as activation of IFN-regulated cytokines in IgG4-RD and BD.^{3 4} The JAK-STAT pathway is critical for transmitting signals from proinflammatory cytokines,¹⁶ including interleukin (IL) 2–7 and IFNs. Inhibiting JAK1, a key player in these pathways,^{17 18} could reduce the activation of cytokines and chemokines, offering a potential therapeutic strategy for controlling inflammation in these IMIDs.¹⁹

Objectives

Primary

• To determine the effect of the JAK1 inhibitor filgotinib after 26 weeks on disease activity in refractory BD, IIM and IgG4-RD, measured by Behçet’s Disease Current Activity Form (BDCAF), the total improvement score (TIS) of the International Myositis Assessment Clinical Studies (IMACS) group and the IgG4-RD responder index (IgG4-RD RI). The TIS consists of the physician’s global activity, the patient’s global activity, manual muscle testing, the health assessment questionnaire, laboratory of muscle enzymes and the Myositis Disease Activity Assessment Tool.

• To determine the effect of the JAK1 inhibitor filgotinib after 26 weeks on quality of life in refractory BD, IIM and IgG4-RD, measured by the EuroQol 5D-5L (EQ-5D-5L) form.

Secondary

• To further determine the effect of filgotinib on disease activity, measured by area under the curve (AUC) for number of oral ulcers in BD; a change in disease activity core set domains as defined by the IMACS group and the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) in IIM; the total number of flares in each disease, measured by a≥1 point increase in physician global assessment on a scale from 0 to 3 and the visual analogue scale (VAS) of disease activity, based on the clinical view of the local principal investigator.

• To determine the effect of filgotinib on the need for corticosteroids, and as a consequence of corticosteroid use, corticosteroid toxicity, measured by the Glucocorticoid Toxicity Index.

• To determine the effect of filgotinib on patient-reported outcome measures, that is, the VAS score of pain, the Functional Assessment of Chronic Illness Therapy-Fatigue and the Patient Acceptable Symptom State.

• To determine the safety of filgotinib, measured by exposure-adjusted incidence rates for treatment-emergent adverse events (AEs).

Methods and analysis

Study setting

Drug rediscovery in IMID (DRIMID) is a multicentre (involving six sites), investigator-initiated phase 2 open-label study conducted in Netherlands from May 2024 to December 2027. All participating sites are hospitals with a patient database and specialists in these rare IMIDs, whether academic or peripheral hospitals. Eligible patients are 18–65 years of age, with a diagnosis of active BD, IIM or IgG4-RD, refractory or intolerant to immunosuppressants. More detailed inclusion criteria are displayed in Box 1. Patients 65 years of age and older are excluded due to advice from the European Medicines Agency (EMA) regarding using JAK inhibitors in the elderly.²⁰

Box 1. Eligibility criteria DRIMID.

Inclusion criteria

General (all of the following)

1. Patients aged 18–65 years.

2. With refractory disease, defined as symptomatic disease that persists despite a 12-week trial of glucocorticoid therapy as well as lack of response to at least one other immunosuppressive agent or intolerance to standard-of-care treatment.

Disease specific (one of the following)

• 3 1Diagnosis of BD without refractory life, organ or sight-threatening symptoms

  • With active disease, defined as a new BDCAF>2 or an old BDCAF>15 or based on clinical grounds (eg, the need to start new or additional medication).

• 3 2Diagnosis of IIM, according to the DM classification criteria of the European Neuromuscular Centre guidelines 2018* or the ASS classification criteria of the European Neuromuscular Centre guidelines 2003**.

  • With active disease, defined as a CDASI score of≥5, or abnormal levels of CK, aldolase, LDH, AST or ALT or a MRI within the last 3 months indicative of active inflammation or based on clinical grounds (eg, the need to start new or additional medication).

• 3 3Diagnosis of IgG4-RD, according to the 2019 ACR/EULAR guidelines.

  • With active disease, defined as an IgG4-RD RI>10 or based on clinical grounds (eg, the need to start new or additional medication).

Exclusion criteria

General

• 6 1Age<18 years.
• 6 2Age≥65 years.
• 6 3Life expectancy less than 6 months.
• 6 4Juvenile DM, myositis overlapping with other autoimmune diseases, IMNM, inclusion-body myositis or cancer-associated myositis.
• 6 5End-stage IIM where muscle weakness is most likely due to muscle damage rather than myositis disease activity.
• 6 6Inability to comply with study and/or follow-up procedures.
• 6 7Known recent substance abuse (drugs or alcohol).
• 6 8Poor tolerability of venipuncture or lack of adequate venous access for required blood sampling during the study period.
• 6 9Hypersensitivity to the active substance or to any of the excipients.
• 6 10Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Therapies

• 16 1Previous use of other JAK inhibitors.
• 16 2Previous non-adherence to immunosuppressants.
• 16 3Use of any investigational drug within 1 month prior to screening or within 5 half-lives of the investigational agent, whichever is longer.

Safety

• 19 1Increased risk of major cardiovascular problems.
• 19 2Current smoker of smoked for a long time in the past.
• 19 3Pregnancy or lactation.
• 19 4HIV infection.
• 19 5Presence of an active infection or viral hepatitis type B or C.
• 19 6History of shingles or recurrent herpes simplex infection.
• 19 7No evidence of active or latent or inadequately treated infection with mycobacterium tuberculosis.
• 19 8Concomitant malignancies or previous malignancies within the last 5 years (with exception of adequately treated basal or squamous cell carcinoma of the skin) or an increased risk of cancer.
• 19 9Kidney injury with estimated glomerular filtration rate<15 mL/min/1.73m².
• 19 10Liver failure Child-Pugh C.
• 19 11Blood count abnormalities, including:

  • ANC<1*10⁹ cells/L.

  • Absolute leucocyte count<0.5*10⁹ cells/L.

  • Haemoglobin<5 mmol/L.

Trial design

This trial is based on a two-stage trial design (figure 1) previously published by Simon.²¹ The decision to conduct an open-label trial without a control group is due to the limited number of patients with these rare IMIDs. This trial design is built on two principles: exposing as few people as possible to a drug that may be ineffective and, in the meantime, determining whether the effectiveness is sufficient for further research. A small cohort of patients per disease category is tested during the first stage of the trial. If in the first stage (after the first 9 patients per disease), the response rate is higher than a minimal chance of response (Box 2) in a cohort, this disease category progresses to stage 2. These response criteria and cut-off points are validated to show a significant change in disease activity.²²,²⁶

Figure 1. Two-staged trial design; flowchart of enrolment and duration. SoC, Standard-of-Care.

Box 2. Response criteria.

Definition of response per disease category

BD (one of the following)

1. Decrease in the score in the BDCAF of>30%.

2. Decrease in oral ulcers with 20%, measured with the AUC of ulcers.

IIMs (one of the following)

1. TIS of>20, based on the 2016 ACR/EULAR myositis response criteria.

2. A decrease on the activity scale of the CDASI of≥7 points.

IgG4-RD

1. ≥2 points reduction on the IgG4-RD RI.

In the second stage, we will test whether there is a substantial clinical benefit. In this stage, a new cohort (stage 2) will be tested only in the disease categories with sufficient response during stage 1. If no patient in a disease category responds in stage 1, this disease category will be terminated and not proceed to stage 2.

Patients and public involvement

Patients were involved in the study’s design through the advisory board of the Autoimmune Research and Collaboration Hub (ARCH). They helped shape the research question and outcome measures based on their priorities, experiences and preferences. Additionally, they will be involved in disseminating study results, helping determine which findings are most relevant and the best ways to communicate them to the broader patient community.

Sample size calculations

Based on previous studies, placebo effects in similar populations can cause changes of up to 20% in the EQ-5D-5L utility score and up to 15% in disease activity scores.²⁷,³⁰ Given these possible placebo effects, we need to ensure that the overall improvement observed in the primary endpoint is significantly greater than an improvement that could be due to placebo alone. To achieve this, we set a target for the average proportion of improvement at 0.35 (or 35%), with an SD of 0.3. Using these parameters, a two-sided α of 0.05 and statistical power of 80%, we calculated that a total of 32 patients would be required to detect an actual treatment effect beyond the placebo effect.

Following the calculations outlined by Simon’s two-stage design method, nine patients per disease are needed in the first stage to determine whether there is a sufficient response to move forward. In the second stage, an additional seven patients per disease are required to assess whether a substantial response can be observed. An α of 0.05 and a β of 0.20 are chosen for this.²¹ However, we decided to increase the number of patients in the second stage to 11 to account for potential dropouts and ensure that the trial maintains sufficient power in case one patient group may not progress to the second stage. In this case, we still achieve our target of enrolling 40 patients in total. This design ensures that even if patients drop out, we can still reach reliable conclusions from the study.

Interventions

Each patient will receive filgotinib, 200 mg, once daily for 26 weeks. Following the latest EMA guideline, dose adjustments are applied, namely 100 mg once daily dose in patients with an increased risk of venous thromboembolism (VTE).²⁰ Filgotinib is an oral, selective, adenosine triphosphate (ATP)-competitive, reversible JAK1 preferential inhibitor. It modulates the JAK-STAT signalling pathway by preventing the phosphorylation and activation of STATs. Therefore, it inhibits IL-2, IL-4, IL-6, IL-15 and type 1 IFN activity.³¹ Previous studies in filgotinib showed a preference for JAK1 inhibition over JAK2 and JAK3.¹⁸ The EMA already authorises filgotinib with the indication of the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs. Filgotinib may be used as monotherapy or in combination with methotrexate in this disease.³² Filgotinib is also indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biological agent.³²

Concomitant therapy

During the study, prednisolone and conventional immunosuppressive medication can be continued in accordance with standard clinical care. Permitted medication includes, but is not limited to, methotrexate, mycophenolate mofetil, azathioprine, tacrolimus and intravenous immunoglobulin. Concomitant medication dosages must remain stable during the study unless there are safety issues, except for prednisone, which may be tapered at the investigator’s discretion in the event of substantial clinical improvement of the patient. Tapering will be included as a covariate in the statistical analyses. Concomitant use of other JAK inhibitors is not permitted.

Discontinuation of individual subjects

Participants can exit the study at any time, for any reason, without facing any consequences. Additionally, the research physician reserves the right to remove a participant from the study due to urgent medical concerns, such as follows.

• Onset of herpes zoster infection (temporary interruption of study treatment until the episode resolves). This will be reported as an AE.

• Development of any (opportunistic) infection (study participation temporarily halted until infection resolves). This will be reported as an AE. There are no specific precautions to prevent the recurrence of infections with the use of JAK inhibitors. If neutropenia occurs, the participant should refrain from restarting filgotinib until their absolute neutrophil count (ANC) exceeds 1*10⁹ cells/L.

• Decline in kidney function with an estimated glomerular filtration rate of 15 mL/min/1.73 m². This will be reported as an AE.

• Elevation of liver enzymes to≥3 times the upper limit of normal (if normal at baseline). This will be reported as an AE.

• Changes in lipid profile, including the following:

  • Total cholesterol increase to≥8.0 mmol/L.

  • Low Density Lipoprotein (LDL)-cholesterol increase to≥4.0 mmol/L.

  • Triglyceride level of≥5.6 mmol/L.

This will be reported as an AE.

• Meeting any of the following laboratory criteria at two separate time points.

  • ANC of <0.75*10⁹ cells/L.

  • Absolute platelet count of<75*10⁹ cells/L.

This will be reported as an AE.

• Undergoing surgical intervention.

• Diagnosis of cancer during the study period. This will be reported as an AE.

• Clinical necessity to adjust the dosage of existing corticosteroids or immunosuppressants, or to initiate a new immunosuppressant.

The AEs mentioned above are of special interest and must be reported to the sponsor within 7 days of awareness. Serious AEs need to be reported without undue delay after becoming aware of them. The sponsor will notify the Medical Research Ethics Committee and the drug safety unit of Alfasigma S.p.A. of any potential safety issues.

Recruitment and informed consent procedures

At a routine visit to the rheumatology or immunology outpatient clinic, the treating physician will inform eligible patients about this study. If the patient is interested, the study team will provide the patient with the information letter. The trial will also be announced through a press release, which will include the contact details of the study team. Interested potential subjects can get in touch, after which the study team will provide them with the information letter. Every patient has a minimum of 7 days to consider his/her decision, conform Clinical Trial Regulation (CTR) article 29. The patient’s participation should be confirmed in a multidisciplinary consultation. In case of multidisciplinary consultation and patient approval, informed consent is dated and signed by the investigator or research nurse and the patient. The subject will be provided with a copy of the document by which informed consent has been given. The treating physician will be informed about the patient’s participation in this study, if the treating physician is not a part of the study team. On enrollment, the study site will make every reasonable effort to follow the participant throughout the entire study period.

Study assessments

After the informed consent is signed, the participant will be screened for eligibility. The first dose of Investigational Medicinal Product (IMP) will be received at baseline. Follow-up measurements will be conducted after 1 month, 3 months and at the end of the trial after 26 weeks (table 1). For participants who discontinue or deviate from the intervention, the outcome data from the 26-week visit will be collected. To promote adherence, patients will receive their IMP in two batches: one at baseline and one at the 3-month visit. Drug accountability will be performed after 3 months and at the end of the trial at 26 weeks. The study assessments will be conducted by the study physician.

Table 1. Schematic overview of study assessments.

Assessment	Screening	Baseline	Safety	Home measurement	FU	Home measurement	Home measurement	FU
Month number	n.a.	0	1	2	3	4	5	6
Informed consent	✓
Medical history, family history	✓
Medication history	✓
Current medication	✓
Tuberculosis diagnostics	✓
Current health status*	✓	✓	✓		✓			✓
Possible side effects			✓		✓			✓
Disease activity score†	✓	✓			✓			✓
BDCAF
CDASI
TIS
IgG4-RD RI
PGA
Total amount of oral ulcers‡		✓	✓§	✓§	✓	✓§	✓§	✓
Current glucocorticoid dose and GTI		✓						✓
Physical examination¶	✓	✓			✓			✓
Routine laboratory assessment**	✓		✓		✓			✓
Specific laboratory assessment††		✓						✓
Biopsies‡‡		✓			✓			✓
PROMs		✓			✓			✓
EQ-5D-5L
VAS pain
FACIT-F
PASS

Patient-Reported Outcome Measures.

^*Including any changes in medication and visits to the general practitioner and hospital.

^†questionnaires depending on disease.

^‡only in patients with BD.

^§Self-measurement at home.

^¶Blood pressure, auscultation of heart and lungs and disease-specific physical examination.

^**liver- and kidney function, creatinine kinasecreatine kinase, aldolase, lipid spectrum, blood count, CRP and ESR.

^††ferritin and (SAA), IgG4 and complement 3 and 4 levels, RNA sequence analysis, (PBMCs), biomarker identification and dynamics of biomarker expression.

^‡‡If applicable.

BDBehҫet’s diseaseBDCAFBehcet’s disease current activity formCDASIcutaneous dermatomyositis disease area and severity indexCRPC-reactive proteinEQ-5D-5LEuroQoL 5D-5LESRerythrocyte sedimentation rateFACIT-Ffunctional assessment of chronic illness therapy-fatigueFUfollow-upGTIglucocorticoid toxicity indexIgG4-RD RIIgG4-related disease responder indexn.a.not applicablePASSpatient acceptable symptom statePBMCsperipheral blood mononuclear cellsPGAphysical global assessmentPROMspatient-reported outcome measuresSAAserum amyloid ATIStotal improvement scoreVASvisual analogue scale

End of study

After 26 weeks of treatment, non-responders will go back to standard-of-care. In responders, the treating physician and patient can make a shared decision to continue treatment with filgotinib, which will be provided by Alfasigma S.p.A. until the drug is officially reimbursed for these indications, or a suitable therapeutic alternative is available, or (a) major safety concern(s) urges to stop treatment.

Data and sample collection

All collected data are entered in an electronic case record file. Data will be pseudonymised and the key will be stored in a separate, secured folder. Principal investigators will have access to their own site’s datasets and will have access to other sites data by request.

Blood samples are gathered at various time points throughout the study (see table 1). Furthermore, blood samples are obtained to monitor drug safety. To determine the effect of filgotinib on disease activity on tissue level, samples will be obtained where possible. In IgG4-RD, taking biopsies is highly invasive due to the organ involvement of this systemic disease and will, therefore, not be standard procedure in the context of this trial. If these patients require biopsies for diagnosis, additional permission will be requested to use the residual material from these biopsies. In BD, biopsies are not a part of standard care. However, a swab of oral ulcers is possible in these patients and is minimally invasive. These swabs might detect elevated levels of inflammatory cytokines and other markers, reflecting the heightened immune response in BD. This could help understand the level of local inflammation in the ulcers. Swabs will be performed on these patients two times during the study: at baseline and at the end of the trial. Patients in IIM with skin involvement (DM) will be asked for additional permission to take skin biopsies at baseline and 3 months. Collected samples will be coded to protect patient confidentiality.

An independent monitor will oversee the study. Each site will be monitored two times per year, during which the investigator site files will be checked, and a source data review of at least 25% of the total patients included per centre will be conducted. A Data Safety Monitoring Board (DSMB) will monitor the trial’s safety and progress (online supplemental file 1).

Data analysis plan

Following the initial stage, an interim analysis will be conducted. In the initial nine patients per disease category, the impact of filgotinib on disease activity will be evaluated. The criteria for defining response are established based on the prior research and are detailed in Box 2. The outcomes of these scoring systems result in a binary outcome, namely, response or no response. The result of this interim analysis will determine whether a patient group proceeds to stage 2. A patient group needs at least one responder to continue.

The coprimary endpoints are change in quality of life and change in disease activity between baseline (before start treatment) and 26 weeks, which are both continuous parameters. As different disease activity indices are used between diseases, we will first standardise these scores per disease to obtain a z-score, which will be used in the primary analysis of the full cohort. The primary analysis will compare scores at 26 weeks with baseline scores using a paired t-test. To control the overall significance level, we will use the principle of a priori ordered hypotheses: first, the effect on disease activity is tested, and only in case of statistical significance there, the scores for quality of life will be tested. If both are significant, we will declare improvement statistically significant. We will also use linear regression with change from baseline as outcome, adjusting for baseline disease activity (z-score) and baseline quality of life, respectively. Change scores with 95% CIs will be calculated and reported. Using the above linear regression approach, disease groups will also be explored as covariates to evaluate differences in treatment effect between diseases separately for the coprimary endpoints. The same analysis will also be performed for changes over 13 weeks of treatment. To take the two time points of measurement of disease activity and quality of life into account, we will use a mixed model analysis adjusted for the repeated observations within patients using a random intercept (at patient level) as well as adjusting for baseline values of quality of life and disease activity, respectively.

Missing data will be replaced by multiple imputations by chained equations. The variables that will be included as predictors are the variables that we use in the main analysis of the study (both the outcomes and baseline data), more specifically age, sex at birth, number of hospitalisations in the last year, usage of immunosuppressants, disease category, number of oral ulcers in BD, TIS in myositis, IgG4-RD RI and EQ-5D-5L. A patient with missing data on disease activity in the interim analysis is considered a non-responder.