F Thion

K Isoird

D Planson

M-L Locatelli

H Ding

Simulation and design of junction termination structures for diamond Schottky diodes

In this paper, the first step of the design of a junction termination structure usable on diamond Schottky diodes is introduced. Through the collaboration AMPERE and LAAS laboratories, a study of junction termination structures using field plates and semiresistive materials was carried out. Several results from simulations of P type Schottky diodes protected by MESA coated with several layers of dielectric materials are shown in this paper. The analysis of those simulations, conducted on pseudo-vertical diodes protected by a field plate on a semi-resistive layer deposited on top of a dielectric, shows a great efficiency of such junction termination structures.

I. Introduction:

Diamond is well known for being an exceptional material. It has one of the best thermal conductivity and is amongst the toughest. It is also a promising candidate for power electronics, seeing its numerous theoretical qualities. As a wide band-gap semiconductor [START_REF] Nesladek | Conventional n-type doping in diamond: state of the art and recent progress[END_REF], [START_REF] Butler | Exceptionally high voltage schottky diamond diodes and low boron doping[END_REF], it is expected to be the material best suited for working under extreme conditions [START_REF] Raynaud | Comparison of high voltage and high temperature performances of wide bandgap semiconductors for vertical power devices[END_REF], [START_REF] Shenai | Optimum semiconductors for high-power electronics[END_REF]. The first unipolar diodes made on diamond start to appear in laboratories. They are elaborated on homo-epitaxied and in-situ doped substrates.

All power electronics components need a junction termination structure to limit the peripheral electric field. The particular properties of diamond (like permittivity, band gap, critical electric field) imply an adaptation of this structure.

With those first batches of components, we need to develop junction termination structures that will allow the diamond components to reach their full potential, mainly in terms of breakdown voltage. Since diamond has a huge theoretical critical electric field, the junction termination structure is going to have a major impact on the performance of the components. Those structures will allow us to demonstrate the efficiency of such diamond components.

II. Simulation platform:

The simulation platform has been developed using TCAD SENTAURUS, software based on a finite elements method. We have worked with models already implemented in the software, such as the ones used for silicon or for silicon carbide, tuning them to the diamond properties. The latter values are taken from a large bibliographic study (for instance [START_REF] Rashid | Numerical parameterization of chemical-vapor-deposited single-crystal diamond for device simulation and analysis[END_REF], [START_REF] Teraji | Highly efficient doping of boron into high quality homoepitaxial diamond films[END_REF]). However, it is reasonable to mention the fact that some values collected throughout the bibliographic study are extrapolated from other semiconductors, or underestimate its theoretical capabilities, mostly because of the poor quality of the samples on which the different studies were carried out. Nevertheless, the parameter file is regularly updated with the latest experimental results.

III. Junction termination structure: A: Introduction

The peripheral protection is a structure implemented during the process and is part of the design. This device is developed to reach the theoretical breakdown voltage (equivalent to the breakdown voltage of a plane parallel infinite junction), by spreading out the equipotentials at the junction periphery, hence avoiding local increases in the electric field which can lead to premature breakdown voltage. The efficiency of a peripheral junction protection is evaluated using the percentage of the theoretical breakdown voltage. Some steps of the process, like ion implant in diamond, are yet to be perfected and do not allow the use of standard peripheral protections, like guard rings or JTE (Junction Termination Extension). We then need to imagine peripheral protections based upon etching and layers of dielectrics and metals, such as the field plate protection technique as described in [START_REF] Brezeanu | Termination structures for diamond schottky barrier diodes[END_REF].

Using a layer of semi-resistive material is an alternative technique to minimize local increases of the electric field in the surface dielectric layer at the edge of the metallic contact. Since diamond electronic devices are intended to work at high temperatures, it seems interesting to study the behavior of semi-resistive materials used as field plate Indeed, resistivity decreases in a lot of dielectrics when the temperature rises. The simulated structure is introduced in Fig. 1. To make this pseudo-vertical structure, Schottky contact is deposited on top of the p-layer, doped at 8.10 15 cm -3 and 7 µm thick. To get to the p+ layer (doped at 3.10 20 cm -3 and 5 µm thick) and further to deposit the ohmic contact, the p-layer is etched. One or several layers of dielectric materials and a field plate are what make this peripheral protection. First, we studied the field plate with only one dielectric material. Then, we tested the result of the combination of a semi-resistive layer deposited on the chosen dielectric. The theoretical breakdown voltage of such a structure is 1500V at 600K. This breakdown voltage reaches 1990V at 800K. Taking into account an efficiency of 80% for the peripheral protection, we should reach the breakdown voltage of 1200V at 600K for the real structure.

B: Field plate on a dielectric material

A field plate is defined by two main parameters: the thickness of the dielectric and the length of the field plate.

First, the kind of dielectric used in the simulations is chosen between SiO2 and Si3N4, which are both available in the clean room of the laboratory. Simulations show that the bigger the permittivity is, the better is the breakdown voltage, as shown in Fig. 2. shows that the best breakdown voltage is obtained for field plates on Si3N4. We notice that the behavior is similar with both dielectrics: the thickness allows obtaining a critical value for the breakdown voltage and the field plate length provokes a saturation of the breakdown voltage for its higher values. Fig 3 . shows how the electric field spreads across the AA' axis of the structure. We notice two maximums: one at the edge of the Schottky contact and one at the edge of the field plate.

The best configuration is obtained when the two maxima have the same value, which is when the field plate is 10µm long. Hence, the maximum breakdown voltage is 1720V (84% efficiency) for a Si3N4 layer with a thickness of 900nm and a field plate of 10µm. In this case, simulations indicate that the carrier generation in diamond due to avalanche multiplication occurs at the Schottky contact edge. show respectively the equipotentials in the structure and the electric field in the silicon nitride at breakdown voltage. These results show that the value of the electric field in the dielectric layer is twice as much as its value in diamond (see Fig . 3), risking a rupture of the dielectric. Hence using a semi-resistive material may help the device breakdown value being closer to the theoretical one.

C: Field plate on a semi-resistive deposited on a layer of dielectric

1The simulated structure is the same, with an added layer of a semi-resistive material on a layer of Si3N4. 4Simulations show that the thickness of the semi-resistive layer does not influence the breakdown voltage: only its resistivity changes the level of leakage currents. 3The resistivity of a typical semi-resistive material is between 10 7 and 10 12 Ω.cm, depending mostly on the temperature. 2The main parameters used to tune the breakdown voltage of the structure are the thickness of the nitride, the thickness of the semi-resistive layer, the resistivity of the semi-resistive layer and the length of the field plate. 5Thus, the breakdown voltage is tuned using the same method as previously with the same two parameters: field plate length and Si3N4 thickness. Fig. 6 and Fig. 7 results show that the maximum breakdown voltage obtained is 1830V, for an efficiency of 92%, with a thickness of 540nm and a field plate length between 5 and 10 µm. Equipotentials are spread out along the whole semi-resistive layer (Fig. 6), which contributes to avoid the breakdown to occur at the edge of the field plate and instead puts it at the side of the p-layer, where the equipotentials tighten. Moreover, in Fig. 6 b), we notice that the value of the electric field is more than twice less in the nitride layer. By moving the position of the electrode of the ohmic contact, we can "choose" where the breakdown is going to happen, hence being able to deduce where the device is the most fragile.

D. Conclusion and perspectives

The peripheral junction protection based upon a combination of semi-resistive material resting upon a layer of silicon nitride seems to give promising results. The returned simulation efficiencies are respectively of 84% for a field plate on silicon nitride and of 92% with the help of a semi-resistive material. Optimizations can still be made on those designs. Hence extensive studies of diamond etching process and of the behavior of semi-resistive materials with temperature have to be carried out. New optimized devices will be realized in the near future.

Fig 1 :

 1 Fig 1: Simulated pseudo-vertical structure. The question marks are relative to the parameters we have modified.

Fig 2 :Fig 3 :

 23 Fig 2:3D views of the simulations of the diamond diode reverse characteristics protected by a field plate on two different dielectric materials. SiO2 is used on the left and Si3N4 is used on the right.

Fig 2 .

 2 Fig 2. shows that the best breakdown voltage is obtained for field plates on Si3N4. We notice that the behavior is similar with both dielectrics: the thickness allows obtaining a critical value for the breakdown voltage and the field plate length provokes a saturation of the breakdown voltage for its higher values.

Fig 4 :

 4 Fig 4: Equipotential lines in the structure, corresponding to the best structure configuration, while at breakdown.

Fig 5 :

 5 Fig 5: Electric field in the Si3N4 at the nitride/field plate interface, for different field plate length (between 5 µµ and 18 µµ), at the corresponding breakdown voltage values .

Fig 4 and 5

 5 Fig 4 and 5 show respectively the equipotentials in the structure and the electric field in the silicon nitride at breakdown voltage. These results show that the value of the electric field in the dielectric layer is twice as much as its value in diamond (see Fig .3), risking a rupture of the dielectric. Hence using a semi-resistive material may help the device breakdown value being closer to the theoretical one.

Fig 7 :

 7 Fig 7: Equipotential lines in the structure protected by a semi-resistive layer on top of a dielectric for the best structure configuration, while at breakdown.

Fig 6 :

 6 Fig 6: a) 3D view of the simulations of diamond diodes reverse characteristics protected by a field plate on a semi-resistive layer deposited on a Si3N4 layer. b) Value of the electric field at breakdown voltage on the AA' axis (top curves) and on the top edge of the nitride (bottom curves)


MD, PhD Julien Kirchgesner
email: julien.kirchgesner@gmx.com

PhD Rishi J Desai

MD Maria C Schneeweiss

MD, PhD Laurent Beaugerie

MD, ScD Sebastian Schneeweiss

MD, ScD Seoyoung C Kim

Decreased risk of

Introduction

Vedolizumab is the first biologic agent approved for the treatment of both inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD), after the era of tumor necrosis factor antagonists (anti-TNF). [START_REF] Feagan | Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis[END_REF][START_REF] Sandborn | Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease[END_REF] While the combination of infliximab and thiopurines is more effective than monotherapy with either of these drugs in patients with IBD, [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF][START_REF] Panaccione | Combination Therapy With Infliximab and Azathioprine Is Superior to Monotherapy With Either Agent in Ulcerative Colitis[END_REF] the impact of adding thiopurines with vedolizumab remains controversial. A meta-analysis including 2,053 patients with CD and 1,260 patients with UC treated with vedolizumab, among whom 933 patients were treated with the combination of vedolizumab and either thiopurines or methotrexate, reported no benefit of concomitant immunosuppressive therapy on clinical benefit in either CD or UC. [START_REF] Yzet | No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis[END_REF] In addition to the heterogeneous definition of clinical benefit across studies included, none of these studies were aimed to address this question and no adjustment for disease severity was possible, which limits the validity of the results. A recent study including 131 patients with IBD treated with the combination of vedolizumab and either thiopurines or methotrexate reported no differences in clinical response between combination therapy and vedolizumab monotherapy in the overall cohort of patients with IBD, but the effect differed according to IBD subtype, suggesting potential incremental effectiveness by adding a co-immunosuppressant with vedolizumab in CD but not UC. [START_REF] Hu | Combination Therapy Does Not Improve Rate of Clinical or Endoscopic Remission in Patients with Inflammatory Bowel Diseases Treated With Vedolizumab or Ustekinumab[END_REF] Ideally, this question would be addressed by a randomized controlled trial (RCT), but no dedicated RCTs are planned, [7] and it is unlikely that we will have RCT evidence any time soon. In the absence of RCT evidence, real-world evidence (RWE) derived from real-world data (RWD) can provide valuable information on treatment effectiveness based on the headto-head comparison. [START_REF] Schneeweiss | Real World Data in Adaptive Biomedical Innovation: A Framework for Generating Evidence Fit for Decision-Making[END_REF] We recently successfully conducted an RWD cohort study in the US and French claims databases and replicated the findings of the SONIC and SUCCESS trials for the effectiveness of infliximab and thiopurines compared to infliximab monotherapy by emulating the RCTs as closely as possible. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] This highlights the opportunities of principled RWE analysis by emulating RCT designs to study treatment effectiveness in patients with IBD in clinical practice when corresponding RCT data are lacking. [START_REF] Hernan | Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available[END_REF][START_REF] Franklin | When and How Can Real World Data Analyses Substitute for Randomized Controlled Trials?[END_REF] We aimed to emulate two target trials studying the effectiveness of combination therapy with vedolizumab and thiopurines compared to vedolizumab monotherapy in CD and UC.

Methods

Data source

This study was conducted by using two U.S. health care claims databases, IBM MarketScan databases are representative of a commercially insured population in the U.S.; the SNDS insures 95% of the French population. The two U.S. databases are de-identified and contain demographic data and longitudinal information on all encounters with the professional healthcare system while subjects are enrolled in the health plan, including hospitalisation, outpatient visits, procedures, and pharmacy dispensing. Similarly, the SNDS contains data on all drug reimbursements, inpatient and outpatient medical care prescribed or provided by healthcare professionals. [START_REF] Bezin | The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology[END_REF] The SNDS also includes the patient's status with respect to full reimbursement of care for long-term diseases (LTDs), which includes IBD and allows to assess the date of IBD diagnosis. [START_REF] Kirchgesner | Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014[END_REF] The study was approved by the institutional review board of the Brigham and Women's Hospital, and the French Data Protection Authority.

Design and study population

This observational study emulated two pragmatic clinical trials comparing the effectiveness of vedolizumab and thiopurines combined compared to vedolizumab monotherapy in patients with CD and UC, and it generally follows the approach used in the SONIC and SUCCESS trials. [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF][START_REF] Panaccione | Combination Therapy With Infliximab and Azathioprine Is Superior to Monotherapy With Either Agent in Ulcerative Colitis[END_REF] Variables assessed in clinical trials studying drugs for the treatment of IBD may not be included in RWD, notably clinical scores usually considered as effectiveness outcomes.

The emulation of RCTs by RWE studies may help to calibrate an effectiveness outcome measurable in RWD, that could be applied to other treatment comparisons within the same indication. Thus, we first developed an effectiveness outcome measure and a methodological approach for confounding adjustment, which allowed us to successfully replicate findings of the SONIC and the SUCCESS trials using the same databases included in this study. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] The same data and analytic framework was applied in this study. Supplementary table 1 outlines the protocol of such a trial and the emulation procedure.

We identified adults (≥18 years) with at least one visit for CD and UC using the International Classification of Diseases 9 th (ICD-9) or 10 th (ICD-10) Revision codes for CD and UC. In the SNDS database, CD and UC diagnoses were based on previously published algorithms, [START_REF] Kirchgesner | Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014[END_REF][15][16], and the date of CD or UC diagnosis was defined as the earliest diagnosis date either from hospital discharge diagnosis or from LTD diagnosis. Patients included in MarketScan and Optum databases were required to have continuous enrolment during the baseline period of 180 days before initiation of vedolizumab. Patients with CD and UC were separately assessed. Some patients may have diagnosis codes for both CD and UC during the baseline period.

While these patients are usually included in studies assessing the safety of IBD-related treatment, we excluded these patients in this study to increase the validity of the IBD subtype diagnosis.

Based on the previously emulated trials of SONIC and SUCCESS, [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] we excluded patients with tuberculosis, opportunistic infections within the previous 6 months, and patients with a previous history of cancer (excluding nonmelanoma skin cancer) any time prior. Since vedolizumab was only available in patients previously treated with or intolerant to anti-TNF in France during the study period and the majority of patients initiating vedolizumab are previously exposed to immunosuppressants,[17] we could not limit the study to immunosuppressants and biologic-naïve patients. However, we excluded patients previously exposed to other biologics or immunosuppressants than thiopurines, methotrexate, and anti-TNF, i.e., ustekinumab, tofacitinib, natalizumab. In order to select patients treated with only thiopurines combined with vedolizumab, we excluded patients exposed to methotrexate within 60 days prior cohort entry. Finally, the exclusion criteria related to IBD disease activity applied in the replicated trials of SONIC and SUCCESS were considered, [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] to minimize differences regarding IBD disease activity across these studies. For both CD and UC cohorts, patients with an ostomy, stricture, abscess, abdominal surgery, within the previous six months were excluded. Additionally, patients with UC hospitalized at vedolizumab initiation were excluded, as patients hospitalized for extensive severe UC were excluded in SUCCESS.

Patients initiating vedolizumab after January 1, 2014, were considered for inclusion, and the cohort entry date was defined as the date of treatment initiation. We considered an incident new user design as vedolizumab initiation was defined as not having used vedolizumab any time prior to first identification in the database. We performed an intention-to-treat analysis, and patients were followed up from the day after the cohort entry date until outcome occurrence, death, 112 days of follow-up (week 16) for patients with UC and 180 days of followup (week 26) for patients with CD, similarly as in SONIC and SUCCESS. [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF][START_REF] Panaccione | Combination Therapy With Infliximab and Azathioprine Is Superior to Monotherapy With Either Agent in Ulcerative Colitis[END_REF] Patients were allowed to enter the study cohort only once.

Treatment groups

Since a majority of patients who are initiating vedolizumab in real life are previously exposed to thiopurines, patients previously exposed to thiopurines were not excluded. Combination therapy was defined as starting vedolizumab with a concomitant exposure of thiopurines within 30 days before vedolizumab initiation. Since thiopurines have a long half-life of several days and a delayed immunological recovery upon discontinuation of therapy is expected, [18] we extended the wash-out period to 60 days without any thiopurines exposure before vedolizumab initiation for the definition of vedolizumab monotherapy.

Thiopurines exposure was based on the collected days' supply for each prescription fill registered in the US databases. In the French databases, patients were considered as being exposed to thiopurines for one month following delivery, as thiopurines are dispensed by French pharmacies, which are authorized to deliver one month supply of treatment. These definitions were previously used. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF]15,19]

Outcome

We used the same outcome definition that was validated in the emulated trials of SONIC and SUCCESS. This outcome definition allowed us to replicate RCTs relative risk of corticosteroids-free clinical remission based on a CD Activity Index less than 150 points without any systemic corticosteroid use in SONIC and a total Mayo score of two points or less, with no individual subscore exceeding one point and without any systemic corticosteroid use in SUCCESS. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] The composite effectiveness outcome measure was based on three surrogate endpoints for treatment failure: (1) hospitalisation or surgery related to CD or UC;

(2) treatment switch to another biologic drug (infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, or ustekinumab) or a small molecule (tofacitinib); or (3) exposure to systemic corticosteroids at week 16 in patients with UC or week 26 in patients with CD. Related codes are summarized in Supplementary Table 2.

Adverse events including serious infections were also assessed based on previously published identification algorithms and hospitalisation not related to IBD during follow-up. [16,20]

Patient characteristics

The same range of covariates assessed in the two emulated trials of SONIC and SUCCESS were assessed. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] Patients previously exposed to anti-TNFs were included in the present study, while they were excluded in the two replicated trials; we therefore additionally assessed anti-TNFs exposure within 180 days before vedolizumab initiation and the number of previous anti-TNF agents was assessed within all data available since first identification in the database.

Baseline patient characteristics and markers of CD and UC phenotype and severity were considered, including demographics and comorbidities (previous serious infections, Clostridioides difficile infection, cardiovascular disease, chronic kidney failure, chronic liver disease, chronic pulmonary disease, venous thromboembolism, and diabetes). Comorbidities were assessed in the 180 days before cohort entry in MarketScan and Optum and any time prior to cohort entry in the SNDS. CD phenotype included Montreal phenotype,[21] including inflammatory (B1), stricturing (B2), and penetrating phenotype (B3), as well as perianal involvement. Hospitalization for complicated CD courses (stricture or abscess) and surgery related to CD occurring more than 180 days before cohort entry were also assessed. CD and UC severity and healthcare use intensity were assessed in the 180 days before cohort entry in all databases. CD and UC severity was assessed by corticosteroids and aminosalicylates exposure, the occurrence of CD-related hospitalization or surgery or UC-related hospitalization, abdominal imaging, gastrointestinal endoscopy, fecal pathogen, and the number of C-reactive protein tests ordered. Healthcare use was assessed by hospitalizations not related to CD or UC and the number of gastroenterologist visits.

Statistical analysis

To control for confounding, we calculated a propensity score (PS) for each patient predicting the probability of initiating vedolizumab and thiopurines combined versus vedolizumab monotherapy with logistic regression, including all measured baseline covariates without further variable selection and the year of cohort entry. [22] We matched treatment groups 1:1 on their PS within a caliper of 0.02 on the PS scale.[23] After matching, standardized differences were calculated to assess the balance between patients exposed to combination therapy and those exposed to vedolizumab monotherapy. [24] After PS matching, Log-binomial regression models were used to estimate adjusted risk ratios (RR) with their 95% CIs comparing the risk of treatment failure associated with combination therapy versus vedolizumab monotherapy.[25] PS and outcome models were separately applied for each IBD subtype and each database. Database-specific RRs were combined separately for each IBD subtype by an inverse variance-weighted, fixed-effects model. [26] Additional prespecified analyses included secondary analyses assessing the risk of each component of the composite endpoint, and subgroup analyses stratified on previous exposure to anti-TNF, exposure to corticosteroids at vedolizumab initiation, on Montreal phenotype (B1 and B2-B3 combined) and the presence of perianal involvement in patients with CD. Sensitivity analyses were performed to test the robustness of our results. First, variables with an absolute standardized difference greater than 0.1 after PS-matching were included as covariates for further adjustment in log-binomial regression models.[27] Second, we performed a PS matched analysis with a variable ratio up to 1:4 with a caliper of 0.02 on the PS scale. Third, we excluded patients with an enrollment period of less than one year before cohort entry in the US databases. Finally, we performed a post-hoc sensitivity analysis assessing treatment failure at week 26 in patients with UC, to assess a potential delayed response associated with thiopurines at week 26.

Analyses were performed using the validated Aetion Evidence Platform (v4.30) including R(v3. 4.2) [28-31] and SAS (v9.4) statistical software (SAS Institute).

Patient involvement

Patients and the public were not involved in the design, conduct, or dissemination plans of this research.

Results

Patient characteristics

A total of 6615 and 6649 patients with CD and UC who initiated vedolizumab were identified across the three databases, respectively. After applying the exclusion criteria (Supplementary Figures 1 and2), 4674 CD and 5625 UC patients were included. Of those, 829 (18.2%) CD and 1120 (16.8%) UC patients were treated with combination therapy (Supplementary Tables 3 and4). Among patients included in the combination therapy group, 1828 (93.8%) (CD, n=787

[94.9%]; UC, n=1041 [92.9%]) were exposed to thiopurines more than 30 days before cohort entry.

Overall, 97.0% and 97.1% of patients with CD and UC treated with combination therapy were matched to patients with vedolizumab monotherapy. Among patients treated with vedolizumab monotherapy, 89.8% and 93.2% of patients with CD and UC were able to match with at least one patient treated with combination therapy. After PS matching, the cohorts contained 804 and 1088 pairs of patients with CD and UC, respectively. Anti-TNF agents were previously used in 1343 (83.5%) and 1620 (74.4%) patients with CD and UC, while 515 (32.0%) and 929 (42.7%) patients with CD and UC were treated with corticosteroids at vedolizumab initiation, respectively (Tables 1 and2). Overall, 96% of the covariates had an absolute standardized difference lower than 0.1 which typically indicates adequate balance. [27] No covariates had an absolute standardized difference greater than 0.2 (Supplementary Figure 3). patients initiating combination therapy and vedolizumab monotherapy, respectively (Figure 1).

Among patients with treatment failure, hospitalization or surgery related to CD was the most frequent outcome, accounting for 47% and 43% of outcomes in patients initiating combination therapy and vedolizumab monotherapy. The proportion of patients with treatment failure according to databases after PS-matching is provided in Supplementary Table 5.

Patients initiating combination therapy had a 15% decreased risk of treatment failure compared to patients initiating infliximab monotherapy (RR 0.85, 95%CI 0.74 to 0.98) (Figure 2). Results

were similar across the three databases (RR 0.87, 95%CI 0.68 to 1.12, RR 0.88, 95%CI 0.64 to 1.21, and RR 0.83, 95%CI 0.68 to 0.98) in MarketScan, Optum, and SNDS, respectively).

A similar trend was observed for all secondary endpoints, notably for hospitalization or surgery related to CD (RR 0.78, 95% CI 0.62 to 0.99) (Figure 2).

Ulcerative colitis

In the PS matched cohort, 236 (21.7%) and 263 (24.2%) patients were in treatment failure at week 16 after initiating combination therapy and vedolizumab monotherapy, respectively.

Exposure to corticosteroids at week 16 was the most frequent outcome, accounting for 62% and 66% of outcomes in patients initiating combination therapy and vedolizumab monotherapy.

Treatment switch only accounted for 19% and 27% of outcomes in patients initiating combination therapy and vedolizumab monotherapy.

The risk of treatment failure differed little between combination therapy and vedolizumab monotherapy (RR 0.90, 95%CI 0.77 to 1.05), with similar findings across all secondary endpoints (Figure 3).

Secondary analysis, subgroup and sensitivity analyses

Rates of serious infections and hospitalisations not related to IBD did not differ between the two treatment groups. (Supplementary Table 6)

Overall, we observed no meaningful variation in treatment failure risks across subgroups (Figure 4). While the risk of treatment failure associated with combination therapy versus vedolizumab monotherapy appeared to be lower in anti-TNF experienced compared to anti-TNF naïve patients with CD (RR 0.90, 95%CI 0.77 to 1.05, and RR 1.26, 95%CI 0.71 to 2.25, respectively), this trend was not observed in anti-TNF experienced compared to anti-TNF naïve patients with UC (RR 0.93, 95%CI 0.79 to 1.10, and RR 0.98, 95%CI 0.65 to 1.46, respectively). In patients treated with corticosteroids at vedolizumab initiation, the combined RR was 0.87 (95%CI 0.71 to 1.08) and 1.01 (95%CI 0.83 to 1.23) in CD and UC, respectively.

In patients with CD, the combined RR for treatment failure associated with combination therapy versus vedolizumab monotherapy was 0.95 (95%CI 0.78 to 1.15) and 0.87 (95%CI 0.69 to 1.11) in patients with inflammatory phenotype and patients with stricturing or penetrating phenotypes, respectively. The various sensitivity analyses yielded consistent results

(Supplementary Table 7). Extending follow-up to week 26 in UC did not modify the results (RR 0.94, 95%CI 0.83 to 1.06). [32] Since IBD disease activity is an independent risk factor for serious infections, these findings may be related to effectiveness differences of combination therapy compared to vedolizumab monotherapy between IBD subtypes. Our findings are in line with these studies, while we included more than 10,000 patients starting vedolizumab and the number of PS-matched patients treated with vedolizumab and thiopurines was two-fold higher than that of the meta-analysis. This allows us to perform two dedicated target trials according to the IBD subtype with an adequate sample size.

Although statistically not significant, the magnitude in relative risk reduction associated with combination therapy was 10% at week 16 in patients with UC, compared to 15% at week 26 in patients with CD. In a post-hoc sensitivity analysis, we extended the follow-up to week 26 in patients with UC, to assess a potential delayed response of thiopurines, which was not supported by the results with a magnitude in relative risk reduction of 5%. The relative risk reduction of 15% of treatment failure associated with combination therapy should be interpreted in light of the relative risk reduction of treatment failure reported with the combination of anti-TNF and thiopurines. In the SONIC trial, the relative risk reduction associated with the combination of infliximab and thiopurines compared to infliximab monotherapy was of 22% (RR 0.78, 95%CI 0.62 to 0.97), [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF] which, along with the decreased risk of immunogenicity, led to recommend combination therapy in patients with moderate-tosevere CD initiating infliximab.

[33] It highlights the clinical relevance of the relative risk reduction observed with the combination of vedolizumab and thiopurines in patients with CD.

Adding thiopurines to vedolizumab was associated with a lower risk of treatment failure in CD, and possibly to a lesser extent in UC. The mechanism of action for incremental effectiveness by adding thiopurines to vedolizumab remains to be elucidated. Vedolizumab clearance may not be influenced by the addition of an immunosuppressant and the development of anti-drug antibodies is uncommon.

[34] Vedolizumab effectiveness may differ according to IBD subtypes with potential lower effectiveness in anti-TNF experienced patients with CD,[35] the incremental effectiveness of thiopurines observed in our study may be related to its individual effectiveness per se. Notably, we observed a trend for higher effectiveness of combination therapy in anti-TNF experienced compared to anti-TNF naïve patients with CD.

Calibration of RWE studies against treatment effect assessed in RCTs allows evaluating whether RWE can support causal conclusions if conducted using robust methodology. [31] We first replicated the findings of the SONIC and SUCCESS trials assessing the effectiveness of combination therapy with infliximab and thiopurines compared to infliximab monotherapy in patients with IBD. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] Using this approach, we were able to develop an effectiveness outcome measure that could be used in future studies assessing the effectiveness of IBD related treatment, notably add-on strategies with other treatments than infliximab. Similarly, we considered the same exclusion criteria related to IBD disease activity and the same covariates in the propensity score model, only adding in the PS model the number of previous anti-TNF agents and previous exposure to anti-TNF in the 180 days before vedolizumab initiation, since we included anti-TNF experienced patients and previous anti-TNF exposure has an impact on vedolizumab effectiveness. [36] This robust methodology strengthens our findings.

We used PS matching, as the PS focuses directly on the indications for use and non-use of the drug under study compared to conventional multivariable methods. Discarding unmatched observations is a consequence of limited overlap in patients' covariate distributions and as such increase validity and reduce generalizability to those patients that have treatment equipoise.

[37] In this study, 97% of patients treated with combination therapy were matched to patients with vedolizumab monotherapy.

One of the main strengths of our study is the generalizability and large size as we used two large U.S. and one French nationwide population-based cohorts, which allows assessing not only the impact of differences in population selection, data collection and follow-up between the databases but also treatment effectiveness in different healthcare schemes and potential prescribing patterns. While healthcare is guaranteed for all French residents and patients are followed from birth to emigration or death in the French database, the US databases only included commercially insured patients and health insurance enrollment changes may reduce the enrollment period to assess covariates. Results were consistent across databases, which suggests that these differences had a minimal impact on the treatment estimate observed.

Some limitations should be noted. We were not able to exclude prevalent users of thiopurines in the combination therapy group, since the vast majority of patients exposed to vedolizumab are previously treated with thiopurines in a real-life setting. In our study, prevalent users of thiopurines accounted for 94% of patients included in the combination therapy group before PS-matching. However, we applied a stringent definition to define vedolizumab monotherapy with a mandatory wash-out period of 60 days without any thiopurines exposure. Thiopurines dose and 6-tioguanine levels were not available. Further research is needed to assess if a specific threshold is applied to vedolizumab. [38] There is no validation study assessing the accuracy of the Montreal classification in the U.S or French databases. However, assessing

IBD phenotype may decrease the potential for confounding by indication.

[36] Endoscopic and histological data were not available, and residual confounding by these factors cannot be entirely ruled out. To minimize potential confounding by indication, we used a previously validated definition of treatment failure and adjusted for IBD disease severity similarly as in the two replicated trials of SONIC and SUCCESS. [START_REF] Kirchgesner | Calibrating Real-World Evidence Studies Against Randomized Trials: Treatment Effectiveness of Infliximab in Crohn's Disease[END_REF][START_REF] Kirchgesner | Emulation of a randomized controlled trial in ulcerative colitis with US and French claims data: Infliximab with thiopurines compared to infliximab monotherapy[END_REF] Follow-up was censored at week 26 and 16 in CD and UC. [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF][START_REF] Panaccione | Combination Therapy With Infliximab and Azathioprine Is Superior to Monotherapy With Either Agent in Ulcerative Colitis[END_REF] The impact of continuing thiopurines during a longer period should be further assessed.

In summary, this study based on three large population-based cohorts of patients with IBD in both the U.S. and France provides evidence that combination therapy with vedolizumab and thiopurines is more effective compared to vedolizumab monotherapy in patients with CD and possibly less so with UC. These findings will help guide clinical decision-making in patients with IBD starting vedolizumab.

(

  MarketScan) 2009-2018 and Optum's de-identified Clinformatics® Data Mart Database (Optum) 2009-2020, and the French administrative health database 2009-2018 (Système National des Données de Santé, SNDS). Patients enrolled in the MarketScan and Optum

Figure 1 .Figure 2 .Figure 3 .

 123 Figure 1. Outcomes, propensity score-matched with a 1:1 fixed ratio in Crohn's disease (A) and ulcerative colitis (B)

Figure 4 .

 4 Figure 4. Risk ratios for treatment failure associated with combination therapy with vedolizumab and thiopurines compared to vedolizumab monotherapy in Crohn's disease (A) and ulcerative colitis (B): subgroup analysis

Figure 1 .Figure 2 .Figure 3 .Figure 4 .

 1234 Figure 1. Outcomes, propensity score-matched with a 1:1 fixed ratio in Crohn's disease (A) and ulcerative colitis (B)

Table 1 . Characteristics of study patients with Crohn's disease treated with vedolizumab monotherapy or vedolizumab and thiopurines, propensity score-matched with a 1:1 fixed ratio

 1

	MarketScan	Optum	SNDS

Table 1 . Characteristics of study patients with Crohn's disease treated with vedolizumab monotherapy or vedolizumab and thiopurines, propensity score-matched with a 1:1 fixed ratio (continued)

 1

		MarketScan	Optum	SNDS
		Vedolizumab monotherapy (n=325)	Vedolizumab and thiopurines (n=325)	Vedolizumab monotherapy (n=211)	Vedolizumab and thiopurines (n=211)	Vedolizumab monotherapy (n=268)	Vedolizumab and thiopurines (n=268)
	Crohn's disease complicated disease
	course
	More than 180 days before cohort entry	33 (10.2)	41 (12.6)	25 (11.8)	18 (8.5)	(24.6)	63 (23.5)
	Surgery related to Crohn's disease
	More than 180 days before cohort entry	50 (15.4)	54 (16.6)	34 (16.1)	29 (13.7)	102 (38.1)	106 (39.6)
	Number of prior anti-TNFs
	0	65 (20.0)	69 (21.2)	65 (30.8)	66 (31.3)	-	-
	1	167 (51.4)	157 (48.3)	102 (48.3)	101 (47.9)	(28.4)	81 (30.2)
	2	72 (22.2)	81 (24.9)	34 (16.1)	33 (15.6)	166 (61.9)	167 (62.3)
	3	21 (6.5)	18 (5.5)	10 (4.7)	11 (5.2)	26 (9.7)	20 (7.5)
	Anti-TNF within 180 days before
	cohort entry	172 (52.9)	171 (52.6)	102 (48.3)	107 (50.7)	215 (80.2)	214 (79.9)
	Corticosteroids (oral)
	within 180 days before cohort entry	214 (65.8)	217 (66.8)	130 (61.6)	134 (63.5)	156 (58.2)	140 (52.2)
	at cohort entry	102 (31.4)	98 (30.2)	62 (29.4)	69 (32.7)	(36.9)	85 (31.7)
	Aminosalicylates (oral)	151 (46.5)	147 (45.2)	82 (38.9)	84 (39.8)	176 (65.7)	169 (63.1)
	Opioids	140 (43.1)	131 (40.3)	87 (41.2)	86 (40.8)	(11.9)	33 (12.3)
	Crohn's disease activity assessment †
	Hospitalisation related to Crohn's
	disease	32 (9.8)	25 (7.7)	11 (5.2)	12 (5.7)	(20.5)	57 (21.3)
	Abdominal imaging	113 (34.8)	113 (34.8)	91 (43.1)	89 (42.2)	130 (48.5)	120 (44.8)
	Lower GI endoscopy	163 (50.2)	153 (47.1)	92 (43.6)	90 (42.7)	130 (48.5)	129 (48.1)
	Upper GI endoscopy	45 (13.8)	46 (14.2)	33 (15.6)	27 (12.8)	(17.2)	45 (16.8)
	CRP tests ordered, mean (SD)	1.23 (1.47)	1.28 (1.63)	1.78 (3.98)	1.76 (2.07)	3.38 (2.72)	3.53 (2.67)
	Fecal pathogen tests ordered	68 (20.9)	60 (18.5)	42 (19.9)	45 (21.3)	(17.2)	39 (14.6)
	Comorbidities
	Clostridioides difficile infection	8 (2.5)	5 (1.5)	1 (0.5)	3 (1.4)	9 (3.4)	5 (1.9)
	Serious infection	13 (4.0)	6 (1.8)	6 (2.8)	4 (1.9)	4 (1.5)	4 (1.5)
	Cardiovascular disease	14 (4.3)	16 (4.9)	25 (11.8)	23 (10.9)	20 (7.5)	22 (8.2)
	Chronic kidney failure	2 (0.6)	4 (1.2)	12 (5.7)	11 (5.2)	5 (1.9)	5 (1.9)
	Chronic liver disease	3 (0.9)	5 (1.5)	19 (9.0)	16 (7.6)	6 (2.2)	3 (1.1)
	Chronic pulmonary disease	44 (13.5)	44 (13.5)	53 (25.1)	41 (19.4)	(29.1)	85 (31.7)
	Venous thromboembolism	7 (2.2)	7 (2.2)	9 (4.3)	7 (3.3)	7 (2.6)	11 (4.1)
	Diabetes	15 (4.6)	16 (4.9)	17 (8.1)	15 (7.1)	10 (3.7)	9 (3.4)
	Healthcare use characteristics †
	Hospitalizations not related to
	Crohn's disease	32 (9.8)	20 (6.2)	27 (12.8)	21 (10.0)	18 (6.7)	23 (8.6)
	Gastroenterologist visits, mean (SD) 5.69 (7.41)	5.42 (7.13)	7.06 (8.13)	6.69 (9.80)	3.74 (4.89)	3.71 (5.76)

Data are n (%) unless otherwise stated. † Assessed within 180 days before cohort entry

Table 2 . Characteristics of study patients with ulcerative colitis treated with vedolizumab monotherapy or vedolizumab and thiopurines, propensity score-matched with a 1:1 fixed ratio

 2

	MarketScan	Optum	SNDS

Data are n (%) unless otherwise stated. † Assessed within 180 days before cohort entry

Table 3

 3

	. Characteristics of study patients with Crohn's disease
	treated with vedolizumab monotherapy or vedolizumab and thiopurines, before propensity
	score-matching
	Page 7-8. Supplementary Table 4. Characteristics of study patients with ulcerative colitis
	treated with vedolizumab monotherapy or vedolizumab and thiopurines, before propensity
	score-matching
	Page 9. Supplementary

Table 5 .

 5 Outcomes, propensity score-matched with a 1:1 fixed ratio Page 10. Supplementary Table6. Adverse events, propensity score-matched with a 1:1 fixed ratio Page 11. Supplementary Table7. Relative risk of treatment failure in patients treated with combination therapy versus vedolizumab monotherapy, sensitivity analyses Page 12. Supplementary Figure1. Study population flowchart, patients with Crohn's disease Page 13. Supplementary Figure2. Study population flowchart, patients with ulcerative colitis

	Page 14. Supplementary Figure 3. Standardized differences before and after propensity score
	matching (Crohn's disease, MarketScan [A], Optum[B], and SNDS [C]; ulcerative colitis,
	MarketScan [D], Optum[E], and SNDS [F])

Table 3 . Characteristics of study patients with Crohn's disease treated with vedolizumab monotherapy or vedolizumab and thiopurines, before propensity score-matching

 3

		MarketScan	Optum	SNDS
	Variable	Vedolizumab monotherapy (n=1471)	Vedolizumab and thiopurines (n=326)	Vedolizumab monotherapy (n=1233)	Vedolizumab and thiopurines (n=214)	Vedolizumab monotherapy (n=1141)	Vedolizumab and thiopurines (n=289)
	Age, mean (SD), year	42.3 (14.3)	41.2 (12.7)	46.5 (17.2)	43.1 (14.5)	39.2 (13.6)	36.1 (12.0)
	Sex
	Male	608 (41.3)	128 (39.3)	527 (42.7)	91 (42.5)	(36.9)	112 (38.8)
	Female	863 (58.7)	198 (60.7)	706 (57.3)	123 (57.5)	(63.1)	177 (61.2)
	Crohn's disease duration, mean (SD), year	-	-	-	-	9.9 (6.5)	9.4 (6.4)
	Montreal phenotype
	B1	784 (53.3)	158 (48.5)	695 (56.4)	104 (48.6)	(64.9)	208 (72.0)
	B2	348 (23.7)	85 (26.1)	288 (23.4)	50 (23.4)	(19.3)	55 (19.0)
	B3	339 (23.0)	83 (25.5)	250 (20.3)	60 (28.0)	(15.9)	26 (9.0)
	Perianal Crohn's disease	156 (10.6)	40 (12.3)	64 (5.2)	19 (8.9)	(28.1)	91 (31.5)
	Crohn's disease complicated
	disease course
	More than 180 days before cohort entry	142 (9.7)	41 (12.6)	114 (9.2)	18 (8.4)	(27.6)	69 (23.9)
	Surgery related to Crohn's
	disease
	More than 180 days before cohort entry	236 (16.0)	54 (16.6)	171 (13.9)	30 (14.0)	(40.2)	115 (39.8)
	Number of prior anti-TNFs
	0	421 (28.6)	69 (21.2)	509 (41.3)	66 (30.8)	-	-
	1	707 (48.1)	157 (48.2)	543 (44.0)	101 (47.2)	(37.2)	84 (29.1)
	2	294 (20.0)	81 (24.8)	155 (12.6)	33 (15.4)	(55.0)	183 (63.3)
	3	49 (3.3)	18 (5.5)	26 (2.1)	14 (6.5)	(7.0)	22 (7.6)
	4	0 (0.0)	1 (0.3)	0 (0.0)	0 (0.0)	8 (0.7)	0 (0.0)
	Anti-TNF within 180 days
	before cohort entry	678 (46.1)	172 (52.8)	488 (39.6)	110 (51.4)	(70.2)	233 (80.6)
	Corticosteroids (oral)
	within 180 days before
	cohort entry	924 (62.8)	218 (66.9)	645 (52.3)	137 (64.0)	(52.9)	152 (52.6)
	at cohort entry	443 (30.1)	99 (30.4)	326 (26.4)	70 (32.7)	(27.5)	99 (34.3)
	Aminosalicylates (oral)	648 (44.1)	148 (45.4)	467 (37.9)	86 (40.2)	(64.8)	183 (63.3)
	Opioids	643 (43.7)	132 (40.5)	412 (33.4)	88 (41.1)	(15.4)	33 (11.4)
	Crohn's disease activity
	assessment †
	Hospitalization related to
	Crohn's disease	91 (6.2)	26 (8.0)	83 (6.7)	12 (5.6)	(19.0)	66 (22.8)
	Abdominal imaging	495 (33.7)	114 (35.0)	475 (38.5)	90 (42.1)	(41.3)	136 (47.1)
	Lower GI endoscopy	530 (36.0)	154 (47.2)	512 (41.5)	90 (42.1)	(46.0)	144 (49.8)
	Upper GI endoscopy	186 (12.6)	47 (14.4)	187 (15.2)	27 (12.6)	(14.5)	50 (17.3)
	CRP tests ordered, mean
	(SD)	0.97 (1.35)	1.30 (1.67)	1.46 (2.23)	1.76 (2.06)	3.12 (2.64)	3.84 (3.25)
	Fecal pathogen tests
	ordered	230 (15.6)	61 (18.7)	247 (20.0)	46 (21.5)	(11.7)	43 (14.9)

Table 3 . Characteristics of study patients with Crohn's disease treated with vedolizumab monotherapy or vedolizumab and thiopurines, before propensity score-matching (continued)

 3

		MarketScan	Optum	SNDS
	Variable	Vedolizumab monotherapy (n=1471)	Vedolizumab and thiopurines (n=326)	Vedolizumab monotherapy (n=1233)	Vedolizumab and thiopurines (n=214)	Vedolizumab monotherapy (n=1141)	Vedolizumab and thiopurines (n=289)
	Comorbidities
	clostridioides difficile
	infection	33 (2.2)	5 (1.5)	28 (2.3)	3 (1.4)	37 (3.2)	6 (2.1)
	Serious infection	26 (1.8)	6 (1.8)	21 (1.7)	4 (1.9)	16 (1.4)	7 (2.4)
	Cardiovascular disease	113 (7.7)	16 (4.9)	142 (11.5)	23 (10.7)	120 (10.5)	22 (7.6)
	Chronic kidney failure	38 (2.6)	4 (1.2)	54 (4.4)	11 (5.1)	30 (2.6)	5 (1.7)
	Chronic liver disease	34 (2.3)	6 (1.8)	96 (7.8)	16 (7.5)	25 (2.2)	3 (1.0)
	Chronic pulmonary disease	231 (15.7)	44 (13.5)	205 (16.6)	41 (19.2)	393 (34.4)	90 (31.1)
	Venous thromboembolism	36 (2.4)	8 (2.5)	28 (2.3)	7 (3.3)	60 (5.3)	11 (3.8)
	Diabetes	94 (6.4)	16 (4.9)	128 (10.4)	15 (7.0)	60 (5.3)	9 (3.1)
	Healthcare use characteristics †
	Hospitalizations not related
	to Crohn's disease	124 (8.4)	20 (6.1)	95 (7.7)	21 (9.8)	108 (9.5)	26 (9.0)
	Gastroenterologist visits,
	mean (SD)	4.63 (6.25)	5.40 (7.12)	5.72 (6.98)	6.70 (9.74)	3.74 (4.81)	3.61 (5.72)
	Data are n (%) unless otherwise stated.

† Assessed within 180 days before cohort entry Supplementary

Table 4 . Characteristics of study patients with ulcerative colitis treated with vedolizumab monotherapy or vedolizumab and thiopurines, before propensity score-matching

 4

		MarketScan	Optum	SNDS
	Variable	Vedolizumab monotherapy (n=1684)	Vedolizumab and thiopurines (n=445)	Vedolizumab monotherapy (n=1649)	Vedolizumab and thiopurines (n=325)	Vedolizumab monotherapy (n=1172)	Vedolizumab and thiopurines (n=350)
	Age, mean (SD), year	41.6 (14.5)	41.2 (13.6)	45.0 (17.0)	43.2 (15.6)	44.1 (15.9)	39.3 (13.8)
	Sex
	Male	840 (49.9)	211 (47.4)	783 (47.5)	155 (47.7)	(49.8)	188 (53.7)
	Female	844 (50.1)	234 (52.6)	866 (52.5)	170 (52.3)	(50.2)	162 (46.3)
	Ulcerative colitis disease duration (years), mean (SD)	-	-	-	-	7.8 (5.8)	6.7 (5.2)
	Number of prior anti-TNFs
	0	640 (38.0)	135 (30.3)	831 (50.4)	138 (42.5)	-	-
	1	760 (45.1)	226 (50.8)	660 (40.0)	145 (44.6)	(47.4)	162 (46.3)
	2	255 (15.1)	72 (16.2)	146 (8.9)	39 (12.0)	(42.6)	172 (49.1)
	3	27 (1.6)	12 (2.7)	10 (0.6)	3 (0.9)	112 (9.6)	16 (4.6)
	4	2 (0.1)	0 (0)	2 (0.1)	0 (0)	5 (0.4)
	Anti-TNF within 180 days before cohort entry	824 (48.9)	246 (55.3)	688 (41.7)	158 (48.6)	(82.1)	315 (90.0)
	Aminosalicylates (oral) at cohort entry	563 (33.4)	170 (38.2)	553 (33.5)	119 (36.6)	(30.0)	95 (27.1)
	Corticosteroids (oral)
	within 180 days before cohort entry	1234 (73.3)	345 (77.5)	1137 (69.0)	240 (73.8)	(65.8)	244 (69.7)
	at cohort entry	702 (41.7)	193 (43.4)	652 (39.5)	134 (41.2)	(37.5)	156 (44.6)
	Opioids	537 (31.9)	151 (33.9)	341 (20.7)	55 (16.9)	(10.2)	27 (7.7)
	Ulcerative colitis activity
	assessment †
	Hospitalization related to ulcerative colitis	147 (8.7)	43 (9.7)	160 (9.7)	28 (8.6)	(14.3)	55 (15.7)
	Abdominal imaging	233 (13.8)	77 (17.3)	364 (22.1)	54 (16.6)	(14.8)	69 (19.7)
	Lower GI endoscopy	912 (54.2)	245 (55.1)	929 (56.3)	195 (60.0)	(64.8)	255 (72.9)
	Upper GI endoscopy	127 (7.5)	21 (4.7)	128 (7.8)	17 (5.2)	100 (8.5)	34 (9.7)
	CRP tests ordered, mean (SD)	1.03 (1.34)	1.44 (2.10)	1.60 (1.80)	1.60 (1.91)	3.59 (2.75)	4.27 (3.57)
	Fecal pathogen tests ordered	563 (33.4)	182 (40.9)	666 (40.4)	133 (40.9)	(25.3)	97 (27.7)
	Comorbidities
	clostridioides difficile infection	89 (5.3)	30 (6.7)	87 (5.3)	13 (4.0)	(3.6)	17 (4.9)
	Serious infection	25 (1.5)	3 (0.7)	30 (1.8)	5 (1.5)	(1.5)	6 (1.7)
	Cardiovascular disease	144 (8.6)	25 (5.6)	190 (11.5)	29 (8.9)	(12.3)	27 (7.7)
	Chronic kidney failure	37 (2.2)	6 (1.3)	52 (3.2)	5 (1.5)	(1.5)	3 (0.9)
	Chronic liver disease	26 (1.5)	2 (0.4)	106 (6.4)	17 (5.2)	(2.2)	7 (2.0)
	Chronic pulmonary disease	227 (13.5)	52 (11.7)	230 (13.9)	38 (11.7)	(29.1)	74 (21.1)
	Venous thromboembolism	40 (2.4)	6 (1.3)	46 (2.8)	15 (4.6)	(4.1)	10 (2.9)
	Diabetes	117 (6.9)	38 (8.5)	173 (10.5)	32 (9.8)	108 (9.2)	27 (7.7)

Table 4 . Characteristics of study patients with ulcerative colitis treated with vedolizumab monotherapy or vedolizumab and thiopurines, before propensity score-matching (continued)

 4 Data are n (%) unless otherwise stated. † Assessed within 180 days before cohort entry Supplementary

		MarketScan	Optum	SNDS
	Variable	Vedolizumab monotherapy (n=1684)	Vedolizumab and thiopurines (n=445)	Vedolizumab monotherapy (n=1649)	Vedolizumab and thiopurines (n=325)	Vedolizumab monotherapy (n=1172)	Vedolizumab and thiopurines (n=350)
	Healthcare use
	characteristics †
	Hospitalizations not
	related to ulcerative	85 (5.0)	21 (4.7)	109 (6.6)	20 (6.2)	99 (8.4)	16 (4.6)
	colitis
	Gastroenterologist visits, mean (SD)	5.39 (6.61)	5.96 (7.81)	6.32 (7.19)	6.65 (7.89)	5.33 (6.26)	5.41 (6.86)

Table 5 . Outcomes, propensity score-matched with a 1:1 fixed ratio

 5

		MarketScan	Optum	SNDS	Overall cohort
	Crohn's disease	Vedolizumab monotherapy (n=325)	Vedolizumab and thiopurines (n=325)	Vedolizumab monotherapy (n=211)	Vedolizumab and thiopurines (n=211)	Vedolizumab monotherapy (n=268)	Vedolizumab and thiopurines (n=268)	Vedolizumab monotherapy (n=804)	Vedolizumab and thiopurines (n=804)
	Treatment failure	95 (29.2)	83 (25.5)	59 (28.0)	52 (24.6)	122 (45.5)	101 (37.7)	276 (34.3)	236 (29.4)
	Hospitalisation or surgery related to CD	40 (12.3)	30 (9.2)	25 (11.8)	23 (10.9)	71 (26.5)	54 (20.1)	136 (16.9)	107 (13.3)
	Switch to another biologics or tofacitinib	18 (5.5)	20 (6.2)	15 (7.1)	15 (7.1)	57 (21.3)	45 (16.8)	90 (11.2)	80 (10.0)
	Corticosteroids exposure at week 26	47 (14.5)	47 (14.5)	27 (12.8)	22 (10.4)	37 (13.8)	30 (11.2)	111 (13.8)	99 (12.3)
		MarketScan	Optum	SNDS	Overall cohort
	Ulcerative colitis	Vedolizumab monotherapy (n=440)	Vedolizumab and thiopurines (n=440)	Vedolizumab monotherapy (n=325)	Vedolizumab and thiopurines (n=325)	Vedolizumab monotherapy (n=323)	Vedolizumab and thiopurines (n=323)	Vedolizumab monotherapy (n=1088)	Vedolizumab and thiopurines (n=1088)
	Treatment failure	101 (23.0)	96 (21.8)	72 (22.2)	58 (17.8)	90 (27.9)	82 (25.4)	263 (24.2)	236 (21.7)
	Hospitalisation related to UC or colectomy	18 (4.1)	26 (5.9)	11 (3.4)	16 (4.9)	25 (7.7)	25 (7.7)	54 (5.0)	67 (6.2)
	Switch to another biologics or tofacitinib	15 (3.4)	9 (2.0)	7 (2.2)	7 (2.2)	22 (6.8)	16 (5.0)	44 (4.0)	38 (3.5)
	Corticosteroids exposure at week 16	74 (16.8)	74 (16.8)	58 (17.8)	46 (14.2)	61 (18.9)	52 (16.1)	193 (17.7)	172 (15.8)

French National Society of Gastroenterology (SNFGE), and has received consulting fees from Roche and Pfizer, and research support from Abbvie for unrelates studies. Rishi J. Desai has received research support to the Brigham and Women's Hospital from Novartis, Vertex, and Bayer for unrelated studies. Laurent Beaugerie has received consulting fees from Janssen, Pfizer and Allergan, lecture fees from Abbvie, Janssen, MSD, Ferring Pharmaceuticals, Mayoly-Spendler, Takeda, and Tillots, and research support from Abbott, Ferring Pharmaceuticals, Hospira-Pfizer, Janssen, MSD, Takeda, and Tillots for unrelated studies.

Sebastian Schneeweiss is participating in investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Vertex, and Boehringer Ingelheim unrelated to the topic of this study. He is a consultant to Aetion Inc., a software manufacturer of which he owns equity.

Seoyoung C. Kim has received research support to the Brigham and Women's Hospital from Roche, AbbVie, and Bristol-Myers Squibb for unrelated studies.

Funding:

The investigators conducted the research independently through funding from internal sources of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School. Julien Kirchgesner received research support (Robert Tournut 2019 grant) from the French National Society of Gastroenterology (SNFGE).

Contributors:

Dr Kirchgesner had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Kirchgesner, Schneeweiss S., Kim. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kirchgesner. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Kirchgesner, Schneeweiss S., Kim. Supervision: Kirchgesner, Schneeweiss S., Kim.

Conflict of Interest Disclosures:

The authors disclose the following: Julien Kirchgesner received research support from the

Supplementary Material

Page 2-3. Supplementary Table 1. Specification and emulation of a target trial studying the effectiveness of vedolizumab and thiopurines combined compared to vedolizumab monotherapy in patients with Crohn's disease and ulcerative colitis Same as for the target trial We defined the date of vedolizumab and thiopurines initiations to be the first date of treatment perfusion or delivery, respectively Combination therapy was defined as starting vedolizumab with a concomitant exposure of thiopurines within 30 days before vedolizumab initiation.

A wash-out period of 60 days without any thiopurines exposure before vedolizumab initiation was required for the definition of vedolizumab monotherapy.

Treatment assignment

Individuals are randomly assigned to a strategy at baseline and will be aware of the strategy to which they have been assigned

We classified individuals according to the strategy that their data were compatible with at baseline and attempted to emulate randomization by adjusting for baseline confounders Primary end point


Julien Kirchgesner
email: jkirchgesner@bwh.harvard.edu

Keywords: Pharmacoepidemiology, gastrointestinal, biologics, immunosuppressants

Real-world evidence (RWE) on the effectiveness of treatments in Crohn's disease (CD) derived from clinical practice data will help fill many evidence gaps left by randomized controlled trials (RCTs). Emulating RCTs with healthcare database studies may calibrate RWE studies in CD.

We aimed to emulate the SONIC trial on the effectiveness of infliximab in patients with CD using U.S. and French healthcare claims data. SONIC had shown improved remission with combination therapy (i.e., infliximab plus thiopurines) compared to infliximab monotherapy.

Using claims data (2004-2019) from commercially insured patients in the U.S. (IBM 'MarketScan' and Optum) and France (SNDS), we conducted a cohort study of patients with CD who initiated combination therapy and compared them with patients who initiated infliximab alone. The primary outcome was a composite endpoint of treatment failure including hospitalization or surgery related to CD, treatment switch, or continuation of corticosteroids 26 weeks after infliximab initiation. Risk ratios (RRs) with 95% confidence intervals (CIs) were estimated in propensity score (PS) matched cohorts. We identified 1,437 PS-matched pairs of combination therapy versus infliximab monotherapy users. Like in SONIC, the risk of treatment failure was decreased with combination therapy in the overall cohort (RR, 0.71; 95%CI 0.62-0.82; RR, 0.78; 95%CI 0.62-0.97 in SONIC). Findings were consistent across MarketScan, Optum, and SNDS databases: RR (95%CI), 0.83 (0.63-1.10), 0.66 (0.46-0.93), and 0.68 (0.57-0.82), as well as component endpoints.

These robust findings highlight opportunities of RWE analysis to study treatment effectiveness in patients with CD in clinical practice.

Introduction

Real world evidence (RWE) has been used for decades to inform decisions about treatment safety, while it has been used only in limited circumstances to inform regulatory decisions about effectiveness complementing randomized controlled trials (RCTs). [START_REF] Schneeweiss | A review of uses of health care utilization databases for epidemiologic research on therapeutics[END_REF][2][START_REF] Franklin | Evaluating the Use of Nonrandomized Real-World Data Analyses for Regulatory Decision Making[END_REF][START_REF] Schneeweiss | Real-World Evidence of Treatment Effects: The Useful and the Misleading[END_REF] Following the mandate of the 21st Century Cures Act of 2016, FDA proposed a framework to conduct studies from data generated from the routine operation of the healthcare system, or real world data (RWD), for effectiveness regulatory decision. [START_REF]Framework for FDA's realworld evidence program[END_REF] The framework acknowledged challenges of RWE including that clinically meaningful measures of effectiveness outcomes may not be consistently captured in electronic health records or medical claims data. The emulation of RCTs by RWE studies may help to calibrate effectiveness outcome measurable in RWD, that could be applied to other treatment comparison within the same indication.

Additionally, calibration of RWE against RCTs faces the challenge of interpreting differences between treatment effect estimates from the two study types, that can be driven by residual bias in RWE but also emulation differences. [START_REF] Franklin | Emulation Differences vs. Biases When Calibrating Real-World Evidence Findings Against Randomized Controlled Trials[END_REF][START_REF] Franklin | Emulating Randomized Clinical Trials with Nonrandomized Real-World Evidence Studies: First Results from the RCT DUPLICATE Initiative[END_REF] The therapeutic armamentarium in immune-mediated inflammatory diseases, notably Crohn's disease (CD), dramatically increased in the last decade, highlighting the need of RWE to complement RCT evidence. As in many chronic conditions, evidence of head-tohead comparisons, add-on therapies, and various ways to stage treatments are lacking and it is unlikely that we will have RCT evidence for all these clinically important questions any time soon. The optimal position of each drug remains largely unknown, [START_REF] Torres | ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment[END_REF] while RWE could provide head-to-head comparison; however, for RWE to be actionable we need to gain confidence that such studies can measure clinically meaningful endpoints reliably and come to causal conclusions on the treatment effectiveness.

The aim of this study was to emulate an RCT, the Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) trial, studying the effectiveness of a biologic agent in patients with CD using data from two large U.S. and a French nationwide healthcare claims database. The SONIC trial was a parallel-group RCT assessing treatment failure in patients treated with infliximab and azathioprine combined compared to patients treated with either infliximab or thiopurines alone for CD. 9

Methods

Data source

This study was conducted by using two U.S. health care claims databases, IBM MarketScan longitudinal information on all encounters with the professional healthcare system, including outpatient visits, ER visits, and hospitalizations with diagnosis and procedure information, as well as pharmacy drug dispensing. Similarly, the SNDS contains data on all drug reimbursements, inpatient and outpatient medical care prescribed or provided by health-care professionals. [START_REF] Bezin | The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology[END_REF] It does not provide any information on the medical indication for each reimbursement, but contains the patient's status with respect to full reimbursement of care for long-term diseases (LTDs), which includes CD and allows to assess the date of CD diagnosis. [START_REF] Kirchgesner | Therapeutic management of inflammatory bowel disease in reallife practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014[END_REF] The study was approved by the institutional review board of the Brigham and Women's Hospital, and the French Data Protection Authority.

Study population

Infliximab is a tumor necrosis factor antagonist (anti-TNF) and was approved for the treatment of CD in 1998 in the US and in 1999 in Europe, [START_REF] Hanauer | Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial[END_REF] while thiopurines have been used for the treatment of CD since the nineteen seventies. [START_REF] Summers | National Cooperative Crohn's Disease Study: results of drug treatment[END_REF] The SONIC trial was an RCT conducted between 2005 and 2008 aimed to assess the effectiveness of infliximab and thiopurines combined (i.e., the combination therapy) compared to either infliximab or thiopurines alone in patients with CD naïve to immunosuppressants or anti-TNF. It concluded that the combination therapy of infliximab and thiopurines was superior to treatment with its component alone.

The emulation study's inclusion/exclusion criteria were tailored to replicate SONIC whenever possible. [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF] The SONIC trial included adult patients with moderate to severe CD with a Crohn's Disease Activity Index (CDAI) of 220 to 450 points, despite corticosteroids and/or aminosalicylates. Patients were naïve to thiopurines, methotrexate, and anti-TNF. To emulate this design, we identified all patients aged 18 years or older initiating infliximab and with at least one visit for CD using the International Classification of Diseases 9 th (ICD-9) or 10 th (ICD-10). In the SNDS database, CD diagnosis was based on previous published algorithms, [START_REF] Kirchgesner | Therapeutic management of inflammatory bowel disease in reallife practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009-2014[END_REF][START_REF] Lemaitre | Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease[END_REF][START_REF] Kirchgesner | Risk of acute arterial events associated with treatment of inflammatory bowel diseases: nationwide French cohort study[END_REF][START_REF] Kirchgesner | Risk of serious infections with vedolizumab versus tumor necrosis factor antagonists in patients with inflammatory bowel disease[END_REF] and the date of CD diagnosis was defined as the earliest diagnosis date either from hospital discharge diagnosis or from LTD diagnosis. Cohort entry date was defined as the date of infliximab initiation. Patients in MarketScan and Optum databases were required to have continuous enrolment during the baseline period of 180 days before cohort entry date. Patients were followed from the day after cohort entry date to 180 days after cohort entry date (week 26).

In analogy to SONIC, we excluded patients previously exposed to methotrexate, and to any anti-TNF agents. Treatment with thiopurines was only allowed in the month prior infliximab initiation, and patients exposed to thiopurines more than one month before infliximab initiation were excluded. Patients with an ostomy, stricture, abscess, abdominal surgery, tuberculosis, opportunistic infections, hepatitis B and C within the previous 6 months were excluded. We also excluded patients with HIV infection, multiple sclerosis, and previous history of cancer (excluding non-melanoma skin cancer). Additional exclusion criteria compared to the SONIC trial were considered. First, patients with a diagnosis code related to ulcerative colitis were excluded in order to only include patients with CD. Second, patients with a diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis were excluded in order to only include patients among whom anti-TNF was prescribed for CD. Lastly, exposure to biologics and immunosuppressant that were available after 2010 were considered as exclusion criteria, namely, natalizumab, vedolizumab, ustekinumab, and tofacitinib.

Treatment groups

Two treatment groups were considered. Since thiopurines may be started before the first infliximab infusion and thiopurines may take up to 3 months to be effective as monotherapy, combination therapy was defined as starting thiopurines within 30 days before infliximab initiation. Infliximab monotherapy was defined as infliximab initiation without thiopurines exposure any time prior. We did not consider patients only exposed to thiopurines monotherapy, since recent guidelines recommend again its use as monotherapy for the induction of remission in patients with CD. [START_REF] Torres | ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment[END_REF]

Outcome

In the SONIC trial, the primary end point was corticosteroid-free clinical remission at week 26, defined by a CDAI less than 150 points without any systemic corticosteroid use. Since the CDAI is not available in the US or French healthcare databases, we developed a composite effectiveness outcome measure based on three surrogate endpoints for treatment failure: (1) hospitalization or surgery related to CD; (2) treatment switch to another biologics (adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, ustekinumab) or small molecules (tofacitinib); or (3) exposure to systemic corticosteroids at week 26. Related codes are summarized in Table S1.

Follow-up started the day after cohort entry and ended on the earliest occurrence of 180 days of follow-up, outcome occurrence, or death, for all subjects started on either one of the treatments.

Patient characteristics

Baseline patient characteristics and markers of CD phenotype and severity were considered, including demographics and comorbidities (previous serious infections, Clostridioides difficile infection, cardiovascular disease, chronic kidney failure, chronic liver disease, chronic pulmonary disease, venous thromboembolism, and diabetes). Comorbidities were assessed in the 180 days before cohort entry in MarketScan and Optum and in all data available in the SNDS. CD phenotype included Montreal phenotype, [START_REF] Satsangi | The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications[END_REF] including inflammatory (B1), stricturing (B2), and penetrating phenotype (B3), as well as perianal involvement. Hospitalization for complicated CD course (stricture or abscess) and surgery related to CD occurring more than 180 days before cohort entry were also assessed. CD severity and healthcare use intensity were assessed in the 180 days before cohort entry in all databases. CD severity was assessed by corticosteroids and aminosalicylates exposure, occurrence of CD-related hospitalization or surgery, abdominal imaging, gastrointestinal endoscopy, fecal pathogen, and the number of C-reactive protein tests ordered. Healthcare use was assessed by hospitalizations not related to CD and the number of gastroenterologist visits.

Statistical analysis

To control for confounding, we calculated a propensity score (PS) for each patient predicting the probability of initiating combination therapy with infliximab and thiopurines versus infliximab monotherapy with logistic regression, including all measured baseline covariates without further variable selection and the year of cohort entry. [START_REF] Glynn | Indications for propensity scores and review of their use in pharmacoepidemiology[END_REF] We matched treatment groups 1:1 on their PS using optimal-matching within a caliper of 0.02. [START_REF] Rassen | One-to-many propensity score matching in cohort studies[END_REF] After matching, standardized differences matching were calculated to assess balance between patients exposed to combination therapy and their controls exposed to infliximab monotherapy. [START_REF] Franklin | Metrics for covariate balance in cohort studies of causal effects[END_REF] After PS matching we estimated the 180 day risk of the outcomes in percent including 95% confidence intervals (CIs). Log-binomial regression models were used to estimate adjusted risk ratios (RR) with their 95% CIs comparing the risk of treatment failure associated with combination therapy versus infliximab monotherapy. [START_REF] Robbins | What's the relative risk? A method to directly estimate risk ratios in cohort studies of common outcomes[END_REF] Cohort-specific RRs were combined by an inverse variance-weighted, fixed-effects model.

Additional prespecified analyses included secondary analyses assessing the risk of each individual component of the composite endpoint, and subgroups analyses stratified on Montreal phenotype (B1 and B2-B3 combined), the presence of perianal involvement, and exposure to corticosteroids at infliximab initiation. Several sensitivity analyses were performed to test the robustness of our results. First, variables with an absolute standardized difference greater than 0.1 after PS-matching were included as covariate in log-binomial regression models. Second, cox proportional hazards regression models were used to estimate hazard ratios (HR). Lastly, we performed a PS matched analysis with a variable ratio up to 1:4 with a caliper of 0.02.

Analyses were performed using the validated Aetion Evidence Platform (V 4.10) using R [START_REF]Software for real-world data analysis[END_REF][START_REF] Wang | Transparency and Reproducibility of Observational Cohort Studies Using Large Healthcare Databases[END_REF][START_REF] Patorno | Using Real-World Data to Predict Findings of an Ongoing Phase IV Cardiovascular Outcome Trial: Cardiovascular Safety of Linagliptin Versus Glimepiride[END_REF] and SAS (version 9.4) statistical software (SAS Institute).

Results

Patient characteristics

A total of 43 844 patients with CD who initiated infliximab were identified across the three databases. After applying exclusion criteria (Figure 1), 15 007 immunosuppressants and anti-TNF naive patients with CD were included, initiating either combination therapy with infliximab and thiopurines (n=1452) or infliximab monotherapy (n=13 555).

More than 70% of patients had an inflammatory phenotype according to Montreal classification (B1). In the SNDS cohort, the mean (SD) duration of CD was 3.9 (6.0) and 2.9

(5.4) years in the combination therapy and infliximab monotherapy groups, respectively (Table S2). After PS-matching, the cohorts contained 1437 pairs, with mean age between 33 and 38 years, which was similar to SONIC. [START_REF] Colombel | Infliximab, azathioprine, or combination therapy for Crohn's disease[END_REF] Conversely, around half of the patients were treated with corticosteroids at infliximab initiation, compared to 27.4% of patients in SONIC (Table 1). Only two covariates had an absolute standardized difference greater than 0.1 (Figure S1).

Risk of treatment failure

After PS-matching, treatment failure occurred in 263 (18.3%; 95% CI 16.2-20.2) and 369 (25.7%; 95% CI 24.6-30.1) patients initiating combination therapy and infliximab monotherapy, respectively (Table 2). Among patients with treatment failure, hospitalization or surgery related to CD was the most frequent outcome, accounting for 59% and 63% of outcomes in patients initiating combination therapy and infliximab monotherapy. The proportion of patients with treatment failure according to databases before PS-matching is provided in Table S3.

Patients initiating combination therapy had a 29% decreased risk of treatment failure compared to patients initiating infliximab monotherapy (RR, 0.71, 95% CI 0.62-0.82). Results were similar across the three databases (RR, 0.83, 95% CI 0.63-1.10, RR, 0.66, 95% CI, 0.46-0.93, and RR, 0.68, 95% CI, 0.57-0.82 in MarketScan, Optum, and SNDS, respectively). Risk ratios of treatment failure in the emulated cohort and in the SONIC trial are provided in Figure 2. The reduced risk of treatment failure with combination therapy was observed for all secondary endpoints, with a 25% (9-37%) reduced risk of hospitalization or surgery related to CD, a 44% (21-60%) reduced risk of treatment switch, and a 43% (25-57%) reduced risk of persistent corticosteroids exposure at week 26 (Figure 3).

Subgroup and sensitivity analyses

Overall, there was no statistically significant heterogeneity in the risk of treatment failure across subgroups (Figure 4 and Table S4). The combined RR for treatment failure associated with combination therapy versus infliximab monotherapy was 0.75 (95%CI, 0.64-0.89) and 0.86 (95%CI, 0.64-1.15) in patients with inflammatory phenotype and patients with stricturing or penetrating phenotypes, respectively. In patients treated with corticosteroids at infliximab initiation, the combined RR was 0.69 (95%CI, 0.58-0.83).

The various sensitivity analyses yielded consistent results (Table S5). The risk of treatment failure was notably decreased by 27% (16-37%) with combination therapy after propensity score matching with a 1:4 variable ratio.

Discussion

Based on three large population-based cohorts in the U.S. and France, we emulated a RCT assessing the effectiveness of combination therapy with infliximab and thiopurines compared to infliximab monotherapy in patients with CD. Our analysis replicated the findings of the SONIC trial by using a composite effectiveness outcome based on hospitalization or surgery related to CD, treatment switch, or corticosteroids continuation. Findings were consistent across databases and for each individual components of the composite outcome.

Calibration of RWE studies against treatment effect assessed in RCTs allows to evaluate whether RWE can support causal conclusions if conducted using robust methodology. [START_REF] Franklin | Emulating Randomized Clinical Trials with Nonrandomized Real-World Evidence Studies: First Results from the RCT DUPLICATE Initiative[END_REF] Our study design was as close as possible to the design of the SONIC trial, including exclusion and inclusion criteria, and outcome definition. Our findings support the concept of using database analysis to provide evidence for comparisons that are not assessed in RCTs. In CD, all recent phase III RCTs compared the active treatment with placebo, whereas standard first line treatment is available and the European Medicines Agency recommended a direct comparison with current generally accepted standard first line treatment in this setting. [START_REF]Guideline on the development of new medicinal products for the treatment of Crohn's Disease[END_REF] RWE may be used to assess effectiveness in head to head comparison in addition to safety studies. [START_REF] Kirchgesner | Risk of serious infections with vedolizumab versus tumor necrosis factor antagonists in patients with inflammatory bowel disease[END_REF] The main strength of our study is the generalizability and large size as we used two large U.S. and one French nationwide population-based cohorts, which allows to assess treatment effectiveness in different healthcare schemes and potential prescribing patterns. A multidatabase study contributes to assess the impact of differences in population selection, data collection and follow-up between databases. While patients are followed from birth to emigration or death in the SNDS database, patients could have a shorter enrollment period to assess covariates due to health insurance enrollment changes in Optum and MarketScan.

The U.S databases also only included commercially insured patients, while the SNDS database included all French residents, since universal healthcare is guaranteed for all French residents. Results were consistent across databases, which suggest that these differences had a minimal impact on the treatment estimate observed. Additionally, the use of a new-user design, the inclusion of an active comparator, and the assessment of CD disease activity allowed us to rigorously control for confounding. Lastly, findings were consistent for each individual component of the composite outcome, which strengthens the robustness of the results. Some limitations should be noted. The study population differs from the population included in the SONIC trial, notably regarding the exposure to corticosteroids at infliximab initiation.

Higher rates of corticosteroids exposure reported in our study population may suggest that patients included in the SONIC trial had a less severe disease compared to real-life setting. It might be related to the selected profile of patients included in RCTs, with more than 60% of patients with CD followed in tertiary referral centers who would have not been eligible to participate in recent RCTs, mainly due to disease severity. [START_REF] Ha | Patients Enrolled in Randomized Controlled Trials Do Not Represent the Inflammatory Bowel Disease Patient Population[END_REF] We also performed stratified analyses according to baseline disease severity (stricturing or penetrating phenotype, exposure to corticosteroid at cohort entry), and results were consistent with the main analysis. The CDAI score used in SONIC includes clinical and biological parameters that are not collected in claims data. We decided to define treatment failure based on hospitalization or surgery related to CD, treatment switch, and corticosteroids continuation at week 26. Our definition may select higher degree of disease activity, as we reported a lower rate of treatment failure compared to SONIC. Additionally, a CDAI score above 150, which defined treatment failure in SONIC, may be not specific to CD activity and has been reported in patients with irritable bowel syndrome. [START_REF]The Crohn's disease activity index (CDAI) is similarly elevated in patients with Crohn's disease and in patients with irritable bowel syndrome[END_REF] Effectiveness outcome measure developed in real world data may be only appropriate in the setting where they were developed. Furthermore, as we did not assess effectiveness in non-users of immunosuppressive treatment, [START_REF] Spoendlin | Using Healthcare Databases to Replicate Trial Findings for Supplemental Indications: Adalimumab in Patients with Ulcerative Colitis[END_REF] this should be further assessed. However, add-on strategies with thiopurines are used in the therapeutic management of CD, notably with recently approved biologics such as vedolizumab and ustekinumab. The effectiveness outcome measure developed in this study may be used in future studies assessing the impact of adding thiopurines with other treatment than infliximab.

In summary, this study based on three large population-based cohorts of patients with CD in both the U.S. and France provided evidence that RWE studies can contribute to the assessment of treatment effectiveness for CD in clinical practice. These findings support the concept of using RWE analysis to complement evidence gained from RCTs.

(

  MarketScan) 2004-2018 and Optum Clinformatics (Optum) 2005-2019, and the French administrative health database 2009-2018 (Système National des Données de Santé, SNDS). Patients enrolled in the MarketScan and Optum databases are representative of a commercially insured population in the U.S.; the SNDS insures 95% of the French population. The two U.S. databases are de-identified and contain demographic data and

Figure 1 .Figure 2 .Figure 3 .Figure 4 .

 1234 Figure 1. Study Population Flowchart

Table Legends :Table 1 .

 Legends1 Characteristics of study patients, propensity score-matched with a 1:1 fixed ratio

Table 2 .

 2 Proportion of patients with treatment failure after propensity score matching

Table 1 . Characteristics of study patients treated with infliximab and thiopurines or infliximab monotherapy, propensity score-matched with a 1:1 fixed ratio

 1 Assessed within 180 days before cohort entry. Abbreviation: CRP, C-reactive protein

		MarketScan, n (%)	Optum, n (%)	SNDS, n (%)
		Infliximab	Infliximab	Infliximab	Infliximab	Infliximab	Infliximab
	Variable	monotherapy	and thiopurines	monotherapy	and thiopurines	monotherapy	and thiopurines
		(n=436)	(n=436)	(n=237)	(n=237)	(n=764)	(n=764)
	Age, mean (SD), years	38.2 (15.2)	37.6 (13.7) 36.4 (13.7)	36.4 (12.5)	33.6 (14.2)	33.0 (12.8)
	Sex
	Male	246 (56.4)	249 (57.1) 131 (55.3)	126 (53.2)	312 (40.8)	313 (41.0)
	Female	190 (43.6)	187 (42.9) 106 (44.7)	111 (46.8)	452 (59.2)	451 (59.0)
	Crohn's disease duration, mean (SD), years	-	-	-	-	2.85 (4.82)	2.90 (5.42)
	Montreal phenotype
	B1	328 (75.2)	323 (74.1) 164 (69.2)	166 (70.0)	660 (86.4)	655 (85.7)
	B2	70 (16.1)	72 (16.5)	38 (16.0)	39 (16.5)	61 (8.0)	58 (7.6)
	B3	38 (8.7)	41 (9.4)	35 (14.8)	32 (13.5)	43 (5.6)	51 (6.7)
	Perianal Crohn's disease	76 (17.4)	72 (16.5)	38 (16.0)	42 (17.7)	102 (13.4)	96 (12.6)
	Hospitalization for Crohn's disease
	complication more than 180 days before	4 (0.9)	11 (2.5)	2 (0.8)	2 (0.8)	37 (4.8)	41 (5.4)
	cohort entry
	Surgery related to Crohn's disease more than 180 days before cohort entry	13 (3.0)	16 (3.7)	12 (5.1)	10 (4.2)	57 (7.5)	57 (7.5)
	Corticosteroids (oral)
	within 180 days before cohort entry	299 (68.6)	298 (68.3) 161 (67.9)	154 (65.0)	478 (62.6)	473 (61.9)
	at cohort entry	210 (48.2)	222 (50.9) 112 (47.3)	110 (46.4)	360 (47.1)	364 (47.6)
	Aminosalicylates (oral) at cohort entry	241 (55.3)	249 (57.1) 115 (48.5)	115 (48.5)	380 (49.7)	387 (50.7)
	Opioids a	221 (50.7)	223 (51.1) 110 (46.4)	106 (44.7)	121 (15.8)	117 (15.3)
	Crohn's disease activity assessment a
	Hospitalization related to Crohn's
	disease	116 (26.6)	110 (25.2) 51 (21.5)	54 (22.8)	313 (41.0)	307 (40.2)
	Abdominal imaging	228 (52.3)	222 (50.9) 134 (56.5)	138 (58.2)	564 (73.8)	541 (70.8)
	Lower GI endoscopy	290 (66.5)	288 (66.1) 158 (66.7)	151 (63.7)	572 (74.9)	574 (75.1)
	Upper GI endoscopy	107 (24.5)	101 (23.2) 60 (25.3)	55 (23.2)	389 (50.9)	392 (51.3)
	CRP tests ordered, mean (SD)	0.82 (1.15)	0.75 (1.08) 1.21 (1.78)	1.06 (1.55)	2.76 (2.61)	2.86 (2.46)
	Fecal pathogen tests ordered	87 (20.0)	79 (18.1)	55 (23.2)	57 (24.1)	153 (20.0)	166 (21.7)
	Comorbidities
	Clostridioides difficile infection	6 (1.4)	9 (2.1)	3 (1.3)	4 (1.7)	8 (1.0)	9 (1.2)
	Serious infection	4 (0.9)	5 (1.1)	1 (0.4)	2 (0.8)	7 (0.9)	8 (1.0)
	Cardiovascular disease	33 (7.6)	30 (6.9)	19 (8.0)	15 (6.3)	29 (3.8)	29 (3.8)
	Chronic kidney failure	8 (1.8)	5 (1.1)	6 (2.5)	4 (1.7)	3 (0.4)	2 (0.3)
	Chronic liver disease	9 (2.1)	10 (2.3)	11 (4.6)	9 (3.8)	4 (0.5)	4 (0.5)
	Chronic pulmonary disease	62 (14.2)	48 (11.0)	21 (8.9)	23 (9.7)	187 (24.5)	184 (24.1)
	Venous thromboembolism	12 (2.8)	12 (2.8)	7 (3.0)	5 (2.1)	15 (2.0)	14 (1.8)
	Diabetes	20 (4.6)	17 (3.9)	15 (6.3)	13 (5.5)	35 (4.6)	29 (3.8)
	Healthcare use characteristics
	Hospitalizations not related to Crohn's disease a	48 (11.0)	43 (9.9)	17 (7.2)	18 (7.6)	101 (13.2)	95 (12.4)
	Gastroenterologist visits, mean (SD) a 5.56 (5.83)	5.67 (5.25) 8.76 (15.6)	7.87 (8.07)	5.35 (6.07)	5.37 (6.16)

a

Table 2 . Outcomes, propensity score-matched with a 1:1 fixed ratio

 2 Secondary outcomes are assessed without censoring at the first outcome occurrence in case of multiple outcome occurrences during follow-up. Abbreviation: CD, Crohn's disease

		MarketScan, n (%)	Optum, n (%)	SNDS, n (%)	Overall cohort, n (%)
		Infliximab	Infliximab	Infliximab	Infliximab	Infliximab	Infliximab	Infliximab	Infliximab
	Variable	monotherapy	and thiopurines	monotherapy	and thiopurines	monotherapy	and thiopurines	monotherapy	and thiopurines
		(n=436)	(n=436)	(n=237)	(n=237)	(n=237)	(n=764)	(n=764)	(n=764)
	Treatment failure 89 (20.4)	74 (17.0)	64 (27.0)	42 (17.7)	216 (28.3)	147 (19.2) 369 (25.7)	263 (18.3)
	Hospitalization
	or surgery related to CD a	57 (13.1)	45 (10.3)	39 (16.5)	28 (11.8)	127 (16.6)	95 (12.4)	223 (15.5)	168 (11.7)
	Switch to
	another tofacitinib a biologics or	16 (3.7)	12 (2.8)	15 (6.3)	6 (2.5)	55 (7.2)	30 (3.9)	86 (6.0)	48 (3.3)
	Corticosteroids
	exposure at week 26 a	33 (7.6)	22 (5.0)	27 (11.4)	14 (5.9)	68 (8.9)	37 (4.8)	128 (8.9)	73 (5.1)

a

Kirchgesner received research support from the French National Society of Gastroenterology (SNFGE). Rishi J. Desai has received research support to the Brigham and Women's Hospital from Novartis, Vertex, and Bayer for unrelated studies. Laurent Beaugerie has received Sebastian Schneeweiss is participating in investigator-initiated grants to the Brigham and Women's Hospital from Bayer, Vertex, and Boehringer Ingelheim unrelated to the topic of this study. He is a consultant to Aetion Inc., a software manufacturer of which he owns equity. Seoyoung C. Kim has received research support to the Brigham and Women's Hospital from Pfizer, Roche, AbbVie, and Bristol-Myers Squibb for unrelated studies. The investigators conducted the research independently through funding from internal sources of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital and Harvard Medical School.

Conflict of Interest Disclosures:

Study Highlights

What is the current knowledge on the topic? Real world evidence (RWE) is increasingly used to assess treatment effectiveness, emulating randomized clinical trials (RCTs) with healthcare database studies may calibrate RWE studies.

What question did this study address?

We aimed to calibrate RWE in Crohn's disease (CD) by replicating a RCT (SONIC) using US and French administrative health databases. The SONIC trial assessed in 2010 the effectiveness of the combination of infliximab and thiopurines compared to infliximab monotherapy in patients with CD at week 26 (primary end point; CDAI score). Based on the inclusion and exclusion criteria of SONIC, we assessed the risk of treatment failure at week 26 in patient initiating combination therapy or infliximab monotherapy. The primary endpoint was a composite endpoint based on hospitalization or surgery related to CD, treatment switch, and corticosteroids exposure at week 26.

What does this study add to our knowledge?

Our comparison replicated the effectiveness of combination therapy with infliximab and thiopurines in SONIC. Results were consistent across the three databases and for all individual components of the composite outcome.

How might this change clinical pharmacology or translational science?

Calibrating RWE against RCT using a robust methodology and multiple databases supports the use of RWE to assess effectiveness in real life setting.

Author Contributions:

A list of each author's contributions. The standard contributions include: J.K. and S.S. wrote manuscript, J.K., R.J.D., L.B., S.C.K., and S.S. designed research, J.K. and S.S. performed research, JK. analyzed data.

Supplementary Material:

Table S1. Effectiveness outcome measure with related codes Table S2. Characteristics of study patients treated with infliximab and thiopurines or infliximab monotherapy, before propensity score-matching Table S3. Outcomes, before propensity-score matching Table S4. Relative risks (95% confidence intervals) of treatment failure in patients treated with combination therapy versus infliximab monotherapy, subgroups analyses Table S5. Relative risks (95% confidence intervals) of treatment failure in patients treated with combination therapy versus infliximab monotherapy, sensitivity analyses