Crohn Disease
Conditions
Keywords
biological markers, endoscopy, gastrointestinal
Brief summary
This study will evaluate biomarkers that reflect changes in gut mucosal status during therapy with infliximab and determine whether changes in the levels of the selected biomarkers can be used to predict endoscopically assessed gut mucosal status changes.
Interventions
DRUGInfliximab
Infliximab administered intravenously at a dose of 5 mg/kg at study Weeks 0, 2, 6, 14, and 22.
Sponsors
Merck Sharp & Dohme LLC
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of Crohn's Disease (CD) of at least 6 weeks duration, or acute diagnosis of sufficiently severe CD warranting initiation of infliximab sooner than allowed by fecal calprotectin turnaround time * History of colonic involvement verified by prior endoscopy or radiography * Indicated for treatment with infliximab according to current best medical practice * Body Mass Index (BMI) between 15 kg/m\^2 and 35 kg/m\^2 * Women of childbearing potential and non-vasectomized men agree to use medically-acceptable contraception * Negative pregnancy test * No signs or symptoms of active tuberculosis (TB) and has a negative TB test within 6 weeks of first study drug administration
Exclusion criteria
* Pregnancy, intention to become pregnant, or breastfeeding * Evidence of a colon unaffected by CD * Indication for surgery * Perianal disease likely to interfere with study participation * Presence of a stoma or history of colectomy * Symptomatic diarrhea unrelated to CD * Strictures or evidence of bowel obstruction * Presence of abscess unless completed definitive treatment can be documented one week prior to screening * Presence of fistulas * Contraindication to infliximab * Intolerance to sedatives or other medications required for endoscopy * Any prior use of anti-inflammatory biologic therapy * Moderate or severe congestive heart failure * History of demyelinating disease or symptoms suggestive of multiple sclerosis or optic neuritis * Major surgery or donation/loss of at least one unit of blood within 4 weeks of screening * Positive for hepatitis B surface antigen, hepatitis C antibodies, or Human Immunodeficiency Virus (HIV) * History of any tumor except adequately treated basal cell carcinoma or carcinoma in situ of the cervix * History of systemic granulomatous infection * History of nontuberculous mycobacterial disease, or any opportunistic infection within 12 months of study entry * Transplanted organ including bone marrow or hematopoietic stem cell-derived marrow
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Coefficient of Determination (R^2) For Predicting The Change From Baseline In Blinded CDEIS Score From The Changes From Baseline In Four Biomarkers At Weeks 6 and 22 | Baseline and Week 6 or 22 | To determine R\^2 a multiple linear regression analysis was conducted with the change from baseline in CDEIS score as the response variable and the baseline CDEIS score, changes from baseline in the four biomarkers serum hsCRP, serum lipocalin-2, serum Reg3-A, and stool calprotectin (their concentrations were log-transformed to make the mean function of the response more linear) at Weeks 6 and 22 as the predictor variables. CDEIS scores were provided by a blinded observer who viewed procedural videotape while blinded to the allocation number and visit of the endoscopy. The R\^2 can range from 0 to 1; with higher values indicating greater predictability of the model. The primary hypothesis is that the true R\^2 at weeks 6 and 22 is approximately 0.7. |
| Change From Baseline in Regenerating Islet-Derived 3-Alpha (REG3-A) at Week 6 | Baseline and Week 6 | Concentrations of the serum biomarker REG3-A were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline. |
| Change From Baseline in REG3-A at Week 22 | Baseline and Week 22 | Concentrations of the serum biomarker REG3-A were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline. |
| Change From Baseline in the Crohn's Disease Endoscopic Index of Severity (CDEIS) Blinded Score at Week 6 | Baseline and Week 6 | CDEIS endoscopically assesses mucosal status, by summing the following six component scores: number of bowel segments with deep ulcerations divided by number of visualized bowel segments; number of bowel segments with superficial ulcerations divided by number of visualized bowel segments; mean proportion of bowel segment surface involved by disease measured on 0-10 cm visual analog scale (VAS); mean proportion of bowel segment surface area involved by ulcerations measured on 0-10 cm VAS; presence of ulcerated stenosis anywhere; and presence of non-ulcerated stenosis anywhere. An observer who viewed procedural videotape while blinded to the allocation number and visit of the endoscopy scored the CDEIS. The sum of the six components can range from 0-44, with a higher sum indicating greater severity of mucosal inflammation. Change from baseline is defined as Week 6 minus baseline CDEIS scores, with a negative change from baseline indicating improvement. |
| Change From Baseline in CDEIS Blinded Score at Week 22 | Baseline and Week 22 | CDEIS endoscopically assesses mucosal status, by summing the following six component scores: number of bowel segments with deep ulcerations divided by number of visualized bowel segments; number of bowel segments with superficial ulcerations divided by number of visualized bowel segments; mean proportion of bowel segment surface involved by disease measured on 0-10 cm visual analog scale (VAS); mean proportion of bowel segment surface area involved by ulcerations measured on 0-10 cm VAS; presence of ulcerated stenosis anywhere; and presence of non-ulcerated stenosis anywhere. An observer who viewed procedural videotape while blinded to the allocation number and visit of the endoscopy scored the CDEIS. The sum of the six components can range from 0-44, with a higher sum indicating greater severity of mucosal inflammation. Change from baseline is defined as Week 22 minus baseline CDEIS scores, with a negative change from baseline indicating improvement. |
| Change From Baseline in Serum High Sensitivity C-reactive Protein (hsCRP) at Week 6 | Baseline and Week 6 | Concentrations of the serum biomarker hsCRP were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline. |
| Change From Baseline in Serum hsCRP at Week 22 | Baseline and Week 22 | Concentrations of the serum biomarker hsCRP were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline. |
| Change From Baseline in Stool Calprotectin at Week 6 | Baseline and Week 6 | Concentrations of the stool biomarker calprotectin were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline. |
| Change From Baseline in Stool Calprotectin at Week 22 | Baseline and Week 22 | Concentrations of the stool biomarker calprotectin were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline. |
| Change From Baseline in Serum Lipocalin-2 at Week 6 | Baseline and Week 6 | Concentrations of the serum biomarker lipocalin-2 were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline. |
| Change From Baseline in Serum Lipocalin-2 at Week 22 | Baseline and Week 22 | Concentrations of the serum biomarker lipocalin-2 were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | Baseline, Week 6, Week 22 | The CCC of blinded (central) versus unblinded (site) scores from either CDEIS or the Simple Endoscopic Score for Crohn's Disease (SES-CD) was determined at Baseline, Week 6 and Week 22. SES-CD sums the following scores: presence and size of ulcers in five visualized bowel segments; extent of ulcerated surface in five visualized bowel segments; extent of affected surface in five visualized bowel segments; presence and type of narrowings in five visualized bowel segments; and can range from 0-56, with a higher sum indicating greater severity of mucosal inflammation. The CCC can range from 0 to 1 with higher values indicating greater concordance between the 2 measurements. |
| Concordance Correlation Coefficient for Comparison of Repeat Baseline Measurements of Biochemical Biomarkers | Baseline Visit 1 (one week prior to dosing), Baseline Visit 2 (1-2 days prior to dosing) | Based on two measurements at baseline, the concordance correlation coefficient (CCC) was computed for each of four biomarkers, using a mixed effects model with a fixed factor for repeat measurements and a random factor for participant. The CCC can range from 0 to 1 with higher values indicating greater concordance between the 2 measurements. |
Participant flow
Recruitment details
Participants 18 to 60 years of age, with moderate to severe Crohn's Disease (CD) who had not been previously treated with anti-inflammatory biologic agents were enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Infliximab 5mg/kg Infliximab administered intravenously at a dose of 5 mg/kg at study weeks 0, 2, 6, 14, and 22 | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Infliximab 5mg/kg |
|---|---|
| Age, Continuous | 25.0 Years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 15 | 13 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 2 / 15 | 0 / 15 |
Outcome results
Primary
Change From Baseline in CDEIS Blinded Score at Week 22
CDEIS endoscopically assesses mucosal status, by summing the following six component scores: number of bowel segments with deep ulcerations divided by number of visualized bowel segments; number of bowel segments with superficial ulcerations divided by number of visualized bowel segments; mean proportion of bowel segment surface involved by disease measured on 0-10 cm visual analog scale (VAS); mean proportion of bowel segment surface area involved by ulcerations measured on 0-10 cm VAS; presence of ulcerated stenosis anywhere; and presence of non-ulcerated stenosis anywhere. An observer who viewed procedural videotape while blinded to the allocation number and visit of the endoscopy scored the CDEIS. The sum of the six components can range from 0-44, with a higher sum indicating greater severity of mucosal inflammation. Change from baseline is defined as Week 22 minus baseline CDEIS scores, with a negative change from baseline indicating improvement.
Time frame: Baseline and Week 22
Population: Participants who had a blinded CDEIS score at both baseline and at Week 22.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in CDEIS Blinded Score at Week 22 | -7.3 Score on a scale | Standard Deviation 5.5 |
Primary
Change From Baseline in REG3-A at Week 22
Concentrations of the serum biomarker REG3-A were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline.
Time frame: Baseline and Week 22
Population: Participants with measurements for REG3-A at both baseline and at Week 22.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in REG3-A at Week 22 | -21.2 ng/mL | Standard Deviation 30.3 |
Primary
Change From Baseline in Regenerating Islet-Derived 3-Alpha (REG3-A) at Week 6
Concentrations of the serum biomarker REG3-A were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline.
Time frame: Baseline and Week 6
Population: Participants with measurements for REG3-A at both baseline and at Week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Regenerating Islet-Derived 3-Alpha (REG3-A) at Week 6 | -20.7 ng/mL | Standard Deviation 20.9 |
Primary
Change From Baseline in Serum High Sensitivity C-reactive Protein (hsCRP) at Week 6
Concentrations of the serum biomarker hsCRP were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline.
Time frame: Baseline and Week 6
Population: Participants with measurements for hsCRP at both baseline and at Week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Serum High Sensitivity C-reactive Protein (hsCRP) at Week 6 | -38.1 mg/L | Standard Deviation 30.4 |
Primary
Change From Baseline in Serum hsCRP at Week 22
Concentrations of the serum biomarker hsCRP were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline.
Time frame: Baseline and Week 22
Population: Participants with measurements for hsCRP at both baseline and at Week 22.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Serum hsCRP at Week 22 | -28.0 mg/L | Standard Deviation 39.3 |
Primary
Change From Baseline in Serum Lipocalin-2 at Week 22
Concentrations of the serum biomarker lipocalin-2 were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline.
Time frame: Baseline and Week 22
Population: Participants with measurements for lipocalin-2 at both baseline and at Week 22.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Serum Lipocalin-2 at Week 22 | -104.6 ng/mL | Standard Deviation 108.9 |
Primary
Change From Baseline in Serum Lipocalin-2 at Week 6
Concentrations of the serum biomarker lipocalin-2 were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline.
Time frame: Baseline and Week 6
Population: Participants with measurements for lipocalin-2 at both baseline and at Week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Serum Lipocalin-2 at Week 6 | -103.7 ng/mL | Standard Deviation 108.3 |
Primary
Change From Baseline in Stool Calprotectin at Week 22
Concentrations of the stool biomarker calprotectin were determined at baseline and at Week 22. The change from baseline was Week 22 minus baseline.
Time frame: Baseline and Week 22
Population: Participants with measurements for calprotectin at both baseline and at Week 22.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Stool Calprotectin at Week 22 | 98.3 µg/g | Standard Deviation 3236.7 |
Primary
Change From Baseline in Stool Calprotectin at Week 6
Concentrations of the stool biomarker calprotectin were determined at baseline and at Week 6. The change from baseline was Week 6 minus baseline.
Time frame: Baseline and Week 6
Population: Participants with measurements for calprotectin at both baseline and at Week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in Stool Calprotectin at Week 6 | 231.1 µg/g | Standard Deviation 4099.6 |
Primary
Change From Baseline in the Crohn's Disease Endoscopic Index of Severity (CDEIS) Blinded Score at Week 6
CDEIS endoscopically assesses mucosal status, by summing the following six component scores: number of bowel segments with deep ulcerations divided by number of visualized bowel segments; number of bowel segments with superficial ulcerations divided by number of visualized bowel segments; mean proportion of bowel segment surface involved by disease measured on 0-10 cm visual analog scale (VAS); mean proportion of bowel segment surface area involved by ulcerations measured on 0-10 cm VAS; presence of ulcerated stenosis anywhere; and presence of non-ulcerated stenosis anywhere. An observer who viewed procedural videotape while blinded to the allocation number and visit of the endoscopy scored the CDEIS. The sum of the six components can range from 0-44, with a higher sum indicating greater severity of mucosal inflammation. Change from baseline is defined as Week 6 minus baseline CDEIS scores, with a negative change from baseline indicating improvement.
Time frame: Baseline and Week 6
Population: Participants who had a blinded CDEIS score at both baseline and at Week 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Infliximab 5 mg/kg | Change From Baseline in the Crohn's Disease Endoscopic Index of Severity (CDEIS) Blinded Score at Week 6 | -4.8 Score on a scale | Standard Deviation 4.2 |
Primary
Coefficient of Determination (R^2) For Predicting The Change From Baseline In Blinded CDEIS Score From The Changes From Baseline In Four Biomarkers At Weeks 6 and 22
To determine R\^2 a multiple linear regression analysis was conducted with the change from baseline in CDEIS score as the response variable and the baseline CDEIS score, changes from baseline in the four biomarkers serum hsCRP, serum lipocalin-2, serum Reg3-A, and stool calprotectin (their concentrations were log-transformed to make the mean function of the response more linear) at Weeks 6 and 22 as the predictor variables. CDEIS scores were provided by a blinded observer who viewed procedural videotape while blinded to the allocation number and visit of the endoscopy. The R\^2 can range from 0 to 1; with higher values indicating greater predictability of the model. The primary hypothesis is that the true R\^2 at weeks 6 and 22 is approximately 0.7.
Time frame: Baseline and Week 6 or 22
Population: Participants who had a blinded CDEIS score and measurements for each of the biomarkers included in the models at both baseline and at Week 6 or 22.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab 5 mg/kg | Coefficient of Determination (R^2) For Predicting The Change From Baseline In Blinded CDEIS Score From The Changes From Baseline In Four Biomarkers At Weeks 6 and 22 | Week 6 (n = 9) | 0.920 Coefficient of Determination |
| Infliximab 5 mg/kg | Coefficient of Determination (R^2) For Predicting The Change From Baseline In Blinded CDEIS Score From The Changes From Baseline In Four Biomarkers At Weeks 6 and 22 | Week 22 (n = 10) | 0.638 Coefficient of Determination |
Comparison: Week 6p-value: 0.071Multiple Linear Regression
Comparison: Week 22p-value: 0.381Multiple Linear Regression
Secondary
Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation
The CCC of blinded (central) versus unblinded (site) scores from either CDEIS or the Simple Endoscopic Score for Crohn's Disease (SES-CD) was determined at Baseline, Week 6 and Week 22. SES-CD sums the following scores: presence and size of ulcers in five visualized bowel segments; extent of ulcerated surface in five visualized bowel segments; extent of affected surface in five visualized bowel segments; presence and type of narrowings in five visualized bowel segments; and can range from 0-56, with a higher sum indicating greater severity of mucosal inflammation. The CCC can range from 0 to 1 with higher values indicating greater concordance between the 2 measurements.
Time frame: Baseline, Week 6, Week 22
Population: Participants who had both blinded and unblinded scores available for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | CDEIS Baseline (n = 15) | 0.662 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | CDEIS Week 6 (n = 13) | 0.693 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | CDEIS Week 22 (n = 12) | 0.743 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | SES-CD Baseline (n = 15) | 0.453 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | SES-CD Week 6 (n = 13) | 0.937 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison Between Central Endoscopic Evaluation and Site Endoscopic Evaluation | SES-CD Week 22 (n = 13) | 0.753 Correlation coefficient |
Secondary
Concordance Correlation Coefficient for Comparison of Repeat Baseline Measurements of Biochemical Biomarkers
Based on two measurements at baseline, the concordance correlation coefficient (CCC) was computed for each of four biomarkers, using a mixed effects model with a fixed factor for repeat measurements and a random factor for participant. The CCC can range from 0 to 1 with higher values indicating greater concordance between the 2 measurements.
Time frame: Baseline Visit 1 (one week prior to dosing), Baseline Visit 2 (1-2 days prior to dosing)
Population: Participants who had both baseline serum or stool measurements available for analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison of Repeat Baseline Measurements of Biochemical Biomarkers | stool calprotectin (n=15) | 0.792 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison of Repeat Baseline Measurements of Biochemical Biomarkers | serum hsCRP (n=14) | 0.954 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison of Repeat Baseline Measurements of Biochemical Biomarkers | serum REG3-A (n=15) | 0.974 Correlation coefficient |
| Infliximab 5 mg/kg | Concordance Correlation Coefficient for Comparison of Repeat Baseline Measurements of Biochemical Biomarkers | serum lipocalin-2 (n=15) | 0.910 Correlation coefficient |