Introduction: Limited data exist on the efficacy of combination therapy with ustekinumab and budesonide in patients with Crohn’s disease. Our objective was to compare the clinical outcomes of ustekinumab and budesonide combination therapy with those of ustekinumab monotherapy. Methods: In this phase 2 single-center, double-blind, randomized controlled trial, we assigned 19 patients with Crohn’s disease with a Crohn’s disease activity index (CDAI) equal to or greater than 220 and less than 450 in a 1:1 ratio to receive ustekinumab and budesonide or ustekinumab for 32 weeks. The primary endpoint was the clinical remission rate at 8 weeks. The secondary endpoints were the clinical remission rate at 32 weeks and mucosal healing rates at 8 and 32 weeks. Results: Of 19 patients, the mean age was 37.8 years, and 42.1% were women (CDAI ≥220 and <450). There was no difference between combination therapy and ustekinumab monotherapy in terms of clinical remission rates (50.0% vs. 30.0%, p = 0.39 at 8 weeks and 37.5% vs. 20.0%, p = 0.41) and mucosal healing rates (75.0% vs. 90.0%, p = 0.40 and 37.5% vs. 60.0%, p = 0.34 at 8 and 32 weeks, respectively). The most common adverse event was an exacerbation of Crohn’s. There were no differences in safety profiles between the two groups. Conclusions: Our study showed no difference between ustekinumab monotherapy and ustekinumab and budesonide combination therapy in terms of the induction and maintenance of remission (trial registration number: jRCTs021200013).

Crohn’s disease (CD) is a chronic inflammatory bowel disease with repeated episodes of exacerbation and remission. The therapeutic strategy for CD has changed owing to the availability of biologics. Biologics such as infliximab (IFX) [1], adalimumab (ADA) [2], ustekinumab (UST) [3], and vedolizumab (VDZ) [4] have demonstrated effective results in treating CD worldwide, including in Japan [5‒7]. However, several patients have severe clinical courses that require admission and surgery because of primary nonresponse and secondary loss of response (LOR). The development of antidrug antibodies is thought to be the most important mechanism underlying LOR. The SONIC study reported that combination therapy with IFX and azathioprine resulted in higher steroid-free remission and mucosal healing rates than IFX monotherapy [8]. Azathioprine reduces anti-IFX antibodies, which contribute to a higher IFX concentration in the blood [9].

UST has also demonstrated high effectiveness in the treatment of CD in clinical trials [3, 10, 11] and in a real-world setting [12, 13]. Unlike IFX, the clinical benefits of combination therapies remain controversial. A meta-analysis reported that combination therapy with UST and azathioprine did not improve the rates of clinical or endoscopic remission [14].

Budesonide (BDS) is widely used in clinical practice as an induction therapy for CD [15]. The likelihood of adverse events associated with BDS is lower than that associated with conventional steroids [16]. Although combination therapy with UST and BDS is expected to provide better clinical effects and safety than UST monotherapy, no prospective studies have evaluated this combination. This study aimed to investigate whether combination therapy with UST and BDS could demonstrate stronger clinical effects than UST monotherapy in a double-blind randomized control trial (RCT).

Study Design and Ethics

This was a single-center, double-blind, placebo-controlled RCT conducted at Tohoku University Hospital. The study protocol was reviewed and approved by the Tohoku Certified Review Board of Tohoku University (2021-45-1) and the trial was registered in the Japan Registry of Clinical Trials on July 31, 2020 (jRCTs021200013). Written informed consent was obtained from all the participants before they entered the trial.

We estimated that the additional clinical effect of combination therapy was 30% with a type I error (2-sided) of 5%, a power of 80%, and an assumption of an approximately 10% loss to follow-up rate. Therefore, we included 80 participants, with 40 in each group.

Participants

The major inclusion criteria were as follows: (1) patients of Japanese ethnicity with CD and age between 18 and 75 years; (2) those with moderate-to-severe disease activity (CDAI ≥220 and <450); (3) performance status 0–2, and (4) those who were outpatients. The exclusion criteria were as follows: (1) presence of stoma; (2) presence of a lesion requiring surgery, such as stenosis or abscess; (3) inpatients with intravenous hyperalimentation; (4) history of allergy to ustekinumab and budesonide; and (5) pregnant patients. The history of antitumor necrosis factor-α antibody (anti-TNFα) was not considered.

Randomization and Blinding

The participants were randomized into one of the two groups (1:1 allocation) based on the permuted block method of computer-generated randomization. One group was the combination therapy group (ustekinumab and budesonide), and the other was the ustekinumab monotherapy group. One of the authors, Y. Sugawara, who did not meet the participants, conducted the randomization procedure. The adjustment factor was a previous history of anti-TNFα antibody administration. The double-blind random allocation sequence and prescription of intervention drugs (budesonide or placebo) were supported by clinical research coordinators at the Clinical Research, Innovation, and Education Center, Tohoku University Hospital, and the Pharmaceutical Sciences, Tohoku University Hospital. Both participants and medical personnel were blinded to enable anonymity and randomization.

Interventions

The preparation of the intervention drugs and their prescriptions was conducted by Pharmaceutical Sciences at Tohoku University Hospital. Budesonide was purchased from Zeria Pharmaceutical Co. Ltd. (Tokyo, Japan). Budesonide, or placebo, was placed in an opaque capsule. Participants took the intervention drugs in three capsules (9 mg of BDS or placebo) for 8 weeks from the start of UST, two capsules (6 mg of BDS or placebo) for 2 weeks, and finally, one capsule (3 mg of BDS or placebo) for 2 weeks.

Ustekinumab was administered to all the participants in a manner approved by the Japanese insurance system. The first UST administration was via intravenous injection, and the amount was based on the participant’s body weight (6 mg/kg). Thus, patients weighing ≤55 kg received 260 mg. Patients weighing between 55 and 85 kg received 390 mg, and those weighing >85 kg received 520 mg. At week 8, the participants received a second subcutaneous UST administration (90 mg). The participants received 90 mg of UST every 8 or 12 weeks, depending on their condition, from the third UST administration.

Outcomes

The primary outcome of this study was the remission rate (CDAI score <150) at 8 weeks. The secondary outcomes were the remission rate at 32 weeks, the rate of responders (CDAI score <150 or decrease in CDAI score >100) at 8 and 32 weeks, C-reactive protein and serum albumin levels at 8 and 32 weeks, the rate of mucosal healing at 32 weeks, and the number and degree of adverse events. The mucosal healing was defined as follows: (1) SES-CD (simple endoscopic score for Crohn’s) is 4 or less, or (2) SES-CD decreased by 8 or more from baseline. We also compared the clinical remission rate at week 8 between the two groups according to prior administration of the anti-TNF-α antibody.

Statistical Analysis

Outcomes were evaluated using intention-to-treat analysis. We estimated that the primary outcome would occur in 80% and 50% of the patients in the UST monotherapy and UST-BDS groups, respectively, and set the power and type I error to 0.8 and 0.05 (two-sided test), respectively. We calculated a sample size of 72 cases and eventually planned to enroll 80 cases (assuming a 10% rate of loss to follow-up). Comparisons between the UST monotherapy and UST-BDS groups in terms of the rates of remission and responders at 8 and 32 weeks were performed using the χ2 test and Fisher’s exact tests. Continuous variables were compared using the Mann-Whitney U test and the Student’s t test, as appropriate. Statistical significance was set at p < 0.05. All statistical analyses were performed using the SAS statistical software package, version 9.4 (SAS Institute Inc., Cary, NC, USA).

Characteristics of the Study Population

A total of 19 patients were assessed for eligibility and enrolled in this trial between February 2018 and March 2020. Of these, 9 patients were randomly assigned to the UST-BDS group, and the remaining 10 patients were randomly assigned to the UST monotherapy group. One patient from the UST-BDS group withdrew consent. Therefore, 18 patients were finally included in this study. Except for body weight, the other characteristics were not significantly different between the two groups (Table 1). The average CDAI score at inclusion was 289.6 (standard deviation, 49.6). Four patients did not have endoscopically active disease (SES-CD <4).

Table 1.

Clinical characteristics of the study population

Total (n = 18)Combination group (n = 8)Monotherapy group (n = 10)p value
Sex (male/female) 10/8 6/2 4/6 0.14 
Age at inclusion, average (SD) 37.8 years (12.3) 37.5 years (15.3) 38.1 years (10.1) 0.92 
CDAI at inclusion, average (SD) 289.6 (49.6) 283.4 (33.6) 294.6 (60.8) 0.65 
Serum CRP at inclusion, average (SD) 1.1 mg/dL (1.4) 1.6 mg/dL (1.9) 0.8 mg/dL (0.8) 0.41 
Serum albumin at inclusion, average (SD) 3.2 g/dL (0.4) 3.3 g/dL (0.5) 3.1 g/dL (0.4) 0.37 
Montreal classification (L1/L2/L3/L4) 4/14/0/0 1/7/0/0 3/7/0/0 0.38 
Disease duration, average (SD) 13.1 years (9.6) 12.1 years (9.7) 13.9 years (10.0) 0.71 
Previous history of anti-TNF α antibody, % 13 (72.2) 6 (75.0) 7 (70.0) 0.81 
Concomitant azathioprine at inclusion, % 5 (27.8) 2 (25.0) 3 (30.0) 0.82 
Smoke history (never/ex-smoker/current) 9/4/5 3/3/2 6/1/3 0.37 
Anal lesion at inclusion 8 (44.4%) 4 (50.0%) 4 (40.0%) 0.67 
Total (n = 18)Combination group (n = 8)Monotherapy group (n = 10)p value
Sex (male/female) 10/8 6/2 4/6 0.14 
Age at inclusion, average (SD) 37.8 years (12.3) 37.5 years (15.3) 38.1 years (10.1) 0.92 
CDAI at inclusion, average (SD) 289.6 (49.6) 283.4 (33.6) 294.6 (60.8) 0.65 
Serum CRP at inclusion, average (SD) 1.1 mg/dL (1.4) 1.6 mg/dL (1.9) 0.8 mg/dL (0.8) 0.41 
Serum albumin at inclusion, average (SD) 3.2 g/dL (0.4) 3.3 g/dL (0.5) 3.1 g/dL (0.4) 0.37 
Montreal classification (L1/L2/L3/L4) 4/14/0/0 1/7/0/0 3/7/0/0 0.38 
Disease duration, average (SD) 13.1 years (9.6) 12.1 years (9.7) 13.9 years (10.0) 0.71 
Previous history of anti-TNF α antibody, % 13 (72.2) 6 (75.0) 7 (70.0) 0.81 
Concomitant azathioprine at inclusion, % 5 (27.8) 2 (25.0) 3 (30.0) 0.82 
Smoke history (never/ex-smoker/current) 9/4/5 3/3/2 6/1/3 0.37 
Anal lesion at inclusion 8 (44.4%) 4 (50.0%) 4 (40.0%) 0.67 

SD, standard deviation; CRP, C-reactive protein; CDAI, Crohn’s disease activity index; TNF, tumor necrosis factor.

Comparison between the UST-BDS and UST Monotherapy Groups in Short-Term

There was no difference in the clinical remission rates at week 8 between the UST-BDS and UST monotherapy groups (50.0% vs. 30.0%, respectively, p = 0.39) (Table 2). There were also no differences in the response rate (50% vs. 50%, respectively, p = 1.00), the mucosal healing rate (75.0% vs. 90.0%, respectively, p = 0.40) (Table 2), or laboratory data such as C-reactive protein and serum albumin levels at week 8 (Table 3).

Table 2.

Comparison of clinical results between the combination and monotherapy groups at 8 and 32 weeks

Combination group (n = 8)Monotherapy group (n = 10)p value
Clinical remission at week 8, n (%) 4 (50.0) 3 (30.0) 0.39 
 At week 32, n (%) 3 (37.5) 2 (20.0) 0.41 
Clinical responder at week 8, n (%) 4 (50.0) 5 (50.0) 1.00 
 At week 32, n (%) 5 (62.5) 4 (40.0) 0.34 
Mucosal healing at week 8, n (%) 6 (75.0) 9 (90.0) 0.40 
 At week 32, n (%) 3 (37.5) 6 (60.0) 0.34 
Combination group (n = 8)Monotherapy group (n = 10)p value
Clinical remission at week 8, n (%) 4 (50.0) 3 (30.0) 0.39 
 At week 32, n (%) 3 (37.5) 2 (20.0) 0.41 
Clinical responder at week 8, n (%) 4 (50.0) 5 (50.0) 1.00 
 At week 32, n (%) 5 (62.5) 4 (40.0) 0.34 
Mucosal healing at week 8, n (%) 6 (75.0) 9 (90.0) 0.40 
 At week 32, n (%) 3 (37.5) 6 (60.0) 0.34 
Table 3.

Comparison of serum CRP and albumin at 8 and 32 weeks

Combination group (n = 8)Monotherapy group (n = 10)p value
Serum CRP at week 8, average (SD) 0.3 (0.3) 1.6 (2.4) 0.25 
Serum CRP at week 32, average (SD) 0.6 (0.9) 0.8 (1.0) 0.79 
Serum albumin at week 8, average (SD) 3.6 (0.6) 3.3 (0.5) 0.18 
Serum albumin at week 32, average (SD) 3.7 (0.6) 3.4 (0.4) 0.27 
Combination group (n = 8)Monotherapy group (n = 10)p value
Serum CRP at week 8, average (SD) 0.3 (0.3) 1.6 (2.4) 0.25 
Serum CRP at week 32, average (SD) 0.6 (0.9) 0.8 (1.0) 0.79 
Serum albumin at week 8, average (SD) 3.6 (0.6) 3.3 (0.5) 0.18 
Serum albumin at week 32, average (SD) 3.7 (0.6) 3.4 (0.4) 0.27 

CRP, C-reactive protein.

Of the 18 participants, 13 had a history of anti-TNF-α antibody administration. There were no differences in the clinical remission rate at week 8, regardless of previous history of anti-TNF-α antibody administration (Table 4).

Table 4.

Stratification analysis of clinical remission rate at week 8 based on history of anti-TNFα antibody administration

Combination groupMonotherapy groupp value
With history of anti-TNFα antibody administration, n (%) (n = 13) 2/6 (33.3) 0/7 (0) 0.097 
Without history of anti-TNFα antibody administration, n (%) (n = 5) 2/2 (100) 3/3 (100) 0.79 
Combination groupMonotherapy groupp value
With history of anti-TNFα antibody administration, n (%) (n = 13) 2/6 (33.3) 0/7 (0) 0.097 
Without history of anti-TNFα antibody administration, n (%) (n = 5) 2/2 (100) 3/3 (100) 0.79 

Comparison between the UST-BDS and UST Monotherapy Groups in the Middle-Term

The clinical remission rates at week 32 were not different between the UST-BDS and UST monotherapy groups (37.5% vs. 20.0%, respectively; p = 0.41) (Table 2). The response rate (62.5% vs. 40.0%, respectively, p = 0.34), the mucosal healing rate (37.5% vs. 60.0%, respectively, p = 0.34) (Table 2), and laboratory data at week 32 were not different between the two groups (Table 3).

Safety of Combination Therapy

There was no significant difference in the rate of adverse events between the two groups (Table 5). All adverse events were exacerbated by CD. No cases of mortality, infection, or malignancy were observed.

Table 5.

Comparison of safety between the combination and monotherapy groups

Combination group (n = 8)Monotherapy group (n = 10)p value
With adverse events during the study period, n (%) 1 (12.5) 2 (20.0) 0.67 
Combination group (n = 8)Monotherapy group (n = 10)p value
With adverse events during the study period, n (%) 1 (12.5) 2 (20.0) 0.67 

In this double-blinded RCT, we evaluated the efficacy of combination therapy with UST and BDS in patients with CD. There was no difference in clinical remission and mucosal healing rates between combination therapy and UST monotherapy at 8 and 32 weeks. The additional clinical effects of the combination therapy with UST and BDS were not confirmed in this trial. There were no differences in safety profiles between the two groups.

Our results indicate that combination therapy with UST and BDS might not provide additional clinical efficacy in terms of the rates of induction and maintenance of remission compared with UST monotherapy. In other words, UST monotherapy for outpatients who do not need to be admitted to the hospital may potentially induce and maintain remission without additional immunosuppressive modalities. Stratification analysis in our study according to the history of usage of anti-TNF-α antibodies showed no difference between combination therapy and UST monotherapy. This result supports the aforementioned expectations. Furthermore, several retrospective studies reported that concomitant steroids at baseline were not identified as clinical factors that strengthened the induction and maintenance efficacy of UST [17‒25]. One observational prospective study reported similar results [26]. These results are consistent with those of our randomized, double-blind, and placebo-controlled study. To our knowledge, this is the first study to prospectively investigate the efficacy of the combination of UST and BDS in a randomized, double-blind manner. However, our results should be interpreted with caution because the number of participants was too small to evaluate the efficacy of the combination therapy. We were unable to enroll the required number of patients. Although we estimated that 80 participants would be necessary to detect statistical significance, we included only 19 patients. One reason for this was the COVID-19 pandemic, which made it difficult to recruit participants. Due to the COVID-19 pandemic, the final participant was enrolled in March 2020. Thereafter, recruitment was stopped completely. Further investigations are necessary to determine the efficacy of combination therapy.

A meta-analysis reported that the combination of UST and azathioprine was not more effective than monotherapy in the induction and maintenance of remission [14]. Several other studies reported similar results [27‒29]. These results support the hypothesis that UST monotherapy is sufficient to induce remission in outpatients with CD. However, the efficacy of combination therapy differs for each biological agent. IFX is a representative biological agent that demonstrates the clinical efficacy of concomitant azathioprine [8]. In contrast to IFX, the DIAMOND study revealed that the clinical remission rate of combination therapy with ADA and azathioprine did not differ from that of ADA monotherapy, whereas the endoscopic mucosal healing rate after combination therapy was higher than that after monotherapy [5]. IFX is a chimeric monoclonal antibody comprising human and murine antibodies, whereas ADA is a humanized monoclonal antibody. This structural difference might have led to the differences between the SONIC study [8] and the DIAMOND study [5]. Azathioprine is expected to prevent the development of antidrug antibodies. The SONIC study confirmed the clinical efficacy of concomitant azathioprine, whereas the DIAMOND study did not. UST is a monoclonal antibody with low immunogenicity. On the contrary, the UNITI study reported that the anti-UST antibody was only 2.3% in that trial [3]. Another review article reported that the antidrug antibody rate of UST was 3.8–5.4%, which was lower than that of infliximab (5.4–43.6%) and adalimumab (8.8–44.8%) [30]. These results suggest that UST is likely to lead to the development of lower levels of antidrug antibodies. The concentration of the antidrug antibody was so low that the efficacy of concomitant azathioprine might be difficult to recognize. In this trial, combination therapy with UST and BDS did not demonstrate greater clinical efficacy than UST monotherapy because of the same mechanism. We hypothesized that such a mechanism could explain our results.

The safety profile of the UST-BDS combination was not inferior to that of UST monotherapy. This indicates that BDS can be safely added to UST. Our study targeted outpatients and not inpatients, who were expected to have worse disease activity than outpatients. Concomitant BDS therapy might be effective in situations where aggressive therapy needs to be administered while being careful about the side effects of the drugs.

When we designed this study, our plan involved a double-blinded, placebo-controlled, randomized study to ensure the highest quality of evidence. Although a multicenter setup would have allowed us to reach the required number of participants more efficiently, we had to make a decision to conduct the study at a single center because of the complexities involved in managing both placebo and budesonide in a multicenter environment. We have learned that conducting a multicenter, double-blind, placebo-controlled, investigator-initiated RCT is extremely challenging owing to numerous complicated procedures, such as administrative paperwork, study drug management, and the need for ethical approval. We believe that establishing a well-organized trial system with various forms of support, including technical and financial assistance, is indispensable for successfully conducting high-quality clinical trials.

This study has several limitations. First, as previously described, we were unable to enroll the required number of participants. Thus, there is a possibility of failure to determine the clinical efficacy of combination therapy. Several studies have used nationwide databases containing a large number of cases. Although such studies are retrospective and have several limitations, their large sample sizes enable us to perform propensity score matching and simulate RCT [31‒34]. Second, this was a single-center study. Our institution is a referral center. Therefore, the CD disease activity is expected to be higher than that in other community hospitals. Our patients may not be representative of the general population with CD. Therefore, we must be careful when adopting the results of this study in clinical practice.

In conclusion, our study showed no differences between UST-BDS combination therapy and UST monotherapy in terms of the induction and maintenance of remission. These results indicate that UST monotherapy without other immunosuppressive modalities might be an effective treatment option for outpatients with CD (jRCTs021200013).

Ms. Mizue Kusaba (Clinical Research, Innovation and Education Center, Tohoku University Hospital), Ms. Kanami Ashino (Clinical Research, Innovation and Education Center, Tohoku University Hospital), and Ms. Risako Suzuki (Pharmaceutical Sciences, Tohoku University Hospital) helped with the conduction of the study, randomization, and preparation of the placebo. We thank Honyaku Center Inc. for English language editing.

The study protocol was reviewed and approved by the Tohoku Certified Review Board of Tohoku University (2021-45-1) and the trial was registered in the Japan Registry of Clinical Trials on July 31, 2020 (jRCTs021200013). Written informed consent was obtained from all the participants before they entered the trial.

The authors have no conflicts of interest to declare.

The current study was self-funded.

R.M., K.H., and K.N. designed the study. R.M., K.H., Y. Shimoyama, T.N., H.S., and Y. Kakuta recruited the patients. Y. Sugawara conducted randomization. The IT department performed the statistical analyses. The first draft of the manuscript was written by R.M. and critically revised by Y. Kunouchi and A.M. All the authors have read and approved the final version of the manuscript.

All data generated or analyzed in this study are included in this article. Further inquiries can be directed to the corresponding authors.

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