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Research for medicinal predictive marker on Crohn's disease (E6011-CS1 study)

E6011-CS1 study (E6011-CS1 study)

32

Baseline Measures - Study 1 all subjects ; adalimumab (hereafter ADA), infliximab (hereafter INF), ustekinumab (hereafter UST)) [Number analyzed] 20; 6, 3, 11 [Item: Unit] Mean (standard deviation)/ all subjects ; ADA, INF, UST), <analysis of variance (between 3 groups) p-value> [Age: years] 35.3(15.7); 26.8(12.3), 30.7(10.1), 41.2(16.8), <0.1709> [Body weight: kg] 58.29(8.70); 57.32(8.84), 53.25(7.59), 60.20(9.00), <0.4707> [Height: cm] 166.51(7.23); 166.42(8.31), 165.97(5.05), 166.70(7.71), <0.9886> [Disease duration: years] 2.04(4.16); 1.17(1.16), 1.19(1.57), 2.75(5.52), <0.7233> [HBI: score on Scale] 4.5(3.3); 5.2(3.2), 5.3(2.1), 3.8(3.7), <0.6562> [CRP: mg/dL] 0.577(0.678); 1.317(0.731), 0.363(0.234), 0.197(0.266), <0.0008> [CD16+ monocytes/monocytes [FCM]] : %] 8.403(4.618); 6.995(3.033), 8.777(5.229), 9.135(5.432), <0.6859> - Study 2 All subjects (No restrictions on therapeutic agents.) [Number analyzed] 12 [Item: Unit] Mean (standard deviation) [Age: years] 44.1(15.2) [Body weight: kg] 54.59(13.37) [Height: cm] 167.65( 6.19) [Disease duration: years] 15.08(11.36) [HBI: score on Scale] 3.3(3.8) [CRP: mg/dL] 0.116(0.185)

This study consisted of Study 1 and Study 2. In Study 1, clinical trial subjects were recruited at five medical institutions in Japan. The first informed consent was obtained on October 10, 2019, and a total of 20 patients were enrolled : 6 with adalimumab, 3 with infliximab, and 11 with ustekinumab. No clinical trial subjects were discontinued during the study period, and all clinical trial subjects completed the study. In Study 2, clinical trial subjects were recruited at one medical institution in Japan. The first informed consent was obtained on September 30, 2019, and 12 subjects were enrolled. Study 2 was completed with the observation at the beginning of the study.

In Study 1 and Study 2, there were no reports of disease or the like which is suspected of being due to the conduct of this study. In Study 1, three adverse effects attributable to biological agents such as anti-TNF agents occurred in 2 of 20 patients (10.0%). By event, injection site reaction, varicella, and CMV infection occurred in one case each (5.0%). All events were mild or moderate in severity and recovered or mildly resolved. No deaths, other serious diseases or adverse events, or other significant adverse events were reported.

Because this study is the exploratory study, the primary and the secondary outcomes are not defined, but the following outcomes were evaluated with respect to immune cell fractionation (ratio) and correlation between flow cytometry and DNA methylation analysis. - Changes in efficacy metrics and predictive markers of drug efficacy - Changes in the percentage of other immune cells - Evaluation of the relationship between efficacy index and predictive markers of drug response - Investigation of alternative methods to flow cytometry (FCM) - Correlation between flow cytometry and DNA methylation analysis - Investigation of safety -Changes in efficacy metrics and predictive markers of drug efficacy- HBI was 4.5+-3.3 at the beginning of the study and significantly decreased to 2.4+-2.3 at endpoint 1 (P=0.0026) and 3.0+-3.5 at endpoint 2 (P=0.0241). CRP was 0.577+-0.678 mg/dL at the beginning of the study, 0.704+-1.687 mg/dL at endpoint 1 (P=0.6909), and significantly decreased to 0.174+-0.323 mg/dL (P=0.0310) at endpoint 2. CD16+ monocytes/monocytes (FCM) were 8.403+-4.618% at the beginning of the study and did not differ significantly at endpoint 1 with 9.924+-4.437% (P=0.0641) but increased significantly at endpoint 2 with 10.409+-3.604% (P=0.0160) compared with the beginning of the study. -Changes in the percentage of other immune cells- Regarding CX3CR1+ cells (FCM) and other immune cells/each immune cell fraction (FCM) , there were scattered cells that showed significant fluctuations at certain time points compared to the beginning of the study, but in all cases, the fluctuations were isolated, and no cells showed constant fluctuations. -Evaluation of the relationship between efficacy index and predictive markers of drug response- - Based on the HBI, remission/non-remission was determined at endpoint 1, and ROC analysis was performed for CRP and CD16+ monocytes/monocytes (FCM) at endpoint 1 and at the beginning of the study to calculate the cutoff values and AUC for remission/non-remission determination. - The cutoff value for CRP at endpoint 1 was 0.460 mg/dL (sensitivity 0.824, specificity 0.667) and the cutoff value for CD16+ monocytes/monocytes (FCM) were 11.700% (sensitivity 0.438, specificity 1.000). The AUC was 0.716 for CRP and 0.500 for CD16+ monocytes/monocytes (FCM). The cut-off value for CRP at the beginning of the study was 1.770 mg/dL (sensitivity 0.938, specificity 0.333), and the cut-off value for CD16+ monocytes/monocytes (FCM) was 6.470% (sensitivity 0.500, specificity 1.000). The AUC was 0.542 for CRP and 0.750 for CD16+ monocytes/monocytes (FCM). As above, regarding the correlation between the determination of remission/non-remission at endpoint 1 and CRP and CD16+ monocytes/monocytes (FCM) at the beginning of the study, the correlation with CD16+ monocytes/monocytes (FCM) was higher than that with CRP. CD16+ monocytes/monocytes (FCM) showed a higher correlation than CRP for change from the beginning of the study to observation 2 (2 weeks after treatment). - The cut-off value for CRP was 0.040 mg/dL (sensitivity 0.786, specificity 0.667), and the cut-off value for CD16+ monocytes/monocytes (FCM) was 11.800% (sensitivity 0.923, specificity 0.500). The AUC was 0.690 for CRP and 0.628 for CD16+ monocytes/monocytes (FCM). The cutoff value for CRP at endpoint 1 was 0.050 mg/dL (sensitivity 0.643, specificity 0.500), and the cutoff value for CD16+ monocytes/monocytes (FCM) was 5.340% (sensitivity 0.308, specificity 1.000). The AUC was 0.482 for CRP and 0.487 for CD16+ monocytes/monocytes (FCM). The cut-off value for CRP at the beginning of the study was 0.460 mg/dL (sensitivity 0.615, specificity 0.833), and the cut-off value for CD16+ monocytes/monocytes (FCM) was 11.900% (sensitivity 0.857, specificity 0.600). The AUC was 0.673 for CRP and 0.629 for CD16+ monocytes/monocytes (FCM). As above, regarding the correlation between the determination of remission/non-remission at endpoint 2 and CRP and CD16+ monocytes/monocytes (FCM) at the beginning of the study and endpoint 1, none of correlations with CD16+ monocytes/monocytes (FCM) were high, but among them the correlation of CRP at the beginning of the study was higher than that of CD16+ monocytes/monocytes (FCM). The correlation with CRP was higher than that with CD16+ monocytes/monocytes (FCM) in terms of change from endpoint 1 to the time point following endpoint 1. - Remission rates in the two group classifications in median CRP and CD16+ monocytes/monocytes (FCM) were CRP: 60.0% and 55.6% (P=0.8447) and CD16+ monocytes/monocytes (FCM): 70.0% and 55.6% (P=0.51467) at the beginning of the study, CRP: 75.0% and 73.3% (P=0.9464) and CD16+ monocytes/monocytes (FCM): 70. 0% and 75.0% (P=0.8139); for endpoint 1, orCRP: 66.7% and 92.9% (P=0.1328); CD16+ monocytes/monocytes (FCM): 75.0% and 100.0% (P=0.1494); for endpoint 1, CRP: 66.7% and 92.9% (P=0.1328); CD16+ monocytes/monocytes (FCM): 75.0% and 100.0% (P=0.1494); for endpoint 2, CRP: 66.7% and 70.6% (P=0. 8913) and CD16+ monocytes/monocytes (FCM): 68.8% and 66.7% (P=0.9432), respectively, with no difference in either. Note that the remission rate for endpoint 2 were significantly higher (P=0.0455) in clinical trial subjects with a large change in CRP from the start of the study to observation 2 (-0.26 - -1.71). - Stratified analysis of remission rates for endpoint 1 based on median two-group classification by percentage of other immune cells positive for CX3CR1 and percentage of each immune cell at the begining of the study showed a significant correlation for CX3CR1 positivity (% of CD8 T cells), DR+ CD38+ CD4 (% of CD4), NV CD8 (% of CD8), TCRgd+ (% of lymphocytes) and naive Tregs (% of CD4), but otherwise no significant difference in remission rates. -Investigation of alternative methods to flow cytometry (FCM)- Methylated and unmethylated DNA sites specific for monocytes and CD16+ monocytes were searched in 12 patients enrolled in Study 2. Next, the correlation between CD16+ monocytes/whole blood (BSAS) and CD16+ monocytes/whole blood (FCM) and between monocytes/whole blood (BSAS) and monocytes/whole blood (FCM) were examined using samples from the beginning of the study in Study 1. As a result, fourteen loci of one gene were highly specific with respect to CD16+ monocytes(P<0.0001), and a total of three loci of two genes were highly specific for monocytes(P<0.0001). Using these loci, a DNA methylation analysis method was established. -Correlation between flow cytometry and DNA methylation analysis- BSAS using the loci of the genes identified in Study 2 showed a significant correlation (P=0.0466) between CD16+ monocytes/monocytes (BSAS) and CD16+ monocytes/monocytes (FCM), both in samples from the beginning of study and during the entire study period of study 1. -Investigation of safety- In the two patients who developed side effects, there was no variation in either HBI, CRP or CD16+ monocytes/monocytes (FCM) due to the development of side effects, suggesting that the development of such side effects in this study did not affect the correlation between HBI and CRP and CD16+ monocytes/monocytes (FCM).

In Crohn's disease patients treated with anti-TNF and anti-IL-12/23p40 agents, CD16+ monocytes/monocytes [FCM] correlated better than CRP for predicting drug response during the treatment induction phase. (endpoint 1) and CRP correlated better at 1 year (endpoint 2). The AUC in ROC analysis for predicting drug efficacy for endpoint 1 and 2 ranged from 0.482 to 0.750. DNA methylation analysis using the loci may be an alternative method to FCM for measuring CD16+ monocytes/monocytes.

Mar. 31, 2023

Yes

De-identified IPD can be made available to researchers in a closed environment. Supporting Information : Study Protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR) Access Criteria : Data-sharing is subject to the signing of a data-sharing agreement.

https://jrct.mhlw.go.jp/latest-detail/jRCT1031190056

Mikami Yohei

Keio University Hospital

35,Shinanomachi,Shinjuku-ku,Tokyo

yoheimikami@keio.jp

Kokubun Yukimi

RPM Co., Ltd.

5F JRE NishiShinjuku terasu,3-2-4,Nishi-shinjuku, Shinjuku-ku,Tokyo

+81-3-5325-5821

y-kokubun@rpmedical.co.jp

Complete

July. 17, 2019

Interventional

non-randomized controlled trial

open(masking not used)

uncontrolled control

single assignment

other

(1)Patients aged 16 or older when the written agreements made.(Need agreement for deputy for patients under 20 years old)
(2)Patients diagnosed as definitive Crohn's disease according to the Policy Research business for Health and Labor Sciences Research Grant for Intractable diseases and etc. [ Diagnostic criteria and treatment policy for Crohn's disease, Ulcerative colitis](revised in 2017)
(3)Active Crohn's disease.(only Study1)
(4)The patients who are indicated of Biologics(adalimumab,infliximab,ustekinumab) treatment on Crohn's disease.(only Study1)
(5)Patients who voluntarily provided written informed consent to participate in the study.
(6)Patients who are fully explained about the rules of this research and have the will and ability to abide by them.

(1)Patients with history of following intestinal surgery, or patients who are scheduled for following intestinal surgery.
Enterectomy within 12 weeks prior to the beginning of the study, stoma or ileal pouch. (except rectostomy)
(2)Patients who have received cytapheresis (granulocyte apheresis/granulocyte monocyte apheresis[GCAP/GMA], leukocytopheresis[LCAP]) within 2 weeks prior to the beginning of the study.
(3)Patients who tested positive for the following viruses in screening test.
HBV, HCV, HIV and HTLV-1

Both

Crohn's disease

Study1:Evaluate the disease activity and collect the blood according to the schedule as below. Amount of blood collection should be about 15mL at screening test, after the beginning of the study, about 12.5mL per visit.

1.Adalimumab:At the beginning of the study, after that, 2, 4, 12, 24, 52 weeks after or at the termination
2.Infliximab:At the beginning of the study,after that, 2, 6, 14, 22, 54 weeks after or at the termination
3. Ustekinumab:At the beginning of the study,after that, 2, 8, 20, 32, 56weeks after or at the termination

Study2:None.

Crohn's disease

D003424

Because this study is the exploratory study, the primary outcomes and the secondary outcomes are not defined, but, the following outcomes should be evaluated.

1.Immune cell fractionation (ratio)
2.Correlation between flow cytometry and DNA methylation analysis

Not defined

+81-3-5363-3503

July. 12, 2019

none