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Intestinal Inflammation in Ankylosing Spondylitis and the Effects of Adalimumab on Mucosal Healing (INTASAH)

Primary Purpose

Spondyloarthritis, Enterocolitis

Status
Completed
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
Adalimumab
Sponsored by
Regionshospitalet Silkeborg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Spondyloarthritis

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients (18 years and ≤45 years) with axial SpA according to the ASAS criteria
  • Active SpA assessed by physician.
  • Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4.
  • Faecal calprotectin ≥ 100mg/kg.
  • Negative pregnancy test (serum-HCG) for women of childbearing age before the start of the study. (Women not of childbearing age are defined as postmenopausal for at least 1 year or surgically sterilised (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)). Women of childbearing age included in the study will be required to use contraception during the entire study period (i.e. one of the following: contraceptive pills, intrauterine device, depot injection of gestagen, subdermal implant, hormonal vaginal ring or transdermal patch). In addition, contraception must be used following any discontinuation of the study drug for a period of 150 days.
  • Ability and willingness to self-administer the subcutaneous injections or have a person available to administer the injections.
  • Ability and willingness to give written informed consent and meet the requirements of the study protocol.

Exclusion Criteria:

  • Diagnosed inflammatory bowel disease or high risk of intestinal stricture (previous abdominal stricture, radiation of abdomen, major abdominal surgery).
  • Non steroid anti inflammatory Drugs (NSAID) ingestion less than 4 weeks before inclusion.
  • Psoriasis
  • Persons with latent Tuberculosis (TB)(positive Mantoux skin test (>10 mm), positive cultivation for mycobacteria in tissue samples and/or chest X-ray indicating TB) or other risk factors for activation of untreated latent TB.
  • Current or recurrent infections or serious infections requiring hospitalisation or treatment with intravenous antibiotics within the last 30 days or oral antibiotics within the last 14 days before inclusion.
  • Positive serology for Hepatitis B or C indicating active infection.
  • Medical history of positive HIV status (in case of suspicion control of HIV test).
  • Medical history of histoplasmosis or listeriosis.
  • Previous cancer or lymphoid proliferative disease except completely well-treated cutaneous squamous cell carcinoma, basal cell carcinoma or cervical dysplasia.
  • Previous diagnosis or signs of demyelinising diseases of the central nervous system (e.g. optic neuritis, disturbance of vision, disturbed gait/ataxia, facial paresis, apraxia).
  • Severe renal insufficiency (creatinine clearance < 35 ml/min - normogram).Affected hepatic function: Liver enzymes > 3 x above the normal limit.
  • Clinically significant drug or alcohol abuse in the last year or daily current alcohol consumption.
  • Diabetes, unstable ischemic heart disease, heart failure (NYHA III-IV), recent apoplexia cerebri (within 3 months), chronic leg ulcer and any other condition (e.g. indwelling catheter) which at the discretion of the investigator means that participation in the protocol would entail a risk for the person in question.
  • Anticoagulant treatment.
  • Pregnancy or breast-feeding.
  • Other clinically significant inflammatory rheumatologic diseases that cannot be related to spondyloarthritis
  • Current parvovirus B 19 infection.
  • Glucocorticosteroid treatment within the last 4 weeks (except nasal and inhalation steroids).
  • Contraindication to study drug.

Sites / Locations

  • Department of Rheumatology U, Aarhus Hospital
  • Regional Hospital of Horsens, Department of Medicine
  • Regional Hospital of Randers, Department of Medicine
  • Regional Hospital of Silkeborg

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Spondyloarthritis and calprotectin elevated

Spondyloarthritis and calprotectin normal

Arm Description

Spondylitis patients with elevated levels of fecal calprotectin. Patients are treated with adalimumab

Spondylitis patients with normal levels of fecal calprotectin. Patients are treated with adalimumab.

Outcomes

Primary Outcome Measures

Change Lewis Score Index
Lewis' score describes the amount of inflammation seen optically by capsular endoscopy. Gralnek et al. devised and validated the Lewis score index, based on three endoscopic parameters: villous edema, ulcer and stenosis/stricture. Using these parameters, the authors established a score range of 8-4,800 points where: LS < 135 reflects normal mucosal appearances, LS 135-790 mild mucosal inflammatory change and an LS value ≥790 moderate to severe mucosal inflammatory changes. The patients had endoscopy performed at baseline and again after 20 weeks. The number of patients improving was compared to number of patients deteriorating
Change in Intestinal Inflammation Measured by Faecal Calprotectin
Feacal calprotectin is a protein and a marker of the degree of inflammation in the intestine, but not the site of inflammation. We measured the level calprotectin continuously in each of the patients. Difference was inferred by repeated measurement ANOVA

Secondary Outcome Measures

Spondyloarthritis Consortium of Canada Score
Inflammation on MRI assessed by the Spondyloarthritis Consortium of Canada score and a Danish scoring method
Assessment Group in Ankylosing Spondylitis (ASAS) Core Set for Clinical Practice
clinical measurements of inflammation in spondyloarthritis patients as described by the Assessment Group in Ankylosing Spondylitis (ASAS)

Full Information

First Posted
July 16, 2010
Last Updated
November 18, 2014
Sponsor
Regionshospitalet Silkeborg
Collaborators
Abbott, Medtronic - MITG, Central Denmark Region
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1. Study Identification

Unique Protocol Identification Number
NCT01174186
Brief Title
Intestinal Inflammation in Ankylosing Spondylitis and the Effects of Adalimumab on Mucosal Healing
Acronym
INTASAH
Official Title
Intestinal Inflammation in Ankylosing Spondylitis Assessed by Fecal Calprotectin, Capsular Endoscopy and Colonoscopy and the Effects of Adalimumab on Mucosal Healing
Study Type
Interventional

2. Study Status

Record Verification Date
November 2014
Overall Recruitment Status
Completed
Study Start Date
October 2010 (undefined)
Primary Completion Date
June 2013 (Actual)
Study Completion Date
March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Regionshospitalet Silkeborg
Collaborators
Abbott, Medtronic - MITG, Central Denmark Region

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Studies with intestinally asymptomatic patients with spondyloarthritis showed that approximately 1/3 had visible ulcers in the colon by scopic examinations and 2/3 had changes detectable by microscopy. Only those patients who improved in arthritis symptoms showed improvement in colonic changes. In these studies only colon and the terminal ileum was examined. Inflammation of the small intestine was not examined. Newer studies have shown an immunological link between Crohns disease and spondyloarthritis but not ulcerative colitis. The investigators wish to examine the small intestine in these patients before and after treatment, since they expect to find ulcers there linking spondyloarthritis to Crohns disease and healing after treatment.
Detailed Description
Patients with inflammatory axial spondyloarthritis according to the assessment group in ankylosing spondylitis (ASAS) criteria (8) and active disease assessed by a physician are recruited in the outpatient clinics of the rheumatology departments, provided that the patient under normal circumstances is expected to benefit from TNF-alpha inhibitor treatment and full fill the criteria for treatment. Screening with a view to participating in the study is carried out in accordance with the inclusion and exclusion criteria. Oral and written patient information about the study, the patient's signing of the informed consent form and the signing of the patient's power of attorney in accordance with the study protocol are also a condition for the inclusion. The including physician will ensure that a potential participant is informed about the right to at least 1 hour's reflection time and the right to have a friend/family member present at the information interview. If the patient meets the basis for the participation in the study the informed consent form and the power of attorney are signed. The screened patients are not coded but are identified using their Civil Registration Number (CPR) for several reasons. The study is open-label, which removes the need for blinding of patients as well as investigator. Blood samples are booked electronically and printed labels with CPR number are put on the test tubes for both immediate analysis and storage. This guarantees a more fail-safe method for handling of various analyses, since this procedure is similar to the routine procedure. We find this to be the safest system as the method, by which labels with CPR number follow the patient has been thoroughly tested. Source data will be kept in the Danish Biologics Online Registry (DANBIO registry) for clinical measures, the electronic patient file for lab data and the paper file for imaging data. Data validity and completeness is controlled by external "good clinical practice" monitoring. Adalimumab will be supplied as a sterile solution without preservatives for subcutaneous injection in 1 ml prefilled syringes containing adalimumab 40 mg/0.8 ml, to be self-injected by the patient every 2 weeks until week 20. After week 20 patients continue adalimumab treatment 40 mg every other week but may change to injections with pens containing the same drug and dosage. The drug is injected under the skin of the abdomen or the thigh. All patients will be instructed by the study personnel in correct sterile subcutaneous injection of the study drug.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spondyloarthritis, Enterocolitis

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Spondyloarthritis and calprotectin elevated
Arm Type
Active Comparator
Arm Description
Spondylitis patients with elevated levels of fecal calprotectin. Patients are treated with adalimumab
Arm Title
Spondyloarthritis and calprotectin normal
Arm Type
Active Comparator
Arm Description
Spondylitis patients with normal levels of fecal calprotectin. Patients are treated with adalimumab.
Intervention Type
Drug
Intervention Name(s)
Adalimumab
Other Intervention Name(s)
Humira
Intervention Description
Tumor Necrosis Factor (TNF) alpha inhibitor given 40 mg subcutaneously every other week except the first time where 80 mg is given
Primary Outcome Measure Information:
Title
Change Lewis Score Index
Description
Lewis' score describes the amount of inflammation seen optically by capsular endoscopy. Gralnek et al. devised and validated the Lewis score index, based on three endoscopic parameters: villous edema, ulcer and stenosis/stricture. Using these parameters, the authors established a score range of 8-4,800 points where: LS < 135 reflects normal mucosal appearances, LS 135-790 mild mucosal inflammatory change and an LS value ≥790 moderate to severe mucosal inflammatory changes. The patients had endoscopy performed at baseline and again after 20 weeks. The number of patients improving was compared to number of patients deteriorating
Time Frame
20 weeks
Title
Change in Intestinal Inflammation Measured by Faecal Calprotectin
Description
Feacal calprotectin is a protein and a marker of the degree of inflammation in the intestine, but not the site of inflammation. We measured the level calprotectin continuously in each of the patients. Difference was inferred by repeated measurement ANOVA
Time Frame
Baseline to 52 weeks
Secondary Outcome Measure Information:
Title
Spondyloarthritis Consortium of Canada Score
Description
Inflammation on MRI assessed by the Spondyloarthritis Consortium of Canada score and a Danish scoring method
Time Frame
one year
Title
Assessment Group in Ankylosing Spondylitis (ASAS) Core Set for Clinical Practice
Description
clinical measurements of inflammation in spondyloarthritis patients as described by the Assessment Group in Ankylosing Spondylitis (ASAS)
Time Frame
one year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients (18 years and ≤45 years) with axial SpA according to the ASAS criteria Active SpA assessed by physician. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4. Faecal calprotectin ≥ 100mg/kg. Negative pregnancy test (serum-HCG) for women of childbearing age before the start of the study. (Women not of childbearing age are defined as postmenopausal for at least 1 year or surgically sterilised (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)). Women of childbearing age included in the study will be required to use contraception during the entire study period (i.e. one of the following: contraceptive pills, intrauterine device, depot injection of gestagen, subdermal implant, hormonal vaginal ring or transdermal patch). In addition, contraception must be used following any discontinuation of the study drug for a period of 150 days. Ability and willingness to self-administer the subcutaneous injections or have a person available to administer the injections. Ability and willingness to give written informed consent and meet the requirements of the study protocol. Exclusion Criteria: Diagnosed inflammatory bowel disease or high risk of intestinal stricture (previous abdominal stricture, radiation of abdomen, major abdominal surgery). Non steroid anti inflammatory Drugs (NSAID) ingestion less than 4 weeks before inclusion. Psoriasis Persons with latent Tuberculosis (TB)(positive Mantoux skin test (>10 mm), positive cultivation for mycobacteria in tissue samples and/or chest X-ray indicating TB) or other risk factors for activation of untreated latent TB. Current or recurrent infections or serious infections requiring hospitalisation or treatment with intravenous antibiotics within the last 30 days or oral antibiotics within the last 14 days before inclusion. Positive serology for Hepatitis B or C indicating active infection. Medical history of positive HIV status (in case of suspicion control of HIV test). Medical history of histoplasmosis or listeriosis. Previous cancer or lymphoid proliferative disease except completely well-treated cutaneous squamous cell carcinoma, basal cell carcinoma or cervical dysplasia. Previous diagnosis or signs of demyelinising diseases of the central nervous system (e.g. optic neuritis, disturbance of vision, disturbed gait/ataxia, facial paresis, apraxia). Severe renal insufficiency (creatinine clearance < 35 ml/min - normogram).Affected hepatic function: Liver enzymes > 3 x above the normal limit. Clinically significant drug or alcohol abuse in the last year or daily current alcohol consumption. Diabetes, unstable ischemic heart disease, heart failure (NYHA III-IV), recent apoplexia cerebri (within 3 months), chronic leg ulcer and any other condition (e.g. indwelling catheter) which at the discretion of the investigator means that participation in the protocol would entail a risk for the person in question. Anticoagulant treatment. Pregnancy or breast-feeding. Other clinically significant inflammatory rheumatologic diseases that cannot be related to spondyloarthritis Current parvovirus B 19 infection. Glucocorticosteroid treatment within the last 4 weeks (except nasal and inhalation steroids). Contraindication to study drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Henning Glerup, M.D.
Organizational Affiliation
Regional Hospital Silkeborg, medical department
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
René D Oestgaard, M.D.
Organizational Affiliation
Regional Hospital Silkeborg, medical department
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Bent Deleuran, M.D.
Organizational Affiliation
Department of Medical Microbiology and Immunology Aarhus University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Rheumatology U, Aarhus Hospital
City
Aarhus
ZIP/Postal Code
8000
Country
Denmark
Facility Name
Regional Hospital of Horsens, Department of Medicine
City
Horsens
ZIP/Postal Code
8700
Country
Denmark
Facility Name
Regional Hospital of Randers, Department of Medicine
City
Randers
Country
Denmark
Facility Name
Regional Hospital of Silkeborg
City
Silkeborg
ZIP/Postal Code
8600
Country
Denmark

12. IPD Sharing Statement

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Intestinal Inflammation in Ankylosing Spondylitis and the Effects of Adalimumab on Mucosal Healing

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