Biomarkers of Intestinal Mucosal Healing in Crohn's Disease (P08143)

Crohn Disease Clinical Trial

Official title:

An Open Label Study to Discover Biomarkers of Intestinal Mucosal Healing in Crohn's Disease (CD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01349920
• Other study ID #: P08143
• Secondary ID: 2011-000517-40MK
• Status: Completed
• Start date: November 28, 2012
• Est. completion date: September 28, 2015

Study information

• Verified date: September 2018
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: September 28, 2015
• Est. primary completion date: September 28, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Drug:
• Infliximab
Infliximab administered intravenously at a dose of 5 mg/kg at study Weeks 0, 2, 6, 14, and 22.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Baseline and Week 6
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.	Baseline and Week 22
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.	Baseline and Week 6
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.	Baseline and Week 22
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.	Baseline and Week 6
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.	Baseline and Week 22
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.	Baseline and Week 6
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.	Baseline and Week 22
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.	Baseline and Week 6
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.	Baseline and Week 22
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.	Baseline and Week 6 or 22
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.	Baseline Visit 1 (one week prior to dosing), Baseline Visit 2 (1-2 days prior to dosing)
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.	Baseline, Week 6, Week 22